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CONFIDENTIAL 2012N137712_00The GlaxoSmithKline group of companies NGM114840

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Division: Worldwide DevelopmentInformation Type: Clinical Pharmacology Study Report

Title: A randomized, single blind, placebo-controlled, single ascending dose/repeat dose cohort study to assess safety, tolerability, pharmacokinetics and immunogenicity of GSK1223249 in patients with relapsing forms of multiple sclerosis.

Phase: I

Compound Number: GSK1223249

Effective Date: 25-MAR-2013

Subject: [Pharmacokinetics, Pharmacodynamics, Safety, Efficacy]

Author(s): Author(s): [ (Discovery Medicine); (Discovery Medicine); (CPSSO); (Statistics, MDD); (CPMS) ]

Indication Studied: Multiple Sclerosis

Initiation Date: 20-OCT-2011

Completion Date: 23-JAN-2012

Early Termination Date: 15-DEC-2011

Earlier CPSRs: N/A

This study was performed in compliance with Good Clinical Practices and GlaxoSmithKline Standard Operating Procedures for all processes involved, including the archiving of essential documents.

Copyright 2013 the GlaxoSmithKline group of companies. All rights reserved. Unauthorized copying or use of this information is prohibited

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Table of Contents Page

TITLE PAGE ........................................................................................................... ABBREVIATIONS ................................................................................................... ETHICS AND GOOD CLINICAL PRACTICE .......................................................... 1. INVESTIGATOR INFORMATION AND STUDY ADMINISTRATION .................. 2. OBJECTIVES & ENDPOINTS ............................................................................ 3. INVESTIGATIONAL PLAN .................................................................................

3.1. Study Rationale .............................................................................................. 3.2. Study Design .................................................................................................. 3.3. Protocol Amendments .................................................................................... 3.4. Selection of Study Population .........................................................................

3.4.1. Inclusion & Exclusion Criteria .............................................................. 3.4.2. Withdrawal Criteria ..............................................................................

3.5. Treatments ..................................................................................................... 3.5.1. Investigational Product(s) and Reference Therapy .............................. 3.5.2. Treatment Assignment ......................................................................... 3.5.3. Blinding ................................................................................................ 3.5.4. Prior and Concomitant Medications and Non-Drug Therapies ............. 3.5.5. Compliance ..........................................................................................

3.6. Study Assessments and Procedures .............................................................. 3.6.1. Safety Assessments ............................................................................ 3.6.2. Pharmacokinetic Assessments ............................................................ 3.6.3. Pharmacodynamic Assessments ......................................................... 3.6.4. Efficacy Assessments ..........................................................................

3.7. Data Quality Assurance .................................................................................. 3.8. Data Analysis Methods ...................................................................................

3.8.1. Sample size considerations ................................................................. 3.8.2. Interim Analyses .................................................................................. 3.8.3. Final Analyses ..................................................................................... 3.8.4. Changes in Conduct of the Study or Planned Analyses ......................

4. STUDY POPULATION RESULTS ...................................................................... 4.1. Subject Disposition ......................................................................................... 4.2. Protocol Deviations ........................................................................................ 4.3. Populations Analyzed ..................................................................................... 4.4. Demographic and Baseline Characteristics .................................................... 4.5. Prior and Concomitant Medications ................................................................ 4.6. Exposure and Treatment Compliance ............................................................

5. SAFETY RESULTS ............................................................................................ 5.1. Adverse Events .............................................................................................. 5.2. Serious and Other Significant Adverse Events ............................................... 5.3. Clinical Laboratory Evaluations ...................................................................... 5.4. Vital Signs ...................................................................................................... 5.5. Pregnancies ................................................................................................... 5.6. Expanded Disability Status Scale ...................................................................

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CONFIDENTIAL 2012N137712_00NGM114840

5.7. Electrocardiogram .......................................................................................... 5.8. Relapse Evaluations ....................................................................................... 5.9. Magnetic Resonance Imaging ........................................................................

6. PHARMACOKINETIC RESULTS ....................................................................... 7. PHARMACODYNAMIC AND BIOMARKER RESULTS ...................................... 8. RELATIONSHIP BETWEEN PHARMACOKINETIC AND PHARMACODYAMIC

PARAMETERS ........................................................................................ 9. DISCUSSION AND CONCLUSIONS ..................................................................

9.1. Discussion ...................................................................................................... 9.2. Conclusions ....................................................................................................

10. REFERENCES ................................................................................................. 11. CASE NARRATIVES ........................................................................................ SAFETY DATA SOURCE TABLES ........................................................................

Table 1.01 Summary of Demographic Characteristics (Safety Population) ........... Table 1.07 Listing of Exposure Data (All Subjects Population) .............................. Table 1.08 Listing of Concomitant Medications by Generic Term (All Subjects

Population) ............................................................................................. Table 1.14 Listing of Clinical Chemistry Abnormalities of Potential Clinical

Importance (All Subjects Population) ...................................................... Table 1.15 Listing of All Clinical Chemistry Laboratory Data (All Subjects

Population) ............................................................................................. Table 1.16 Listing of Haematology Abnormalities of Potential Clinical

Importance (All Subjects Population) ...................................................... Table 1.17 Listing of All Haematology Laboratory Data (All Subjects

Population) ............................................................................................. Table 1.18 Listing of Urinalysis Data for all Subjects (All Subjects Population) ..... Table 2.02 Listing of MS Medical History (All Subjects Population) ...................... Table 2.06 Listing of Vital Signs of Potential Clinical Importance (All Subjects

Population) ............................................................................................. Table 2.08 Listing of All ECG Values for Subjects with a Value of Potential

Clinical Importance (All Subjects Population) ......................................... Table 2.09 Listing of Abnormal ECG findings (All Subjects Population) ................ Table 2.11 Listing of Suicide Attempts (All Subjects Population) .......................... Table 2.12 Listing of CSSRS Suicidal Ideation and Behavior Data (All Subjects

Population) ............................................................................................. Table 2.13 Listing of All Possible Suicidality-Related Adverse Events (PSRAE)

(Sections 1-2) (All Subjects Population) ................................................. Table 2.14 Listing of All Possible Suicidality-Related Adverse Events (PSRAE)

(Section 3) (All Subjects Population) ...................................................... Table 2.15 Listing of All Possible Suicidality-Related Adverse Events (PSRAE)

(Section 4) (All Subjects Population) ...................................................... Table 2.16 Listing of All Possible Suicidality-Related Adverse Events (PSRAE)

(Sections 5-8) (All Subjects Population) ................................................. Table 2.17 Listing of Subjects Who Became Pregnant During the Study (All

Subjects Population) ...............................................................................

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Table 2.18 Listing of Male Subjects with Female Partners Who Became Pregnant During the Study (All Subjects Population) ............................

Table 2.23 Listing of Patients with Relapses during the study (All Subjects Population) .............................................................................................

Table 2.25 Listing of Expanded Disability Status Scale (EDSS) (All Subjects Population) .............................................................................................

Table 2.26 Listing of Gd-enhancing Lesion Counts (All Subjects Population) ....... Table 2.27 Listing of Gd-enhancing Lesion Volume (All Subjects Population) ...... Table 2.28 Listing of T2- and T1-weighted Lesion Volume (All Subjects

Population) ............................................................................................. PHARMACOKINETIC DATA SOURCE FIGURES .................................................

Figure 1.01 Individual GSK1223249 Plasma Concentration-Time Plots to 25 hours (Linear and Semi-log) by Treatment (PK Population) ...................

Figure 1.02 Individual GSK1223249 Plasma Concentration-Time Plots to end of study (Linear and Semi-log) by Treatment (PK Population) ................

ATTACHMENT 1 - PLANNED STUDY SCHEMATIC ............................................. ATTACHMENT 2 - TIME AND EVENTS TABLE ....................................................

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ABBREVIATIONS

Ae Urinary recovery of unchanged drug Ae(0-x) Urinary recovery of unchanged drug up to fixed nominal time-point x

Ae(0-) Complete urinary recovery of unchanged drug up to time of last measurable urinary concentration

Ae(0-) Urinary recovery over a dosing interval

AE Adverse EventALT Alanine aminotransferaseANOVA Analysis of VarianceAST Aspartate aminotransferaseAUC Area under concentration-time curve

AUC(0-) Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time

%AUCex Percentage of AUC(0-) obtained by extrapolationAUC(0-x) Area under the concentration-time curve from zero (pre-dose) to some

fixed nominal time xAUC(0-t) Area under the concentration-time curve from time zero (pre-dose) to

last time of quantifiable concentration within a subject across all treatments

AUC(0-) Area under the concentration-time curve over the dosing interval

-HCG Beta-Human Chorionic Gonadotropin

BA BioavailabilityBE BioequivalenceBMI Body mass indexBP Blood pressureBPM Beat Per MinuteBQL Below the quantification limitBUN Blood urea nitrogenCBC Complete blood countCI Confidence IntervalCLr Renal clearanceCL Systemic clearance of parent drugCL/F Apparent clearance following oral dosingCmax Maximum observed concentration Cmin Minimum observed concentrationCτ Pre-dose (trough) concentration at the end of the dosing intervalCt Last observed quantifiable concentrationCO2 Carbon dioxideCPK Creatine phosphokinaseCPSR Clinical Pharmacology Study ReportCRF Case Report FormCRO Contract Research OrganizationCRU Clinical Research UnitCV Coefficient of varianceDBP Diastolic blood pressure

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DEC Dose Escalation CommitteeECG ElectrocardiogramEDC Electronic data captureEDSS Expanded Disability Status ScaleEISR Expedited Investigator Safety ReportFabs Absolute bioavailability of drug determined following extra vascular

and intravascular dosingFDA Food and Drug AdministrationFrel Relative bioavailability of drug determined between two formulations of

the same drug following similar or different extra vascular route of administration

FSH Follicle Stimulating HormoneFTIH First time in humansGCP Good Clinical PracticeGGT Gamma glutamyltransferaseGLS Geometric Least-SquaresGSK GlaxoSmithKlinehCG Human chorionic gonadotropinHIV Human Immunodeficiency Virush/hr Hour(s)HR Heart rateIB Investigator’s BrochureICH International Conference on Harmonization of Technical Requirements

for Registration of Pharmaceuticals for Human UseIDMC Independent Data Monitoring CommitteeIDSL Integrated Data Standards LibraryIEC Independent Ethics CommitteeIND Investigational New DrugIP Investigational ProductIRB Institutional Review BoardIU International UnitIV IntravenousKg Kilogram

z Terminal phase rate constant

L LiterLFTs Liver function testsln Naperian (natural) logarithmLOQ Limit of quantificationLLQ Lower limit of quantificationµg MicrogramµL MicroliterMAT Mean absorption timeMedDRA Medical Dictionary for Regulatory ActivitiesMg MilligramsmL MilliliterMRT Mean residence time

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MSDS Material Safety Data Sheetmsec MillisecondsNQ Non-quantifiable concentration measured as below LLQPD PharmacodynamicPGx PharmacogeneticsPK PharmacokineticPSRI Periodic Safety Reports for InvestigatorsQC Quality controlQD Once dailyRAP Reporting and Analysis PlanRBA Relative BioavailabilityRBC Red blood cellsSAE Serious adverse event(s)SAS Statistical Analysis SoftwareSD Standard deviationSOP Standard Operating ProcedureSPM Study Procedures ManualSUSAR Suspected, Unexpected, Serious Adverse drug ReactionT Infusion durationt Time of last observed quantifiable concentrationt½ Terminal phase half-lifeτ Dosing intervaltlag Lag time before observation of drug concentrations in sampled matrixtlast Time of last quantifiable concentrationtmax Time of occurrence of CmaxULN Upper limit of normalUK United KingdomUS United StatesVd Volume of distribution after intra vascular (e.g., iv) administrationWBC White blood cells

Trademark Information

Trademarks of the GlaxoSmithKline group of companies

Trademarks not owned by the GlaxoSmithKline group of companies

RANDALL AvonexCopaxone

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ETHICS AND GOOD CLINICAL PRACTICE

The study protocol, any amendments, the informed consent, and other information that required pre-approval were reviewed and approved by a national, regional, or investigational center ethics committee or institutional review board, in accordance with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) and applicable country-specific requirements, including US 21 Code of Federal Regulations (CFR) 312.3(b) for constitution of independent ethics committees. Ethics committee or institutional review board approvals are maintained in the Sponsor’s study file.

This study was conducted in accordance with ICH GCP and all applicable subject privacy requirements, and, the ethical principles that are outlined in the Declaration of Helsinki 2008.

Investigators were trained to conduct the study in accordance with GCPs and the study protocol as defined in ICH E3, Section 9.6. Written commitments were obtained from investigators to comply with GCP and to conduct the study in accordance with the protocol. The study was monitored in accordance with ICH E6, Section 5.18.

Written informed consent was obtained from each subject prior to the performance of any study-specific procedures. The subject was provided as much time as necessary to review the document, to inquire about details of the trial, and to decide whether or not to participate in the study. The informed consent was signed and dated by the study subject and by the person who conducted the informed consent discussion. Case report forms were provided for each subject’s data to be recorded.

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1. INVESTIGATOR INFORMATION AND STUDY ADMINISTRATION

InvestigatorInvestigator/ Site/Centre Number Hospital/ Institution and Address

MD Centre

Italy

All investigators and responsible study site staff attended an investigator training meeting and separate study site initiation visit to review study protocol procedures, study requirements, and GCP responsibilities. Investigators and staff were given opportunity to discuss any aspect of the study protocol and GCP requirements. Training records were reviewed to ensure investigators and staff were qualified to conduct the study and to document training in GCP. Any staff lacking in GCP training were either sent to a GCP training course or provided an electronic GCP training module. Documentation of GCP training was confirmed prior to staff participation in the study.

Principal investigators signed the investigator page of the protocol to confirm their commitment to conduct the study in accord with the protocol and GCP. The signed documents have been archived within individual investigator study files.

Written informed consent was obtained from each subject prior to the performance of any study-specific procedures. The subject was provided as much time as necessary to review the document, to inquire about details of the trial, and to decide whether or not to participate in the study. The informed consent was signed and dated by the study subject and by the person who conducted the informed consent discussion. Case report forms were provided for each subject’s data to be recorded.

In accordance with applicable regulations, GCP and GSK procedures, GSK monitors contacted the site prior to the start of the study to review with the site staff the protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and GSK requirements. When reviewing data collection procedures, the discussion included identification, agreement and documentation of data items for which the CRF served as the source document. GSK monitored the study to ensure that: (1) the data are authentic, accurate, and complete; (2) the safety and rights of subjects were protected; (3) the study was conducted in accordance with the currently approved protocol and any other study agreements, GCP and all applicable regulatory requirements.

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2. OBJECTIVES & ENDPOINTS

PRIMARY OBJECTIVE ENDPOINTS1 To explore the safety and tolerability of single

and repeat doses of GSK1223249, administered IV in ascending dose cohorts, in subjects with relapsing forms of MS.

Changes in vital signs, ECG monitoring, blood chemistry, haematology, urinalysis, monitoring of AEs and MS relapses (number, incidence, severity)

SECONDARY OBJECTIVES ENDPOINTS2.1 To characterize the PK in plasma

GSK1223249, following single and repeat IV doses infused over approximately 60 minutes, in ascending dose cohorts.

Parameters derived from the population PK model of GSK122349.

In addition, some parameters calculated from individual observed concentration-time profile data.

2.2 To evaluate immunogenicity of GSK1223249 in MS patients

Presence of antibodies to GSK1223249 to be assessed in serum samples using validated ECL assays.

2.3 To determine concentration of GSK1223249 in CSF and a CSF:plasma ratio of GSK1223249

Measurement of GSK1223249 in CSF

EXPLORATORY OBJECTIVES ENDPOINTS3.1 To characterize the PK in CSF of

GSK1223249, in subjects with relapsing forms of MS following single and repeat IV doses infused over approximately 60 minutes, in sequential ascending dose cohorts.

GSK1223249 CSF concentration-time profile.

3.2 To monitor paraclinical activity by MRI in subjects with relapsing forms of MS following single and repeat IV doses of GSK1223249

New Gd-enhancing lesion counts New Gd-enhancing lesion volume T2-weighted lesion volume change T1-weighted lesion volume change Percentage of Gd-enhancing lesion

voxels with increasing magnetization transfer ratio (MTR) on serial study

Percentage of Gd-enhancing lesion voxels with decreased MTR

Change in cerebral normal-appearing white matter MTR

Change in cerebral mean diffusivity3.3 To evaluate the effect of repeat dose

administration of GSK1223249 on disability in subjects with relapsing forms of MS.

EDSS

3.4 To conduct exploratory biomarker analysis related to mechanisms of Multiple Sclerosis and the mechanism of action of GSK1223249 in plasma/serum and CSF

Plasma and serum taken at baseline and after repeat dose

CSF taken from timepoints for PK analysis

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3. INVESTIGATIONAL PLAN

3.1. Study Rationale

GSK1223249 is being developed for treatment of multiple sclerosis based on a combination of scientific data on the target, preclinical efficacy of GSK1223249, and a major unmet need of MS patients for therapies which halt or reverse the progression of neurological dysfunction.

This study explored the safety, tolerability and pharmacokinetic profile of GSK1223249in MS patients. Dose levels were chosen which were expected to achieve appropriate central target binding. In addition, it was intended that the study would allow an assessment of GSK1223249 immunogenicity and an assessment of penetration of GSK1223249 into the Central Nervous System (CNS) compartment.

3.2. Study Design

Three single dose/repeat dose cohorts were planned to be studied, with subjects being exposed to a single intra-venous dose of GSK1223249 at the starting dose level for each cohort, followed by escalation to a higher dose level 4 weeks later, then followed by a repeat higher intra-venous dose a further 4 weeks later:

Cohort 1 – 1mg/kg, 5mg/kg, 5mg/kg



Provision was made to adjust subsequent planned doses based on emergent safety, tolerability and/or pharmacokinetic data.

The study was randomised, placebo-controlled and single-blind (Investigator and Subjectwere blinded). It was planned that enough subjects would be enrolled to achieve a total of 40 patients who completed the dosing and safety assessments up to the day 70 visit (8 subjects in cohort 1, and 16 subjects in each of cohorts 2 & 3).

3.3. Protocol Amendments

Two protocol amendments were produced and implemented. The first protocol amendment, dated 16 Mar 2011, was produced to: document removal of an orthostatic challenge; addition of pre-dose PK blood sample for 3rd dose; and removal of the requirement for an overnight stay after lumbar puncture.

The second protocol amendment, dated 01 Jul 2011, was produced to: document a change of QT stopping criteria; removal of the requirement for central ECG reading; sometypographical corrections; and clarification of brief & full physical exam timepoints.

All protocol amendments were implemented at all study centres, prior to subject enrolment.

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3.4. Selection of Study Population

3.4.1. Inclusion & Exclusion Criteria

Inclusion criteria

1. Suitable as determined by the Principal Investigator, based on his/her overall evaluation. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the Investigator and the GlaxoSmithKline Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.

2. Diagnosed with a relapsing form of MS defined as either

a. RRMS according to revised McDonald Criteria [McDonald, 2001; Polman, 2005] and a history of brain MRI lesions consistent with MS, OR

b. SPMS with relapses and a history of brain MRI lesions

3. Using one of the following ongoing MS treatment strategies, defined as

a. Currently receiving Beta-interferon/Copaxone for treatment of MS and have been receiving the current course of therapy for 3 or more months prior to screening, OR

b. Not currently receiving disease modifying therapies for treatment of MS, and has not received such therapies for at least 3 months prior to screening.

4. Have demonstrated clinical activity in 2 years prior to screening, whilst receiving current/previous treatment regimen or prior to any treatment regimen, by either:

a) One or more documented relapses, or

b) One or more documented Gd enhancing lesions in the brain or spinal cord, or

c) Confirmed disease progression on EDSS by greater than or equal to 0.5 points.

5. Expanded Disability Status Scale (EDSS) score ≤6.0 at either the screening or baseline visit.

6. Male or female between 18 and 60 years of age inclusive, at the time of signing the informed consent.

7. A female subject is eligible to participate as follows:

a. Non-childbearing potential, defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 24 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MlU/mL and estradiol < 40 pg/mL (<140 pmol/L) is confirmatory].

b. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods described in [GlaxoSmithKline Document Number XM2010/00059/02]Section 7.1.1 if they wish to continue their HRT during the study. Otherwise,

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they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least two to four weeks must elapse between the cessation of therapy and the blood draw; this interval depends on the type and dose of HRT. Following confirmation of their post-menopausal status, subjects may resume use of HRT during the study without use of a contraceptive method.

c. Women of childbearing potential should have used one of the contraception methods listed in [GlaxoSmithKline Document Number XM2010/00059/02]Section 7.1.1 for at least 1 month prior to the start of dosing to sufficiently minimize the risk of pregnancy. Women of childbearing potential must agree to continue to use contraception throughout the study and for an additional 6 months after dosing. Their male partners should also use contraception.

8. Male subjects must agree to use one of the contraception methods listed in [GlaxoSmithKline Document Number XM2010/00059/02] Section 7.1.2, even if they have had a vasectomy. This criterion must be followed from the time of the first dose of study medication, during the study, and for 6 months after dosing.

9. Body weight 50 kg .

10. On ECG, QTcB interval < 450 msec; or QTc < 480 msec in subjects with bundle branch block.

11. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form, and authorisation of the release and use of protected health information (PHI).

Exclusion criteria

1. History of, or laboratory findings indicative of any clinically significant (as determined by the Investigator) cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal, and/or other major disease or of known drug sensitivity that would preclude the administration of a recombinant humanized antibody or the use of systemic steroids during the course of the study.

2. Abnormal baseline blood tests exceeding any of the limits defined below:Alanine transaminase (ALT) or aspartate transaminase (AST) >1.5 x the upper limit of normal (ULN)

Alkaline phosphatase (AP) and bilirubin >1.5X ULN (isolated bilirubin >1.5x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).

Total white blood cell count < 2,500/mm3

Platelet count < 95,000/mm3

Creatinine > 2 x ULN

Calculated creatinine clearance < 60 ml/min (per Cockcroft & Gault) at Screening

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International Normalised Ratio (INR) larger than upper limit of the normal reference range (0.9 – 1.3)

3. Treatment with methylprednisolone or any other systemic steroid, for a relapse or otherwise, within 30 days of screening

4. Treatment within the past 12 months or currently with any of the following agents: cyclosporine, cladribine, natalizumab (Tysabri) or other monoclonal antibodies, murine protein, T-cell vaccination, plasmapheresis, IV IgG, stem cell transplantation.

5. Treatment in the past 6 months with any of the following agents: Fingolimod (Gilenya), methotrexate, mitoxantrone, azathioprine, or other small molecule immunosuppressants.

6. History of intolerance to acetominophen, ibuprofen, naproxen or any other non-steroidal anti-inflammatory agent which would preclude use of at least one of these during the study.

7. Previous history of anaphylaxis, severe allergic reaction, generation of neutralizing antibodies, or hypersensitivity to albumin or a protein-based therapeutic, including natalizumab (Tysabri) or any other monoclonal antibody. History of hypersensitivity to any of the components of the formulation.

8. History of alcohol or drug abuse (as defined by DSM-IVR criteria) within 2 years prior to randomisation

9. A positive pre-study hepatitis B surface antigen or positive hepatitis C antibody result.

10. Subjects with evidence of dementia or psychiatric illness which, in the Investigator’s opinion, is likely to prevent them from a full understanding of and/or compliance with the study requirements and procedures.

11. Known diagnosis or history consistent with human immunodeficiency virus (HIV) positivity.

12. Blood donation (1 unit or more) within 3 months prior to investigational drug administration.

13. History of regular alcohol consumption within 6 months of the study defined as: Average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 g of alcohol: a half-pint (~240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.

14. Subjects who have received vaccinations 3 weeks prior to administration of study drug.

15. Contraindications to MRI scanning including but not limited to:

Intracranial aneurysm clips (except Sugita clips) with an appropriate operative conformation;

History of intra-orbital metal fragments that have not been removed by an MD;

Documented:

Pacemakers and non-MRI compatible heart valves

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Inner ear implants

History of severe claustrophobia or inability to lie still on the back for a period of approximately one (1) hour in the MRI scanner.

16. Contraindications for administration of Gd-contrast agents ie. any history of severe renal insufficiency if not already mentioned above.

17. Greater than 10 Gadolinium-enhancing lesions present at screening MRI.

18. Unwillingness or inability to follow the procedures outlined in the protocol.

19. Subjects with a medical history of significant infections (such as tuberculosis, opportunistic or atypical infections) or any congenital or acquired immunodeficiency.

20. Active or latent tuberculosis (TB) infection: All subjects will be tested with QuantiFERON TB Gold test and those with positive test result will be excluded.

[Note: Subjects with an indeterminate test result may undergo one re-test; a subsequent indeterminate or positive result excludes participation]. Chest radiographs may be performed if the investigator determines that it is clinically indicated and any abnormal findings suggestive of active or latent TB will exclude thes patient.

21. Subjects, who in the investigator's judgement, pose a significant suicide risk. Evidence of serious suicide risk may include any history of suicidal behavior in the last 6 months and/or any suicidal ideation of type 4 or 5 on the C-SSRS in the last 2 months.

3.4.2. Withdrawal Criteria

Withdrawal criteria were divided into the below broad classifications:

Dose adjustment and stopping criteria QTc withdrawal criteria Subject withdrawal criteria

See Section 3.5; Section 3.6.2, and Section 9.3 of the NGM114840 clinical protocol [GlaxoSmithKline Document number: XM2010/00059/02] respectively, for details of the above withdrawal criteria.

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3.5. Treatments

3.5.1. Investigational Product(s) and Reference Therapy

Treatment Drug Dose/Form/Route Frequency/Duration Batch Number

Active GSK1223249 1 or 5 or 15 or 30 mg/kg. 200mg/mL solution. Intravenous Infusion

Once every 4 weeks/60 minutes per infusion

081168345

Placebo None Saline solution. Intravenous Infusion

Once every 4 weeks/ 60 minutes per infusion

n/a

Placebo infusions did not require dilution and were taken directly from the bag of 0.9% sodium chloride.

Study treatment was administered by slow IV infusion over approximately 60 minutes by a programmable syringe pump.

3.5.2. Treatment Assignment

Subjects were assigned to study treatment in accordance with the randomisation master schedule. Subjects were randomised and enrolled via the GSK Registration & Medication Ordering System (RAMOS). Randomisation numbers, provided by RAMOS, were matched to a master schedule provided by GSKs randomisation coordinator- to unblinded site pharmacists, whom then matched randomisation numbers to appropriate treatment assignments.

3.5.3. Blinding

Investigational medicinal product (GSK1223249) in 200mg/mL solution is visually distinguishable from saline placebo. Blinding was achieved with the use of visually opaque coverings applied to dosing materials (I.V. bags, lines, infusion sets, canualas), and study centres utilised unblinded pharmacists to prepare individual subject infusions. All other study centre staff were blinded, including staff members transporting andadministering study treatment, and returning used infusion sets to the unblinded pharmacist.

Treatment codes could be unblinded by the investigator or treating physician only in the case of a medical emergency or in the event of a serious medical condition, when knowledge of the investigational product was essential for the clinical management or welfare of the subject. GSK Global Clinical Safety and Pharmacovigilance (GCSP) staff could unblind treatment codes in the event of a SAE.

3.5.4. Prior and Concomitant Medications and Non-Drug Therapies

Section 8 of the NGM114840 clinical protocol contains specific details about concomitant medications and non-drug therapies.

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3.5.5. Compliance

Compliance with drug administration within protocol defined boundries/prerequisites was assessed by suitably qualified study site staff (see Section 10.4 of the NGM114840 clinical protocol [GlaxoSmithKline Document number: XM2010/00059/02].). Details about date, duration and start and finish volumes and masses of the infusion sets were also recorded.

3.6. Study Assessments and Procedures

Study assessments, procedures and timings are listed in Section 3.7 and Section 6 of the NGM114840 protocol [GlaxoSmithKline Document number: XM2010/00059/02].

3.6.1. Safety Assessments

Section 6.3.6 of the clinical protocol contains full details regarding safety assessments. Adverse Event (AE) and Serious Adverse Event (SAE) definitions are also located within the protocol (Section 11.1 and Section 11.2)..

Specialised assessments for the patient population were also included in the study(Section 3.2 of the protocol). Briefly, assessments included were: Neurological examination; EDSS scoring; relapse evaluations; and MRI metrics.

3.6.2. Pharmacokinetic Assessments

Pharmacokinetic samples were collected at time-points outlined in the in the Time and Events Tables (Attachment 2). Samples were collected at nominal times relative to the proposed time of GSK1223249/placebo dosing.

Blood samples (3 mL) were taken via an indwelling cannula (or by direct venepuncture), collected into an ethylenediamine tetra-acetic acid (EDTA) tube and immediately placed on water ice.

Samples were centrifuged in a refrigerated centrifuge (approximately 4°C) at 1500g or 3000 rpm for 10 minutes. Supernatant plasma was transferred to a 1.4 mL microvial labelled polypropylene tube and stored at -20°C before shipment. Samples were shipped frozen on dry ice (or refrigerated as appropriate) at agreed time points throughout the study to:

Department of Worldwide Bioanalysis, Drug Metabolism and Pharmacokinetics, GSK, King of Prussia, PA, United States.

Plasma samples were analyzed for GSK1223249 by GSK, King of Prussia, PA,using a validated analytical method based on sample dilution, followed by Immunoassay analysis. The lower limit of quantification (LLQ) was 100 ng/mL using a 100 µL aliquot of 10-fold diluted EDTA plasma. The higher limit of quantification (HLQ) was 1500 ng/mL [GlaxoSmithKline Document number CD2009/00753/00].

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Quality Control (QC) samples prepared at three different analyte concentrations andstored with study samples, were analysed with each batch of samples against separatelyprepared calibration standards. The QC samples and calibration standards were prepared

using a stock solution of GSK1223249 reference material. For the analysis to be acceptable, no more than one-third of the QC results were to deviate from the nominal concentration by more than 20%, and at least 50% of the results from each QC concentration should be within 20% of nominal.

The raw data are held under the control of US (Upper Merion), GSK R&D GLP archivesfor retention in accordance with their GLP archiving procedures.

3.6.3. Pharmacodynamic Assessments

No specific or formal pharmacodynamic assessments were planned. Exploratory analayses of any relationships between pharmacokinetic, safety assessments and/or other potential markers of efficacy were considered, based on the yield of data.

3.6.4. Efficacy Assessments

None.

3.7. Data Quality Assurance

This study was conducted according to GCP.

Subject data was entered into GSK defined eCRFs, transmitted electronically to GSK and combined with data provided from other sources (e.g., laboratory data) in a validated data system.

Verification of data accuracy and adherence to protocol requirements was achieved through regular monitoring visits at each investigational site. Subsequent data handling and reporting processes were performed according to processes detailed in GSK’s Standard Operating Procedures (SOPs). AEs and concomitant medications were coded using company standard dictionaries, Medical Dictionary for Regulatory Activities (MedDRA) and GSKDrug.

SAE, consistent with the data collected for other AEs, was entered into the database and quality assured, including reconciliation with the GCSP database.

3.8. Data Analysis Methods

3.8.1. Sample size considerations

There was no formal calculation of power or sample size for this exploratory study. Thesample size of 40 subjects who complete the study to day 70 was based on safety and feasibility considerations. Of the 40, 10 subjects were to be allocated to placebo (2 in cohort 1, 4 in cohort 2 and 4 in cohort 3) and 30 to active (6 in cohort 1, 12 in cohort 2

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and 12 in cohort 3). This was intended to allow an initial estimate of the safety and tolerability associated with administration of doses of GSK1223249.

While no formal statistical comparisons were planned, the adverse event rate for relapses (recorded as adverse events if they are atypically severe or unusual in recurrence) were of interest. Due to uncertainty around event rates however an estimate of around 1-10% was assumed.

Further details about sample size considerations and quantification of assumed probablilities can be found in Section 5.2.1 of the clinical protocol.

3.8.2. Interim Analyses

No formal interim statistical analyses were planned or performed.

Escalation from one cohort to the next cohort was to involve a Dose Escalation Committee (DEC). See Section 3.5.2 and Appendix 2 of the clinical protocol for full details. Following receipt of the key safety data once the last subject within a cohort had completed the Day 36 visit (6 days after second dose), and in addition, half the patients had completed the Day 64 visit, it was intended that the unblinded data for each group would be reviewed by the DEC to aid decisions to proceed to the next dose level. As the study was terminated (see Section 3.8.4 for details) before the DEC trigger point was reached, no dose escalation committee meetings took place.

3.8.3. Final Analyses

Population and safety data were planned to be presented in graphical format and summarized descriptively according to GSK’s Integrated Data Standards Library (IDSL) standards. However due to the termination of the study the changes described in the next section were implemented.

The presence of antibodies to GSK1223249 (assessed in serum samples) were to be listed and summarised descriptively by dose, but analysis was not performed since the study was terminated.

Placebo groups were intended to be combined across cohorts in summary outputs, but since the study was terminated early, only one subject received placebo treatment.

Full details of the analysis of other exploratory safety related endpoints are included in the reporting and analysis plan (RAP).

3.8.4. Changes in Conduct of the Study or Planned Analyses

NGM114840 was terminated prematurely on the 15th of December, 2011. As such the study was not conducted to completion as planned.

The study was terminated after 3 subjects had received at least one dose of study treatment, due to emergence of additional preclinical data that, whilst not raising safety concerns, questioned the robustness of the scientific rationale for GSK1223249’s role in

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remyelination. While this data did not change the benefit/risk to subjects in the study, it weakened the benefit/risk assessment for future development in MS.

Data are presented in listing format rather than in tabular format as planned (with the exception of the demography tabulation). Individual results are plotted but no summary plots were produced.

Samples were not analysed for anti-GSK1223249 antibodies because the study was terminated before any of the subjects could attend the day 85 assessment, which would have included the first meaningful immunogenicity sample. Therefore, no listing of immunogenicity results was produced.

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4. STUDY POPULATION RESULTS

4.1. Subject Disposition

Table 1 Subject Disposition & Demographics

Number of Subjects TotalNumber of subjects planned, N: 40Number of subjects randomised, N: 3Number of subjects included in Safety population, n (%): 3 (100)Number of subjects included in Pharmacokinetic population, n (%): 2 (67)Number of subjects completed as planned, n (%): 0 (0)Number of subjects withdrawn (any reason), n (%): 3 (100)Number of subjects withdrawn for SAE, n (%): 0Number of subjects withdrawn for AE, n (%): 0DemographicsAge in years, Mean (range) 40 (36–43)Sex, n (%)

Female: 1 (33)Male: 2 (67)

Height in cm, Mean (range) 171 (163–185)Weight in kg, Mean (range) 72.3 (52–105)Ethnicity, n (%)

Hispanic or Latino: 0Not Hispanic or Latino: 3 (100)

Race, n (%)White – White/Caucasian/European Heritage 3 (100)

Source Data: ICH Listing 1.01, ICH Listing 1.02, ICH Listing 1.04

The reason given was “due to disease exacerbation”.

4.2. Protocol Deviations

No inclusion/exclusion criteria deviations were reported. No other deviations were reported.

4.3. Populations Analyzed

The ‘All Subjects Population’, defined as all subjects who were enrolled into the study, comprised three subjects. This population was used for all listings and figures (with the exception of PK).

The ‘Safety Population’, defined as all enrolled subjects who received at least one of their planned doses of GSK1223249, comprised all three subjects in the study. This population was used for the tabulation of demographic characteristics.

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The ‘Pharmacokinetic Population’, defined as all subjects in the ‘All Subjects Population’ for whom a pharmacokinetic sample was obtained and analysed, comprised two subjects. This population was used for all of the pharmacokinetic listings and figures.

4.4. Demographic and Baseline Characteristics

All three subjects had a diagnosis of a relapsing form of MS, with demonstrated clinical activitiy and/or gadolinium-MRI enhancing lesions in the brain or spinal chord within 2 years prior to screening (Other data listing 2.02 and Other data listing 2.26).

These concomitant medications were not in conflict with the protocol, as per the inclusion criteria. Dosage & frequency remained unchanged throughout the study for all subject treatments. (ICH listing 1.08).

4.5. Prior and Concomitant Medications

Concomitant medications (see ICH listing 1.08 also) other than those listed in the previous section (i.e. not part of the study inclusion/exclusion criteria pre-defined treatment strategy for MS) are as follows:

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4.6. Exposure and Treatment Compliance

Planned study treatment included

provision to dose either GSK1223249 or placebo a total of three times per subject. At the point of study termination, all three subjects were at different stages of study, and none of the subjects received their 3rd dose. The final visit for each subject is as follows:

There were no deviations to actual dosing, nor procedures associated with, dosing of study treatment. There were no treatment compliance issues reported.

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5. SAFETY RESULTS

5.1. Adverse Events

Of the total of 9 AEs, 1 (Asthenia) was judged by the investigator to be related to the investigational medicinal product.

Colubia Suicidality Severity Rating Scale (CSSRS) & PSRAEs

There were no reports of any suicidal attempts, ideation or behaviour. There were no reports of any adverse events that were considered as Possible Suicidality Related Adverse Events (PSRAEs) (Other Data Listing 2.11, Other Data Listing 2.12, Other Data Listing 2.13, Other Data Listing 2.14, Other Data Listing 2.15 and Other Data Listing 2.16).

5.2. Serious and Other Significant Adverse Events

No subjects died during the study. No Serious Adverse Events were reported.

No adverse events leading to discontuniation of study drug or withdrawal from the study were reported (ICH Listing 2.11 and ICH Listing 2.16).

5.3. Clinical Laboratory Evaluations

None of the Clinical Chemistry or Haematology values met the criteria for potential clinical importance (PCI). (ICH Listing 1.14 and ICH Listing 1.16). There was one post baseline urinalysis result which met the PCI criteria.

This returned to normal at the next visit (Day 13) and showed as “trace” at Day 29. (ICH Listing 1.18).

Database issue noted:

Total Neutrophils - The database gives the original units (%) and standardised units (GI/L) combined into one variable rather than in two separate variables. The footnote to listing 1.17 describes the impact of this on the listing.

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5.4. Vital Signs

There were no vital signs assessments which met the PCI criteria. (ICH Listing 2.06).

5.5. Pregnancies

No subjects or female partners of male subjects became pregnant during the study, or during the post-study timeframe for reporting pregnancies. (ICH Listing 2.17 and ICH Listing 2.18).

5.6. Expanded Disability Status Scale

All three subjects had a small reduction in EDSS total score by day 29. (ICH Listing 2.25).

5.7. Electrocardiogram

There were no ECG assessments which met the PCI criteria (ICH Listing 2.08). There were no clinically significant telemetry abnormalities or clinically significant ECG abnormalities (as assessed by the investigator).

Database issue noted:

This is incorrect, it appears the date should read (ICH Listing 2.09).

5.8. Relapse Evaluations

No subjects reported relapses during the study . (ICH Listing 2.23).

5.9. Magnetic Resonance Imaging

A listing of Gd-enhancing lesion counts is provided in Other listing 2.26. A listing of Gd-enhancing lesion volume is provided in Other Listing 2.27 and a listing of T2- and T1-weighted lesion volume in Other listing 2.28.

Table 2 Gadolinium-enhancing lesion counts

Source Data: Other Listing 2.26a. Number of new lesions since the previous visit

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6. PHARMACOKINETIC RESULTS

26

This section

containe

d data from each individual patient,

rather

than in

aggregat

e. They have been excluded to

protect

patient

privacy.

Anonymized

data from each patie

nt may be

made

available subject

to an approved research proposal. For furth

er information

please

see the

Patient

Level

Data section of the

Sponsor Clinical

Study

Register.

This section contained data from each individual

patient, rather than in aggregate. They have

been excluded to protect patient privacy.

Anonymized data from each patient may be

made available subject to an approved research proposal. For further

information please see the Patient Level Data section of the Sponsor Clinical Study Register.


26

7. PHARMACODYNAMIC AND BIOMARKER RESULTS

MRI data is included in the listings, Other Listing 2.26, Other Listing 2.27 and Other Listing 2.28. No further assessment of pharmacodynamics was conducted due to study termination.

No assessment of biomarkers was made due to study termination.

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8. RELATIONSHIP BETWEEN PHARMACOKINETIC AND PHARMACODYAMIC PARAMETERS

Exploratory PK/PD analyses were considered, with the intention to examine the potential relationships between GSK1223249 pharmacokinetics and markers of safety and efficacy, as data permited. As the study was terminated early, no analysis or interpretations regarding relationships between PK/PD was possible.

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9. DISCUSSION AND CONCLUSIONS

9.1. Discussion

The primary objective of this randomised, single-blind, placebo-controlled, single ascending/repeat dose study was to explore the safety and tolerability of GSK1223249, administered IV in ascending dose cohorts, in subjects with relapsing forms of MS.

The study was terminated after 3 subjects had received at least one dose of study treatment. Upon review of additional pre-clinical animal model data GSK decided to suspend the MS clinical development program for GSK1223249 and re-evaluate the overall body of evidence relating to the potential effectiveness of GSK1223249 in this indication with respect to myelination. These additional pre-clinical data did not raise any safety concerns and were not considered to have any bearing on clinical development activities with GSK1223249 for indications other than MS. The study was not terminated on the grounds of safety.

One subject received 2 doses of placebo, one subject received 2 doses of GSK1223249 (1mg/k & 5mg/kg), and one subject received 1 dose of GSK1223249 (1mg/kg).

GSK1223249 was well tolerated in the two subjects that received active drug. There were no SAEs and no AEs leading to discontinuation. There were no trends that were suggestive of a GSK1223249-related effect in terms of AEs, or changes in safety laboratory parameters, vital signs, or ECG intervals.

The key PK parameters observed in this study were consistent with predicted parameters, as stated in the protocol, and from other clinical data generated in separate clinical studies.

The investigator broke the treatment blind approximately 2 months after the last dose of study treatment for the subject that received placebo, giving the reason as disease exacerbation.

9.2. Conclusions

GSK1223249 was well tolerated in the two subjects dosed with 1mg/kg and in the one subject that received an additional dose of 5mg/kg. There were no SAEs and no AEs leading to discontinuation.

None of the haematology, clinical chemistry, vital signs or ECG values met or exceeded the thresholds for potential clinical importance. The investigator broke the treatment blind approximately 2 months after the last dose of study treatment for the subject that received placebo citing disease exacerbation.

One post baseline urinalysis result met the PCI criteria.

The two subjects who received GSK1223249 had quantifiable plasma concentrations in the expected range, based on previous human data.

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10. REFERENCES

GlaxoSmithKline NGM114840 Protocol, 01-Jul-2011, document number: XM2010/00059/02. A randomized, single blind, placebo-controlled, single ascending dose/repeat dose cohort study to assess safety, tolerability, pharmacokinetics and immunogenicity of GSK1223249 in patients with relapsing forms of multiple sclerosis.

GlaxoSmithKline Document number CD2009/00753/00; The Validation of a Method for the Determination of GSK1223249 in Human Plasma (range 100 – 1500 ng/mL) using a Chemiluminescent Immunoassay. Method Reference Number: GSK1223249HUPLVALB.

McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, McFarlandHF, Paty DW, Polman CH, Reingold SC, Sandberg-Wollheim M, Sibley W, ThompsonA, van den Noort S, Weinshenker BY, Wolinsky JS. Recommended diagnostic criteriafor multiple sclerosis: guidelines from the International Panel on the diagnosis of multiplesclerosis. Ann Neurol. 2001;50:121-127.

Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, Lublin FD, MetzLM, McFarland HF, O'Connor PW, Sandberg-Wollheim M, Thompson AJ, WeinshenkerBG, Wolinsky JS. Diagnostic criteria for multiple sclerosis: 2005 revisions to the“MacDonald Criteria”. Ann Neurol. 2005;58:840-846.

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11. CASE NARRATIVES

NONE.

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Protocol: NGM114840 Page 1 of 2Population: Safety Table 1.01 Summary of Demographic Characteristics

GSK1223249 1/ 5/ 5 Pbo/ Pbo/ Pbo mg/kg Total (N=1) (N=2) (N=3) ------------------------------------------------------------------------------------------------ Age (yrs) n 1 2 3 Mean 40.0 39.5 39.7 SD 4.95 3.51 Median 40.0 39.5 40.0 Min. 40 36 36 Max. 40 43 43

Sex n 1 2 3 Female 0 1 (50%) 1 (33%) Male 1 (100%) 1 (50%) 2 (67%)

Ethnicity n 1 2 3 Not Hispanic or Latino 1 (100%) 2 (100%) 3 (100%)

Height (cm) n 1 2 3 Mean 165.0 174.0 171.0 SD 15.56 12.17 Median 165.0 174.0 165.0 Min. 165 163 163 Max. 165 185 185

Weight (kg) n 1 2 3 Mean 60.0 78.5 72.3 SD 37.48 28.57 Median 60.0 78.5 60.0 Min. 60 52 52 Max. 60 105 105

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Protocol: NGM114840 Page 2 of 2Population: Safety Table 1.01 Summary of Demographic Characteristics

GSK1223249 1/ 5/ 5 Pbo/ Pbo/ Pbo mg/kg Total (N=1) (N=2) (N=3) ------------------------------------------------------------------------------------------------ Body Mass n 1 2 3 Index (kg/m2) Mean 22.04 25.13 24.10 SD 7.856 5.834 Median 22.04 25.13 22.04 Min. 22.04 19.57 19.57 Max. 22.04 30.68 30.68

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Protocol: NGM114840 Page 1 of 2Population: All Subjects Listing 1.07 Listing of Exposure Data

Treatment: Pbo/ Pbo/ Pbo Start Date/ Stop Date/ Did Subject Reason ForInv./ Start Time Stop Time Duration Receive Incorrect Dose Formulation/Subj. of Dose of Dose (minutes) Correct Dose? Dose Dose Unit Route

34


This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data

section of the Sponsor Clinical Study Register.

Protocol: NGM114840 Page 1 of 6Population: All Subjects Listing 1.08 Listing of Concomitant Medications by Generic Term

Treatment: Pbo/ Pbo/ Pbo Date ATC Level 1/ Dose/ Started/ Date Ingredient/ Units/ Time Stopped/ Started Inv./ Verbatim Text/ Freq/ Started/ Time Pre- Ongoing Subj. Indication Route Study Day Stopped Trial? Medication?

36


This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register.

Protocol: NGM114840 Page 1 of 1Population: All Subjects Listing 1.14 Listing of Clinical Chemistry Abnormalities of Potential Clinical Importance

No data to report

[1] NR for Normal Range flag. CC for Clinical Importance flag. BL for Change from Baseline flag.H=Above range, L=Below range,I=Normal, N=No criteria defined, P=Pre-therapy, R=Baseline.

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Protocol: NGM114840 Page 1 of 47Population: All Subjects Listing 1.15 Listing of All Clinical Chemistry Laboratory Data

Treatment: Pbo/ Pbo/ Pbo Age (y)/ Date/Time of Inv./ Sex/ Collection/ ____Converted Data_____ Flag[1] Subj. Race Lab test (units) Visit Study Day Value Normal Range NR CC BL


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Protocol: NGM114840 Page 1 of 1Population: All Subjects Listing 1.16 Listing of Haematology Abnormalities of Potential Clinical Importance

No data to report


90


Protocol: NGM114840 Page 1 of 52Population: All Subjects Listing 1.17 Listing of All Haematology Laboratory Data

Treatment: Pbo/ Pbo/ Pbo Age (y)/ Date/Time of Inv./ Sex/ Collection/ ____Converted Data_____ Flag[1] Subj. Race Lab test (units) Visit Study Day Value Normal Range NR CC BL

[1] NR for Normal Range flag. CC for Clinical Importance flag. BL for Change from Baseline flag.H=Above range, L=Below range, I=Normal, N=No criteria defined, P=Pre-therapy, R=Baseline.N.B. Total Neutrophils do not show a standardised normal range. The standard converted values areexpressed in GI/L units, however, the normal range flag is based on the original units (%) and thisdifferential parameters range is: 40-75% (of the corresponding White Blood Cell count).

(all of which are Normal)

91




Protocol: NGM114840 Page 1 of 22Population: All Subjects Listing 1.18 Listing of Urinalysis Data for all Subjects

Treatment: Pbo/ Pbo/ Pbo Age (y)/ Date/Time ofInv./ Sex/ Collection/ Flag[1]Subj. Race Lab test (units) Visit Study Day Value CC

[1] CC for Clinical Importance flag. H=Above range, L=Below range, I=Normal, N=No F3 criteria,U=Missing unconverted lab value.

143




Protocol: NGM114840 Page 1 of 1Population: All Subjects Listing 2.02 Listing of MS Medical History

Date of No. of No. of Date of onset of Date of Disease Tot no. Relapses Relapses No of last Inv./ MS MS duration of in last inlast MRI steroidTreatment Subj. Symptoms Diagnosis (years) Relapses 12m 24m scans use

165




Protocol: NGM114840 Page 1 of 1Population: All Subjects Listing 2.06 Listing of Vital Signs of Potential Clinical Importance

No data to report

Note: L = Low, H = High

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Protocol: NGM114840 Page 1 of 1Population: All Subjects Listing 2.08 Listing of All ECG Values for Subjects with a Value of Potential Clinical Importance

No data to report

Measurements re-derived by GSK (QTcB and QTcF) are denoted as derived in the listing.Potential Clinical Importance is defined as:QTcB Interval or QTcF Interval >450 or where the increase from baseline is >60 (msec) orPR Interval <110 or >220 orQRS Duration <75 or >110

167


Protocol: NGM114840 Page 1 of 8Population: All Subjects Listing 2.09 Listing of Abnormal ECG findings

Treatment: Pbo/ Pbo/ Pbo Age(y)/ Visit/ Clinically Inv./ Sex/ ECG Date/ Study Significant Subj. Race Time Day ECG Finding Abnormality

168




Protocol: NGM114840 Page 1 of 1Population: All Subjects Listing 2.11 Listing of Suicide Attempts

No data to report

176


Protocol: NGM114840 Page 1 of 1Population: All Subjects Listing 2.12 Listing of CSSRS Suicidal Ideation and Behavior Data

No data to report

Note: Only subjects with suicidal ideation or behavior at least one timepoint are displayed.Key: 1=Wish to be dead, 2=Non-specific active suicidal thoughts, 3=Active suicidal ideation with anymethods (not plan) without intent to act, 4=Active suicidal ideation with some intent to act, withoutspecific plan, 5=Active suicidal ideation with specific plan and intent, 6=Actual attempt,7=Engaged in non-suicidal self injurious behavior, 8=Interrupted attempt, 9=Aborted attempt,10=Preparatory acts or behaviour, 11=Suicidal behavior, 12=Completed Suicide.

177


Protocol: NGM114840 Page 1 of 1Population: All Subjects Listing 2.13 Listing of All Possible Suicidality-Related Adverse Events (PSRAE) (Sections 1-2)

No data to report

178


Protocol: NGM114840 Page 1 of 1Population: All Subjects Listing 2.14 Listing of All Possible Suicidality-Related Adverse Events (PSRAE) (Section 3)

No data to report

179


Protocol: NGM114840 Page 1 of 1Population: All Subjects Listing 2.15 Listing of All Possible Suicidality-Related Adverse Events (PSRAE) (Section 4)

No data to report

180


Protocol: NGM114840 Page 1 of 1Population: All Subjects Listing 2.16 Listing of All Possible Suicidality-Related Adverse Events (PSRAE) (Sections 5-8)

No data to report

181


Protocol: NGM114840 Page 1 of 1Population: All Subjects Listing 2.17 Listing of Subjects Who Became Pregnant During the Study

No data to report

182


Protocol: NGM114840 Page 1 of 1Population: All Subjects Listing 2.18 Listing of Male Subjects with Female Partners Who Became Pregnant During the Study

No data to report

183


Protocol: NGM114840 Page 1 of 1Population: All Subjects Listing 2.23 Listing of Patients with Relapses during the study

No data to report

184


Protocol: NGM114840 Page 1 of 3Population: All Subjects Listing 2.25 Listing of Expanded Disability Status Scale (EDSS)

Treatment: Pbo/ Pbo/ Pbo Visit/ Date of Bladder/ EDSSInv./ EDSS/ Visual Brain- Pyram- Cere- Bladder/ Bowel Ambu- TotalSubj. Study Day Visual Converted stem idal bellar Sensory Bowel Converted Cerebral lation Score

185


This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the

Patient Level Data section of the Sponsor Clinical Study Register.

Protocol: NGM114840 Page 1 of 2Population: All Subjects Listing 2.26 Listing of Gd-enhancing Lesion Counts

Treatment: Pbo/ Pbo/ Pbo Age(y)/ Cumulative NewInv./ Sex/ Study Gd-enhancing New Gd-enhancing Gd-enhancingSubj. Race Visit Date Day Lesion Count Lesion Count [1] Lesion Count [2]

[1] New Gd-enhancing lesion count is the number of new lesions since the previous visit.[2] Cumulative new Gd-enhancing lesion count is relative to Baseline.

188




Protocol: NGM114840 Page 1 of 2Population: All Subjects Listing 2.27 Listing of Gd-enhancing Lesion Volume

Treatment: Pbo/ Pbo/ Pbo Cumulative New Age(y)/ Gd-enhancing New Gd-enhancing Gd-enhancingInv./ Sex/ Study Lesion Volume Lesion Volume Lesion VolumeSubj. Race Visit Date Day (cc) (cc) [1] (cc) [2]

[1] New Gd-enhancing lesion volume is the new volume of lesions since the previous visit.[2] Cumulative new Gd-enhancing lesion volume is relative to Baseline.

190




Protocol: NGM114840 Page 1 of 2Population: All Subjects Table 2.28 Listing of T2- and T1-weighted Lesion Volume

Treatment: Pbo/ Pbo/ Pbo Age(y)/ T2-weighted T1-weighted Inv./ Sex/ Visit Study T2-weighted volume change T1-weighted volume change Subj. Race Date Day volume (cc) (cc) [1] volume (cc) (cc) [1]

[1] T2- and T1-weighted volume change is the change in volume from Baseline.

192


This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see

the Patient Level Data section of the Sponsor Clinical Study Register.

Page 1 of 2Page 1 of 2Protocol: NGM114840Population: PK

Figure 1.01Individual GSK1223249 Plasma Concentration-Time Plots to 25 hours (Linear and Semi-log)

by Treatment

Note : LLQ = 100 ng/mL

Dose level 1=1 mg/kg on Day 1, 5=5 mg/kg on Day 29: 1 5

Standardised Result

-999

-998

Actual Rel. Time (Hrs)

-999 -998

Protocol: NGM114840Population: PK


by Treatment


Subject ID=

Linear Scale

Con

cent

ratio

n (n

g/m

L)

0

50000

100000

150000

200000

Actual Relative Time (Hrs)

0 5 10 15 20 25

Semi-Logarithmic Scale

Con

cent

ratio

n (n

g/m

L) 10000

100000

1E6


0 5 10 15 20 25

194




by Treatment


Dose level 1=1 mg/kg on Day 1, 5=5 mg/kg on Day 29: 1 5

Standardised Result

-999

-998

Actual Rel. Time (Hrs)

-999 -998



by Treatment


Subject ID=

Linear Scale

Con

cent

ratio

n (n

g/m

L)

0

50000

100000

150000

200000


0 5 10 15 20 25


Con

cent

ratio

n (n

g/m

L) 10000

100000

1E6


0 5 10 15 20 25

195



Figure 1.02Individual GSK1223249 Plasma Concentration-Time Plots to end of study (Linear and Semi-log)

by Treatment


Dose level 1=1 mg/kg Days 1-29 (Pre-dose), 5=5 mg/kg Day 29 - end of study: 1 5

Standardised Result

-999

-998

Elapsed time from dose to collect - Days

-999 -998



by Treatment


Subject ID=

Linear Scale

Con

cent

ratio

n (n

g/m

L)

0

50000

100000

150000

200000

Actual Relative Time (Days)

0 5 10 15 20 25 30


Con

cent

ratio

n (n

g/m

L) 1000

10000

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1E6


0 5 10 15 20 25 30

196




by Treatment


Dose level 1=1 mg/kg Days 1-29 (Pre-dose), 5=5 mg/kg Day 29 - end of study: 1 5

Standardised Result

-999

-998

Elapsed time from dose to collect - Days

-999 -998



by Treatment


Subject ID=

Linear Scale

Con

cent

ratio

n (n

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L)

0

50000

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0 5 10 15 20 25 30


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197



1

Attachment 1 Planned study schematic

198


1

Attachment 2 Time & Events tables

Time and Events Overall High-Level Study Schedule (All cohorts)

Procedure

Screening 6 weeks prior to dose 2 days

Baseline 7 2 days prior to 1st

dose

Days 1-2

Day 7Day 13

Days 28-30

Day 36 1

Days 42 1

Days 57-58 1

Days 64 3

Days 70 3

Days 85 3

Days 127 3

Days 169 3

Day 197 4 c

Study drug dosing X X XSafety (vitals, labs, ECGs, physical exam e.t.c.), medical history & drugs of abuse assessments a

X X X X X X X X X X X X X X X

Demographic data a XNeurological exam & symptom monitoringIncluding EDSS assessments

X X X X X X X X X X X X

PK sampling (blood) a

X X X X X X X X X X X X X

MRI X X X X X X X XImmunogenicity a X X X X XCSF PK sampling (lumbar puncture)

X b

a. For detailed assessment requirements, refer to individual time & events table for each specific dosing occasion.b. Patients will receive 1 lumbar puncture only. Timings of lumbar punctures for cohort 2 are specified in GlaxoSmithKline Document Number XM2010/00059/02 Table 3, Section

3.2.1.5.. Timings for cohort 3 will be determined based on emergent CSF PK data from cohort 2.c. This visit is an “as needed” visit, the necessity for which will be determined at DEC meetings.

199


2

Time and Events Schedules (all cohorts): Screening, Baseline & Dose 1

Procedure

Screening Baseline Day 1 Day 2

Day 7

Day 13

6 weeks prior to dose 2 days

7 ± 2 days prior to dose

Pre-dose 0h 0.

5h 1h 2h 3h 6h 12h

18h

24h

In Patient Stay =========================X======================Outpatient Visit X X X XAdministration of Study drug

X

Medical History XHeight XHepatitis C Ab, HBsAg XPregnancy Testinga X X XCranial MRI ±Gd-contrast X X X

Physical Examination Xg Xh

Neurological exam & symptom monitoring, EDSS

X X X X

Body Weight X X XUrine Drug / Alcohol Screen X XSafety Labs X X Xf X XVital Signs X X X X X X X X12-Lead ECG X X X Xc Xc Xc Xc X XRandomisation XBlood sample for PK X X X X X X XBlood sample for Immunogenicity

X

Plasma sample for biomarkers

X X

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3

Procedure


Day 7

Day 13

6 weeks prior to dose 2 days


Pre-dose 0h 0.

5h 1h 2h 3h 6h 12h

18h

24h

Continuous ECG monitoring ===========================X=======================C-SSRS X d X e X e X e

Lumbar Puncture X b

Adverse Event Monitoring From Day 1 to completion of follow-up visitConcomitant Medication From screening to completion of follow-up visita. Females only. Serum pregnancy testing at Screening, urine pregnancy testing for all other visits.b. Patients will receive 1 lumbar puncture only. Timings of lumbar punctures for cohort 2 are specified in GlaxoSmithKline Document Number XM2010/00059/02 Table 3, Section

3.2.1.5. Timings for cohort 3 will be determined based on emergent CSF PK data from cohort 2.c. Performed in triplicated. Baseline versione. Since last visit versionf. Results not required prior to dosing unless baseline sample results outside normal range, or warranted in Investigator’s opinion.g. Full physical examh. Brief physical exam

201


4

Time and Events Schedules (all cohorts): Dose 2

Procedure

Day 29 Day 30Day

36 1Day 42 1Pre-dose 0h 0.

5h 1h 2h 3h 6h 12h

24h

In Patient Stay ===========================X==========================

Outpatient Visit X X

Administration of Study drug X

Pregnancy Testinga X

Cranial MRI ±Gd-contrast XNeurological exam & symptom monitoring, EDSS

X X

Body Weight X

Urine Drug / Alcohol Screen XSafety Labs Xe X XVital Signs X X X X X X X

12-Lead ECG X Xc Xc X XPK X X X X X X XBlood sample for ImmunogenicityPlasma sample for biomarkers

Continuous ECG monitoring ============================X=========================

C-SSRS d X X X

Lumbar Puncture X b

Adverse Event Monitoring From Day 1 to completion of Follow-up Visit

Concomitant Medication From Screening to completion of Follow-up Visit

202


5

Time and Events Schedules (all cohorts): Dose 2 (Continued)

a. Females onlyb. Patients will receive 1 lumbar puncture only. Timings of lumbar punctures for cohort 2 are specified in GlaxoSmithKline Document Number XM2010/00059/02 Table 3, Section

3.2.1.5.. Timings for cohort 3 will be determined based on emergent CSF PK data from cohort 2.c. Performed in triplicate.d. Since last visit versione. Results not required prior to dosing unless visit 5 (Day 13) sample results outside normal range, or warranted in Investigator’s opinion.

203


6

Time and Events Schedules (all cohorts): Dose 3

Procedure

Day 57 Day 58 Day 64/65

3

Day 70/71 3

Day 85/86 3

Day 127 3

Pre

-do

se

0h 1h 2h 3h 6h 12h

24h

In Patient Stay =========================X========================Outpatient Visit X X X XAdministration of Study drug XPregnancy Testinga XCranial MRI ±Gd-contrast X XNeurological exam & symptom monitoring, EDSS

X X X X

Body Weight X XUrine Drug / Alcohol Screen XSafety Labs Xe X X X XVital Signs X X X X X X X X X12-Lead ECG X Xc Xc X X X XConcomitant Medication XBlood Sample for PK X X X X X X X X XBlood sample for Immunogenicity X XPlasma sample for biomarkers XContinuous ECG monitoring =========================X========================C-SSRS d X X X X XLumbar Puncture Xb

Adverse Event Monitoring From Day 1 to completion of Follow-up VisitConcomitant Medication From Screening to completion of Follow-up Visita. Females only.b. Patients will receive 1 lumbar puncture only. Timings of lumbar punctures for cohort 2 are specified in GlaxoSmithKline Document Number XM2010/00059/02 Table 3, Section

3.2.1.5.. Timings for cohort 3 will be determined based on emergent CSF PK data from cohort 2.c. Performed in triplicate.d. Since last visit versione. Results not required prior to dosing unless visit 8 (Day 42) sample results outside normal range, or warranted in Investigator’s opinion.

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7

Time and Events Schedules (all cohorts): Follow-up

Procedure Day 169 4 days Day 197 4 days d

Pregnancy Testinga X XCranial MRI ±Gd-contrast X XPhysical Examination Xe Xf

Neurological exam & symptom monitoring X XBody Weight X XUrine Drug / Alcohol Screen X XUrinalysis X XBlood Chemistry X XHaematology X XVital Signs X X12-Lead ECG X XConcomitant Medication X XBlood Sample for PK X XBlood sample for Immunogenicity X Xb

Plasma sample for biomarkers X XC-SSRS c X XAdverse Event Monitoring X Xa. Females only. Urine pregnancy testing sufficient.b. Timing of sample may be changed based on GSK1223249 PK profile in plasma and upper threshold for quantification established for this assay.c. Since last visit versiond. This visit is an “as needed” visit, the necessity for which will be determined at DEC meetings.e. Full physical examf. Brief physical exam

205

XM2010/00059/02 CONFIDENTIAL The GlaxoSmithKline group of companies NGM114840

1

Division: Worldwide Development Retention Category: GRS019 Information Type: Protocol Amendment

Title: A randomized, single blind, placebo-controlled, single ascending dose/repeat dose cohort study to assess safety, tolerability, pharmacokinetics and immunogenicity of GSK1223249 in patients with relapsing forms of multiple sclerosis


Effective Date: 01-JUL-2011

Protocol Amendment Number: 02

Description: This study will be a randomised, placebo-controlled, single-blind (Investigator and Subject), single and repeat ascending dose protocol, in multiple sclerosis patients. The study is designed to evaluate the safety, tolerability, pharmacokinetics, and any potential for immunogenicity of GSK1223249 (a monoclonal antibody raised against Nogo-A), given intravenously in Multiple Sclerosis patients. The study will also evaluate exploratory endpoints including para-clinical activity via magnetic resonance imaging, cerebrospinal fluid pharmacokinetics, and effect of repeat dose administration of GSK1223249 on disability. Furthermore MS symptoms, such as relapses and individual symptom severity will be closely monitored.

Subject: MS, MRI, EDSS, monoclonal antibody, immunogenicity.

Author: (CPMS); (GCSP); (Discovery Medicine); (Discovery Medicine); (Discovery Medicine);

(CPSSO); (GCSP); (MDC Biometrics); (CPSSO); (Discovery Medicine);

(CPSSO); (CPMS)

Copyright 2011 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited.

2012N137712_00

XM2010/00059/02 CONFIDENTIAL The GlaxoSmithKline group of companies NGM114840

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Revision Chronology:

XM2010/00059/00 2010-DEC-21 Original

XM2010/00059/01 2011-MAR-16 Amendment No.: 01 Removal of orthostatic challenge, addition of pre-dose PK blood sample for 3rd dose, and removal of requirement for overnight stay after lumbar puncture.

XM2010/00059/02 2011-JUL-01 Amendment No.:2 Change of QT stopping criteria, removal of requirement for central ECG reading, typographical corrections, and clarification of brief & full physical exam Timepoints.

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XM2010/00059/02 CONFIDENTIAL NGM114840

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SPONSOR/MEDICAL MONITOR INFORMATION PAGE

Medical Monitor and Sponsor Contact Information:

Role Name Day Time Phone Number

After-hours Phone/Cell/ Pager Number

Fax Number

GSK Address

Primary Medical Monitor

Dr

GSK Research Triangle Park, 5 Moore Drive, PO Box 13398, RTP, NC 27709-3398, United States

Secondary Medical Monitor

Dr

GSK Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK

Tertiary Medical Monitor

Dr

GlaxoSmithKline R&D China 898 Halei Road, Zhangjiang Hi-Tech Science Park, Pu Dong, Shanghai, 201203, China

Sponsor Registered Address:

GlaxoSmithKline Research & Development Limited 980 Great West Road Brentford Middlesex, TW8 9GS UK

In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate company (or designee). If applicable, the details of the alternative Sponsor and contact person in the territory will be provided to the relevant regulatory authority as part of the clinical trial application.

Regulatory Agency Identifying Number(s): 2010-022664-12

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INVESTIGATOR PROTOCOL AGREEMENT PAGE

I confirm agreement to conduct the study in compliance with the protocol, as amended by this protocol amendment.

Investigator Name:

Investigator Address:

Investigator Phone Number:

Investigator Signature Date

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TABLE OF CONTENTS

PAGE

ABBREVIATIONS ........................................................................................................... 10

1. INTRODUCTION ..................................................................................................... 13 1.1. Background .................................................................................................. 13 1.2. Multiple Sclerosis ......................................................................................... 13 1.3. Nogo-A in MS ............................................................................................... 14 1.4. Previous Human Experience with GSK1223249 .......................................... 14 1.5. Rationale ...................................................................................................... 15

1.5.1. Study Rationale ............................................................................ 15 1.5.2. Dose Rationale ............................................................................. 16

1.5.2.1. Prediction of Target Binding ........................................ 16 1.5.2.2. Starting dose for each cohort ...................................... 18 1.5.2.3. Calculation of the safety cover .................................... 19

1.6. Summary of Risk Management .................................................................... 20 1.6.1. General risks associated with administration of a

monoclonal antibody ..................................................................... 20 1.6.2. Risks associated with GSK1223249 ............................................. 21 1.6.3. Risks associated with conducting clinical trials in patients

with MS ......................................................................................... 21 1.6.3.1. Administration of GSK1223249 in combination

with current standards of pharmacological interventions for MS .................................................... 21

1.6.3.2. Risk associated with lumbar puncture ......................... 22

2. OBJECTIVES & ENDPOINTS ................................................................................. 23

3. INVESTIGATIONAL PLAN ...................................................................................... 24 3.1. Study Design/Schematic .............................................................................. 24 3.2. Rationale for Specialized Assessments ....................................................... 28

3.2.1. MS-specific Clinical Assessments ................................................ 28 3.2.1.1. Neurological Examination ............................................ 28 3.2.1.2. Functional System Scores and Expanded

Disability Scale Score (EDSS) .................................... 28 3.2.1.3. Relapse Evaluations .................................................... 29 3.2.1.4. Magnetic Resonance Imaging (MRI) ........................... 29 3.2.1.5. Lumbar Puncture (Cohorts 2 & 3 only) ........................ 31

3.3. Description of Study Treatment .................................................................... 31 3.4. Treatment assignment.................................................................................. 32 3.5. Dose Adjustment/Stopping Criteria .............................................................. 32

3.5.1. Planned Doses and Data Required for Dose Escalation .............. 32 3.5.2. Requirements for study continuation between cohorts ................. 33 3.5.3. Requirements for subject continuation within cohorts ................... 33 3.5.4. Criteria for Suspension/Dose Adjustment/Stopping Study ............ 34 3.5.5. Individual Stopping Criteria ........................................................... 34

3.5.5.1. Investigator-driven Stopping Criteria ........................... 34 3.5.5.2. General Stopping Criteria ............................................ 35

3.6. Additional Safety Guidance .......................................................................... 35 3.6.1. Liver Chemistry ............................................................................. 35

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3.6.2. QTc Withdrawal Criteria ................................................................ 36 3.6.3. Suicidal Risk ................................................................................. 36

3.7. Time and Events Tables............................................................................... 37

4. STUDY POPULATION ............................................................................................. 44 4.1. Number of Subjects ...................................................................................... 44 4.2. Replacement of Subjects ............................................................................. 44 4.3. Eligibility Criteria ........................................................................................... 44

4.3.1. Inclusion Criteria ........................................................................... 44 4.3.2. Exclusion Criteria .......................................................................... 46 4.3.3. Other Eligibility Criteria Considerations ........................................ 48

5. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ................................... 48 5.1. Hypotheses and Treatment Comparisons .................................................... 48 5.2. Sample Size Considerations ........................................................................ 49

5.2.1. Sample Size Assumptions ............................................................ 49 5.2.2. Sample Size Sensitivity ................................................................. 50 5.2.3. Sample Size Re-estimation ........................................................... 50

5.3. Data Analysis Considerations ...................................................................... 50 5.3.1. Interim Analysis ............................................................................. 50 5.3.2. Final Analyses ............................................................................... 51

5.3.2.1. Safety Analyses ........................................................... 51 5.3.2.2. Pharmacokinetic Analyses in Plasma ......................... 51 5.3.2.3. Pharmacokinetic Analyses in CSF .............................. 52 5.3.2.4. Pharmacokinetic/Pharmacodynamic Analyses ........... 52

6. STUDY ASSESSMENTS AND PROCEDURES ...................................................... 53 6.1. Demographic/Medical History Assessments ................................................ 53

6.1.1. Informed Consent & Screening ..................................................... 53 6.1.2. Visit 1: Screening (6 weeks plus or minus 2 days prior to

first dose) ...................................................................................... 54 6.1.3. Visit 2: Baseline (Day -7 ± 2days prior to dosing) ......................... 54

6.2. Treatment Phase .......................................................................................... 55 6.2.1. Visit 3: inpatient, Day 1 to Day 2 ................................................... 55 6.2.2. Visit 4: Day 7 ................................................................................. 55 6.2.3. Visit 5: Day 13 ............................................................................... 55 6.2.4. Visit 6: Day 29 & Day 30 ............................................................... 55 6.2.5. Visit 7: Day 36 (±1 day) ................................................................. 56 6.2.6. Visit 8: Day 42 (±1 day) ................................................................. 56 6.2.7. Visit 9: Day 57 to 58 (±1 day) ........................................................ 56

6.3. Follow-up phase ........................................................................................... 56 6.3.1. Visit 10: Day 64 (± 3 days) ............................................................ 56 6.3.2. Visit 11: Day 70 (± 3 days) ............................................................ 56 6.3.3. Visit 12, 13 & 14: Days 85, 127 & 169 (all ±3 days) ...................... 56 6.3.4. Visit 15: Day 197 (± 4 days) End of Study .................................... 57 6.3.5. Additional visits ............................................................................. 57 6.3.6. Safety assessments ...................................................................... 57 6.3.7. MRI scans ..................................................................................... 58 6.3.8. Lumbar puncture ........................................................................... 59 6.3.9. Columbia suicide-severity rating scale .......................................... 59 6.3.10. Clinical Laboratory Assessments .................................................. 59 6.3.11. Urine collection for detection of undeclared drugs ........................ 60

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6.3.12. Alcohol test ................................................................................... 60 6.4. Pregnancy .................................................................................................... 60

6.4.1. Time period for collecting pregnancy information ......................... 60 6.4.2. Action to be taken if pregnancy occurs ......................................... 60 6.4.3. Action to be taken if pregnancy occurs in a female partner

of a male study subject ................................................................. 61 6.5. Pharmacokinetics ......................................................................................... 61

6.5.1. Blood Sample Collection ............................................................... 61 6.5.2. CSF Sample Collection ................................................................. 61 6.5.3. Sample Analysis ........................................................................... 61 6.5.4. Anti-GSK1223249 antibody levels ................................................ 62 6.5.5. Biomarkers .................................................................................... 62

7. LIFESTYLE AND/OR DIETARY RESTRICTIONS ................................................... 62 7.1. Contraception Requirements ........................................................................ 62

7.1.1. Female Subjects ........................................................................... 62 7.1.2. Male Subjects ............................................................................... 63

7.2. Meals and Dietary Restrictions..................................................................... 63 7.2.1. Caffeine, Alcohol, and Tobacco .................................................... 63

7.3. Activity .......................................................................................................... 64

8. CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES .......................... 64 8.1. Permitted Medications .................................................................................. 64 8.2. Prohibited Medications ................................................................................. 64 8.3. Non-Drug Therapies ..................................................................................... 64

9. COMPLETION OR EARLY WITHDRAWAL OF SUBJECTS ................................... 65 9.1. Subject Completion ...................................................................................... 65 9.2. Subject Withdrawal Criteria .......................................................................... 65 9.3. Subject Withdrawal Procedures ................................................................... 66

9.3.1. Subject Withdrawal from Study Treatment ................................... 66 9.4. Treatment After the End of the Study ........................................................... 66 9.5. Screen and Baseline Failures ...................................................................... 66

10. STUDY TREATMENT .............................................................................................. 67 10.1. Blinding ........................................................................................................ 67 10.2. Packaging and Labelling .............................................................................. 67 10.3. Preparation/Handling/Storage/Accountability ............................................... 67 10.4. Assessment of Compliance .......................................................................... 68 10.5. Treatment of Investigational Product Overdose ........................................... 68

11. ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE) .................. 68 11.1. Definition of Adverse Events ........................................................................ 69 11.2. Definition of Serious Adverse Events ........................................................... 70 11.3. Method of Detecting AEs and SAEs............................................................. 71 11.4. Recording of AEs and SAEs ........................................................................ 72 11.5. Evaluating AEs and SAEs ............................................................................ 72

11.5.1. Assessment of Intensity ................................................................ 72 11.5.2. Assessment of Causality ............................................................... 72

11.6. Follow-up of AEs and SAEs ......................................................................... 73 11.7. Prompt Reporting of SAEs to GSK ............................................................... 73 11.8. Regulatory Reporting Requirements For SAEs ............................................ 74

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12. LIVER CHEMISTRY FOLLOW-UP PROCEDURES ................................................ 74

13. STUDY CONDUCT CONSIDERATIONS ................................................................. 76 13.1. Posting of Information on Clinicaltrials.gov .................................................. 76 13.2. Regulatory and Ethical Considerations, Including the Informed

Consent Process .......................................................................................... 76 13.2.1. Urgent Safety Measures ............................................................... 77

13.3. Quality Control (Study Monitoring) ............................................................... 77 13.4. Quality Assurance ........................................................................................ 77 13.5. Study and Site Closure................................................................................. 77 13.6. Records Retention........................................................................................ 78 13.7. Provision of Study Results to Investigators, Posting to the Clinical

Trials Register and Publication ..................................................................... 78 13.8. Data Management ........................................................................................ 79

14. REFERENCES ........................................................................................................ 80

APPENDICES ................................................................................................................. 83 Appendix 1: Liver Safety Algorithms ........................................................................ 83 Appendix 2: Dose Escalation Committee (DEC) ...................................................... 84 Appendix 3: Protocol Amendment Changes ............................................................ 85

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ABBREVIATIONS

AE Adverse event AP Alkaline phosphatase ALS Amyotrophic lateral sclerosis ALT Alanine aminotransferase (SGPT) AST Aspartate aminotransferase (SGOT) AUC Area under the curve AUC(0-∞) Area under the curve from time zero (pre-dose) extrapolated to infinite

time %AUCex Percentage of AUC(0-∞) obtained by extrapolation AUC(0-t) Area under the concentration-time curve from time zero (pre-dose) to last

time of quantifiable concentration within a subject across all treatments BBB Blood brain barrier BMI Body mass index BUN Blood urea nitrogen CGIC-IC Clinical Global Impression of Change – Improvement Score Clinician CGIC-IS Clinical Global Impression of Change – Improvement Score Subject CL Systemic clearance of parent drug Cmax Maximum observed concentration CNS Central nervous system HCO3 Bicarbonate CPK Creatine phosphokinase CRF Case Report Form CSF Cerebrospinal fluid DEC Dose escalation committee DMPK Drug Metabolism and Pharmacokinetics DMTs Disease Modifying Therapies DNA Deoxyribonucleic acid DSM-IVR Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition

Revised EAE Experimental autoimmune encephalitis ECG Electrocardiogram EDSS Expanded Disability Status Scale FDA Food and Drug Administration FSH Follicle Stimulating Hormone GCP Good Clinical Practice GCSP Global Clinical Safety and Pharmacovigilence C-SSRS Columbia Suicide Severity Rating Scale Gd Gadolinium GGT Gamma glutamyltransferase GLP Good Laboratory Practice GSB Global Safety Board GSK GlaxoSmithKline HBsAg Hepatitis B surface antigen HIV Human Immunodeficiency Virus

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h Hour(s) HRT Hormone replacement therapy ICF Informed Consent Form IC50 Half maximal inhibitory concentration IDSL Integrated Data Standards Library IEC Independent Ethics Committee IEP Immunoelectrophoresis IgG Immunoglobulin G INR International normalized ratio IRB Institutional Review Board IV Intravenous IVRS Interactive Voice Response System k12 Inter-compartment distribution rate constant from central to peripheral

compartment CL is the elimination clearance from the central compartment. keq is the equilibration rate constant between central and effect compartments.

k21 Inter-compartment distribution rate constant from peripheral to central compartment

keq Equilibration rate constant between central and effect compartments kg Kilogram L Liter µg Microgram MABEL Minimum anticipated biological effect level MCV Mean corpuscular volume MedDRA Medical Dictionary for Regulatory Activities mg Milligrams mL Milliliter MOG myelin-oligodendrocyte-glycoprotein MR Magnetic Resonance MRI Magentic Resonance Imaging MTI Magnetisation Transfer Ratio mRNA Messenger ribonucleic acid MS Multiple sclerosis msec Milliseconds MTR Magnetization Transfer Ratio NAWM Normal appearing white matter N.B. Nota bene or note well NOAEL No observed adverse effect level nM Nanomolar PBMC Peripheral blood mononuclear cells PHI Protected Health Information PK Pharmacokinetic PPMS Primary progressive multiple sclerosis PT Prothrombin time Q Inter-compartment clearance QTcB QT duration corrected for heart rate by Bazett’s formula

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QTcF QT duration corrected for heart rate by Fridericia’s formula RAP Reporting and Analysis Plan RBC Red blood cells RNA Ribonucleic acid RRMS Relapsing remitting multiple sclerosis SAE Serious adverse event(s) SD Standard deviation SGOT Serum glutamic-oxaloacetic transaminase SGPT Serum glutamic pyruvic transaminase SPM Study Procedures Manual SPMS Secondary progressive multiple sclerosis t½ Terminal phase half-life tlast Time of last quantifiable concentration TSH Thyroid-stimulating hormone ULN Upper limit of normal UK United Kingdom USA United States of America Vdist volume of distribution Vc Volume of distribution in central compartment Vp Volume of distribution in peripheral compartment WBC White blood cells Trademark Information



NONE Avonex Chiron RIBA Copaxone NONMEM Rebif WinNonlin

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1. INTRODUCTION

1.1. Background

GSK1223249 is a humanized mouse monoclonal antibody raised specifically against a unique region of the N-terminal segment of the Nogo-A (neurite outgrowth inhibitor) protein which is not shared with Nogo-B or Nogo-C.

The Nogo-A isoform has been found to be the most potent neurite outgrowth inhibitor. Anti-Nogo-A antibodies have been reported to enhance neurite outgrowth in vitro and functional recovery in vivo of neurons in a number of different animal models (e.g., brain and spinal cord trauma, epilepsy, stroke, amyotrophic lateral sclerosis, glaucoma) where synaptic plasticity and axonal sprouting is anticipated to be important [Buchli, 2005; Fontoura, 2006].

It is hypothesized that Nogo-A mediated biology contributes to the development and/or incomplete repair of demyelinated lesions in the brain and lack of functional recovery. Thus, GSK1223249 has the potential to be the first-in-class CNS repair treatment for multiple sclerosis.

1.2. Multiple Sclerosis

Multiple sclerosis (MS) is a chronic progressive neurologic disorder characterized pathologically by multiple lesions in the CNS (brain, brain stem, optic nerve, and spinal cord) with varying degrees of demyelination and axonal injury.

The etiology of MS is unknown, but the disease appears to be triggered as a consequence of a complex interplay between multiple genetic susceptibility risk factors and exogenous environmental factors [De Jager, 2007]. Lymphocytic infiltrates (T cells, B cells, monocytes) are thought to play a role in triggering and/or maintaining an inflammatory milieu that leads to oligodendrocyte damage, loss of the myelin sheaths surrounding axons and in severe or chronic contexts, to axonal damage or loss. This is the pathology that underlies a significant portion of the disability associated with MS. Cumulative changes in tissue structure contribute to ongoing brain and spinal cord atrophy, with diminution of cortical grey as well as white matter volume--features that are increasingly recognized as significant component of the disease. Additional histologic features in acute MS include hypercellularity (predominantly myelin-laden macrophages, hypertrophic astrocytes), parenchymal edema, loss of oligodendrocytes within demyelinated areas, and accumulation of oligodendrocytes at lesion borders [Frohman, 2006].

Clinically, from onset, the disease course typically appears to be either more obviously episodic (relapsing remitting MS or RRMS) or progressive (primary progressive or PPMS) in nature. RRMS generally evolves, over years to decades, into a progressive phenotype (secondary progressive MS or SPMS) with the degree of overt disease activity (relapses) varying both from patient to patient and over time. Regardless of the pattern of disease progression, presentations are relatively heterogeneous, dependent on when

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lesions develop in more or less eloquent areas (grey matter or white matter fiber tracts subserving obvious motor, sensory, or cognitive functions) of the brain or spinal cord. The inherent heterogeneity in lesion sites results in a constantly changing pattern of clinical need. Disability is acquired cumulatively - the result of failure of the brain to adequately repair itself between attacks and/or an inability to prevent ongoing more subtle and thus far undefined underlying destructive processes.

1.3. Nogo-A in MS

In MS, Nogo-A, as evidenced by immunohistochemical staining techniques, is found robustly in oligodendrocytes and myelin at the edge of chronic active demyelinating lesions and adjacent white matter [Satoh, 2005; Kuhlmann, 2007]. Consistent with the general hypothesis, the following have been either reported in the literature or observed in studies conducted in-house in in vitro studies and in animal models relevant to the study of MS

a. A mouse monocloncal anti-Nogo-A antibody (GSK577548) and its humanized equivalent (GSK1223249) neutralize the inhibitory effect of Nogo-A on neurite outgrowth (Clinical Investigator Brochure (CIB), Section 3.2.1.1), confirming the activity suggested by a wealth of published data [GrandPre, 2000; Prinjha, 2000]

b. Nogo-A deficient mice are protected from Experimental Autoimmune Encephalomyelitis (EAE), a model of CNS inflammation and neurological impairment which shows phenotypic and histopathological similarities to MS [Karnezis, 2004; Fontoura, 2006]

c. Rodents with Nogo-A suppressed (through siRNA) show amelioration of EAE and promotion of axonal repair [Yang, 2010]

d. GSK577548 is protective in a toxin-induced (lysolethicin) model of acute demyelination in mouse corpus callosum (CIB Section 3.2.1.2)

e. GSK1223249 delivered intravenously every week at 30mg/kg, is associated with decreased clinical and histopathologic scores in a myelin-oligodendrocyte-glycoprotein (MOG)-induced EAE non-human primate model of MS (CIB Section 3.2.1.2) Doses of 3 and 0.3mg/kg delivered intravenously do not show decreased clinical and histopathologic scores (Supplement no. 2 to CIB; Section 3.2.1.2).

1.4. Previous Human Experience with GSK1223249

As of November 2010, a single phase I single dose/repeat dose study (Study Protocol NOG111330) in subjects with amyotrophic lateral sclerosis is in progress. This study is being conducted in several countries, including France, Italy, the United Kingdom, and the United States. As of a cut-off date of 11th November, 2010, a total of 48 subjects have completed their study medication (including placebo). Doses in the single dose cohorts 1-5, each including eight subjects (6 randomised to GSK1223249 and 2 to placebo), were 0.01, 0.1, 1, 5, and 15mg/kg. Cohort 6 is the first of 3 ascending repeat dose cohorts (cohorts 6-8), each to include 12 subjects (9 active, 3 placebo), with 2 doses given 28 days apart. The five single dose cohorts have completed study medication. In cohort 6, 8 out of 12 subjects had received both 0.5mg/kg doses. Study treatment has

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been well tolerated thus far. One death and 2 serious adverse events were recorded in a single subject in cohort 4. Neither SAE was considered attributable to study medication by the Investigator and the primary cause of death was the disease under study. Following IV administration, GSK1223249 had a biphasic disposition, with a (geometric) mean volume of distribution of 89 mL/kg (CV=62%) and a mean clearance of 0.15 mL/h/kg (CV=63%), leading to a mean half-life (t1/2) of 21.5 days (CV=63%). Further details are contained within the accompanying CIB supplement.

There is also previous experience of administering GSK1223249 in MS patients. Study NGM112988 was a randomized, placebo-controlled, single-blind (Investigator and Subject), sequential dose escalation, single dose administration study. A total of 3 subjects in Australia received study medication at 0.02mg/kg (2 subjects) or placebo (1 subject). No deaths or serious adverse events were reported. Study NGM112988 intended to explore the preliminary safety, tolerability and pharmacokinetics of single doses of GSK1223249 in subjects with relapsing forms of MS; however this study was terminated early in August 2010 due to poor recruitment.

1.5. Rationale

1.5.1. Study Rationale

GSK1223249 is being developed for treatment of multiple sclerosis based on a combination of scientific data on the target, preclinical efficacy of GSK1223249, and a major unmet need of MS patients for therapies which halt or reverse the progression of neurological dysfunction.

The current study will examine the safety, tolerability and pharmacokinetic profile of GSK1223249 at doses that are expected (based on modelling data; see Section 1.5.2) to achieve appropriate central target binding. In addition, the current study will allow an assessment of GSK1223249 immunogenicity and an assessment of penetration of GSK1223249 into the CNS compartment.

Three single dose/repeat dose cohorts will be studied, with subjects being exposed to a single dose of GSK1223249 at the starting dose level for each cohort, followed by escalation to a higher dose level 4 weeks later , then followed by a repeat higher dose 4 weeks later.. The starting dose levels for each planned cohort in the current study haves previously been administered to subjects with amyotrophic lateral sclerosis (ALS) in study NOG111330. Based on single-dose pharmacokinetic data collected in study NOG111330, GSK1223249 is predicted to have a terminal half life of 21.5 days. Therefore, significant accumulation is not expected with a 4-week dosing interval.

It is anticipated that GSK1223249 will be administered in conjunction with current disease modifying MS treatments. Therefore it is important to begin to understand the effect of Nogo neutralisation in the context of these agents. The current study will examine the effect of GSK1223249 treatment in subjects with a relapsing form of MS who are currently being treated with Disease Modifying Therapies (DMTs). This allows the safety, tolerability, and PK profiles to be established in an MS patient population which is relevant to that which would be enrolled in later phase studies. Furthermore, exposure of subjects to multiple doses of GSK1223249 will provide a robust

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understanding of MS patient safety during a 3 month period of predicted >80% Nogo-A binding in the CNS. GSK1223249 CSF data will help validate these assumptions and provide dose selection information for Phase II studies.

1.5.2. Dose Rationale

Three dose cohorts are planned, with each dose administration in each cohort separated by 4 weeks:




The proposed doses may be modified, if warranted, based on emerging safety and/or repeat-dose PK data from the Phase I study (Study Protocol NOG111330) in subjects with ALS as well as the completed cohorts of this study.

1.5.2.1. Prediction of Target Binding

Target engagement in the CNS is hypothesized to provide therapeutic benefit in MS. The PKPD model used to predict the target binding is illustrated in Figure 1. This model may be updated and refined based on the on-going GSK1223249 PK data in plasma and CSF.

Figure 1 PKPD model used to predict Target Binding

Vc and Vp are the volumes of distribution in the central compartment and peripheral compartments. k12 and k21 are inter-compartment distribution rate constants. CL is the

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elimination clearance from the central compartment. keq is the equilibration rate constant between central and effect compartments.

This model includes:

- A PK model for GSK1223249 after IV infusion, with 2 compartments (central and peripheral) and a linear elimination. The parameters of this model were estimated from the preliminary data in ALS patients and assuming similar pharmacokinetics in plasma between ALS and MS patients. As ALS data did not indicate any target-mediated elimination, the elimination was assumed to be linear.

- A hypothetical effect compartment characterising the target site (CNS) and accounting for any temporal delay between plasma concentration and the binding effect [Sheiner, 1979]. The rate of equilibration between the central and the effect compartment (keq) was assumed to be similar to the rate constant value from the central to the peripheral compartment (k12).

The ratio between CNS and plasma for GSK1223249 was selected to be between 1:400 (upside) and 1:1000 (downside), based on the following pieces of evidence: i) The mouse monoclonal parental antibody of GSK1223249, 2A10, had a CSF:plasma ratio of 1:487 in rat [Tang, 2004]; ii) Rituximab penetrates the intact blood:CSF barrier at 1:400 – 1:1000 [Petereit, 2009]; iii) Trastuzumab penetrates the intact blood:CSF barrier at approximately 1:400 and levels of trastuzumab in CSF are increased in patients with significant BBB disruption due to meningeal carcinomatosis or radiotherapy [Stemmler, 2007]; iv) the CSF albumin quotient in adult healthy volunteers and MS patients is between approximately1:189 – 1:312 [Reiber, 2009].

The predicted percentage of GSK1223249 bound to Nogo-A in the CNS was calculated using the typical binding equation below. A reversible binding between the ligand and GSK1223249 was assumed in this equation.

where L represents Nogo-A, D represents free concentration of GSK1223249 at the target site (CNS), LD represents Nogo-A-GSK1223249 complex and Kd represents GSK1223249 affinity to Nogo-A. Kd was fixed to the measured in-vitro value of 0.05 µg/mL (0.34 nM) GSK1223249 Investigator's Brochure. [GlaxoSmithKline Document Number: AM2010/00015/00. 10th June, 2010]. Figure 2 illustrates the predicted CNS Nogo-A binding curve from the PKPD model at the different doses for Cohorts 1 - 3 of this study and assuming 2 different CNS:plasma ratios for GSK1223249.

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Figure 2 Predicted dose–binding% relationship. The dose is given every 28 days and binding% refers to percentage of Nogo-A in the CNS bound to GSK1223249

GSK1223249 at 1, 5, 15 and 30 mg/kg will be explored in staggered enrolling dose cohorts. Details for the planned dose cohorts and timing for dose escalation can be found in Section 3.1.

1.5.2.2. Starting dose for each cohort

Emerging data from First Time In Patient (FTIP) studies (NGM112988 and NOG111330) have shown that all single doses in subjects with MS or ALS so far have been well tolerated, up to and including 15mg/kg. Therefore, our proposed first dose for Cohort 1 of 1mg/kg is known to be well tolerated in ALS patients. Cohort 2 will start with 5mg/kg; this dose being the dose which the second and third doses of Cohort 1 will have been escalated to. Further dose escalations planned in this study are also consistent with previously used/planned scaling factors for GSK1223249.

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A starting dose of 1mg/kg is predicted to produce 40% Nogo-A binding in the CNS from the PKPD model, using the upside of a CNS/plasma ratio of 1:400 (cf. Figure 2). Therefore it is unlikely that significant pharmacology will be observed at this dose level.

1.5.2.3. Calculation of the safety cover

GSK1223249 was well tolerated in the cynomolgus monkey following fortnightly (one dose every two weeks) IV bolus administration for 52 weeks, at doses of 20, 100 and 500 mg/kg. The no observed adverse effect level (NOAEL) was 500 mg/kg (the highest dose examined). The systemic exposure (as defined by AUC0-2 weeks and Cmax) was similar between male and female monkeys. The mean systemic exposure (males and females combined) of GSK1223249 at 500 mg/kg for the first dose was AUC0-2 weeks of 890 mg.h/mL and Cmax of 19.8 mg/mL; and for the last dose was AUC0-τ of 947 mg.h/mL and Cmax of 15.4 mg/mL. The NOAEL AUC0-2 weeks of 890 mg.h/mL (= 37083 µg.day/mL) and Cmax of 15.4 mg/mL (= 15400 µg/mL) have been conservatively selected for the calculation of safety covers for planned doses of this study, as shown in Table 1 and Table 2. Because of differences in frequency in dosing the monkeys, AUC0-2 weeks represents a conservative estimate over the human cover represented by AUC0-4 weeks.

A dose of 30 mg/kg is the planned maximum dose that will be explored in this study; the corresponding safety margins are 17-fold based on dose, 5-fold based on AUC0-τ and 17-fold based on Cmax.

Table 1 Predicted safety cover of planned 1st dose across the 3 cohorts, using a NOAEL in monkeys of 500 mg/kg once every 2 weeks

Planned dose of GSK1223249

Predicted human exposure based on clinical data from NOG111330

Predicted exposure cover in humans

Dose (mg/kg) AUC0-τ[1] (µg.day/mL)

Cmax (µg/mL)

Based on dose ratio

Based on AUC ratio

Based on Cmax ratio

1 197 26 500x 188x 592x 5 983 132 100x 38x 117x 15 2950 396 33x 13x 39x

1. AUC0-τ represent the AUC from 0 to 4 weeks

Table 2 Predicted safety cover of planned 3rd dose across the 3 cohorts, using a NOAEL in monkeys of 500 mg/kg once every 2 weeks

Planned dose of GSK1223249

Predicted human exposure based on clinical data from NOG111330

Predicted exposure cover in humans

Dose (mg/kg) AUC0-τ [1] (µg.day/mL)

Cmax (µg/mL)

Based on dose ratio

Based on AUC ratio

Based on Cmax ratio

5 1305 149 100x 28x 103x 15 3963 451 33x 9x 34x 30 8046 908 17x 5x 17x

1. AUC0-τ represent the AUC from 0 to 4 weeks

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1.6. Summary of Risk Management

1.6.1. General risks associated with administration of a monoclonal antibody

GSK1223249 is a fully humanised monoclonal antibody with an effector function disabled IgG1-type Fc region. This means that the potential for general immune-mediated AEs (C1q-complement dependent cytotoxicity or antibody-mediated cellular toxicity) has been minimized. Using an in silico algorithm (Algonomics Epibase platform) to profile the CD4 T-helper epitope content of GSK1223249, this antibody was predicted to have a low immunogenicity risk when compared to a benchmark panel of marketed monoclonal antibodies.

Nonetheless, infusion reactions to monoclonal antibodies do occur. The exact mechanism is not known, but these reactions are not felt to be true type 1 IgE-mediated hypersensitivity reactions, i.e., those mediated by release of histamines, leukotrienes, and prostaglandins from mast cells in tissue and basophils in peripheral blood [Lenz, 2007]. Regardless of the underlying mechanism of action, the typical clinical manifestations of infusion reaction to a monoclonal antibody overlap with those of hypersensitivity reactions and include: pruritus/itching, rash/desquamation, urticaria (hives, welts, wheals), drug fever/rigors/chills, headache, arthralgia/myalgia, fatigue (asthenia, lethargy, malaise), dizziness, sweating, nausea/vomiting, cough, dyspnea, bronchospasm, hypotension/hypertension, tachycardia, and in the extreme, anaphylaxis and death.

Mild to moderate reactions can be managed by temporary interruption of the infusion, reduction of the infusion rate, and symptom management. Severe hypersensitivity reactions are not common [Lenz, 2007]. Subjects must notify a clinician immediately if they notice any discomfort during the infusion (see Section 3.5).

Consistent with GlaxoSmithKline guidance for early phase studies, in this study GSK1223249 will be administered in an inpatient setting (sufficient overnight facilities) with concomitant Phase I-like monitoring. At the beginning of each dose cohort, for the first four subjects, only one subject will be dosed in any 24-h period. All subjects will be monitored in-house for at least 24-h post-dose, prior to discharge. Routine safety monitoring in this study consists of physical examinations including vital signs and weight, clinical safety laboratory data, and electrocardiograms (ECGs), as well as continued observation by clinical staff. Therapeutic indication-specific safety monitoring has been included in the form of neurological assessments including MS symptom and relapse monitoring. In addition the effects of multiple dose administration on paraclinical MS activity by brain magnetic resonance imaging (MRI) will be monitored. Additional diagnostic tests may be ordered at the discretion of the Investigator at any time. The decision to proceed to the next dose level, within a subject, will be made by site investigators, together with the GSK medical monitor. Decisions will be based upon clinical judgment, and supported by objective safety data measures e.g. clinical laboratory assessments, AEs, vital signs & ECGs. Input from the GSK medical monitor, and any additional GSK study team members/personnel as appropriate, to agree if safe to proceed with dose escalation within a subject or cohort will be given during the study as necessary. The decision to progress to the next cohort will be taken by the DEC (see Section 3.5.2 and Appendix 2 for details).

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1.6.2. Risks associated with GSK1223249

The preclinical pharmacology data available thus far for GSK1223249 (Investigator Brochure, Section 3) suggest that binding of this particular antibody to Nogo-A is highly specific. The distribution of Nogo-A as assessed by immunohistochemical staining is relatively circumscribed and appears at low levels in healthy non-CNS tissue.

As indicated earlier, clinical precedent for administration of an anti-Nogo-A antibody has already been established in subjects with spinal cord injury see [ClinicalTrials.gov Identifier NCT00406016, 2007 www.clinicaltrials.gov]. Therefore, the potential for adverse off-target effects associated with GSK1223249 administration is estimated to be low, as is the potential for adverse effects associated with Nogo-A blockade, even at supra-pharmacological doses.

1.6.3. Risks associated with conducting clinical trials in patients with MS

The diagnosis of MS is still made based on the classic definition of dissemination of clinical events in time and space. Hence, it must be emphasized that the inherent nature of this disease is periodic relapses (clinically evident exacerbations) followed by improvement. The likelihood of a given subject experiencing a relapse at any given point in time is not readily predicted a priori. Therefore, based on the natural history of the disease, some subjects will experience a relapse, some will improve, and others will remain clinically unchanged over the course of a six-month study.

Each subject is required to undergo a maximum of 8 MRI scans over the course of this study The risks associated with MRI per se are low, provided subjects have no contraindications (see Section 4.3.2). The risk associated with administration of Gd-containing contrast agents is also low, provided subjects do not have underlying renal dysfunction, hence the exclusionary limits for creatinine clearance. MRI does not involve the use of ionizing radiation, but the risks to the unborn fetus are unknown and therefore pregnant women are not eligible to participate in this study. Frequent MRI has been increasingly used as a surrogate endpoint in clinical trials for MS; MRI scan sequences including monthly dosing and double or even triple doses of Gd-containing contrast agents have been used in protocols up to two years in length [Jeffery, 2005].

1.6.3.1. Administration of GSK1223249 in combination with current standards of pharmacological interventions for MS

Most MS patients in Australia, Western Europe, and North America are prescribed beta interferon (Avonex, Rebif) and/or glatiramer acetate (Copaxone). In order to conduct the proposed clinical trial with GSK1223249, it is considered necessary to enrol patients into this study who are already receiving marketed treatments for MS. Combination toxicology studies have not been completed with GSK1223249 and beta interferons or glatiramer acetate. An assessment of potential drug-drug interactions has been conducted on the available data for beta interferons and glatiramer acetate in the context of all available data currently available for GSK1223249. As GSK1223249, glatiramer acetate, and beta interferon have very different chemistry and mechanisms of action, adverse

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pharmacokinetic and/or pharmacodynamic interactions are considered highly unlikely. Therefore, pre-clinical combination toxicology assessment is not considered a requirement at this stage of development.

1.6.3.2. Risk associated with lumbar puncture

The most frequent AEs associated with lumbar puncture are headache and local irritation or discomfort at the puncture site. These events are typically mild to moderate in severity and resolve spontaneously within hours or days, with or without administration of acetaminophen or paracetamol. In the case of prolonged severe headache not responsive to analgesic or caffeine-containing drinks, a blood patch (injection of a small amount of the subject’s own blood locally) is often effective. Less frequent events include anesthetic reaction to lidocaine (the anesthetic used for local numbing of the skin and needle path), irritation of nerve roots in the needle path leading to discomfort, pain or disability, infection, development of a local extradural hematoma and subsequent cauda equina compression (risk limited by ensuring normal blood clotting parameters).The potential of these risks occurring diminishes considerably when a neurologist/anaesthetist experienced in performing LPs carries out the procedure.

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2. OBJECTIVES & ENDPOINTS

PRIMARY OBJECTIVE ENDPOINTS 1 To explore the safety and tolerability of single

and repeat doses of GSK1223249, administered IV in ascending dose cohorts, in subjects with relapsing forms of MS.

• Changes in vital signs, ECG monitoring, blood chemistry, haematology, urinalysis, monitoring of AEs and MS relapses (number, incidence, severity)

SECONDARY OBJECTIVES ENDPOINTS 2.1 To characterize the PK in plasma

GSK1223249, following single and repeat IV doses infused over approximately 60 minutes, in ascending dose cohorts.

• Parameters derived from the population PK model of GSK122349.

• In addition, some parameters calculated from individual observed concentration-time profile data.

2.2 To evaluate immunogenicity of GSK1223249 in MS patients

• Presence of antibodies to GSK1223249 to be assessed in serum samples using validated ECL assays.

2.3 To determine concentration of GSK1223249 in CSF and a CSF:plasma ratio of GSK1223249

• Measurement of GSK1223249 in CSF

EXPLORATORY OBJECTIVES ENDPOINTS 3.1 To characterize the PK in CSF of

GSK1223249, in subjects with relapsing forms of MS following single and repeat IV doses infused over approximately 60 minutes, in sequential ascending dose cohorts.

• GSK1223249 CSF concentration-time profile.

3.2 To monitor paraclinical activity by MRI in subjects with relapsing forms of MS following single and repeat IV doses of GSK1223249

• New Gd-enhancing lesion counts • New Gd-enhancing lesion volume • T2-weighted lesion volume change • T1-weighted lesion volume change • Percentage of Gd-enhancing lesion

voxels with increasing magnetization transfer ratio (MTR) on serial study

• Percentage of Gd-enhancing lesion voxels with decreased MTR

• Change in cerebral normal-appearing white matter MTR

• Change in cerebral mean diffusivity 3.3 To evaluate the effect of repeat dose

administration of GSK1223249 on disability in subjects with relapsing forms of MS.

• EDSS

3.4 To conduct exploratory biomarker analysis related to mechanisms of Multiple Sclerosis and the mechanism of action of GSK1223249 in plasma/serum and CSF

• Plasma and serum taken at baseline and after repeat dose

• CSF taken from timepoints for PK analysis

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3. INVESTIGATIONAL PLAN

3.1. Study Design/Schematic

Protocol waivers or exemptions are not allowed. Therefore, adherence to the study design requirements, including those specified in the Time and Events Table, are essential.

This is a randomised, placebo-controlled, single-blind (Investigator and Subject), single and repeat ascending dose protocol. A sufficient number of subjects with relapsing forms of MS will be enrolled into the study such that approximately 40 subjects complete dosing and safety assessments to at least the day 70 visit.

This study will consist of 3 cohorts of MS patients. Each eligible patient will be enrolled to participate in 1 of the 3 cohorts only.

All doses will be administered by intravenous (IV) infusion. Cohort 1 will consist of a single dose of 1 mg/kg with approximately a 28 day post dose period, followed by 2 doses at 5 mg/kg separated by approximately 28 days. Cohort 2 will consist of a single dose of 5 mg/kg with a 28 day post dose period, followed by 2 doses at 15 mg/kg separated by approximately 28 days. Cohort 3 will consist of a single dose of 15 mg/kg with approximately a 28 day post dose period, followed by 2 doses at 30 mg/kg separated by approximately 28 days. Planned doses and the timing of doses relative to other doses are subject to change during the study based on study assessments, and investigator clinical judgement with the prior agreement of the GSK medical monitor (and study team if appropriate). A follow-up visit will occur after at least 5 half-lives (1 half-life = 21.5 days) of GSK1223249 have elapsed since the last dose of GSK1223249/placebo has been administered.

A placebo group in each cohort has been included in this study in order to help judge whether an AE was caused by GSK1223249; this is a patient population study where change in clinical status is not unexpected, and is part of the clinical definition of the disease.

Each dose cohort will complete the study activities summarized in the Time and Events Tables. Conventional safety assessments include vital signs, physical examination, ECGs, AE collection and standard safety laboratory (hematology, blood chemistry, urinalysis) monitoring. Additional assessments relevant to the patient population include neurological examination including subject and disease specific symptom monitoring, relapse monitoring (number, proportion of subjects experiencing, severity), and brain MRI. CSF will be taken from subjects in Cohorts 2 and 3 to allow for exploratory investigations into CSF PK of GSK1223249. This preliminary PK description of GSK1223249 in CSF will be compared to its corresponding concentration-time course in plasma. These data will be used to inform the predicted percentage of GSK1223249 bound to Nogo-A in the CNS (cf. Section 1.5.2) which may be used to plan likely dosing regimens for proof of mechanism and efficacy studies.

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A dose escalation committee (DEC), consisting of GlaxoSmithKline staff plus a neurologist specializing in MS external to GlaxoSmithKline, will review key safety data and available PK data before recommending escalation to the next dose cohort. Further details are provided in Section 3.5.2. The composition of the DEC is described in Appendix 2.

On dosing days, each subject will receive a single intravenous infusion of GSK1223249 administered over approximately 60 minutes and remain under observation for at least 24 hours before being discharged from the study centre, based on the Principal Investigator’s judgment (see Section 3.7 Time & Events Tables for specific assessments at each visit). Each subject will be followed for approximately 16 weeks after the last dose of study drug, as shown in Section 3.7 Time & Events tables. The Day 169 (or Day 197, if necessary, determined at the first Dose Escalation Committee (DEC; see below) meeting) Visit is the designated End-of- Study Visit for Cohort 1. If, after review of data at the DEC, longer follow up is required for Cohorts 2 and/or 3, the End-of-Study Visit will be moved to an appropriate day (for example 4 weeks later – Day 197).

Dose escalation within a cohort in this study will be investigator driven, within the defined limits of the protocol, see Section 3.5.3 for full details.

The planned dose levels and PK (and cerebrospinal fluid [CSF]) sampling time points may be altered by the DEC members during the course of the study based on emerging data, to better capture potential safety signals or to improve characterization of the PK profile of this antibody. If the profile indicates that more sampling or assessments are needed, additional visits may be scheduled.

A study schematic for each cohort (see Figure 3) is provided to illustrate the planned study visits. Briefly, there will be 3 types of visits, and these are described below:

Pre-randomisation Visits

Pre-randomisation visits include Screening & Baseline visits. These are scheduled prior to any administration of study treatment. Screening will occur 6 weeks (± 2 days) prior to the first dose, and baseline will occur at approximately 1 week (± 2 days) prior to each subject’s first dose. Section 3.7 contains details of specific assessments that will be conducted.

Dosing days

D1-D2, D29-D30 and D57-D58 will involve administration of the study drug, and in addition will involve usual safety assessments plus exploratory assessments. Details of all assessments can be found in Section 3.7, time & events tables. These visits will all involve overnight stays within the clinical pharmacology unit.

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Non dosing days

D7-D8, D13-D14, D36, D42, D64, D70, D85 and D127 will involve safety and exploratory assessments (see Section 3.7 for details on timings), and for cohorts 2 and 3 may involve a lumbar puncture. An overnight stay may be involved, if in the investigators opinion, this is warranted, but is not strictly necessary.

D169 & D197 are intended to constitute the follow-up visits. D197 may not be needed, and will be dependent upon emergent plasma PK data, i.e. if the concentration of GSK1223249 is ≤ 0.1 µg/mL at the D169 visit, then D197 will not be necessary, unless clinically indicated, as judged by the investigator.

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Figure 3 NGM112840 Study Schematic

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3.2. Rationale for Specialized Assessments

This study contains a number of components described in this section that provide either additional safety monitoring relevant to the patient population of interest or exploratory data that may prove useful in informing the design of subsequent studies of GSK1223249 in patients with MS in terms of safety, dose selection, and efficacy.

3.2.1. MS-specific Clinical Assessments

All MS-specific clinical assessments must be conducted by a specialist in the field. The same Rater must perform serial examinations for a given subject. The patient population participating in this study is characterized by their baseline Expanded Disability Scale score (EDSS), [Kurtzke, 1983], a standard, accepted rating scale. Clinically relevant changes in status are being captured through MS-relapse reporting and monitoring of EDSS at regular intervals.

3.2.1.1. Neurological Examination

Neurological examinations will be performed at intervals throughout the course of this study and are part of the safety assessment. The screening examination will be used to determine whether potential participants have atypical features on exam that would make a diagnosis of MS questionable or preclude entry into the study. If no change in clinical status is reported by the subject on admission to the Phase I Unit (Day-1, within 7 ± 2 days of the baseline exam), the exam does not need to be repeated. This is important, because the Investigator at the Phase I Unit may not be the same as the site Investigator; it is required that all neurologic examinations for a given subject be carried out by the same Rater. For visits where both a neurologic exam and MRI scans are required, every attempt should be made to obtain both on the same day. If this is not possible, a window of ± 3 days is permitted. Neurological exam will include all functional system components of the EDSS through the use of the Neurostatus protocol (Kappos©).

3.2.1.2. Functional System Scores and Expanded Disability Scale Score (EDSS)

The EDSS [Kurtzke, 1983] is a standardized, accepted clinical rating scale used in clinical trials for MS, combining scores from assessments of 8 “functional systems” (FS) – cerebellar, pyramidal, sensory, cerebral, visual, bladder/bowel, brainstem, ambulatory - to provide an ordinal scale used to report level of disability in MS. FS scores indicate the severity of symptoms in each system and thus can provide objective measures of pre-existing symptom stability over time. The scale consists of 19 incremental steps--changes of 0.5 on a scale ranging from 0 to 10. Higher scores reflect increasing levels of disability: a score of 0 reflects a normal neurologic exam and a score of 10.0 death due to MS. The transition from a score of 5.5 to 6.0 marks a major milestone as it reflects the transition from being fully ambulatory to requiring assistance (cane or crutch) to walk at least 100 meters. It is important that all FS and EDSS assessments on an individual subject are carried out by the same Rater. Of note, the EDSS has utility in long trials (duration of two or more years) for tracking disease progression, but is also stable over short periods of time. In this study, EDSS at Screening is being used to characterize the

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patient population entering the study, whereas FS and EDSS measurements during the rest of the study will be used to monitor disease specific clinical symptoms characteristic of the individual patient.

3.2.1.3. Relapse Evaluations

In this protocol a relapse is defined as a new or recurrent neurologic symptom(s) lasting for more than 48 h, in the absence of fever, preceded by at least 30 days of clinical stability or improvement.

Documentation and follow-up of each relapse will be conducted throughout the study via both scheduled and, if necessary, unscheduled neurologic assessments. Subjects will be instructed to inform the study site within 24 h of the onset of a suspected relapse. When a subject calls to report a relapse, the study personnel will discuss the symptoms with the subject and determine whether a neurologic examination is indicated. If so, a visit to the study site should be arranged as quickly as possible – preferably within 72 h of the onset of symptoms. Thus, the Investigator will assess the situation and if appropriate, confirm by a Visit (scheduled if one occurs within the requested 3-day time period, or otherwise unscheduled), whether a relapse has indeed occurred.

A single cluster of relapse-related signs and symptoms will not be recorded as an AE and will simply be recorded as a relapse, with the clinical details recorded as part of the neurologic examination, along with a re-evaluation of the EDSS score. If subject relapses are judged by the Investigator as being atypically severe or unusual in recurrence during the study period, the relapse(s) will be reported as an AE(s).

If an Investigator makes the judgment that treatment for relapse symptoms is warranted (i.e., with corticosteroids), the decision to do so and the reasons why will be documented and treatment initiated. If the subject has not yet received study treatment, he/she will be discontinued from the study, but may elect to be re-screened 30 days later once he/she re-meets the study exclusion criteria regarding prior exposure to systemic steroids. If the subject has received study treatment, he/she will be asked to complete the remaining study visits as usual, despite the fact that he/she is on corticosteroids. A subject which experiences a second relapse within the dosing period will be removed from the study (i.e. before administration of the 3rd dose), and he/she will be asked to complete the remaining study visit if the Investigator determines this to be appropriate. An Investigator may decide, in the event of a relapse, that an unscheduled MRI is warranted. If this occurs, every effort should be made to obtain that scan according to the study procedures, and the scan will be included in the unscheduled visit study assessments.

3.2.1.4. Magnetic Resonance Imaging (MRI)

Magnetic resonance imaging of the CNS is an objective, non-invasive technique for quantifying paraclinical activity and burden in MS that has gained increasing importance as a secondary outcome measure in clinical trials. Gadolinium-enhanced T1-weighted scans are used to detect acutely inflamed MS lesions based on increased blood brain barrier (BBB) permeability. T2-weighted and T1-weighted abnormalities are used to quantify the accumulated burden of tissue injury. Serial MRI provides a method of

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monitoring and quantifying disease activity and associated tissue injury that is both more sensitive and reproducibly quantifiable compared to standardized clinical endpoints. Suppression of Gd-enhancing lesions is a reliable predictor of suppression of relapses in clinical trials. Accumulation of T2- and T1-weighted lesion volume has predictive value for long term disability. Most recently, MRI sequences that allow the calculation of a Magnetisation Transfer Ratio (MTR), in conjunction with enhanced analytic techniques, have been shown to carry significant potential for detailing the rate and extent of demyelination and remyelination in the CNS in a meaningful way.

Magnetic resonance imaging scans, with and without Gd-enhancement, will be obtained throughout this protocol to monitor changes in disease activity and to pilot newer exploratory techniques which specifically monitor the integrity of structures which are protected/improved by GSK1223249 i.e. myelin and axons.

Conventional scan sequences (proton density weighted (PDw), T2-weighted (T2w), T1 weighted (T1w) before and 10 min after Gd-contrast) will be used to generate data typical of assessing paraclinical activity in MS trials. The following conventional MR endpoints will be used:

• New Gd-enhancing lesion counts

• New Gd-enhancing lesion volume

• T2-weighted lesion volume change

• T1-weighted lesion volume change

Non-conventional MRI techniques will also be used.

Magnetization transfer MRI is sensitive to changes in brain myelin content with better pathological specificity and enhanced sensitivity than conventional MRI. The MTR decreases with acute demyelination and increases with remyelination [Deloire-Grassin, 2000]. Studies performed on post-mortem brains from subjects with MS have shown a correlation between MTR measurements and histopathologically measured myelin content. In addition, the MTR of remyelinated lesions differs from both normal appearing white matter (NAWM) and demyelinated lesions [Barkhof, 2003; Schmierer, 2004]. Voxel-based MTR analysis demonstrates the marked heterogeneity that accompanies repair within lesions [Chen, 2007]. This approach has been reported to allow for separate quantification of the evolution of the proportion of an initially enhancing (acutely demyelinating) brain lesion undergoing decreases in MTR (indicative of demyelination) and the proportion of the initially enhancing lesion undergoing increases in MTR (indicative of remyelination) over time. In the current study, MTR data will be collected to explore the potential for GSK1223249 to promote remyelination [Chen, 2007; Chen, 2008; Giacomini, 2009].

Diffusion MRI techniques provide a measure of the ability of water molecules to move in the brain, which is normally restricted in white matter by myelin and associated axonal elements. Diffusion-based MRI measures of ‘diffusivity’ and ‘fractional anisotropy’ therefore are sensitive to demyelination, and likely related to structural alterations such as change in calibre and axonal internal organisation.

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• The goals for non-conventional MRI are to determine the percentage of Gd-enhancing lesion voxels with significantly increased MTR

• To determine the percentage of Gd-enhancing lesion voxels with significantly decreased MTR

• To determine the change in mean normal-appearing white matter MTR

• To determine the change in cerebral mean diffusivity

3.2.1.5. Lumbar Puncture (Cohorts 2 & 3 only)

A single lumbar puncture per patient will be carried out in cohorts 2 and 3 only. For each lumbar puncture, a blood sample will be drawn within 1 hour (either before or after) CSF sampling to determine the blood-CSF ratio.

The PK schedule for CSF will be composite. Cohort 2 will include 4 subgroups. Each subgroup (or strata) will be allocated to a specific PK sample time and will include 4 patients; within each strata patients will be randomised to placebo or active in a 1:3 ratio (stratified randomisation). For all cohorts, patients will not be randomised to specific strata for PK sampling time. The first four patients to be randomised to treatment will be assigned to strata 1 (latest sampling time), the next four to strata 2 etc; strata 4 will be associated to the earliest time points.

CSF sample times for cohort 2 are indicated on Table 3 and CSF sample times for cohort 3 will be based on emergent CSF PK data from cohort 2.

Table 3 Cohort 2 Sampling schedule

Cohort 2 (n=16)

n=4 Strata 1 Day 29 after 3rd dose = day 85 n=4 Strata 2 Day 7 after 2nd dose = day 35 n=4 Strata 3 Day 29 after 1st dose = day 29 n=4 Strata 4 Day 7 after 1st dose = day 7

The requirement for, conduct of, and timing relative to study drug dosing of lumbar punctures may be reviewed and changed at any time during the study, based on emerging safety, tolerability and pharmacokinetic data. Lumbar puncture requirement may be removed from either cohort 2 and/or cohort 3 for reasons including but not limited to effect on recruitment.

3.3. Description of Study Treatment

Active treatment is provided as a clear to opalescent, pale brown to brown liquid solution of GSK1223249 (200 mg per mL in 50mM sodium acetate buffer, pH 5.5 containing 0.02% polysorbate 80 and rendered isotonic with sodium chloride) in 1 mL aliquots, filled under nitrogen into type I, clear, glass vials, nominal size 2 mL, closed with Helvoet Omniflex Plus stoppers and over-sealed with aluminium collars with a tear-out tab.

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Placebo for this study will be sodium chloride and will be sourced by site. Because of the difference in physical appearance between active and placebo treatments, masking of the infusion lines and sets will be required to maintain study blind and will be provided by GlaxoSmithKline.

Study treatment will be administered by slow infusion administered intravenously over approximately 60 minutes by a programmable syringe pump. Details of the dilution, preparation and administration of the infusion are found in the Study Procedures Manual (SPM).

3.4. Treatment assignment

Subjects in each cohort will be centrally randomized across all sites via an Interactive Voice Response System (IVRS) to receive either placebo or GSK1223249. No subject may receive study treatment unless they have completed enrolment and have been assigned a unique subject identification number. Once an identification number has been assigned, it may not be re-used, even if the subject does not receive study treatment.

Of note, the first four subjects in each dose cohort will be randomized and dosed sequentially with a minimum interval of 24 h before the next subject is administered study treatment (i.e., only one subject will be randomized and dosed within any 24-h period).

In cohorts 2 & 3, patients are assigned to a strata which determines the lumbar puncture sampling time, see Section 3.2.1.5. The randomisation in cohorts 2 & 3 will therefore be a stratified randomisation and patients will be assigned to placebo or GSK1223249, in a 1:3 ratio.

The CSF sampling schedule for cohort 3 will be finalised after PK data from CSF and blood sampling is available for review from cohort 2. Randomisation for cohort 3 will be completed once the CSF sampling schedule is agreed.

3.5. Dose Adjustment/Stopping Criteria

3.5.1. Planned Doses and Data Required for Dose Escalation

The planned dose cohorts and timing for dose escalation are summarized in Figure 3. Briefly, GSK1223249 at 1, 5, 15 and 30 mg/kg will be explored in staggered enrolling dose cohorts.

Intra-subject dose escalation from single dose level to repeat dose level in each dose cohort will be determined by the investigator together with the GSK Medical Monitor. The decision to commence the next dose cohort will be determined by the DEC

Screening will be paused once the last subject in each cohort has received their first dose. Once the last subject in each dosing cohort has received the second dose, screening for the next highest dose cohort can begin. Once the last subject has completed the Day 36 visit (6 days after second dose), and in addition, half the patients have completed Day 64

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visit, the investigators and DEC will review the non-quality controlled safety data and disease specific assessment data from that cohort along with all available data from any preceding dose groups. The baseline visits for the next cohort cannot occur prior to DEC indication that there are no objections to proceeding to the next higher dose cohort level.

Any available PK data will also be reviewed at the dose escalation meetings. The actual doses recommended for the next dose cohort may be adjusted based on emerging safety, tolerability and PK data; these dose adjustments may involve an increase or a decrease in the planned dose or a repeat of the previous dose level in order to better characterize an event of interest. Should the predicted AUC for the next dose exceed the safety cover associated with the NOAEL in non-human primates (see Section 1.5.2.3), the next dose level may be decreased or a decision may be made not to dose further.

3.5.2. Requirements for study continuation between cohorts

A list of the minimally required data to inform cohort dose escalation for consideration at the DEC is provided in the below list. The information listed is not intended to be exhaustive, and may be supplemented by additional data sets or information as necessary to best inform an appropriate decision about study progression and/or chosen dose(s) to be investigated.

• Clinical haematology, chemistry, urinalysis, adverse events.

• Any available pharmacokinetic data.

The following data sets will be included if available, but will not preclude the conduct of the DEC meeting if not available.

• Immunogenicity

• EDSS scores & group trends.

• MRI data

• Columbia Suicide Severity Rating Scale (C-SSRS) Data

The outcome of DEC meetings will be documented in writing and reviewed by all DEC members. The documented outcome will be retained within trial master files.

Timing of DEC meetings will be scheduled to occur no earlier than once all subjects within the current cohort have received their second dose of study drug, and completed the day 36 visit. In addition half the subjects must have received the 3rd dose of study medication, and completed Day 64 visit, prior to commencement of the DEC.

3.5.3. Requirements for subject continuation within cohorts

As stated previously, intra-individual dose escalation is made by investigator and the GSK medical monitor, using clinical judgement through use of neurological examination and MS symptom monitoring, together with safety data derived from the study up to and including Day13 for escalation to the second dose, and up to and including Day 42 for

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continuation to the third dose. If there are no safety issues or concerns then dose escalation can proceed without formal discussion between investigator and GSK medical monitor. If investigators are not comfortable with escalation there will be a formal discussion between the investigator and medical monitor and consensus reached.

Written summaries of safety information, decision, and narratives (as appropriate), will be provided to the GSK medical monitor for each subject once the investigator has reviewed applicable information and made a decision about a subject’s continuation to the next planned dose of study drug. This information must be provided to the GSK medical monitor within 24 to 48 hours from when the decision is made for each subject, regardless of whether the subject continues in the study or is withdrawn.

3.5.4. Criteria for Suspension/Dose Adjustment/Stopping Study

The DEC may suspend the study based on consideration of any of the following:

a. If a serious adverse event (SAE) deemed at least possibly related to study drug occurs at any time

b. If a severe AE deemed at least possibly related to study drug is observed during the course of dosing for a given subject

c. As a result of review of safety data at the end of a cohort, or

d. As a result of ongoing monitoring and analysis of disease specific assessments from previous cohorts

If dosing is suspended for any of the reasons above, all available cumulative safety data from the study may be reviewed by the DEC and the GlaxoSmithKline Global Safety Board (GSB) so that a decision can be made to either continue or terminate the study. GSB is an internal GlaxoSmithKline panel of senior clinicians with drug safety expertise and final accountability for medical governance for all GlaxoSmithKline clinical studies.

3.5.5. Individual Stopping Criteria

3.5.5.1. Investigator-driven Stopping Criteria

In addition to Section 3.5.3., other Investigator-driven decisions relating to subject continuation in the study are described below:

• If at any time during the study the subject experiences a relapse, the subject can be removed from the study at the discretion of the Investigator, dependent upon their judgement regarding severity of event and the need for commencement of an alternative DMT. If a subject experiences a second relapse prior to receiving the 3rd dose within a cohort, the subject will be withdrawn from the study. If a subject is removed from the study, replacement subjects may be considered.

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• An increase of 5 or more Gd-enhancing lesions above the number of Gd-enhancing lesions observed at baseline or screening will trigger an alert from the central MRI reader to the Investigator. Withdrawal of the subject from the study is then at the discretion of the Investigator. If a subject is removed from the study, replacement subjects may be considered.

3.5.5.2. General Stopping Criteria

If a subject experiences any of the conditions noted below while receiving GSK1223249 by infusion, the infusion must be terminated immediately and the subject monitored and treated appropriately over the next 24 h.

• anaphylaxis

• angioedema

• urticaria

• clinical symptoms suggestive of serum sickness

• General symptoms associated with vasculitis, including (but not limited to):

• Fever

• Fatigue

• Weight loss

• Muscle and joint pain

• Loss of appetite

• Nerve problems, such as numbness or weakness

The reason(s) for discontinuation of the study treatment must be recorded in the subject’s electronic case report form (CRF). No lumbar puncture will be performed on any subject whose infusion is terminated prematurely. However, subjects whose infusion is terminated prematurely will be expected to complete the remainder of the study visits so that safety data are collected. If a subject is removed from the study, replacement subjects may be considered.

3.6. Additional Safety Guidance

3.6.1. Liver Chemistry

Should a subject develop impaired liver function meeting the criteria for an SAE (see Section 11), the required assessments provided in Liver Chemistry Follow-up Procedures (see Section 12) should be undertaken.

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3.6.2. QTc Withdrawal Criteria

Both QT duration corrected for heart rate by Bazett’s formula (QTcB) and QT duration corrected for heart rate by Fridericia’s formula (QTcF) will be calculated in this study. If a subject develops QTc prolongation during the course of infusion of GSK1223249, as defined below, the infusion must be stopped immediately. Two additional ECGs should be obtained separated by approximately 5 minutes and the subject should be monitored appropriately. Re-challenge with study treatment will not be allowed.

• QT (machine or manual over-read), QTcB or QTcF > 500msec

• If subject has bundle branch block then criterion is QTcB or QTcF > 530 msec

3.6.3. Suicidal Risk

GSK1223249 is considered to be a CNS active drug. There has been some concern that some CNS active drugs may be associated with an increased risk of suicidal thinking or behaviour when given to some patients with certain conditions. Although this drug has not been shown to be associated with an increased risk of suicidal thinking or behaviour when given to this patient population, GSK considers it important to monitor for such events before or during clinical studies with compounds such as this.

Subjects being treated with GSK1223249 should be assessed appropriately for suicidality and unusual changes in behaviour. Consideration should be given to discontinuing GSK1223249 in subjects who experience signs of suicidal ideation or behaviour. Baseline assessment of suicidality and treatment emergent suicidality will be monitored during Study NGM114840 using C-SSRS. See Section 3.7 for timings of assessments. See Section 6.3.9 for additional information.

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3.7. Time and Events Tables

Table 4 Time and Events Overall High-Level Study Schedule (All cohorts)

Procedure Screening 6 weeks prior to dose ± 2 days

Baseline 7 ± 2 days prior to 1st dose

Days 1-2 Day 7 Day

13 Days 28-30

Day 36 ± 1

Days 42± 1

Days 57-58 ± 1

Days 64± 3

Days 70± 3

Days 85± 3

Days 127 ± 3

Days 169 ± 3

Day 197 ± 4 c

Study drug dosing X X X Safety (vitals, labs, ECGs, physical exam e.t.c.), medical history & drugs of abuse assessments a

X X X X X X X X X X X X X X X

Demographic data a X Neurological exam & symptom monitoring Including EDSS assessments

X X X X X X X X X X X X

PK sampling (blood) a X X X X X X X X X X X X X

MRI X X X X X X X X Immunogenicity a X X X X X CSF PK sampling (lumbar puncture) X b a. For detailed assessment requirements, refer to individual time & events table for each specific dosing occasion. b. Patients will receive 1 lumbar puncture only. Timings of lumbar punctures for cohort 2 are specified in Table 3, Section 3.2.1.5. Timings for cohort 3 will be determined based on

emergent CSF PK data from cohort 2. c. This visit is an “as needed” visit, the necessity for which will be determined at DEC meetings.

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Table 5 Time and Events Schedules (all cohorts): Screening, Baseline & Dose 1

Procedure


Day 7

Day 13

6 weeks prior to dose ± 2 days


Pre-dose 0h

0.5h

1h

2h

3h

6h

12h

18h

24h

In Patient Stay =========================X====================== Outpatient Visit X X X X Administration of Study drug X Medical History X Height X Hepatitis C Ab, HBsAg X Pregnancy Testinga X X X Cranial MRI ±Gd-contrast X X X Physical Examination Xg Xh Neurological exam & symptom monitoring, EDSS X X X X

Body Weight X X X Urine Drug / Alcohol Screen X X Safety Labs X X Xf X X Vital Signs X X X X X X X X 12-Lead ECG X X X Xc Xc Xc Xc X X Randomisation X Blood sample for PK X X X X X X X Blood sample for Immunogenicity X Plasma sample for biomarkers X X

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Procedure


Day 7

Day 13

6 weeks prior to dose ± 2 days


Pre-dose 0h

0.5h

1h

2h

3h

6h

12h

18h

24h

Continuous ECG monitoring ===========================X======================= C-SSRS X d X e X e X e Lumbar Puncture X b Adverse Event Monitoring From Day 1 to completion of follow-up visit Concomitant Medication From screening to completion of follow-up visit a. Females only. Serum pregnancy testing at Screening, urine pregnancy testing for all other visits. b. Patients will receive 1 lumbar puncture only. Timings of lumbar punctures for cohort 2 are specified in Table 3, Section 3.2.1.5. Timings for cohort 3 will be determined based on

emergent CSF PK data from cohort 2. c. Performed in triplicate d. Baseline version e. Since last visit version f. Results not required prior to dosing unless baseline sample results outside normal range, or warranted in Investigator’s opinion. g. Full physical exam h. Brief physical exam

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Table 6 Time and Events Schedules (all cohorts): Dose 2

Procedure Day 29 Day 30

Day 36 ± 1

Day 42 ± 1 Pre-dose 0h

0.5h

1h

2h

3h

6h

12h

24h

In Patient Stay ===========================X========================== Outpatient Visit X X Administration of Study drug X Pregnancy Testinga X Cranial MRI ±Gd-contrast X Neurological exam & symptom monitoring, EDSS X X

Body Weight X Urine Drug / Alcohol Screen X Safety Labs Xe X X Vital Signs X X X X X X X 12-Lead ECG X Xc Xc X X PK X X X X X X X Blood sample for Immunogenicity Plasma sample for biomarkers Continuous ECG monitoring ============================X========================= C-SSRS d X X X Lumbar Puncture X b Adverse Event Monitoring From Day 1 to completion of Follow-up Visit Concomitant Medication From Screening to completion of Follow-up Visit

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Table 6 Time and Events Schedules (all cohorts): Dose 2 (Continued)

a. Females only b. Patients will receive 1 lumbar puncture only. Timings of lumbar punctures for cohort 2 are specified in Table 3, Section 3.2.1.5. Timings for cohort 3 will be determined based on

emergent CSF PK data from cohort 2. c. Performed in triplicate. d. Since last visit version e. Results not required prior to dosing unless visit 5 (Day 13) sample results outside normal range, or warranted in Investigator’s opinion.

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Table 7 Time and Events Schedules (all cohorts): Dose 3

Procedure Day 57 Day 58 Day

64/65 ± 3

Day 70/71 ± 3

Day 85/86 ± 3

Day 127 ± 3

Pre-

dose

0h

1h

2h

3h

6h

12h

24h

In Patient Stay =========================X======================== Outpatient Visit X X X X Administration of Study drug X Pregnancy Testinga X Cranial MRI ±Gd-contrast X X Neurological exam & symptom monitoring, EDSS X X X X

Body Weight X X Urine Drug / Alcohol Screen X Safety Labs Xe X X X X Vital Signs X X X X X X X X X 12-Lead ECG X Xc Xc X X X X Concomitant Medication X Blood Sample for PK X X X X X X X X X Blood sample for Immunogenicity X X Plasma sample for biomarkers X Continuous ECG monitoring =========================X======================== C-SSRS d X X X X X Lumbar Puncture Xb

Adverse Event Monitoring From Day 1 to completion of Follow-up Visit Concomitant Medication From Screening to completion of Follow-up Visit a. Females only. b. Patients will receive 1 lumbar puncture only. Timings of lumbar punctures for cohort 2 are specified in Table 3, Section 3.2.1.5. Timings for cohort 3 will be determined based on

emergent CSF PK data from cohort 2. c. Performed in triplicate. d. Since last visit version e. Results not required prior to dosing unless visit 8 (Day 42) sample results outside normal range, or warranted in Investigator’s opinion.

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Table 8 Time and Events Schedules (all cohorts): Follow-up

Procedure Day 169 ± 4 days Day 197 ± 4 days d Pregnancy Testinga X X Cranial MRI ±Gd-contrast X X Physical Examination Xe Xf

Neurological exam & symptom monitoring X X Body Weight X X Urine Drug / Alcohol Screen X X Urinalysis X X Blood Chemistry X X Haematology X X Vital Signs X X 12-Lead ECG X X Concomitant Medication X X Blood Sample for PK X X Blood sample for Immunogenicity X Xb Plasma sample for biomarkers X X C-SSRS c X X Adverse Event Monitoring X X a. Females only. Urine pregnancy testing sufficient. b. Timing of sample may be changed based on GSK1223249 PK profile in plasma and upper threshold for quantification established for this assay. c. Since last visit version d. This visit is an “as needed” visit, the necessity for which will be determined at DEC meetings. e. Full physical exam f. Brief physical exam

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4. STUDY POPULATION

4.1. Number of Subjects

A sufficient number of subjects will be enrolled into the study such that approximately 40 subjects complete dosing and critical assessments (defined as completing dosing and safety assessments to at least the day 70 visit).

The number of subjects per cohort is stated in the table below:

Table 9 Number of subjects per cohort

Cohort Total number of subjects Number receiving active drug

Number receiving placebo

1 8 6 2 2 16 12 4 3 16 12 4

If dose de-escalation to an unplanned lower dose is recommended, a decision may be made to expand a given dose level, by the DEC.

4.2. Replacement of Subjects

If subjects prematurely discontinue from the study, additional subjects may be enrolled as replacement subjects at the discretion of the Sponsor in consultation with the investigator. Replacement subjects will be assigned the same treatment sequence as the dropout subject that they are replacing.

4.3. Eligibility Criteria

4.3.1. Inclusion Criteria

Deviations from inclusion criteria are not allowed because they can potentially jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.

Additional information regarding warnings, precautions, contraindications, AEs, and other pertinent information on the investigational product that may impact subject eligibility/inclusion in this study is provided in the GlaxoSmithKline Investigator Brochure. However, a subject will be eligible for inclusion in this study if all of the following criteria apply:

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1. Suitable as determined by the Principal Investigator, based on his/her overall evaluation. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the Investigator and the GlaxoSmithKline Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.

2. Diagnosed with a relapsing form of MS defined as either

a. RRMS according to revised McDonald Criteria [McDonald, 2001; Polman, 2005] and a history of brain MRI lesions consistent with MS, OR

b. SPMS with relapses and a history of brain MRI lesions

3. Using one of the following ongoing MS treatment strategies, defined as

a. Currently receiving Beta-interferon/Copaxone for treatment of MS and have been receiving the current course of therapy for 3 or more months prior to screening, OR

b. Not currently receiving disease modifying therapies for treatment of MS, and has not received such therapies for at least 3 months prior to screening.

4. Have demonstrated clinical activity in 2 years prior to screening, whilst receiving current/previous treatment regimen or prior to any treatment regimen, by either:

a) One or more documented relapses, or

b) One or more documented Gd enhancing lesions in the brain or spinal cord, or

c) Confirmed disease progression on EDSS by greater than or equal to 0.5 points.

5. Expanded Disability Status Scale (EDSS) score ≤6.0 at either the screening or baseline visit.

6. Male or female between 18 and 60 years of age inclusive, at the time of signing the informed consent.

7. A female subject is eligible to participate as follows:


b. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods described in Section 7.1.1 if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least two to four weeks must elapse between the cessation of therapy and the blood draw; this interval depends on the type and dose of HRT. Following confirmation of their post-menopausal status, subjects may resume use of HRT during the study without use of a contraceptive method.

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c. Women of childbearing potential should have used one of the contraception methods listed in Section 7.1 for at least 1 month prior to the start of dosing to sufficiently minimize the risk of pregnancy. Women of childbearing potential must agree to continue to use contraception throughout the study and for an additional 6 months after dosing. Their male partners should also use contraception.

8. Male subjects must agree to use one of the contraception methods listed in Section 7.1.2, even if they have had a vasectomy. This criterion must be followed from the time of the first dose of study medication, during the study, and for 6 months after dosing.

9. Body weight ≥ 50 kg .

10. On ECG, QTcB interval < 450 msec; or QTc < 480 msec in subjects with bundle branch block.

11. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form, and authorisation of the release and use of protected health information (PHI).

4.3.2. Exclusion Criteria

Deviations from exclusion criteria are not allowed because they can potentially jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.

Subjects with abnormalities (clinical or otherwise) detected during the screening evaluations which, in the Principal Investigator’s medical judgment, are sufficiently significant to exclude them from participation in the study.

A subject will not be eligible for inclusion in this study if any of the following criteria apply:

1. History of, or laboratory findings indicative of any clinically significant (as determined by the Investigator) cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal, and/or other major disease or of known drug sensitivity that would preclude the administration of a recombinant humanized antibody or the use of systemic steroids during the course of the study.

2. Abnormal baseline blood tests exceeding any of the limits defined below: Alanine transaminase (ALT) or aspartate transaminase (AST) >1.5 x the upper limit of normal (ULN)

• Alkaline phosphatase (AP) and bilirubin >1.5X ULN (isolated bilirubin >1.5x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).

• Total white blood cell count < 2,500/mm3

• Platelet count < 95,000/mm3

• Creatinine > 2 x ULN

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• Calculated creatinine clearance < 60 ml/min (per Cockcroft & Gault) at Screening

• International Normalised Ratio (INR) larger than upper limit of the normal reference range (0.9 – 1.3)

3. Treatment with methylprednisolone or any other systemic steroid, for a relapse or otherwise, within 30 days of screening

4. Treatment within the past 12 months or currently with any of the following agents: cyclosporine, cladribine, natalizumab (Tysabri) or other monoclonal antibodies, murine protein, T-cell vaccination, plasmapheresis, IV IgG, stem cell transplantation.

5. Treatment in the past 6 months with any of the following agents: Fingolimod (Gilenya), methotrexate, mitoxantrone, azathioprine, or other small molecule immunosuppressants.

6. History of intolerance to acetominophen, ibuprofen, naproxen or any other non-steroidal anti-inflammatory agent which would preclude use of at least one of these during the study.

7. Previous history of anaphylaxis, severe allergic reaction, generation of neutralizing antibodies, or hypersensitivity to albumin or a protein-based therapeutic, including natalizumab (Tysabri) or any other monoclonal antibody. History of hypersensitivity to any of the components of the formulation.

8. History of alcohol or drug abuse (as defined by DSM-IVR criteria) within 2 years prior to randomization

9. A positive pre-study hepatitis B surface antigen or positive hepatitis C antibody result.

10. Subjects with evidence of dementia or psychiatric illness which, in the Investigator’s opinion, is likely to prevent them from a full understanding of and/or compliance with the study requirements and procedures.

11. Known diagnosis or history consistent with human immunodeficiency virus (HIV) positivity.

12. Blood donation (1 unit or more) within 3 months prior to investigational drug administration.

13. History of regular alcohol consumption within 6 months of the study defined as: Average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 g of alcohol: a half-pint (~240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.

14. Subjects who have received vaccinations 3 weeks prior to administration of study drug.

15. Contraindications to MRI scanning including but not limited to:

Intracranial aneurysm clips (except Sugita clips) with an appropriate operative conformation;

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• History of intra-orbital metal fragments that have not been removed by an MD;

• Documented:

• Pacemakers and non-MRI compatible heart valves

• Inner ear implants

• History of severe claustrophobia or inability to lie still on the back for a period of approximately one (1) hour in the MRI scanner.

16. Contraindications for administration of Gd-contrast agents ie. any history of severe renal insufficiency if not already mentioned above.

17. Greater than 10 Gadolinium-enhancing lesions present at screening MRI.

18. Unwillingness or inability to follow the procedures outlined in the protocol.

19. Subjects with a medical history of significant infections (such as tuberculosis, opportunistic or atypical infections) or any congenital or acquired immunodeficiency

20. Active or latent tuberculosis (TB) infection: All subjects will be tested with QuantiFERON TB Gold test and those with positive test result will be excluded.

21. [Note: Subjects with an indeterminate test result may undergo one re-test; a subsequent indeterminate or positive result excludes participation]. Chest radiographs may be performed if the investigator determines that it is clinically indicated and any abnormal findings suggestive of active or latent TB will exclude thes patient

22. Subjects, who in the investigator's judgement, pose a significant suicide risk. Evidence of serious suicide risk may include any history of suicidal behavior in the last 6 months and/or any suicidal ideation of type 4 or 5 on the C-SSRS in the last 2 months.

4.3.3. Other Eligibility Criteria Considerations

To assess any potential impact on subject eligibility with regard to safety, the investigator must refer to the following documents for detailed information regarding warnings, precautions, contraindications, adverse events, and other significant data pertaining to the GSK investigational products or other study treatment being used in this study: Investigator Brochure [GlaxoSmithKline Document Number AM2010/00015/00], Investigator Brochure Supplement [GlaxoSmithKline Document Number 2010N105512_00].

5. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS

5.1. Hypotheses and Treatment Comparisons

This study is designed to estimate the effect of GSK1223249 relative to Placebo on safety, tolerability and pharmacokinetics. No formal hypothesis will be tested. Where appropriate, an estimation approach will be taken and point estimates and 90% confidence intervals will be constructed.

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5.2. Sample Size Considerations

5.2.1. Sample Size Assumptions

There was no formal calculation of power or sample size for this exploratory study. This sample size is based on safety and feasibility. The sample size is sufficient to ensure that approximately 40 subjects complete the Day 70 visit. Of the 40, 10 subjects will be allocated to placebo (2 in cohort 1, 4 in cohort 2 and 4 in cohort 3) and 30 to active (6 in cohort 1, 12 in cohort 2 and 12 in cohort 3). This allows an initial estimate of the safety and tolerability associated with administration of doses of GSK1223249.

While no formal statistical comparisons will be performed, the adverse event rate for relapses (recorded as adverse events if they are atypically severe or unusual in recurrence) will be of interest. There is uncertainty around this event rate however an estimate of around 1-10% will be assumed.

The table below gives the probability of seeing such an adverse event rate at least once in 12 patients assigned to GSK1223249 (e.g. in either cohorts 2 or 3) and the probability for the total of 30 patients assigned to GSK1223249.

AE Incidence Probability of AE seen at least once in 12 patients

Probability of AE seen at least once in 30 patients

0.01 0.114 0.260 0.05 0.460 0.785 0.10 0.718 0.958 As an example of how informative the study could be, confidence intervals may be constructed for a particular AE rate and sample size. This is illustrated in the following tables for 50%, and 90% confidence intervals.

For 12 active patients in a cohort:

No. with AE No. without AE Proportion Exact 90% CI Exact 50% CI 0 12 0.0000 (0.0000, 0.2209) (0.0000, 0.1091) 1 11 0.0833 (0.0043, 0.3387) (0.0237, 0.2091) 2 10 0.1667 (0.0305, 0.4381) (0.0803, 0.3012) 3 9 0.2500 (0.0719, 0.5273) (0.1459, 0.3888) 4 8 0.3333 (0.1229, 0.6091) (0.2162, 0.4731) 5 7 0.4167 (0.1810, 0.6848) (0.2898, 0.5547) 6 6 0.5000 (0.2453, 0.7547) (0.3663, 0.6337)

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For 30 active patients over all cohorts:

No. with AE No. without AE Proportion Exact 90% CI Exact 50% CI 0 30 0.0000 (0.0000, 0.0950) (0.0000, 0.0452) 3 27 0.1000 (0.0278, 0.2386) (0.0579, 0.1644) 5 25 0.1667 (0.0681, 0.3190) (0.1136. 0.2374) 10 20 0.3333 (0.1933, 0.4994) (0.2638, 0.4112) 15 15 0.5000 (0.3389, 0.6611) (0.4229, 0.5771) Therefore, for example, if an AE is reported in one out of 12 subjects (8.33%) exposed to GSK1223249 in either cohort 2 or 3, the 90% confidence interval would be (0.43%, 33.87%) and the 50% confidence interval would be (2.37%, 20.91%). If three out of thirty subjects exposed GSK1223249 in all cohorts experience the event (10.00%) the 90% confidence interval would be (2.78%, 23.86%) and the 50% confidence interval would be (5.79%, 16.44%)

5.2.2. Sample Size Sensitivity

No sample size sensitivity was performed

5.2.3. Sample Size Re-estimation

No sample size re-estimation will be performed.

5.3. Data Analysis Considerations

5.3.1. Interim Analysis

No formal interim statistical analyses are planned.

Following receipt of the required key safety data in a given cohort, unblinded data will be reviewed by the Dose Escalation Committee to aid decisions to proceed to the next cohort. This analysis can include review of individual subject data, summaries and graphical presentations. Full details of the selected endpoints for this informal analysis will be included in the reporting and analysis plan (RAP). Due to the short time intervals required between the last subjects visit and the DEC all data to be used for dose escalation decisions will be preliminary data that has not necessarily been quality controlled.

The GSK Clinical Pharmacology Modelling and Simulation (CPMS) representative will extract PK data (including treatment information) using unscrambled subject IDs. PK data will provide supporting evidence for each dose modification decision. Importantly, if the emerging PK data is significantly different from the predicted values, adjustment may have to be made to the planned doses. Dose modification decisions will take into account the emerging PK data, new PK Prediction for the next dose and thus the expected safety cover for the next dose.

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Interim PK analysis will be conducted using non-compartmental and population approaches, where data permit. Standard pharmacokinetic parameters will be derived for each subject by the GSK pharmacokineticist representative, when possible. These parameters will be summarised by planned dose.

5.3.2. Final Analyses

5.3.2.1. Safety Analyses

Population and safety data will be presented in tabular and/or graphical format and summarized descriptively according to GSK’s Integrated Data Standards Library (IDSL) standards.

The presence of antibodies to GSK1223249 (assessed in serum samples) will be listed and summarised descriptively by dose.

Placebo groups will be combined across cohorts in summary outputs.

Full details of the analysis of other exploratory safety related endpoints will be included in the analysis and reporting plan (RAP).

5.3.2.2. Pharmacokinetic Analyses in Plasma

Raw Plasma Concentrations

Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacokinetics Modelling & Simulation department within GlaxoSmithKline. GSK1223249 plasma concentration-time data will be analyzed by a population pharmacokinetic analysis using the NONMEM software in the PME environment (version 2.4 or later), and by non-compartmental methods with WinNonlin (version 5.2 or later) if needed. The analyses will be based on the actual sampling times recorded during the study.

Derived Pharmacokinetic Parameters

Given the study design, a population compartmental PK analysis will be used to account for the different doses administered within each subject. If the PK model described on Figure 1 (Section 1.5.2.1) fits satisfactory the observed data, the following parameters will be estimated:

• The central volume (Vc) which represents the plasma volume

• The peripheral volume (Vp) which represents the volume in the peripheral compartment

• Q which represent the inter-compartment clearance

• Cl which represents the linear elimination clearance from the central compartment

If the fit is not judged satisfactory, another PK model might be considered.

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The final PK model and its parameter estimates will be used to simulate individual plasma concentrations profiles of GSK1223249 after various single and repeat doses. From these individual PK profiles, GSK1223249 systemic exposure (Cmax values and AUC(0-∞)) will be calculated.

In addition, the following parameters will be calculated for each subject from the observed concentration-time profile data: maximum plasma concentration after the first dose (Cmax1) and after the third dose (Cmax3), time of last quantifiable concentration (tlast), elimination phase half life (t1/2).

Statistical Analyses of Pharmacokinetic Parameters

Statistical analyses of the pharmacokinetic parameter data will be performed by, or under the direct auspices of, Neurosciences MDC Analytic Sciences, GlaxoSmithKline. Pharmacokinetic data will be presented in graphical and/or tabular form and will be summarized descriptively. All pharmacokinetic data will be stored in the Archives, GlaxoSmithKline Pharmaceuticals, R&D.

Assessment of Dose Proportionality

An initial assessment of dose proportionality will be explored for AUC and Cmax following single doses of GSK1223249 using summary statistics and graphical presentations, if data permits. Further exploratory statistical analysis to assess dose proportionality may be performed, to be detailed in the RAP.

5.3.2.3. Pharmacokinetic Analyses in CSF

GSK1223249 concentrations in CSF will be listed by dose and by visit and, if data permit, the ratio between concentrations in CSF and concentrations in plasma will be calculated at the same time point, for the same subject. Depending on the quality of the data obtained, an exploratory PK analysis in CSF might be performed via a population approach in NONMEM, using the composite PK samples for all subjects. This exploratory analysis will further detailed in the RAP.

The PK analysis in CSF might provide more confidence in predictions of NOGO target binding, assuming that the potential PK profile measured in CSF would be similar to the one in CNS

5.3.2.4. Pharmacokinetic/Pharmacodynamic Analyses

Exploratory PK/PD analyses may be performed to examine the potential relationships between GSK1223249 pharmacokinetics and markers of safety and efficacy, if data permits.

Full details of the PK/PD analyses will be further detailed in the RAP.

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6. STUDY ASSESSMENTS AND PROCEDURES

This section lists the parameters of each planned study assessment. The exact timing of each assessment is listed in the Time and Events Table (Section 3.7). Detailed procedures for obtaining each assessment are provided in the Study Procedures Manual (SPM). Whenever vital signs, 12-lead ECGs and blood draws are scheduled for the same nominal time, the assessments should occur in the following order: 12-lead ECG, vital signs, blood draws. The timing of the assessments should allow the blood draw to occur at the exact nominal time.

The timing and number of planned study assessments, including safety, pharmacokinetic, exploratory assessments may be altered during the course of the study based on newly available data (e.g. to obtain data closer to the time of peak plasma concentrations) to ensure appropriate monitoring. The change in timing or addition of time points for any planned study assessments must be approved and documented by GSK, but this will not constitute a protocol amendment. The IRB/IEC will be informed of any safety issues that require alteration of the safety monitoring scheme. No more than 500 mL of blood will be collected over the duration of the study, including any extra assessments that may be required.

The assessments and procedures for this study are summarised in the Time and Events Tables, Section 3.7.

It is important to note that timings of lumbar puncture assessments for subjects in cohort 3 are subject to the outcome of emergent data from cohorts 1 & 2, and thus have not been specified below. Timings of lumbar punctures for subjects in cohort 3 will be confirmed to study sites in a timely manner, after cohort 2 data has been reviewed, and will follow a similar format to that of cohort 2. Subjects in cohort 3 will also be limited to no more than 1 lumbar puncture each, during the study.

6.1. Demographic/Medical History Assessments

6.1.1. Informed Consent & Screening

After providing full informed consent, subjects will undergo a medical screen to determine their eligibility for participation based on the criteria outlined in this protocol. Subjects will be screened within 6 weeks ± 2 days prior to first dosing visit. The site Principal Investigator must review the nature of the study, its requirements, and its restrictions with each potential participant. Written informed consent must be obtained prior to any screening procedures.

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6.1.2. Visit 1: Screening (6 weeks plus or minus 2 days prior to first dose)

The study objectives, requirements and potential risks will be carefully reviewed once more with potential study participants, so that they have a final opportunity to have all their questions answered before deciding to participate in the study. If the subject elects to participate, the informed consent form will be signed and the IVRS will assign the subject a unique study identification number. Eligibility for the study based on the specified inclusion/exclusion criteria must then be determined within 6 weeks ± 2 days of the first dose visit. The pre-study evaluation includes the following:

• Demographic data including date of birth, gender and race

• Medical history, including history of smoking and alcohol use

• Assessment of Suicidality (completion of C-SSRS)

• Disease history, including: date of diagnosis, date of first symptoms, first

• symptoms, classification (RRMS, SPMS with relapses, PPMS), number of

• relapses within the past 12 months, past 24 months, treatment history.

• Physical examination, including vital signs

• Neurologic examination (including EDSS; see Section 3.2.1.1, and Section 3.2.1.2)

• Assessment of baseline symptoms, concomitant medications, and concomitant procedures

• Twelve-lead ECG

• Blood and urine safety samples

• Serum pregnancy test (for female participants of childbearing potential – additional serum or urine pregnancy tests will be permitted throughout the study

• period if required by country-specific regulations)

• MRI (see Section 3.2.1.4)

6.1.3. Visit 2: Baseline (Day -7 ± 2days prior to dosing)

Subjects will return for a Baseline Visit 7±2 days before the day of dosing. Inclusion/exclusion criteria and any interim changes in clinical status are reviewed with the subject. A second baseline MR scan sequence is obtained along with a physical and neurological examination. The visit timing and window ensures that there is adequate time to repeat the MR scan, if required because of poor scan quality.

Safety blood draws taken at this visit will determine if a subject is eligible to be admitted to the in-patient phase of the trial and be subsequently randomised to receive treatment.

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6.2. Treatment Phase

6.2.1. Visit 3: inpatient, Day 1 to Day 2

Subjects are admitted to their designated Phase I type Unit in the morning of day of dosing (Day 1; see Table 4 and Table 5). This will allow subjects to acclimatize to their surroundings and allow the specified pre-dose assessments to be completed. The neurologic exam should be completed by the same Rater as for Screening and Baseline. If it is not possible to complete the neurologic exam the same day, a window of ± 3 days is permitted. Results from safety assessments must be available in time to inform the decision to dose the next day. The results of pre-dose safety laboratory samples from visit 3 are only required prior to dosing if visit 2 safety sample results indicate it is necessary, as judged by the investigator. The subjects’ weight must be accurately obtained and recorded, as drug dosing is based on body weight. On the day of dosing (Day 1) single dose safety assessments (vital signs, 12-lead ECG and telemetry, AE monitoring) are conducted and PK samples are obtained at pre-dose and 1, 6, 12, and 24 h post-dosing (the last timepoint occurs at the beginning of Day 2).

A blood draw for serum anti-GSK1223249 antibody level (negative control) is included.

6.2.2. Visit 4: Day 7

Subjects return to the clinical unit on day 7 to complete standard safety procedures, (see Table 5), and potentially, a lumbar puncture for CSF sampling. See Table 3 and text in Section 3.2.1.5 for details of CSF sampling timings and information. Note that CSF sampling will be conducted in cohort 2 & 3 only, not in cohort 1.

6.2.3. Visit 5: Day 13

Subjects will attend the clinical unit on Day 13 for standard safety procedures, an MRI scan, neurological exam & EDSS, and pharmacokinetic sampling. Details are contained in Section 3.2.1 and Table 4 & Table 5.

6.2.4. Visit 6: Day 29 & Day 30

Visit 6 involves the 2nd administration of study drug, at the planned next dose level. The investigator will have previously reviewed appropriate study information (safety, tolerability etc.) for individual subjects before dosing occurs. The results of pre-dose safety laboratory samples from visit 6 are only required prior to dosing if visit 5 safety sample results indicate it is necessary, as judged by the investigator. See Section 3.5.3 for details. Additional assessments/procedures include standard safety procedures, neurological exam & EDSS, and pharmacokinetic sampling. Detailed assessments are listed in Table 6.

A lumbar puncture for CSF sampling may be performed. See Table 3 and text in Section 3.2.1.5 for details of CSF sampling timings and information. Note that CSF sampling will be conducted in cohorts 2 & 3 only.

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6.2.5. Visit 7: Day 36 (±1 day)

Visit 7 at the clinical unit will involve the standard safety procedures, see Table 6, and may involve a lumbar puncture, see Section 3.2.1.5.

6.2.6. Visit 8: Day 42 (±1 day)

Visit 8 will include an MRI scan, standard safety procedures and pharmacokinetic sampling, see Table 6, at the clinical unit.

6.2.7. Visit 9: Day 57 to 58 (±1 day)

This visit is the 3rd and final administration of study drug. Subjects will return to the clinical unit for the usual safety procedures, neurological exam & EDSS, and pharmacokinetic sampling. The results of pre-dose safety laboratory samples from visit 9 are only required prior to dosing if visit 8 safety sample results indicate it is necessary, as judged by the investigator. Detailed assessments are listed in Table 7.

6.3. Follow-up phase

6.3.1. Visit 10: Day 64 (± 3 days)

Subjects return to the clinical unit on day 64 to complete standard safety procedures, and PK sampling (see Table 7).

6.3.2. Visit 11: Day 70 (± 3 days)

Subjects will attend the clinical unit for standard safety measures, PK sampling, plasma sample for biomarkers, and neurological & EDSS assessments. See Table 7 for details.

6.3.3. Visit 12, 13 & 14: Days 85, 127 & 169 (all ±3 days)

These three visits all involve standard safety measures, blood sample for PK, and Neurological & EDSS assessments. Table 7 details all assessments & timings.

Visit 12 (day 85) will additionally involve:

• Potential lumbar puncture (Cohorts 2 & 3 only)

• Body weight

Visit 14 (day 169) will additionally involve (and may mark the end of study visit, as determined by the DEC):

• An MRI scan

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6.3.4. Visit 15: Day 197 (± 4 days) End of Study

If necessary, this visit is the final planned visit, and marks the end of the study. The visit will involve standard safety measures, PK sampling, plasma sample for biomarkers, and neurological & EDSS assessments. See Table 8 for specific details. The timing of the visit may be changed dependent upon emerging data from the study.

The necessity of this visit will be determined at the DEC meetings.

6.3.5. Additional visits

A subject may be asked to return for an unscheduled visit at the discretion of the Investigator or at the request of the Medical Monitor to undergo additional safety evaluations or as follows:

• Within 72 h of the onset of any new neurologic symptom(s), for the evaluation of a suspected MS clinical relapse

• Because of premature withdrawal from the study.

Data from unscheduled visits will be collected in the electronic CRF.

6.3.6. Safety assessments

Planned timepoints for all safety assessments are listed in the Time and Events Table (Section 3.7). Additional time points for safety tests (such as vital signs, physical exams and laboratory safety tests) may be added during the course of the study based on newly available data to ensure appropriate safety monitoring.

Physical Exams

• A complete physical examination will include assessments of the head, eyes, ears, nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes and extremities. Height and weight will also be measured and recorded.

• A brief physical examination will include assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen).

Vital Signs

Heart rate and blood pressure (systolic and diastolic) measurements will be collected in the sitting position at the time points described in the Time and Events Tables. The number of assessments may be adjusted depending upon the emerging safety profile in subjects and additional assessments may be added. Heart rate and blood pressure measurements will be made with automated monitors with the subject in the sitting position: subjects must be in a seated position with legs uncrossed, back & arm supported for at least 5 minutes prior to each reading.

Measurements that deviate substantially in the opinion of the supervising physician from previous readings will be repeated.

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Electrocardiogram (ECG)

Standard 12-lead ECGs will be obtained at each timepoint during the study as described in the Time and Events Tables.

Supine 12-lead ECGs will be made after the subject has been resting supine (lying flat with maximum one pillow) for a period of at least 5 minutes. Screening, Baseline and pre-dose 12-lead ECG readings will be averaged and the mean taken as the baseline measurement for post-dose comparisons. Machine generated readings for heart rate and PR, QRS, QT, RR, and QTc intervals will be printed and read in real time at each site. The paper tracings must be retained in the source documents for each subject. The ECG assessment date time, and metrics values will be recorded in the electronic CRF. The number of assessments may be adjusted depending upon the emerging safety in man, and additional assessments may be added. The Investigator or other medically qualified study team member will evaluate the screening ECG for any abnormalities that exclude the subject from the study. All subsequent ECGs are to be evaluated for any new abnormalities or clinically significant worsening.

Continuous Lead II ECG monitoring (using telemetry or a bedside ECG monitor) will also be performed during the study as described in the Time and Events Tables. Any abnormal findings on continuous ECG monitoring should be confirmed by 12-lead ECG. Refer to Section 3.6.2 for QTc withdrawal criteria and additional QTc readings that may be necessary.

6.3.7. MRI scans

This component of the study is being overseen by NeuroRx Inc. (Montreal, Canada), a contract research organization specializing in MRI. All scans will be performed according to a standard protocol detailed in the NeuroRx MRI User’s Manual and transmitted electronically to their central facility for blinded interpretation and analysis. Prior to screening their first subject, each study site will be asked to send a ‘phantom’ scan to assess image quality and the accessibility of the electronic data system, and to assess the site’s ability to correctly reposition subjects. MRI site participation is contingent on this approval process. In this study, MR images will be obtained seven times over the course of this study: at Screening, Baseline (Day -7 ± 2 Dosing), Day 13, Day 42, Day 85, Day 127, and Day 169. As detailed in the inclusion/exclusion criteria for this study, subjects with a history of metal fragments, paramagnetic metal in the form of aneurysm clips, or pacemakers are excluded from participating. Each MRI session will last approximately one hour and consists of a sequence of T1-weighted (T1w), T2-weighted (T2w), MTR, and diffusion weighted scans. Subjects will lie supine in the scanner and scanning volumes will be prescribed by the use of a standardized localizer sequence. High resolution T1 and T2-weighted scans including Gd-enhanced scans covering the entire brain will be acquired. The same MRI machine must be used for a given subject throughout the course of the study.

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6.3.8. Lumbar puncture

Procedural details are found in the SPM. A lumbar puncture may not be performed on any subject whose infusion was terminated prematurely. Blood for prothrombin time, partial thromboplastin time, and platelet count must be drawn the morning of the intended procedure and reviewed prior to performing the lumbar puncture. Subject with abnormal findings may not be allowed to undergo the procedure.

6.3.9. Columbia suicide-severity rating scale

Procedural details and examples of the 2 versions of the forms are found in the SPM. The baseline C-SSRS version of the form should be completed only once, at the first scheduled timepoint. The ‘since last visit’ version should be completed at all subsequent scheduled timepoints. See Section 3.7 for timings of assessment.

6.3.10. Clinical Laboratory Assessments

Hematology, clinical chemistry, urinalysis and additional parameters to be tested are listed below:

Hematology Platelet Count RBC Indices: Automated WBC Differential: RBC Count MCV Neutrophils WBC Count (absolute) MCH Lymphocytes Reticulocyte Count MCHC Monocytes Hemoglobin Eosinophils Hematocrit Basophils Clinical Chemistry BUN Potassium AST (SGOT) Total and direct bilirubin Creatinine Chloride ALT (SGPT) Uric Acid Glucose Total CO2 GGT Albumin Sodium Calcium Alkaline phosphatase Total Protein Routine Urinalysis Specific gravity pH, glucose, protein, blood and ketones by dipstick Microscopic examination (if blood or protein is abnormal) Other screening tests HIV Hepatitis B (HBsAg) Hepatitis C (Hep C antibody -- if second generation Hepatitis C antibody positive, a hepatitis C antibody Chiron RIBA immunoblot assay should be reflexively performed on the same sample to confirm the result) FSH and estradiol (as needed in women of non-child bearing potential only)

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Alcohol and drug screen (to include at minimum: amphetamines, barbiturates, cocaine, opiates, cannabinoids and benzodiazepines). Quantiferon Tuberculosis blood sample if no chest X-ray completed within 6 months prior to screening. INR for AST & ALT.

6.3.11. Urine collection for detection of undeclared drugs

A urine sample for an undeclared drug screen will be collected and tested at the local laboratory at Screening and on entry to the Unit pre-dose (see SPM for details).

6.3.12. Alcohol test

A urine or an alcohol breath test will be collected and tested at the local lab at Screening and on entry to the Unit pre-dose (see SPM for details).

6.4. Pregnancy

6.4.1. Time period for collecting pregnancy information

All pregnancies in female subjects and/or female partners of male subjects will be collected after the start of dosing and until 15 weeks post-last dose].

6.4.2. Action to be taken if pregnancy occurs

The investigator will collect pregnancy information on any female subject, who becomes pregnant while participating in this study. The investigator will record pregnancy information on the appropriate form and submit it to GSK within 2 weeks of learning of a subject's pregnancy. The subject will also be followed to determine the outcome of the pregnancy. Information on the status of the mother and child will be forwarded to GSK. Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. Any premature termination of the pregnancy will be reported.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or elective termination of a pregnancy for medical reasons will be recorded as an AE or SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as such. Furthermore, any SAE occurring as a result of a post-study pregnancy and is considered reasonably related to the study treatment by the investigator, will be reported to GSK as described in Section 11. While the investigator is not obligated to actively seek this information in former study participants, he or she may learn of an SAE through spontaneous reporting.

Any female subject who becomes pregnant while participating will be withdrawn from the study.

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6.4.3. Action to be taken if pregnancy occurs in a female partner of a male study subject

The investigator will attempt to collect pregnancy information on any female partner of a male study subject who becomes pregnant while participating in this study. The investigator will record pregnancy information on the appropriate form and submit it to GSK within 2 weeks of learning of the partner’s pregnancy. The partner will also be followed to determine the outcome of the pregnancy. Information on the status of the mother and child will be forwarded to GSK. Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. Any premature termination of the pregnancy will be reported.

6.5. Pharmacokinetics

6.5.1. Blood Sample Collection

Blood samples for pharmacokinetic analysis of GSK1223249 and anti-GSK1223249 antibodies will be collected at the time points indicated in Section 3.7, Time and Events Table. The actual date and time of each blood sample collection will be recorded. The timing of PK samples may be altered and/or PK samples may be obtained at additional time points to ensure thorough PK monitoring.

Details of PK blood sample collection (including volume to be collected), processing, storage and shipping procedures are provided in the Study Procedures Manual (SPM).

6.5.2. CSF Sample Collection

CSF samples for pharmacokinetic analysis of GSK1223249 will be collected at the time points indicated in Section 3.7, Time and Events Table. The actual date and time each CSF sample collections will be recorded. The timing of PK samples may be altered.

Details of CSF sample collection (including volume to be collected), processing, storage and shipping procedures are provided in the Study Procedures Manual (SPM).

6.5.3. Sample Analysis

Plasma and CSF analysis will be performed under the management of Worldwide Bioanalysis, DMPK, GlaxoSmithKline. Concentrations of GSK1223249 will be determined in the samples using the currently approved analytical methodology. Raw data will be stored in the GLP Archives, GlaxoSmithKline. Once the plasma and CSF has been analyzed for GSK1223249 any remaining samples may be analyzed qualitatively for other circulating metabolites and the results reported under a separate DMPK protocol.

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6.5.4. Anti-GSK1223249 antibody levels

Blood samples for determination of anti-GSK1223249 antibodies will be taken at the time-points specified in the Time and Events Schedule (Section 3.7). For further instructions on the collection and handling of samples refer to the SPM. Samples will be analysed for the presence of anti-GSK1223249 antibodies with a validated ECL screening assay. If sera contain anti- GSK1223249 antibodies, they will further analysed for specificity and titre. The incidence of anti-GSK1223249 antibodies will then be summarised by dose cohort and by treatment group.

6.5.5. Biomarkers

Plasma and CSF samples will also be used to detect biomarkers of interest to both the mechanism of action of GSK1223249 and also to Multiple Sclerosis disease mechanisms. These may include, but are not limited to

a. Nogo-A

b. Inflammatory cytokines

c. Other soluble factors related to MS

7. LIFESTYLE AND/OR DIETARY RESTRICTIONS

7.1. Contraception Requirements

7.1.1. Female Subjects

Female subjects of childbearing potential must not become pregnant and so must be sexually inactive by abstinence or use contraceptive methods with a failure rate of < 1%.

Abstinence

Sexual inactivity by abstinence must be consistent with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.

Contraceptive Methods with a Failure Rate of < 1%

• Oral contraceptive, either combined or progestogen alone

• Injectable progestogen

• Implants of levonorgestrel

• Estrogenic vaginal ring

• Percutaneous contraceptive patches

• Intrauterine device (IUD) or intrauterine system (IUS) that meets the <1% failure rate as stated in the product label

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• Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study, and this male is the sole partner for that subject. For this definition, “documented” refers to the outcome of the investigator's/designee’s medical examination of the subject or review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject’s medical records.

• Double barrier method: condom and occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent (foam/gel/film/cream/suppository)

These allowed methods of contraception are only effective when used consistently, correctly and in accordance with the product label. The investigator is responsible for ensuring subjects understand how to properly use these methods of contraception.

7.1.2. Male Subjects

Male subjects with female partners of child-bearing potential must use one of the following contraceptive methods after the first dose of study treatment and until at least 6 months have elapsed since the last dose of study medication:

• Condom plus partner use of a highly effective contraceptive such as occlusive cap (diaphragm or cervical/vault cap) plus spermicidal agent (foam/gel/film/cream/suppository), oral contraceptive, injectable progesterone, implant of etonogestrel or levonorgestrel, estrogenic vaginal ring, percutaneous contraceptive patches, or intrauterine device. OR

• Abstinence, defined as sexual inactivity consistent with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception

7.2. Meals and Dietary Restrictions

7.2.1. Caffeine, Alcohol, and Tobacco

• During each visit, subjects will abstain from ingesting caffeine- or xanthine-containing products (e.g. coffee, tea, cola drinks, chocolate) for 24 hours prior to the start of dosing/visit until collection of the final pharmacokinetic and or pharmacodynamic sample during each session/visit.

• During each visit, subjects will abstain from alcohol for 24 hours prior to the start of dosing/visit until collection of the final pharmacokinetic and or pharmacodynamic sample during each visit.

• Subjects who use tobacco products will be instructed that use of nicotine-containing products (including nicotine patches) will not be permitted while they are in the Clinical Unit.

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7.3. Activity

Subjects will abstain from strenuous exercise for 48 hours prior to each blood collection for clinical laboratory tests. Subjects may participate in light recreational activities during studies (e.g., watch television, read).

8. CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES

8.1. Permitted Medications

Paracetamol/Acetaminophen, at doses of ≤ 2 grams/day is permitted. Other concomitant medication may be considered on a case by case basis by the GSK Medical Monitor.

IV methylprednisolone can be administered for treatment of relapse if deemed necessary by the investigator.

Other medications for the treatment of MS symptoms may be permitted, as long as they do not fall into the category of medicines referred to in Section 8.2. If the investigator is in any doubt about whether a concomitant medication is allowed during the study he/she should discuss it with the GSK medical monitor.

8.2. Prohibited Medications

Subjects must not use any disease modifying agents for the treatment of relapsing forms of MS, other than those permitted in the Inclusion Criteria, Section 4.3.1.

Excluded medications include cyclosporine, azathioprine, methotrexate, cladribine, fingolimod (Gilenya) natalizumab (Tysabri) or other monoclonal antibodies, mitoxanthrone, murine protein, T-cell vaccination, plasmapheresis, IV IgG, stem cell transplantation.

Subjects must abstain from taking prescription or non-prescription drugs (including vitamins and dietary or herbal supplements), within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication until completion of the follow-up visit, unless in the opinion of the Investigator and sponsor the medication will not interfere with the study.

8.3. Non-Drug Therapies

Subjects must abstain from taking any vitamins, herbal and dietary supplements within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication until completion of the follow-up visit, unless in the opinion of the Investigator and sponsor the medication will not interfere with the study.

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9. COMPLETION OR EARLY WITHDRAWAL OF SUBJECTS

9.1. Subject Completion

A completed subject is one who has completed all phases of the study including the follow-up visit.

The end of the study is defined as the last subject’s last visit.

9.2. Subject Withdrawal Criteria

Refer to Section 3.5 for dose adjustment/stopping criteria based on safety/PK criteria.

A subject may withdraw from study treatment at any time at his/her own request, or may be withdrawn at any time at the discretion of the investigator for safety, behavioral or administrative reasons.

Subject withdrawal from the study may be due to, but not limited to the following reasons.

• Subject voluntarily discontinues participation in the study at any time (consent withdrawn).

• The investigator at his/her discretion discontinues a subject from participation in the study at any time.

• The Sponsor at their discretion discontinues a subject from participation in the study at any time.

• A clinically significant serious adverse event (SAE) as described in Section 11, and deemed possibly related to study drug. In the event that a subject is prematurely discontinued from the study at any time due to an SAE, the SAE reporting procedures stated in Section 11.7 and Section 11.8 must be followed.

• Elevated ALT and/or bilirubin values as described in Section 12.

• The subject significantly deviates from the protocol. Prior to withdrawing a subject due to a protocol deviation, contact the GSK study manager or GSK medical monitor.

• The subject is lost to follow-up.

• A female subject becomes pregnant.

• Treatment blind is broken by investigator or site.

• Permanent discontinuation or withdrawal of investigational product as described in Section 9.3.1.

Withdrawn subjects will not be replaced, and reasons for subject withdrawal from the study will be recorded on the eCRF.

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If a subject experiences a relapse during the study, they may continue in the study and at the investigators discretion, receive a 3-5 day course of IV methylprednisolone as described in Section 3.2.1.3. However, if the investigator decides that it is clinically warranted, the subject can be withdrawn from the study and treated as the investigator feels is appropriate.

9.3. Subject Withdrawal Procedures

9.3.1. Subject Withdrawal from Study Treatment

Subject withdrawal from investigational product will be defined as occurring when investigational product is discontinued for any reason during the Treatment phase. Withdrawal from investigational product can be either permanent or temporary.

If a subject is withdrawn from the treatment phase or prematurely discontinues from investigational product permanently, the subject will be considered to be withdrawn from the study (i.e., from the Treatment phase) and the investigator must make every effort to perform the assessments and procedures as described in Section 3.7 and Section 6.3

9.4. Treatment After the End of the Study

Subjects will not receive any additional treatment from GSK after completion of the study because other treatment options are available.

The investigator is responsible for ensuring that consideration has been given to the post-study care of the patient’s medical condition, whether or not GSK is providing specific post-study treatment.

9.5. Screen and Baseline Failures

Data for screen and baseline failures will be collected in source documentation at the site but will not be transmitted to GSK.

Re-screening of screen/baseline failure patients may be permitted after discussion and agreement between Investigator and the GSK medical monitor, based on clinical judgement and on a case-by-case basis, that it is considered safe to do so. Examples of where this may be appropriate could include (but is not limited to): a clinical laboratory parameter falling outside pre-defined thresholds/ranges, but is considered associated with a transient event, e.g. brief minor infection.

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10. STUDY TREATMENT

Study treatment dosage and administration details are listed in Section 3.3.

10.1. Blinding

This will be a single-blind study. However GSK personnel will be unblinded. Study site staff and subjects will be blinded to treatment assignment.

The investigator or treating physician may unblind a subject’s treatment assignment only in the case of an emergency, when knowledge of the study treatment is essential for the appropriate clinical management or welfare of the subject. Whenever possible, the investigator must first discuss options with the GSK Medical Monitor or appropriate GSK study personnel before unblinding the subject’s treatment assignment. If this is impractical, the investigator must notify GSK as soon as possible, but without revealing the treatment assignment of the unblinded subject, unless that information is important for the safety of subjects currently in the study. The date and reason for the unblinding must be recorded in the appropriate data collection tool.

GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the treatment assignment for any subject with an SAE. If the SAE requires that an expedited regulatory report be sent to one or more regulatory agencies, a copy of the report, identifying the subject’s treatment assignment, may be sent to clinical investigators in accordance with local regulations and/or GSK policy.

10.2. Packaging and Labelling

The contents of the label will be in accordance with all applicable regulatory requirements.

10.3. Preparation/Handling/Storage/Accountability

A description of the methods and materials required for GSK1223249 are provided in the SPM.

Investigational product must be dispensed or administered according to procedures described herein. Only subjects enrolled in the study may receive investigational product and in accord with this study protocol, if randomized to receive study treatment, and may only receive a single dose. Only authorized site staff may supply or administer investigational product. All investigational products must be stored in a secure (locked) area with access limited to the Investigator and authorized site staff. Investigational product is to be stored at 2 to 8°C, protected from light. Maintenance of a temperature log (manual or automated) is required.

The Investigator, institution, or the head of the medical institution (where applicable) is responsible for investigational product accountability, reconciliation, and record maintenance. The Investigator or the head of the medical institution (where applicable), or designated site staff (e.g., storage manager, where applicable) must maintain investigational product accountability records throughout the course of the study. The

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responsible person(s) will document the amount of investigational product received from and returned to GlaxoSmithKline and the amount administered to subjects. The accountability unit for this study will be the glass vials containing investigational product, shipped to the site. Discrepancies must be reconciled or resolved. Procedures for final disposition of unused investigational product are found in the SPM. Investigational product is not expected to pose occupational safety risk to site staff under normal conditions of use and administration. A Material Safety Data Sheet equivalent document describing occupational hazards and recommended handling precautions either will be provided to the Investigator, where this is required by local laws, or is available upon request from GlaxoSmithKline. However, precautions are to be taken to avoid direct skin contact, eye contact, and generating aerosols or mists. In the case of unintentional occupational exposure notify the monitor, Medical Monitor, and/or study manager.

10.4. Assessment of Compliance

When the individual dose for a subject is prepared from a bulk supply, the preparation of the dose will be confirmed by a second member of the study site staff.

When subjects are dosed at the study site, they will receive study treatment directly from the investigator or designee, under medical supervision. The date and time of each dose administered in the clinic will be recorded in the source documents. The dose of study treatment and study participant identification will be confirmed at the time of dosing by a member of the study site staff other than the person administering the study treatment. Treatment of Study Treatment Overdose

10.5. Treatment of Investigational Product Overdose

An overdose is defined as any dose greater than that specified in the randomization code for that subject. Any overdose must be reported to the GlaxoSmithKline Medical Monitor and documented in the Study File. The active study treatment is a monoclonal antibody; there is no pre-specified treatment for overdose. The Investigator will use clinical judgment to treat any overdose.

11. ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE)

The investigator or site staff is responsible for detecting, documenting and reporting events that meet the definition of an AE or SAE.

AEs will be collected from the start of study treatment and until the follow-up visit. Medical occurrences that begin prior to the start of study treatment but after obtaining informed consent may be recorded on the Medical History/Current Medical Conditions CRF.

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SAEs will be collected over the same time period as stated above for AEs. However, any SAEs assessed as related to study participation (e.g. study treatment, protocol-mandated procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant medication will be recorded from the time a subject consents to participate in the study up to and including any follow-up contact. All SAEs will be recorded and reported to GSK within 24 hours, as indicated in Section 11.7.

Investigators are not obligated to actively seek AEs or SAEs in former study participants. However, if the investigator learns of any SAE, including a death, at any time after a subject has been discharged from the study, and he/she considers the event reasonably related to the study treatment or study participation, the investigator would promptly notify GSK.

11.1. Definition of Adverse Events

An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

Note: An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product.

Events meeting the definition of an AE include:

• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety assessments (e.g., ECGs, radiological scans, vital signs measurements), including those that worsen from baseline, and felt to be clinically significant in the medical and scientific judgement of the investigator.

• Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or intensity of the condition.

• New conditions detected or diagnosed after study treatment administration even though it may have been present prior to the start of the study.

• Signs, symptoms, or the clinical sequelae of a suspected interaction.

• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment or a concomitant medication (overdose per se will not be reported as an AE/SAE).

• "Lack of efficacy" or "failure of expected pharmacological action" per se will not be reported as an AE or SAE. However, the signs and symptoms and/or clinical sequelae resulting from lack of efficacy will be reported if they fulfil the definition of an AE or SAE.

Events that do not meet the definition of an AE include:

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• Any clinically significant abnormal laboratory findings or other abnormal safety assessments that are associated with the underlying disease, unless judged by the investigator to be more severe than expected for the subject’s condition.

• The disease/disorder being studied, or expected progression, signs, or symptoms of the disease/disorder being studied, unless more severe than expected for the subject’s condition. In particular, a single cluster of MS relapse-related signs and symptoms will not be recorded as an AE and will simply be recorded as a relapse, with the clinical details recorded as part of the neurologic examination, along with a re-evaluation of the EDSS score. However, if subject relapses are judged by the Investigator as being atypically severe or unusual in recurrence during the study period, the relapse(s) will be reported as an AE(s).

• Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads to the procedure is an AE.

• Situations where an untoward medical occurrence did not occur (social and/or convenience admission to a hospital).

• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the study that do not worsen.

11.2. Definition of Serious Adverse Events

If an event is not an AE per Section 11.1, then it cannot be an SAE even if serious conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to progression of disease, etc).

An SAE is any untoward medical occurrence that, at any dose:

d. Results in death

e. Is life-threatening

NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject was at risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it were more severe.

f. Requires hospitalization or prolongation of existing hospitalization

NOTE: In general, hospitalization signifies that the subject has been detained (usually involving at least an overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in the physician’s office or out-patient setting. Complications that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not considered an AE.

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g. Results in disability/incapacity, or

NOTE: The term disability means a substantial disruption of a person’s ability to conduct normal life functions. This definition is not intended to include experiences of relatively minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday life functions but do not constitute a substantial disruption.

h. Is a congenital anomaly/birth defect

i. Medical or scientific judgment should be exercised in deciding whether reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the subject or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. These should also be considered serious. Examples of such events are invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or development of drug dependency or drug abuse.

j. Is associated with liver injury and impaired liver function defined as:

• ALT ≥ 3xULN, and

• total bilirubin ≥ 2xULN or INR > 1.5.

NOTES: Bilirubin fractionation should be performed if testing is available. If fractionation is unavailable, urinary bilirubin is to be measured via dipstick (a measurement of direct bilirubin, which would suggest liver injury).

INR measurement is not required; if measured, the threshold value stated will not apply to patients receiving anticoagulants. If INR measurement is obtained, the value is to be recorded on the SAE form.

• Refer to Section 12 for the required liver chemistry follow-up instructions.

11.3. Method of Detecting AEs and SAEs

Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-leading verbal questioning of the subject is the preferred method to inquire about AE occurrence. Appropriate questions include:

• “How are you feeling?”

• “Have you had any (other) medical problems since your last visit/contact?”

• “Have you taken any new medicines, other than those provided in this study, since your last visit/contact?”

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11.4. Recording of AEs and SAEs

When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) relative to the event. The investigator will then record all relevant information regarding an AE/SAE in the appropriate data collection tool.

It is not acceptable for the investigator to send photocopies of the subject’s medical records to GSK in lieu of completion of the GSK, AE/SAE data collection tool. However, there may be instances when copies of medical records for certain cases are requested by GSK. In this instance, all subject identifiers, with the exception of the subject number, will be blinded on the copies of the medical records prior to submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or other clinical information. In such cases, the diagnosis will be documented as the AE/SAE and not the individual signs/symptoms.

11.5. Evaluating AEs and SAEs

11.5.1. Assessment of Intensity

The investigator will make an assessment of intensity for each AE and SAE reported during the study and will assign it to one of the following categories:

Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not interfering with everyday activities.

Moderate: An event that is sufficiently discomforting to interfere with normal everyday activities.

Severe: An event that prevents normal everyday activities.

An AE that is assessed as severe will not be confused with an SAE. Severity is a category utilized for rating the intensity of an event; and both AEs and SAEs can be assessed as severe. An event is defined as ‘serious’ when it meets at least one of the pre-defined outcomes as described in the definition of an SAE.

11.5.2. Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and the occurrence of each AE/SAE. A "reasonable possibility" is meant to convey that there are facts/evidence or arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. The investigator will use clinical judgment to determine the relationship. Alternative causes, such as natural history of the underlying diseases, concomitant therapy, other risk factors, and the temporal relationship of the event to the study treatment will be considered and investigated. The investigator will also consult the Investigator Brochure (IB) and/or Product Information, for marketed products, in the determination of his/her assessment.

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There may be situations when an SAE has occurred and the investigator has minimal information to include in the initial report to GSK. However, it is very important that the investigator always make an assessment of causality for every event prior to the initial transmission of the SAE data to GSK. The investigator may change his/her opinion of causality in light of follow-up information, amending the SAE data collection tool accordingly. The causality assessment is one of the criteria used when determining regulatory reporting requirements.

11.6. Follow-up of AEs and SAEs

After the initial AE/SAE report, the investigator is required to proactively follow each subject at subsequent visits/contacts. All AEs and SAEs will be followed until resolution, until the condition stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up.

The investigator is obligated to perform or arrange for the conduct of supplemental measurements and/or evaluations as may be indicated or as requested by GSK to elucidate as fully as possible the nature and/or causality of the AE or SAE. The investigator is obligated to assist. This may include additional laboratory tests or investigations, histopathological examinations or consultation with other health care professionals. If a subject dies during participation in the study or during a recognized follow-up period, the investigator will provide GSK with a copy of any post-mortem findings, including histopathology.

New or updated information will be recorded in the originally completed data collection tool. The investigator will submit any updated SAE data to GSK within the designated reporting time frames.

11.7. Prompt Reporting of SAEs to GSK

Once the investigator determines that an event meets the protocol definition of an SAE, the SAE will be reported to GSK within 24 hours. Any follow-up information on a previously reported SAE will also be reported to GSK within 24 hours.

If the investigator does not have all information regarding an SAE, he/she will not wait to receive additional information before notifying GSK of the event and completing the appropriate data collection tool. The investigator will always provide an assessment of causality at the time of the initial report as described in Section 11.5.2, Assessment of Causality.

The primary mechanism for reporting SAEs to GSK will be the electronic data collection tool (e.g., InForm system). If the electronic system is unavailable for greater than 24 hours, the site will use the paper SAE data collection tool and fax it to the GSK Medical Monitor. Then the site will enter the serious adverse event data into the electronic system as soon as it becomes available.

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After the study is completed at a given site, the electronic data collection tool (e.g., InForm system) will be taken off-line to prevent the entry of new data or changes to existing data. If a site receives a report of a new SAE from a study participant or receives updated data on a previously reported SAE after the electronic data collection tool has been taken off-line, the site can report this information on a paper SAE form or to their GSK protocol contact by telephone.

GSK contacts for SAE receipt can be found at the beginning of this protocol on the Sponsor/Medical Monitor Contact Information page.

11.8. Regulatory Reporting Requirements For SAEs

Prompt notification of SAEs by the investigator to GSK is essential so that legal obligations and ethical responsibilities towards the safety of subjects are met.

GSK has a legal responsibility to notify both the local regulatory authority and other regulatory agencies about the safety of a product under clinical investigation. GSK will comply with country specific regulatory requirements relating to safety reporting to regulatory authorities, IRBs/IECs and investigators.

Investigator safety reports are prepared for suspected unexpected serious adverse reactions according to local regulatory requirements and GSK policy and are forwarded to investigators as necessary. An investigator who receives an investigator safety report describing an SAE(s) or other specific safety information (e.g., summary or listing of SAEs) from GSK will file it with the IB and will notify the IRB/IEC, if appropriate according to local requirements.

12. LIVER CHEMISTRY FOLLOW-UP PROCEDURES

Refer to the diagram in Appendix 1 for a visual presentation of the procedures listed below.

The procedures listed below are to be followed if a subject meets the liver chemistry stopping criteria defined in. Appendix 1:

• Immediately and permanently withdraw the subject from study treatment

• Notify the GSK medical monitor within 24 hours of learning of the abnormality to confirm the subject’s study treatment cessation and follow-up.

• Complete the “Safety Follow-Up Procedures” listed below.

• Complete the liver event case report forms. If the event also meets the criteria of an SAE (see Section 11.2), the SAE data collection tool will be completed separately with the relevant details.

• Upon completion of the safety follow-up permanently withdraw the subject from the study and do not rechallenge with study treatment.

Safety Follow-Up Procedures for subjects with ALT ≥ 3xULN:

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• Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) resolve, stabilize or return to within baseline values.

Safety Follow-Up Procedures for subjects with ALT ≥3xULN and bilirubin ≥2xULN (or ALT ≥ 3xULN and INR1 > 1.5):

• This event is considered an SAE (see Section 11.2). Serum bilirubin fractionation should be performed if testing is available. If fractionation is unavailable, urinary bilirubin is to be measured via dipstick (a measurement of direct bilirubin, which would suggest liver injury).

• Make every reasonable attempt to have subjects return to the clinic within 24 hours for repeat liver chemistries, additional testing, and close monitoring (with specialist or hepatology consultation recommended).

• Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) resolve, stabilize or return to within baseline values.

In addition, for all subjects with ALT ≥ 3xULN, every attempt must be made to also obtain the following:

• Viral hepatitis serology including:

• Hepatitis A IgM antibody.

• Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM).

• Hepatitis C RNA.

• Cytomegalovirus IgM antibody.

• Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody or monospot testing).

• Hepatitis E IgM antibody.

• Blood sample for pharmacokinetic (PK) analysis, obtained within [insert time interval recommended by Clinical pharmacokinetics representative] of last dose. Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best approximation. If the date/time of the last dose can not be approximated OR a PK sample can not be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are included in the SPM.

• Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).

• Fractionate bilirubin, if total bilirubin ≥ 2xULN.

• Assess eosinophilia

1. 1 INR testing not required per protocol and the threshold value does not apply to subjects receiving

anticoagulants.

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• Record the appearance or worsening of clinical symptoms of hepatitis (fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia) on the AE CRF.

• Record use of concomitant medications, acetaminophen, herbal remedies, other over the counter medications, or putative hepatotoxins on the Concomitant Medications CRF.

• Record alcohol use on the Liver Events CRF.

The following are required for subjects with ALT ≥ 3xULN and bilirubin ≥ 2xULN but are optional for other abnormal liver chemistries:

• Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney microsomal antibodies.

• Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to evaluate liver disease.

• The Liver Imaging and/or Liver Biopsy CRFs are also to be completed if these tests are performed.

13. STUDY CONDUCT CONSIDERATIONS

13.1. Posting of Information on Clinicaltrials.gov

Study information from this protocol will be posted on clinicaltrials.gov before enrollment of subjects begins.

13.2. Regulatory and Ethical Considerations, Including the Informed Consent Process

GSK will obtain favorable opinion/approval to conduct the study from the appropriate regulatory agency in accordance with any applicable country-specific regulatory requirements prior to a site initiating the study in that country.

The study will be conducted in accordance with all applicable regulatory requirements.

The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), all applicable subject privacy requirements, and, the guiding principles of the 2008 Declaration of Helsinki. This includes, but is not limited to, the following:

• IRB/IEC review and favorable opinion/approval to conduct the study and of any subsequent relevant amended documents

• Written informed consent (and any amendments) to be obtained for each subject before participation in the study

• Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations to IRB/IEC)

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13.2.1. Urgent Safety Measures

If an event occurs that is related to the conduct of the study or the development of the study treatment, and this new event is likely to affect the safety of subjects, the sponsor and the investigator will take appropriate urgent safety measures to protect subjects against any immediate hazard.

The sponsor will work with the investigator to ensure the IEC/IRB is notified.

13.3. Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, GSK monitors will contact the site prior to the start of the study to review with the site staff the protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and GSK requirements. When reviewing data collection procedures, the discussion will also include identification, agreement and documentation of data items for which the eCRF will serve as the source document.

GSK will monitor the study and site activity to verify that the:

• Data are authentic, accurate, and complete.

• Safety and rights of subjects are being protected.

• Study is conducted in accordance with the currently approved protocol and any other study agreements, GCP, and all applicable regulatory requirements.

The investigator and the head of the medical institution (where applicable) agrees to allow the monitor direct access to all relevant documents

13.4. Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK may conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory inspection of this study. Such audits/inspections can occur at any time during or after completion of the study. If an audit or inspection occurs, the investigator and institution agree to allow the auditor/inspector direct access to all relevant documents and to allocate his/her time and the time of his/her staff to the auditor/inspector to discuss findings and any relevant issues.

13.5. Study and Site Closure

Upon completion or premature discontinuation of the study, the monitor will conduct site closure activities with the investigator or site staff, as appropriate, in accordance with applicable regulations including GCP, and GSK procedures.

In addition, GSK reserves the right to temporarily suspend or prematurely discontinue this study at any time for reasons including, but not limited to, safety or ethical issues or severe non-compliance. For multicenter studies, this can occur at one or more or at all sites. If GSK determines such action is needed, GSK will discuss this with the

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investigator or the head of the medical institution (where applicable), including the reasons for taking such action. When feasible, GSK will provide advance notification to the investigator or the head of the medical institution, where applicable, of the impending action prior to it taking effect.

If the study is suspended or prematurely discontinued for safety reasons, GSK will promptly inform investigators or the head of the medical institution (where applicable) and the regulatory authorities of the suspension or premature discontinuation of the study and the reason(s) for the action. If required by applicable regulations, the investigator or the head of the medical institution (where applicable) must inform the IRB/IEC promptly and provide the reason for the suspension or premature discontinuation.

13.6. Records Retention

Following closure of the study, the investigator or the head of the medical institution (where applicable) must maintain all site study records, except for those required by local regulations to be maintained by someone else, in a safe and secure location. The records must be maintained to allow easy and timely retrieval, when needed (e.g., audit or inspection), and, whenever feasible, to allow any subsequent review of data in conjunction with assessment of the facility, supporting systems, and staff. Where permitted by local laws/regulations or institutional policy, some or all of these records can be maintained in a format other than hard copy (e.g., microfiche, scanned, electronic); however, caution needs to be exercised before such action is taken. The investigator must assure that all reproductions are legible and are a true and accurate copy of the original, and meet accessibility and retrieval standards, including re-generating a hard copy, if required. Furthermore, the investigator must ensure there is an acceptable back-up of these reproductions and that an acceptable quality control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to comply with all applicable regulatory requirements. The minimum retention time will meet the strictest standard applicable to that site for the study, as dictated by any institutional requirements or local laws or regulations, or GSK standards/procedures; otherwise, the retention period will default to 15 years.

The investigator must notify GSK of any changes in the archival arrangements, including, but not limited to, archival at an off-site facility or transfer of ownership of the records in the event the investigator leaves the site.

13.7. Provision of Study Results to Investigators, Posting to the Clinical Trials Register and Publication

Where required by applicable regulatory requirements, an investigator signatory will be identified for the approval of the clinical study report. The investigator will be provided reasonable access to statistical tables, figures, and relevant reports and will have the opportunity to review the complete study results at a GSK site or other mutually-agreeable location.

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GSK will also provide the investigator with the full summary of the study results. The investigator is encouraged to share the summary results with the study subjects, as appropriate.

GSK will provide the investigator with the randomization codes for their site only after completion of the full statistical analysis.

The results summary will be posted to the Clinical Study Register at the time of the first regulatory approval or within 12 months of any decision to terminate development. In addition, a manuscript will be submitted to a peer reviewed journal for publication no later than 12 months after the first approval or any decision to terminate development. When manuscript publication in a peer reviewed journal is not feasible, further study information will be posted to the GSK Clinical Study Register to supplement the results summary.

13.8. Data Management

GSK Data Management will identify and implement the most effective data acquisition and management strategy for each clinical trial protocol and deliver datasets which support the protocol objectives. Subject data will be entered into GSK defined CRFs and combined with data provided from other sources (e.g. diary data, laboratory data) in a validated data system. Subject initials will not be transmitted to GSK for inclusion in the datasets. Clinical data management will be performed in accordance with applicable GSK standards and data cleaning procedures with the objective of removing errors and inconsistencies in the data which would otherwise impact on the analysis and reporting objectives, or the credibility of the Clinical Study Report. Adverse events and concomitant medications terms will be coded using validated dictionaries. Original CRFs will be retained by GSK, while the investigator will retain a copy.

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GrandPre T, Nakamura F, Vartanian T, and Strittmatter SM. Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein. Nature. 2000; 403:439-444.

GSK1223249 Investigator's Brochure. GlaxoSmithKline document number: AM2010/00015/00. 10th June, 2010.

Jeffery DR, Chepuri N, Durden D, Burdette J. A pilot trial of combination therapy with Mitoxantrone and interferon beta-1b using monthly gadolinium-enhanced magnetic resonance imaging. Mult Scler. 2005; 11:296-301.

Karnezis T, Mandemakers W, McQualter JL, Zheng B, Ho PP, Jordan KA, Murray BM, Barres B,Tessier-Lavigne M, and Bernard CC. The neurite outgrowth inhibitor Nogo A is involved in autoimmune-mediated demyelination. Nat. Neurosci. 2004; 7:736-744.

Kuhlmann T, Remington L, Maraschak B, Owens T and Bruck W. Nogo-A is a relaiable oligodendroglial marker in adult human and mouse CNS and in demyelinated lesions. J Neurpathol Exp Neurol 2007;66:238-246.

Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33:1444–1452.

Lenz H-J. Mangement and preparedness for infusion and hypersensitivity reactions. The Oncologist. 2007;12:601-609.

McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, McFarland HF, Paty DW, Polman CH, Reingold SC, Sandberg-Wollheim M, Sibley W, Thompson A, van den Noort S, Weinshenker BY, Wolinsky JS. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol. 2001;50:121-127.

Petereit HF, Rubbert-Roth A. Rituximab levels in cerebrospinal fluid of patients with neurological autoimmune disorders. Multiple Sclerosis 2009; 15:189-192.

Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, Lublin FD, Metz LM, McFarland HF, O'Connor PW, Sandberg-Wollheim M, Thompson AJ, Weinshenker BG, Wolinsky JS. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “MacDonald Criteria”. Ann Neurol. 2005;58:840-846.

Prinjha R, Moore SE, Vinson M, Blake S, Morrow R, Chirstie G, Michalovich D, Simmons DL and Walsh FS. Inhibitor of neurite outgrowth in humans. Nature 2000;403:383-384.

Reiber H, Teut M, Pohl D, Rostasy KM, Hanefeld F. Paediatric and adult multiple sclerosis: age-related differences and time course of the neuroimmunological response in cerebrospinal fluid. Mult Scler. 2009;15:1466-1480.

Satoh J-I, Onoue H, Arima K and Yamamura T. Nogo-A and Nogo receptor expression in demyelinating lesions of multiple sclerosis. J Neuropathol Exp Neurol. 2005; 64:129-138.

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Schmierer K, Scaravilli F, Altmann DR, Barker GJ, Miller DH. Magnetization transfer ratio and myelin in postmortem multiple sclerosis brain. Ann Neurol. 2004;56:407-415.

Sheiner LB, Stanski DR, Vozeh S, Miller RD, Ham J. Simultaneous modeling of pharmacokinetics and pharmacodynamics: application to d-tubocurarine. Clin Pharmacol Ther. 1979; 25:358-371.

Stemmler HJ, Schmitt M, Willems A, Bernhard H, Harbeck N, Heinemann V. Ratio of trastuzumab levels in serum and cerebrospinal fluid is altered in HER2-positive breast cancer patients with brain metastases and impairment of blood-brain barrier. Anticancer Drugs. 2007;18:23-28.

Anti-NOGO 2A10: Investigation of the iv pharmacokinetics (3 mg/kg) in the male rat. 2004. GlaxoSmithKline document (Neurology CEDD DMPK/04/080-1).

Yang Y, Liu Y, Wei P, Peng H, Winger R, Hussain RZ, Ben LH, Cravens PD, Gocke AR, Puttaparthi K, Racke MK, McTigue DM, Lovett-Racke AE. Silencing Nogo-A promotes functional recovery in demyelinating disease. Ann Neurol. 2010;67:498-507.

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Appendices

Appendix 1: Liver Safety Algorithms

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Appendix 2: Dose Escalation Committee (DEC)

An unblinded DEC will convene to review key safety and available PK/MRI data before recommending escalation to the next dosing cohort after the last subject within a cohort has completed the Day 36 visit (6 days after second dose), and in addition, half the patients have completed Day 64 visit.

Full details of the data to be reviewed will be detailed in the RAP.

DEC Core Members Line Function Representative

GSK Medical Monitor

Independenta External MS Expert

Clinical Pharmacology Science and Study Operations

Global Clinical Safety and Pharmacovigilance (GCSP)

Statistician

Clinical Pharmacology Modelling & Simulation a’Independent’ is defined as an expert who is external to GSK.

Voting members will include the following individuals: a GCSP physician who supports the Nogo-A program, an independent external MS expert, and a GSK Medical Monitor.

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Appendix 3: Protocol Amendment Changes

AMENDMENT 2

Where the amendment applies

This protocol amendment applies globally, to all study sites participating in the clinical trial.

Summary of Amendment Changes with Rationale

This amendment incorporates the requirement from the French regulatory authority (AFSSAPS) to change the uncorrected QT withdrawal criteria from >600ms to >500ms. This amendment also contains typographical corrections, in addition to clarification of when which type of physical exam (either brief or full) should be performed during the trial.

List of Specific Changes

Section 3.1 Non Dosing Days

PREVIOUS TEXT

D7-D8, D13-D14, D37-D38, D42-D43, D64-D65, D70-D71, D85-D86 and D127 will involve safety and exploratory assessments (see Section 3.7 for details on timings), and for cohorts 2 and 3 may involve a lumbar puncture. An overnight stay may be involved, if in the investigators opinion, this is warranted, but is not strictly necessary.

REVISED TEXT

D7-D8, D13-D14, D36, D42, D64, D70, D85 and D127 will involve safety and exploratory assessments (see Section 3.7 for details on timings), and for cohorts 2 and 3 may involve a lumbar puncture. An overnight stay may be involved, if in the investigators opinion, this is warranted, but is not strictly necessary.

Section 3.6.2 QTc withdrawal criteria PREVIOUS TEXT

• QTcB or QTcF > 500 msec or uncorrected QT > 600 msec (machine or manual over-read)

REVIED TEXT

• QT (machine or manual over-read), QTcB or QTcF > 500msec

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Section 3.7 Table 5 PREVIOUS TEXT

Procedure


Day 7

Day 13

6 weeks prior to

dose ± 2 days

7 ± 2 days

prior to dose

Pre-dose 0h

0.5h

1h

2h

3h

6h

12h

18h

24h

In Patient Stay =========================X====================== Outpatient Visit X X X X Administration of Study drug X Medical History X Height X Hepatitis C Ab, HBsAg X Pregnancy Testinga X X X Cranial MRI ±Gd-contrast X X X Physical Examination X X

Neurological exam & symptom monitoring, EDSS X X X X

Body Weight X X X Urine Drug / Alcohol Screen X X Safety Labs X X Xf X X Vital Signs X X X X X X X X 12-Lead ECG X X X Xc Xc Xc Xc X X Randomisation X Blood sample for PK X X X X X X X Blood sample for Immunogenicity X Plasma sample for X X

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Procedure


Day 7

Day 13

6 weeks prior to

dose ± 2 days

7 ± 2 days

prior to dose

Pre-dose 0h

0.5h

1h

2h

3h

6h

12h

18h

24h

biomarkers Continuous ECG monitoring ===========================X======================= C-SSRS X d X e X e X e Lumbar Puncture X b Adverse Event Monitoring From Day 1 to completion of follow-up visit Concomitant Medication From screening to completion of follow-up visit a. Females only. Serum pregnancy testing at Screening, urine pregnancy testing for all other visits. b. Patients will receive 1 lumbar puncture only. Timings of lumbar punctures for cohort 2 are specified in Table 3, Section 3.2.1.5. Timings for cohort 3 will be determined based on

emergent CSF PK data from cohort 2. c. Performed in triplicate d. Baseline version e. Since last visit version f. Results not required prior to dosing unless baseline sample results outside normal range, or warranted in Investigator’s opinion.

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REVISED TEXT

Procedure


Day 7

Day 13

6 weeks prior to

dose ± 2 days

7 ± 2 days

prior to dose

Pre-dose 0h

0.5h

1h

2h

3h

6h

12h

18h

24h

In Patient Stay =========================X====================== Outpatient Visit X X X X Administration of Study drug X Medical History X Height X Hepatitis C Ab, HBsAg X Pregnancy Testinga X X X Cranial MRI ±Gd-contrast X X X Physical Examination Xg Xh

Neurological exam & symptom monitoring, EDSS X X X X

Body Weight X X X Urine Drug / Alcohol Screen X X Safety Labs X X Xf X X Vital Signs X X X X X X X X 12-Lead ECG X X X Xc Xc Xc Xc X X Randomisation X Blood sample for PK X X X X X X X Blood sample for Immunogenicity X Plasma sample for biomarkers X X

Continuous ECG monitoring ===========================X=======================

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Procedure


Day 7

Day 13

6 weeks prior to

dose ± 2 days

7 ± 2 days

prior to dose

Pre-dose 0h

0.5h

1h

2h

3h

6h

12h

18h

24h

C-SSRS X d X e X e X e Lumbar Puncture X b Adverse Event Monitoring From Day 1 to completion of follow-up visit Concomitant Medication From screening to completion of follow-up visit a. Females only. Serum pregnancy testing at Screening, urine pregnancy testing for all other visits. b. Patients will receive 1 lumbar puncture only. Timings of lumbar punctures for cohort 2 are specified in Table 3, Section 3.2.1.5. Timings for cohort 3 will be determined based on

emergent CSF PK data from cohort 2. c. Performed in triplicate d. Baseline version e. Since last visit version f. Results not required prior to dosing unless baseline sample results outside normal range, or warranted in Investigator’s opinion. g. Full physical exam h. Brief physical exam

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Section 3.7 Table 8

PREVIOUS TEXT

Procedure Day 169 ± 4 days Day 197 ± 4 days d Pregnancy Testinga X X Cranial MRI ±Gd-contrast X X Physical Examination X X

Neurological exam & symptom monitoring X X Body Weight X X Urine Drug / Alcohol Screen X X Urinalysis X X Blood Chemistry X X Haematology X X Vital Signs X X 12-Lead ECG X X Concomitant Medication X X Blood Sample for PK X X Blood sample for Immunogenicity Xb Plasma sample for biomarkers X X C-SSRS c X X Adverse Event Monitoring X X a. Females only. Urine pregnancy testing sufficient. b. Timing of sample may be changed based on GSK1223249 PK profile in plasma and upper threshold for quantification established for this assay. c. Since last visit version d. This visit is an “as needed” visit, the necessity for which will be determined at DEC meetings.

REVISED TEXT

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Procedure Day 169 ± 4 days Day 197 ± 4 days d Pregnancy Testinga X X Cranial MRI ±Gd-contrast X X Physical Examination Xe Xf

Neurological exam & symptom monitoring X X Body Weight X X Urine Drug / Alcohol Screen X X Urinalysis X X Blood Chemistry X X Haematology X X Vital Signs X X 12-Lead ECG X X Concomitant Medication X X Blood Sample for PK X X Blood sample for Immunogenicity X Xb Plasma sample for biomarkers X X C-SSRS c X X Adverse Event Monitoring X X a. Females only. Urine pregnancy testing sufficient. b. Timing of sample may be changed based on GSK1223249 PK profile in plasma and upper threshold for quantification established for this assay. c. Since last visit version d. This visit is an “as needed” visit, the necessity for which will be determined at DEC meetings. e. Full physical exam f. Brief physical exam

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Section

Section 6.3.6 ECG

PREVIOUS TEXT

Supine 12-lead ECGs will be made after the subject has been resting supine (lying flat with maximum one pillow) for a period of at least 5 minutes. Screening, Baseline and pre-dose 12-lead ECG readings will be averaged and the mean taken as the baseline measurement for post-dose comparisons. The same digital ECG machine will be used across sites. Machine generated readings for heart rate and PR, QRS, QT, RR, and QTc intervals will be printed and read in real time at each site. The paper tracings must be retained in the source documents for each subject. The ECG assessment date and time will be recorded in the electronic CRF. In addition, all ECGs will be transmitted to a central ECG facility for formal interpretation and the data returned within 72 h to the site.

REVISED TEXT

Supine 12-lead ECGs will be made after the subject has been resting supine (lying flat with maximum one pillow) for a period of at least 5 minutes. Screening, Baseline and pre-dose 12-lead ECG readings will be averaged and the mean taken as the baseline measurement for post-dose comparisons. The same digital ECG machine will be used across sites. Machine generated readings for heart rate and PR, QRS, QT, RR, and QTc intervals will be printed and read in real time at each site. The paper tracings must be retained in the source documents for each subject. The ECG assessment date time, and metrics values will be recorded in the electronic CRF. In addition, all ECGs will be transmitted to a central ECG facility for formal interpretation and the data returned within 72 h to the site.

Section 1.6.3 Risks associated with MRI

PREVIOUS TEXT

Each subject is required to undergo a maximum of 7 MRI scans over the course of this study The risks associated with MRI per se are low, provided subjects have no contraindications (see Section 4.3.2). The risk associated with administration of Gd-containing contrast agents is also low, provided subjects do not have underlying renal dysfunction, hence the exclusionary limits for creatinine clearance. MRI does not involve the use of ionizing radiation, but the risks to the unborn fetus are unknown and therefore pregnant women are not eligible to participate in this study. Frequent MRI has been increasingly used as a surrogate endpoint in clinical trials for MS; MRI scan sequences including monthly dosing and double or even triple doses of Gd-containing contrast agents have been used in protocols up to two years in length [Jeffery, 2005].

REVISED TEXT

Each subject is required to undergo a maximum of 8 MRI scans over the course of this study The risks associated with MRI per se are low, provided subjects have no contraindications (see Section 4.3.2). The risk associated with administration of Gd-

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containing contrast agents is also low, provided subjects do not have underlying renal dysfunction, hence the exclusionary limits for creatinine clearance. MRI does not involve the use of ionizing radiation, but the risks to the unborn fetus are unknown and therefore pregnant women are not eligible to participate in this study. Frequent MRI has been increasingly used as a surrogate endpoint in clinical trials for MS; MRI scan sequences including monthly dosing and double or even triple doses of Gd-containing contrast agents have been used in protocols up to two years in length [Jeffery, 2005].

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AMENDMENT 1

Where the Amendment Applies

This protocol amendment applies globally, to all study sites participating in the clinical trial.

Summary of Amendment Changes with Rationale

This amendment incorporates the removal of orthostatic challenge when assessing Vital Signs, as well as the addition of a pre-dose blood sample for PK on the day of 3rd dose of study medication.

List of Specific Changes

Section 6.3.6 Safety Assessments, Vital Signs

PREVIOUS TEXT

Vital Signs

Heart rate and blood pressure (systolic and diastolic) measurements will be collected in the supine and standing positions at the timepoints described in the Time and Events Tables. The number of assessments may be adjusted depending upon the emerging safety profile in man and additional assessments may be added. Heart rate and blood pressure measurements will be made with automated monitors with the subject in two positions: supine - subjects must be lying flat with maximum of one pillow for at least 5 minutes prior to each reading

• standing – immediately after the subject has been standing for 1 minute


REVISED TEXT

Vital Signs

Heart rate and blood pressure (systolic and diastolic) measurements will be collected in the supine and standing positions sitting position at the time points described in the Time and Events Tables. The number of assessments may be adjusted depending upon the emerging safety profile in subjects and additional assessments may be added. Heart rate and blood pressure measurements will be made with automated monitors with the subject in two positions: supine - subjects must be lying flat with maximum of one pillow in the sitting position: subjects must be in a seated position with legs uncrossed, back & arm supported for at least 5 minutes prior to each reading.

• standing – immediately after the subject has been standing for 1 minute

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Section 1.3 sub-bullet e.

PREVIOUS TEXT

GSK1223249 delivered intravenously every week at 30mg/kg, is associated with decreased clinical and histopathologic scores in a myelin-oligodendrocyte-glycoprotein (MOG)-induced EAE non-human primate model of MS (CIB Section 3.2.1.2)

REVISED TEXT

GSK1223249 delivered intravenously every week at 30mg/kg, is associated with decreased clinical and histopathologic scores in a myelin-oligodendrocyte-glycoprotein (MOG)-induced EAE non-human primate model of MS (CIB Section 3.2.1.2) Doses of 3 and 0.3mg/kg delivered intravenously do not show decreased clinical and histopathologic scores (Supplement no. 2 to CIB; Section 3.2.1.2).

Section 3.1 - NON DOSING DAYS

PREVIOUS TEXT

D7-D8, D13-D14, D37-D38, D42-D43, D64-D65, D70-D71, D85-D86 and D127 will involve safety and exploratory assessments (see Section 3.7 for details on timings), and for cohorts 2 and 3 may involve a lumbar puncture, in which case an overnight stay will be involved.

REVISED TEXT

D7-D8, D13-D14, D37-D38, D42-D43, D64-D65, D70-D71, D85-D86 and D127 will involve safety and exploratory assessments (see Section 3.7 for details on timings), and for cohorts 2 and 3 may involve a lumbar puncture. An overnight stay may be involved, if in the investigators opinion, this is warranted, but is not strictly necessary.

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Section 3.7 Time & Events Tables

Table 7 – Addition of pre-dose Blood Sample for PK on Day 57.

PREVIOUS TEXT


64/65 ± 3

Day 70/71 ± 3

Day 85/86 ± 3

Day 127 ± 3

Pre-

dose

0h

1h

2h

3h

6h

12h

24h


Body Weight X X Urine Drug / Alcohol Screen X Safety Labs Xe X X X X Vital Signs X X X X X X X X X 12-Lead ECG X Xc Xc X X X X Concomitant Medication X Blood Sample for PK X X X X X X X X Blood sample for Immunogenicity X X Plasma sample for biomarkers X Continuous ECG monitoring =========================X======================== C-SSRS d X X X X X Lumbar Puncture Xb

Adverse Event Monitoring From Day 1 to completion of Follow-up Visit Concomitant Medication From Screening to completion of Follow-up Visit

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Table 7 – Addition of pre-dose Blood Sample for PK on Day 57 (Continued)

g. Females only. h. Patients will receive 1 lumbar puncture only. Timings of lumbar punctures for cohort 2 are specified in Table 3, Section 3.2.1.5. Timings for cohort 3 will be determined based on

emergent CSF PK data from cohort 2. i. Performed in triplicate. j. Since last visit version k. Results not required prior to dosing unless visit 8 (Day 42) sample results outside normal range, or warranted in Investigator’s opinion. REVISED TEXT


64/65 ± 3

Day 70/71 ± 3

Day 85/86 ± 3

Day 127 ± 3

Pre-

dose

0h

1h

2h

3h

6h

12h

24h


Body Weight X X Urine Drug / Alcohol Screen X Safety Labs Xe X X X X Vital Signs X X X X X X X X X 12-Lead ECG X Xc Xc X X X X Concomitant Medication X Blood Sample for PK X X X X X X X X X Blood sample for Immunogenicity X X Plasma sample for biomarkers X Continuous ECG monitoring =========================X======================== C-SSRS d X X X X X

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64/65 ± 3

Day 70/71 ± 3

Day 85/86 ± 3

Day 127 ± 3

Pre-

dose

0h

1h

2h

3h

6h

12h

24h

Lumbar Puncture Xb

Adverse Event Monitoring From Day 1 to completion of Follow-up Visit Concomitant Medication From Screening to completion of Follow-up Visit l. Females only. m. Patients will receive 1 lumbar puncture only. Timings of lumbar punctures for cohort 2 are specified in Table 3, Section 3.2.1.5. Timings for cohort 3 will be determined based on

emergent CSF PK data from cohort 2. n. Performed in triplicate. o. Since last visit version p. Results not required prior to dosing unless visit 8 (Day 42) sample results outside normal range, or warranted in Investigator’s opinion.

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CONFIDENTIAL The GlaxoSmithKline group of companies NGM114840

1

Division: World Wide Development Retention Category: GRS019 Information Type: Reporting and Analysis Plan Title: Reporting and Analysis Plan for NGM114840: A randomized,

single blind, placebo-controlled, single ascending dose/repeat dose cohort study to assess safety, tolerability, pharmacokinetics and immunogenicity of GSK1223249 in patients with relapsing forms of multiple sclerosis


Effective Date: 20-FEB-2012

Description: This document details the planned statistical outputs for the final reporting for study NGM114840.

Subject: MS, MRI, EDSS, monoclonal antibody,

Author’s Name, Title and Functional Area:

Manager, Statistics and Programming

Neurosciences Clinical Statistics, QSci

Clinical Pharmacology Modelling and Simulation

Discovery Medicine Unit, RDC

Approved by Email:

Manager, Statistics and Programming

20-FEB-2012

Copyright 2012 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited.

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CONFIDENTIAL NGM114840

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TABLE OF CONTENTS

PAGE

ABBREVIATIONS ............................................................................................................. 4

1. INTRODUCTION ....................................................................................................... 6

2. STUDY OBJECTIVE(S) AND ENDPOINT(S) ............................................................ 7 2.1. Statistical Hypotheses .................................................................................... 7

3. STUDY DESIGN ........................................................................................................ 8

4. PLANNED ANALYSES .............................................................................................. 9 4.1. Interim Analyses ............................................................................................. 9

4.1.1. Intra subject dose escalation within a cohort .................................. 9 4.1.2. Escalation to the next cohort ........................................................... 9 4.1.3. Unblinding of patient data ............................................................... 9

4.2. Final Analysis ................................................................................................. 9

5. SAMPLE SIZE CONSIDERATIONS .......................................................................... 9 5.1. Sample Size Assumptions.............................................................................. 9 5.2. Sample Size Sensitivity ................................................................................ 10 5.3. Sample Size Re-estimation .......................................................................... 10

6. ANALYSIS POPULATIONS ..................................................................................... 11 6.1. Analysis Datasets ......................................................................................... 11

7. TREATMENT COMPARISONS ............................................................................... 11 7.1. Data Display Treatment and Other Sub-group Descriptors .......................... 11

8. GENERAL CONSIDERATIONS FOR DATA ANALYSES ....................................... 11 8.1. Reporting Conventions ................................................................................. 11 8.2. Data Management ........................................................................................ 12

9. DATA HANDLING CONVENTIONS......................................................................... 12 9.1. Premature Withdrawal and Missing Data ..................................................... 12 9.2. Baseline Definition ....................................................................................... 13 9.3. Derived and Transformed Data .................................................................... 13

9.3.1. Change from Baseline .................................................................. 13 9.3.2. Pharmacokinetic Parameters ........................................................ 13 9.3.3. QTc Parameters ............................................................................ 13 9.3.4. MRI Parameters ............................................................................ 14

9.4. Assessment Windows .................................................................................. 15 9.4.1. Multiple Measurements at One Timepoint .................................... 15 9.4.2. Unscheduled Repeat Assessments .............................................. 15

9.5. Values of Potential Clinical Importance ........................................................ 15

10. STUDY POPULATION ............................................................................................. 18

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11. SAFETY ANALYSES ............................................................................................... 18

12. CLINICAL PHARMACOLOGY DATA ANALYSES ................................................... 20 12.1. Pharmacokinetic Analyses ........................................................................... 20

12.1.1. Drug Concentration Measures ...................................................... 20 12.1.2. Deriving and Summarizing Pharmacokinetic Parameters ............. 20 12.1.3. Data specifications for PK File of study NGM114840 ................... 20

13. REFERENCES ........................................................................................................ 21

14. ATTACHMENTS ...................................................................................................... 22 14.1. Table of Contents for Data Display Specifications ....................................... 22 14.2. Data Display Specifications .......................................................................... 28

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ABBREVIATIONS

AE Adverse Event ALT Alanine aminotransferase (SGPT) AST Aspartate aminotransferase (SGOT) AUC Area under concentration-time curve AUC(0-∞) Area under the concentration-time curve from time zero

(pre-dose) extrapolated to infinite time Cmax Maximum observed concentration CSF Cerebrospinal fluid CSSRS Columbia Suicide Severity Rating Scale (CSSRS) DEC Dose Escalation Committee DM Data management DMPK Discovery Medicine Pharmacokinetics ECG Electrocardiogram EDSS Expanded Disability Status Gd Gadolinium GSK GlaxoSmithKline HARP Harmonisation for Analysis and Reporting Program IDSL Integrated Data Standards Library IV Intravenous LLN Lower Limit of Normal MRI Magnetic Resonance Imaging µg Microgram µL Microliter Mg Milligrams mL Milliliter MS Multiple sclerosis MTR Magnetization Transfer Ratio NOAEL No observed adverse effect level PK Pharmacokinetic QSci Quantitative Sciences QC Quality control QTcB QT duration corrected for heart rate by Bazett’s formula QTcF QT duration corrected for heart rate by Fridericia’s formula PSRAE Possible Suicidality Related Adverse Events RAP Reporting and Analysis plan RDC Research and Development China SAE Serious adverse event(s) SAS Statistical Analysis Software SD Standard deviation SGOT Serum glutamic-oxaloacetic transaminase SGPT Serum glutamic pyruvic transaminase t1/2 Terminal phase half-life tmax Time of occurrence of Cmax

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ULN Upper limit of normal Vss Volume of Distribution WBC White blood cells Trademark Information



None SAS WinNonlin

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1. INTRODUCTION

The purpose of this reporting and analysis plan (RAP) is to describe the planned statistical outputs to be produced for the final reporting for Protocol NGM114840.

In review of additional preclinical data GSK decided to suspend the Multiple Sclerosis clinical development program for GSK1223249. The additional preclinical data that have been considered do not raise safety concerns and they do not impact GSK’s ongoing ALS clinical development program for GSK1223249. This study was terminated early after 3 patients had received study treatment (no patient completed the full treatment period). Therefore, for the majority of endpoints, summary tables and graphics are not appropriate and only listings will be produced.

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2. STUDY OBJECTIVE(S) AND ENDPOINT(S)

2.1. Statistical Hypotheses

This study was designed to explore the effect of GSK1223249 relative to Placebo on safety, tolerability and pharmacokinetics. No formal hypothesis will be tested.

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3. STUDY DESIGN

This is a randomised, placebo-controlled, single-blind (Investigator and Subject), single and repeat ascending dose protocol. A sufficient number of subjects with relapsing forms of MS were to be enrolled into the study such that approximately 40 subjects completed dosing and safety assessments to at least the day 70 visit.

This study was intended to consist of 3 cohorts of MS patients. Each eligible patient was to be enrolled to participate in 1 of the 3 cohorts only. All doses would be administered by intravenous infusion. Cohort 1 would consist of a single dose of 1 mg/kg with approximately a 28 day post dose period, followed by 2 doses at 5 mg/kg separated by approximately 28 days. Cohort 2 would consist of a single dose of 5 mg/kg with a 28 day post dose period, followed by 2 doses at 15 mg/kg separated by approximately 28 days. Cohort 3 would consist of a single dose of 15 mg/kg with approximately a 28 day post dose period, followed by 2 doses at 30 mg/kg separated by approximately 28 days.

Within each cohort patients would be randomised to GSK1223249 or placebo in a 3:1 ratio. The number of patients planned in each cohort is given below.

Cohort Total number of subjects

Number receiving active drug

Number receiving placebo

1 8 6 2 2 16 12 4 3 16 12 4

However, the study was terminated after three patients had been randomised into Cohort 1. None of these subjects completed all three doses. No subjects were randomised to cohorts 2 or 3.

The randomisation schedules were generated by the GSK RANDALL package. Subjects were centrally randomized across all sites via an Interactive Voice Response System (IVRS) to receive either placebo or GSK1223249. The study medication was prepared by unblinded pharmacists at the investigator sites.

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4. PLANNED ANALYSES

4.1. Interim Analyses

4.1.1. Intra subject dose escalation within a cohort

Intra-subject dose escalation from single dose level to repeat dose level was determined by the investigator together with the GSK Medical Monitor. All decisions on patient dose escalation were documented.

4.1.2. Escalation to the next cohort

A Dose Escalation Committee (DEC) was intended to be used to review key safety data and available PK data before recommending escalation to the next dose cohort. As only three patients had been randomised into Cohort 1 when the study was terminated, the Dose Escalation Committee did not meet to review Cohort 1 data.

4.1.3. Unblinding of patient data

The study is single blind but it is set-up as a blinded study in the GSK randomisation system (RANDALL) and will remain blinded in this system until all subjects have finished their participation in the study and the final database has been frozen.

The intention had been that after all subjects in a cohort had been randomised the study statistician would contact the randomisation co-ordinator to request the treatment codes. These would be sent directly to the study statistician (without unblinding the study in RANDALL) for use in the programming of the DEC outputs. However, this did not occur due to the termination of the study and therefore the study statistician and programmers remained blinded until the final database had been frozen.

4.2. Final Analysis

The final planned analyses will be performed after all subjects have completed participation in the study and after database freeze and unblinding. These final analyses are described in this RAP. As this study was terminated early after 3 patients had received study treatment, for the majority of endpoints summary tables and graphics are not appropriate and only listings will be produced.

5. SAMPLE SIZE CONSIDERATIONS

5.1. Sample Size Assumptions

There was no formal calculation of power or sample size for this exploratory study. This sample size was based on safety and feasibility. The sample size was planned to be sufficient to ensure that approximately 40 subjects completed the Day 70 visit. Of the 40, 10 subjects were to be allocated to placebo (2 in cohort 1, 4 in cohort 2 and 4 in cohort 3)

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and 30 to active (6 in cohort 1, 12 in cohort 2 and 12 in cohort 3). This would allow an initial estimate of the safety and tolerability associated with administration of doses of GSK1223249. While no formal statistical comparisons were to be performed, the adverse event rate for relapses (recorded as adverse events if they are atypically severe or unusual in recurrence) was of interest. There was uncertainty around this event rate however an estimate of around 1-10% was assumed.

The table below gives the probability of seeing such an adverse event rate at least once in 12 patients assigned to GSK1223249 (e.g. in either cohorts 2 or 3) and the probability for the total of 30 patients assigned to GSK1223249.

AE Incidence

Probability AE seen at least once in 12 patients

Probability AE seen at least once in 30 patients

0.01 0.114 0.260 0.05 0.460 0.7850.10 0.718 0.958 As an example of how informative the study could be, confidence intervals may be constructed for a particular AE rate and sample size. This was illustrated in the following tables for 50%, and 90% confidence intervals.

For 1 2 active patients in a cohort:

No. with AE

No. without AE

Proportion Exact 90% CI Exact 50% CI

0 12 0.0000 (0.0000, 0.2209) (0.0000, 0.1091) 1 11 0.0833 (0.0043, 0.3387) (0.0237, 0.2091) 2 10 0.1667 (0.0305, 0.4381) (0.0803, 0.3012) 3 9 0.2500 (0.0719, 0.5273) (0.1459, 0.3888) 4 8 0.3333 (0.1229, 0.6091) (0.2162, 0.4731) 5 7 0.4167 (0.1810, 0.6848) (0.2898, 0.5547) 6 6 0.5000 (0.2453, 0.7547) (0.3663, 0.6337)

Therefore, for example, if an AE was reported in one out of 12 subjects (8.33%) exposed to GSK1223249 in either cohort 2 or 3, the 90% confidence interval would be (0.43%, 33.87%) and the 50% confidence interval would be (2.37%, 20.91%).

5.2. Sample Size Sensitivity

No Sample size sensitivity was performed

5.3. Sample Size Re-estimation

No sample size re-estimation was planned or performed

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6. ANALYSIS POPULATIONS

Three populations will be used for these analyses. The populations used for each output are detailed in Section 14.

All Subjects Population: All subjects who were randomised.

Safety Population: All subjects who were randomised and received at least one dose of study medication.

PK Concentration Population: Subjects in the ‘All Subjects’ population for whom a pharmacokinetic sample was obtained and analysed.

6.1. Analysis Datasets

All outputs will be produced using the observed cases dataset.

7. TREATMENT COMPARISONS

This study was designed to estimate the effect of GSK1223249 relative to Placebo on safety, tolerability and pharmacokinetics. No formal hypothesis will be tested.

7.1. Data Display Treatment and Other Sub-group Descriptors

The following treatment descriptions will be used for the statistical displays of the cohort 1 data:

Randomisation code

(sequence)

Description in Randall (sequence) Description used in Statistical Displays

P/P/P Pbo/Pbo/Pbo Placebo

A/B/B GSK1223249 1/ 5/ 5 mg/kg GSK1223249 1/5/5 mg/kg

8. GENERAL CONSIDERATIONS FOR DATA ANALYSES

8.1. Reporting Conventions

All listings, tables and figures documented in this RAP will be produced by Quantitative Sciences (QSci), GSK, unless noted otherwise.

All data displays will be presented according to IDSL statistical display principles and all approved IDSL TST standards, where applicable.

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Unless otherwise stated, all statistical reporting will be performed using SAS version 8.2 or higher on a UNIX platform, and the final outputs will be generated using the HARP system. The actual version of SAS used will be documented in the study report.

The following conventions will be applied to the analyses/figures/tables/listings described in this RAP:

• All data will be reported according to the actual treatment regimen the subject received.

• Relative days/times will be relative to the day/time of the first dose of study drug unless otherwise specified.

• This is a multicentre study. Therefore listings will include the Investigator, while results will be summarised with all centres combined.

8.2. Data Management

Data Type Source Format of Data

Responsibility

Other data not mentioned below Inform database/CRF SAS file Data management

(DM)

Safety Labs External vendor – Quest SAS file DM MRI External vendor – NeuroRx SAS file DM PK SMS2000 data files dat file DMPK

PKCNC (Winnonlin file)

PK concentration data merged with SI PK, exposure and demography datasets

CSV file Clinical Statistics & programming

PK PAR CSV file PK Harp GSK CPMS

9. DATA HANDLING CONVENTIONS

9.1. Premature Withdrawal and Missing Data

All subjects who withdraw prematurely from the study will be documented and the reason for their withdrawal recorded. All available data from the subjects who withdraw will be included in the listings and summaries according to the populations defined in Section 6 and according to Section 14. Missing data will not be imputed. Data from the early withdrawal visit for subjects who drop out will be captured as “unscheduled” in the CRF and then inserted into the SI dataset based on date and time of assessment. This information will therefore be treated as unscheduled assessments as described in

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Section 9.4.2. Data from the follow-up visits for any subject who drops out will be entered onto the appropriate follow-up form on the eCRF.

9.2. Baseline Definition

The following table indicates the baseline day to be used in the analysis:

Parameter Baseline (Predose) Days Collected Baseline (Predose) Day Used in Analysis

Screening Baseline Day1 Pre-dose

Laboratory X X X Latest value pre- treatment Vital signs X X Day 1 Pre-dose ECG X X X Mean of screening, baseline

and Day 1 Pre-dose

EDSS X X X Day 1 Pre-dose MRI X X Baseline PK X Day 1 Pre-dose If the specified baseline value is missing then the latest pre-dose value will be used as the baseline. If there is no pre-dose result then baseline will be set to missing.

9.3. Derived and Transformed Data

9.3.1. Change from Baseline

The change from baseline will be calculated by subtracting the baseline values (as specified in the table in Section 9.2) from the individual post- randomisation values. If either the baseline or post-randomisation value is missing, the change from baseline is also set to missing.

9.3.2. Pharmacokinetic Parameters

PK parameters for subjects who received active treatment, if determined, will be listed.

9.3.3. QTc Parameters

QtcB and QtcF

The current IDSL guidance will be followed: I) If QTcB and QTcF are both machine collected, no re-derivation is required. II) If QTcB is machine read and QTcF is not provided, then the following derivations are required: RR = [(QT/QTcB)^(2) ] *1000

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QTcF = QT / ((RR/1000)^1/3), where RR is in msec III) If QTcF is machine read and QTcB is not provided, then the following derivations are required: RR = [(QT/QTcF)^(3) ]*1000 QTcB = QT / ((RR/1000)^1/2), where RR is in msec IV) If ECGs are manually read, and only QT interval and the preceding RR value have been collected then the following derivations are required: QTcB = QT / ((RR/1000)^1/2) QTcF = QT / ((RR/1000)^1/3)

9.3.4. MRI Parameters

Cumulative New Gd-enhancing lesion count

For each visit occurring after the first dose of study drug: The Cumulative New Gd-enhancing lesion count is the cumulative sum of the New-GD enhancing lesion counts from all visits occurring after the first dose of study drug up to and including the current visit.

For all visits prior to the first dose of drug: The Cumulative New Gd-enhancing lesion count will be missing.

In the event that a subject has missing New Gd-enhancing lesion count after the first dose of medication, the cumulative New Gd-enhancing lesion count will be missing for that visit and all subsequent visits.

Cumulative New Gd-enhancing lesion Volume

For each visit occurring after the first dose of drug: The Cumulative New Gd-enhancing lesion volume will be the cumulative sum of the New-GD enhancing lesion volumes from all visits occurring after the first dose of study drug up and including the current visit.

For all visits prior to the first dose of drug: The Cumulative New Gd-enhancing lesion volume will be missing.

In the event that a subject has missing New Gd-enhancing lesion volume after the first dose of medication, the cumulative New Gd-enhancing lesion volume will be missing for that visit and all subsequent visits.

T1-weighted volume change

This will be calculated as specified in Section 9.3.1.

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T2-weighted volume change

This will be calculated as specified in Section 9.3.1.

9.4. Assessment Windows

The outputs for this study will use the planned time point as specified on the eCRF. Visit windows will not be applied to visit dates.

If there is only one assessment per visit then the planned timepoint will be the planned visit label (i.e. either the day number (for any post randomisation visit) or screening or baseline).

• For example for MRI the following planned timepoints would be presented: Screening, Baseline, Day 13, Day 42, Day 85-86, Day 127, Day 169, Day 197

If there is more than one assessment at a visit the planned timepoint will incorporate both the planned visit label and the planned time.

• For example for vital signs the following planned timepoints would be presented: Screening, Day 1: pre dose, Day 1: 1 hour, Day 1: 3 hours, Day 1: 12 hours, Day 2: 24 hours, Day 7, Day 13, Day 29:Pre-dose, Day 29: 1 hour, Day 29: 3 hours, Day 29: 12 hours, Day 30: 24 hours, Day 36, Day 42, Day 57:Pre-dose, Day 57: 1 hour, Day 57: 3 hours, Day 57: 12 hours, Day 58:24 hours, Day 64-65, Day 70-71, Day 85-86, Day 127, Day 169, Day 197

9.4.1. Multiple Measurements at One Timepoint

ECGs are recorded in triplicate at some dates/times. All three records will be used in listings.

9.4.2. Unscheduled Repeat Assessments

Unscheduled repeat assessments will be included in the listings, but will not be included in summary tabulations or figures.

9.5. Values of Potential Clinical Importance

Laboratory Values of Potential Clinical Importance

Note that all of the PCI criteria for haematological, chemistry and LFT parameters (with the exception of eosinophils) are GSK standard Criteria for Healthy Volunteers. These are identifiable with the drug code CLINPHARM_PCI_HVT in the LABCRIT dataset supplied by data management.

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Hematology Analyte Effect Potential Clinical Importance (PCI) Range

Unit

White Blood Cell Count (WBC) Low < 3 GI/L High > 20 GI/L

Neutrophils Low < 1.5 GI/L Lymphocytes Low < 0.8 GI/L Hemoglobin Low >25 change from baseline (F2) G/L

High >180 (F3) G/L Hematocrit Low > 0.075 change from baseline (F2) Ratio of 1

High >0.54 (F3) Ratio of 1 Platelet Count Low < 100 GI/L

High > 550 GI/L Eosinophils High >2x ULN GI/L Chemistry Analyte Effect Potential Clinical Importance (PCI)

Range/Value Unit

Total CO2 Low <18 MMOL/L High >32 MMOL/L

Albumin Low < 30 G/L Calcium Low < 2.0 mmol/L

High > 2.75 mmol/L Creatinine High > 1.3x ULN (F3) µmol/L

High > 44.2 Change from baseline (F2) µmol/L Glucose Low < 3.0 mmol/L

High > 9 mmol/L Potassium Low < 3.0 mmol/L

High > 5.5 mmol/L Sodium Low < 130 mmol/L

High > 150 mmol/L

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Liver Function Test Analyte Effect Potential Clinical Importance (PCI) Range

Unit

ALT/SGPT High ≥ 2x ULN IU/L AST/SGOT High ≥ 2x ULN IU/L Alkaline Phosphatase High ≥ 2x ULN IU/L Total Bilirubin High ≥ 1.5xULN µmol/L

Urinalysis Values of Potential Clinical Importance

Urinalysis Normal F3 Low F3 High Specific Gravity 1001-1035 n/a

pH 4.6-8.1 4.5 8.2

Protein Negative More than a trace Glucose Negative Any

Ketones Negative Any

Occult Blood Negative More than a trace

RBC’s / HPF < 3 4+ WBCs / HPF <10 11+

ECG Values of Potential Clinical Importance ECG Parameter Potential Clinical Importance Range (PCI) Unit

Absolute QTc interval (QTcB and QTcF

>450 msec

Increase from baseline QTc >60 msec

PR interval <110 and >220 msec

QRS interval <75 and >110 msec

Vital Sign Values of Potential Clinical Importance Parameter Potential Clinical Importance Range (PCI) Unit Systolic Blood Pressure < 85 and > 160 mmHg

Diastolic Blood Pressure < 45 and > 100 mmHg

Heart Rate < 40 and > 110 bpm

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10. STUDY POPULATION

Study Population data will be listed by, or under the direct auspices of the clinical statistics group within QSci.

The precise format and content of the Study Population listings are detailed in Section 14 The listings will use the “All Subjects population”.

A summary table of the demography data will be produced using the “Safety population”.

Note that Protocol Deviations will not be defined for this study, however violations of the inclusion/exclusion criteria which are detailed in the eCRF will be listed.

As patients were only recruited to cohort 1 no information is presented on strata or CSF sampling (as these were not used in cohort 1)

11. SAFETY ANALYSES

Safety data will be listed by, or under the direct auspices of the clinical statistics group within Qsci.

The precise format and content of the Safety listings are shown in Section 14 The listings will use the “All Subjects population”. The Listing of Adverse Events leading to withdrawal will also be produced using the “Safety Population” as this is required for future Development Safety Update Reports.

No tables or figures will be produced for the safety data.

MRI

Listings will be provided for MRI endpoints. The percentage change in Cerebral NAWM MTR will be presented rather than the change in Cerebral NAWM MTR. This was recommended by NeuroRx as the variability of the percentage change is typically lower. Similarly the percentage change in Cerebral mean diffusivity will be presented rather than the absolute change. The percentage of Gd-enhancing lesion voxels with increasing magnetization ratio (MTR) and the percentage with decreasing MTR will not be presented. This is because these endpoints were only collected at day 169 and day 197 and no subjects completed these visits.

EDSS

Listings will be provided for the Expanded Disability Status (EDSS) total score and functional scores. The individual function system questions will not be listed.

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Relapses

Relapse information will be listed

Immunogenicity

Due to the limited number of patients enrolled before the study was terminated, immunogenicity cannot be assessed.

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12. CLINICAL PHARMACOLOGY DATA ANALYSES 12.1. Pharmacokinetic Analyses All figures and listings will use the PK Concentration Population. No tables will be produced for PK data. Derivation of the PK Parameters will be the responsibility of the Clinical Pharmacokinetics Modelling and Simulation (CPMS) department within GlaxoSmithKline , using SMS2000 data. The listings will be the responsibility of clinical statistics.

12.1.1. Drug Concentration Measures Individual plasma concentration-time profiles for the 25 hours post each dose will be plotted (note that the figure will plot any values up to 25 hours, rather than 24 hours, to ensure that assessments with a nominal time of 24 hours which are taken slightly late are included). For each subject the figure will contain two plots, one plot on the untransformed scale (i.e. a linear plot) and one plot on the log transformed scale (i.e. log-linear plot). In both these plots a separate line will be used for each dose the subject received. The actual time will be used on the horizontal axis.

Similar individual plasma concentration time profiles will be produced for quantifiable PK concentrations up to the end of the subjects participation in the study. Separate lines will be used to plot each dose the subject received. The line for all doses except the last one the patient received, will continue to cover all assessments up to but not including the pre-dose assessment of the next dose. The line for the final dose will continue till the last quantifiable assessment in the study.

The drug concentration will also be listed using the “PK Concentration population”.

12.1.2. Deriving and Summarizing Pharmacokinetic Parameters Depending on the data available, a non compartmental analysis using WinNonlin might be considered. All calculations of non-compartmental parameters will be based on actual sampling times.

For subjects who received active treatment some relevant pharmacokinetic parameters like the maximal concentration (Cmax), the AUC for the 1st and 2nd dose (AUC(0-t)), the AUC extrapolated to infinity (AUC(0-∞)), the half life (t1/2), the volume of distribution (Vss) and the clearance (CL), might be determined from the plasma concentration-time data for GSK1223249.

The PK parameters will be listed using the “PK Concentration population”.

12.1.3. Data specifications for PK File of study NGM114840

A PK concentration Analysis and Reporting dataset (PKCNC) will be produced by Clinical Statistics for use in the PK reporting. This will follow the GSK standard dataset specification.

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13. REFERENCES

NONE

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14. ATTACHMENTS

14.1. Table of Contents for Data Display Specifications

Safety Tables

Table No. Population IDSL No. / Example Shell

Title Programming Notes

1.01 Safety IDSL DM1 Summary of Demographic Characteristics

PK Figures

Figure No. Population

IDSL No. / Example Shell


1.01 PK IDSL PK16a Individual GSK1223249 Plasma Concentration-Time Plots to 25 hours (Linear and Semi-log) by Treatment

1.02 PK IDSL PK16a Individual GSK1223249 Plasma Concentration-Time Plots to end of study (Linear and Semi-log) by Treatment

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ICH Listings

Listing Number

Population



1.01 All Subjects IDSL DM2 Listing of demographic characteristics

1.02 All Subjects IDSL DM9 Listing of Race

1.0 3 All Subjects IDSL IE3 Listing of Subjects with Inclusion/Exclusion Criteria

Deviations

1.0 4 All Subjects POP Listing of Study Population

1.0 5 All Subjects IDSL TA1 Listing of Randomised and Actual Treatments

Please add Cohort to this listing. Note that Strata will not be presented as patients were only recruited to Cohort 1 which has no strata.

1.0 6 All Subjects IDSL ES2 Listing of Reasons for Withdrawal “Subreason” column is not required

1.0 7

All Subjects IDSL EX3 Listing of Exposure Data

Duration should be in minutes rather than days Frequency and Cumulative dose not required. Add two further Columns

(a) Did the subject receive the correct dose? The response will be Yes or No

(b) Detail The response will be text entered into the comment field

1.0 8 All Subjects IDSL CM3

Listing of Concomitant Medications by Generic Term Add column for “Reason for Medication”

1.09 All Subjects

IDSL CP_AE8 Listing of All Adverse Events Note Clinpharm standard used as this has

additional information to core standard 1.10 All

Subjects IDSL CP_AE8a Listing of Serious Adverse Events

include both Fatal and Non-Fatal Note Clinpharm standard used as this has additional information to core standard

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Listing Number

Population



1.11 All Subjects IDSL AE7 Listing of Subject Numbers for Individual Adverse Events

1.12 All Subjects

IDSL CP_AE8

Listing of Adverse Events leading to Leading to Permanent Discontinuation of Study Drug or Withdrawal from Study

1.13 Safety IDSL

CP_AE8 Listing of Adverse Events leading to Leading to Permanent Discontinuation of Study Drug or Withdrawal from Study

This listing is required for the DSUR. Note the population used is the safety population

1.14 All Subjects IDSL LB5 Listing of Clinical Chemistry Abnormalities of Potential

Clinical Importance only display PCI values in this listing Include the sample time as well as the date

1.15 All Subjects IDSL LB5 Listing of All Clinical Chemistry Laboratory Data display ALL chemistry labs for all subjects

Include the sample time as well as the date 1.16 All

Subjects IDSL LB5 Listing of Haematology Abnormalities of Potential Clinical Importance

only display PCI values in this listing Include the sample time as well as the date

1.17 All Subjects IDSL LB5 Listing of All Haematology Laboratory Data display ALL haematology labs for all subjects

Include the sample time as well as the date 1.18 All

Subjects IDSL UR2a Listing of Urinalysis Data for all Subjects display ALL urinalysis labs for all subjects Include the sample time as well as the date

1.19 All Subjects IDSL BL1 Listing of Subjects for Whom the Treatment Blind

was Broken During the Study

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Other Listings

Listing Number Populatio

n IDSL No. / Example Shell


2.01 All Subjects IDSL MH2 Listing of Medical Conditions

2.02 All Subjects MSHIST1 Listing of MS Medical History

2.0 3 All Subjects MSHIST2 Listing of MS Medical History-Relapses in last 12

months

2.0 4 All Subjects NEUREXAM Listing of Neurological Examination

2.0 5 All Subjects IDSL VS4 Listing of Vital Signs

Display for all subjects Include the sample time as well as the date. Include height, weight, bmi, SBP, DBP, heart rate

2.0 6 All Subjects IDSL VS4 Listing of Vital Signs of Potential Clinical Importance

only display PCI values in this listing Include the sample time as well as the date Include height, weight, bmi, SBP, DBP, heart rate

2.0 7 All Subjects IDSL EG3 Listing of ECG Values

Display for all subjects Also include RR interval

2.0 8 All Subjects IDSL EG3

Listing of All ECG Values for Subjects with a Value of Potential Clinical Importance

Also include RR interval The “ECG Values of Potential Clinical Importance” in Section 9.5should be used

2.0 9 All Subjects IDSL EG5 Listing of Abnormal ECG findings

only display Abnormal Values in this listing. “Clinically Significant Change from Baseline” column is not required

2.10 All Subjects TELEM Listing of Telemetry Findings

2.11 All Subjects CSSRS1 Listing of Suicide Attempts

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2.12 All Subjects CSSRS2 Listing of CSSRS Suicidal Ideation and Behavior Data

Note column added to template for “completed Suicide” Note: Only patients with suicidal ideation or behavior at least one timepoint are displayed.

2.13 All Subjects PSRAE1a Listing of All Possible Suicidality- Related Adverse

Events (PSRAE)(Section 1- Section 2)

2.14 All Subjects PSRAE1b Listing of All Possible Suicidality- Related Adverse

Events (PSRAE)(Section 3)

2.15 All Subjects PSRAE1c Listing of All Possible Suicidality- Related Adverse

Events (PSRAE)(Section 4)

2.16 All Subjects PSRAE1d Listing of All Possible Suicidality- Related Adverse

Events (PSRAE)(Section 5- Section 8)

2.17 All Subjects

IDSL PREG 1a

Listing of Subjects Who Became Pregnant During the Study

2.18 All Subjects PREGM Listing of Male Subjects with Female Partners Who

Became Pregnant During the Study 2.19 All

Subjects IDSL LIVER5 Listing of Liver Event Results and Time of Event Relative to Treatment

2.20 All Subjects IDSL LIVER6 Listing of Liver Events Information for RUCAM Score

2.21 All Subjects IDSL LIVER7 Listing of Liver Biopsy Details

2.22 All

Subjects IDSL LIVER8 Listing of Liver Imaging Details 2.23 All

Subjects RELAPSE1 Listing of Patients with Relapses during the study

2.24 All Subjects RELPASE2 Listing of Details of Relapses (Neurological

Deficits)

2.25 All Subjects EDSS Listing of Expanded Disability Status (EDSS)

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2.26 All Subjects MRI1 Listing of Gd-enhancing Lesion Counts

2.27 All Subjects MRI2 Listing of Gd-enhancing Lesion Volume

2.28 All Subjects MRI3 Listing of T2- and T1-weighted Lesion Volume

2.29

All Subjects MRI4

Listing of Cerebral NAWM MTR and Cerebral mean diffusivity

Note that “Median MTR in supra NAWM” is the variable in the database that corresponds to “Cerebral NAWM MTR”. Cerebral NAWM MTR and Cerebral mean diffusivity are only collected at the screening visit and the % change for these variables is collected at post screening visits.

2.30 PK IDSL PK07 Listing of GSK1223249 Pharmacokinetic Concentration-Time Data

2.31

PK IDSL PK13

Listing of Derived Plasma GSK1223249 Primary and Secondary Pharmacokinetic Parameters

Primary parameters to include in the listing: volume of distribution (Vss) and clearance (CL)

Secondary parameters to include in the listing:: Cmax for the 1st and 2nd dose, AUC(0-t) for the 1st and 2nd dose, AUC(0-inf) for the 1st and 2nd dose, and t1/2

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14.2. Data Display Specifications

Example POP Protocol: NGM114840 Page 1 of n Population: All Subjects

Listing X

Listing of Study Population

Treatment Inv. Subject All Subjects Safety PK Concentration

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Example MSHIST1

Protocol: NGM114840 Page 1 of n Population: All Subjects

Listing X Listing of MS Medical History No of No of Date of Date of Disease Tot no. Relapses Relapses No of Date of onset of date of duration of in last in last MRI last steroid Treatment Inv. Subj. MS Symptoms MS Diag (years) Relapses 12m 24m Scans use ------------------------------------------------------------------------------------------------------------ XXXXXXXX XXXXXX XXX XXXXXXX XXXXXXX X X X XX XX XXXXXXXXX XXXXXX XXX XXXXXXX XXXXXXX X X X XX XX XXXXXXXXX XXXXXX XXX XXXXXXX XXXXXXX X X X XX XX XXXXXXXXX XXXXXX XXX XXXXXXX XXXXXXX X X X XX XX XXXXXXXXX XXXXXX XXX XXXXXXX XXXXXXX X X X XX XX XXXXXXXXX USER ID:directory/program.sas DDMMMYYYY HH:MM

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Example MSHIST2 Protocol: NGM114840 Page 1 of n Population: All Subjects

Listing X Listing of MS Medical History-Relapses in last 12 months Treatment: Placebo Inv./ Subj

Date symptom started

Date seen in clinic

Admitted to hospital

Date of admission/Date of discharge

Neurological Deficit

Onset Date/ Resolved date/ Duration (days)

Outcome Event Course

Number Of Episodes

Max Inten- sity

XXXX/ XXXX

XXXXXXX XXXXXX Y XXXXXX/ XXXXXX

Visual/ Brainstem

XXXXXXX/ XXXXXXX/ XX

Ongoing Constant Mod- erate

XXXX/ XXXX

XXXXXXX XXXXXX N Brainstem XXXXXXX/ XXXXXXX/ XX

Resolved Inter-mittent

2 Mild

USER ID:directory/program.sas DDMMMYYYY HH:MM

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Example NEUREXAM Protocol: NGM114840 Page 1 of n Population: All Subjects

Listing X

Listing of Neurological Examination

Treatment Inv. Subject Exam Date/Time/ Study Day

Classification Status Details


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This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the

Sponsor Clinical Study Register.


32

Example TELEM Protocol: NGM114840 Page 1 of n Population: All Subjects

Listing X

Listing of Telemetry Findings Treatment= Treatment A

Inv./ Subj

Age/ Sex/ Race

Planned Rel Time/ Start Date/Time Study Day

Stop Date/Time

Result

Clinically Significant Abnormality


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Example CSSRS1


Listing X Listing of Suicide Attempts

Treatment: Placebo

Inv ID/ Subj

Planned Visit

Assessment date/ study day

EvaluationInterval

Most Recent Attempt Date/ Actual Lethality/ Potential Lethality

Most lethal Attempt Date/ Actual Lethality/ Potential Lethality

First Attempt Date/ Actual Lethality/ Potential Lethality

XXX/ XXX

XXXXX XXXXXX/ X

Lifetime XXXXXX/ XXXXXXXXXXXXXXXXX/ XXXXXXXXXXXXXXXXXXX

XXXXXX/ XXXXXXXXXXXXXXXXX/ XXXXXXXXXXXXXXXXXXX


XXX/ XXX

XXXXX XXXXXX/ X

Current XXXXXX/ XXXXXXXXXXXXXXXXX/ XXXXXXXXXXXXXXXXXXX



XXX/ XXX

XXXXX XXXXXX/ X

Since last visit





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Example CSSRS2


Listing X Listing of CSSRS Suicidal Ideation and Behavior Data

Treatment: Placebo Inv ID/ Planned Date/ Evaluation _Suicidal Ideation_ ____Suicidal Behaviour___ Subj. Visit Study Day Interval 1 2 3 4 5 6 7 8 9 10 11 12 ------------------------------------------------------------------------------------------------------- XXXXXX/ XXXXXXXXX XXXXXXXXX/ Lifetime Yes Yes Yes No No No No No Yes No No No XX XX XXXXX XXXXXXXXX/ Since last Yes Yes Yes No No No No No No No No No X visit XXXXXX XXXXXXXXX/ Since last Yes No No No No No No No No XX visit Note: Only patients with suicidal ideation or behavior at least one timepoints are displayed. Key: 1=Wish to be dead, 2=Non-specific active suicidal thoughts, 3=Active suicidal ideation with any methods (not plan) without intent to act, 4=Active suicidal ideation with some intent to act, without specific plan, 5=Active suicidal ideation with specific plan and intent, 6=Actual attempt, 7=Engaged in non-suicidal self injurious behavior, 8=Interrupted attempt, 9=Aborted attempt, 10=Preparatory acts or behavior, 11=Suicidal Behavior, 12=Completed Suicide


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Example PSRAE1a Protocol: NGM114840 Page 1 of n Population: All Subjects Listing X Listing of All Possible Suicidality-Related Adverse Events (PSRAE) (Section 1- Section 2) Event/ Inv./ Start Date/ Treatment Subj Start Day Brief Description

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Example PSRAE1b

Protocol: NGM114840 Page 1 of n Population: All Subjects Listing X Listing of All Possible Suicidality-Related Adverse Events (PSRAE) (Section 3) Inv./ Start Date/ Treatment Subj Event Start Day Possible cause of AE Response

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Example PSRAE1c

Protocol: NGM114840 Page 1 of n Population: All Subjects Listing X Listing of All Possible Suicidality-Related Adverse Events (PSRAE) (Section 4) Event/ Inv./ Start Date/ Treatment Subj Start Day Question Response Additional information

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Example PSRAE1d

Protocol: NGM114840 Page 1 of n Population: All Subjects Listing X Listing of All Possible Suicidality-Related Adverse Events (PSRAE) (Section 5- Section 8) Event/ Inv./ Start Date/ Treatment Subj Start Day Section Question Response

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Example PREGM Protocol: NGM114840 Page 1 of n Population: All Subjects

Listing X

Listing of Male Subjects with Female Partners Who Became Pregnant During the Study

Treatment Investigator Subject


2012N137712_00

This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient

privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further

information please see the Patient Level Data section of the Sponsor Clinical Study Register.


40

Example RELAPSE1 Protocol: NGM114840 Page 1 of n Population: All Subjects

Listing x

Listing of Patients with Relapses during the study Treatment: Placebo Inv. Subject Date symptoms

started/ study day

Date seen in clinic Was the subject admitted to Hospital?

Date of Admission

Date of Discharge

XXXXXX XXX XXXXXXXX/XXXXXXX XXXXXX Yes XXXXXX XXXXXX XXXXXX XXX XXXXXXXX/XXXXXXX XXXXXX No USER ID:directory/program.sas DDMMMYYYY HH:MM

2012N137712_00


41

Example RELAPSE2 Protocol: NGM114840 Page 1 of n Population: All Subjects

Listing X Listing of Details of Relapses (Neurological Deficits) Treatment: Placebo Inv/ Subj

Date symptoms started/ study day

Neurological Deficit

Onset Date/ Resolved date/Duration(days)

Outcome Event Course

Number Of Episodes

Maximum Intensity

Concomitant Medication Taken?

XXX/ XXX

XXXXXXXX/ XX

Visual XXXXXXX/ XXXXXXX/ XX

Ongoing Constant Moderate Yes

XXX/ XXX

XXXXXXXX/ XX

Brainstem XXXXXXX/ XXXXXXX/ XX

Resolved Intermittent 2 Mild No


2012N137712_00


42

Example EDSS Protocol: NGM114840 Page 1 of n Population: All Subjects Listing X Listing of Expanded Disability Status (EDSS) Treatment: Placebo Planned Rel. Timepoint/ Bladder/ EDSS Inv./ Date of EDSS/ Visual Brain- Pyram- Cere- Bladder/ Bowel Total Subj. Study Day Visual Converted stem idal bellar Sensory Bowel Converted Cerebral Ambulation Score ------------------------------------------------------------------------------------------------------------------------ XXXXX/ Screening/ X X X X X X X X X X X XXX XXXXXXXXX/ -XX Run-in Week 0/ X X X X X X X X X X X XXXXXXXXX / -1 Week 4/ 1 X X X X X X X X X X X XXXXXXXXX/ 28 Etc…… USER ID:directory/program.sas DDMMMYYYY HH:MM

2012N137712_00


43

Example MRI1 Protocol: NGM114840 Page 1 of n Population: All Subjects

Listing X Listing of Gd-enhancing Lesion Counts

Treatment: Placebo

Inv/ Subj.

Age(y)/ Sex/ Race

Planned Relative Time

Date

Study Day

Gd-enhancing Lesion Count

New Gd-enhancing Lesion Count [1]

Cumulative New Gd-enhancing Lesion Count [2]

xxxxx/ xx/x/ Screening DDMMMYYYY -x 2 NA NA xxx xxxxx xxxx Baseline DDMMMYYYY xx 5 3 NA Day 13 DDMMMYYYY xx 6 1 1 … … … … … … xxxxx/ xx/x/ Screening DDMMMYYYY -x 2 NA NA xxx xxxxx xxxx Baseline DDMMMYYYY xx 5 3 NA … … … … … …

Programming note: continue for all visits where an MRI was performed and all treatment groups. [1] New Gd-enhancing lesion count is the number of new lesions since the previous visit. [2] Cumulative new Gd-enhancing lesion count is relative to Baseline. USER ID:directory/program.sas DDMMMYYYY HH:MM

2012N137712_00


44

Example: MRI2 Protocol: NGM114840 Page 1 of n Population: All Subjects

Listing X Listing of Gd-enhancing Lesion Volume

Treatment: Placebo

Inv/ Subj.

Age(y)/ Sex/ Race


Date

Study Day

Gd-enhancing Lesion Volume (cc)

New Gd-enhancing Lesion Volume (cc) [1]

Cumulative New Gd-enhancing Lesion Volume (cc) [2]

xxxxx/ xx/x/ Screening DDMMMYYYY -x xx.x NA NA xxx xxxxx xxxx Baseline DDMMMYYYY xx xx.x xx.x NA Day 13 DDMMMYYYY xx xx.x xx.x xx.x … … … … … … xxxxx/ xx/x/ Screening DDMMMYYYY -x xx.x NA NA xxx xxxxx xxxx Baseline DDMMMYYYY xx xx.x xx.x NA … … … … … …

Programming note: continue for all visits where an MRI was performed and all treatment groups. [1] New Gd-enhancing lesion volume is the new volume of lesions since the previous visit. [2] Cumulative new Gd-enhancing lesion volume is relative to Baseline. USER ID:directory/program.sas DDMMMYYYY HH:MM

2012N137712_00


45


Listing X Listing of T2- and T1-weighted Lesion Volume

Treatment: Placebo Inv/ Subj.

Age(y)/ Sex/ Race


Date

Study Day

T2-weighted volume (cc)

T2-weighted volume change (cc) [1]

T1-weighted volume (cc)

T1-weighted volume change (cc) [1]

xxxxx/ xx/x/ Screening DDMMMYYYY -x xx.x NA xx.x NA xxx xxxxx xxxx Baseline DDMMMYYYY xx xx.x NA xx.x NA Day 13 DDMMMYYYY xx xx.x xx.x xx.x xx.x … … … xxxxx/ xx/x/ Screening DDMMMYYYY -x xx.x NA xx.x NA xxx xxxxx xxxx Baseline DDMMMYYYY xx xx.x NA xx.x NA … … …

Programming note: continue for all visits where an MRI was performed and all treatment groups. [1] T2- and T1-weighted volume change is the change in volume from Baseline. USER ID:directory/program.sas DDMMMYYYY HH:MM

2012N137712_00


46


Listing X Listing of Cerebral NAWM MTR and Cerebral mean diffusivity

Treatment: Placebo

Inv/ Subj.

Age(y)/ Sex/ Race

Planned Relative Time Date

Study Day

Cerebral NAWM MTR (p.u.)

Percentage change in Cerebral NAWM MTR [1]

Cerebral mean diffusivity (10-3mm2/s)

Percentage change in cerebral mean diffusivity [1]

xxxxx/ xx/x/ Screening DDMMMYYYY -x xx.x NA xx.x NA xxx xxxxx xxxx

Baseline DDMMMYYYY xx NA xx.x NA xx.x

Day 13 DDMMMYYYY xx NA xx.x NA xx.x

… … … … …

xxxxx/ xx/x/ Screening DDMMMYYYY -x xx.x NA xx.x NA xxx xxxxx xxxx

Baseline DDMMMYYYY xx NA xx.x NA xx.x

… … … … … … …

Programming note: continue for all visits where an MRI was performed and all treatment groups.

[1] Percentage change is from Screening. Note: NAWM = Normal-Appearing White Matter.


2012N137712_00

[Unspecified]

Annotated Design For Trial: NGM114840_mjo

Protocol: NGM114840

Generated By InForm Architect™

August 8, 2011 12:02PM

Page 1 of 152Annotated Trial Design

Time and Events Schedule For Study: NGM114840_mjo

Assessment CRF Screen

(Screen) [ S ]

Baseline

(Baseline) [ S ]

Days 1-2

(Days 1-2) [ S ]

Day 7

(Day 7) [ S ]

Day 13

(Day 13) [ S ]

Days 29-30

(Days 29-30) [ S ]

Day 36

(Day 36) [ S ]

Day 42

(Day 42) [ S ]

Days 57-58

(Days 57-58) [ S ]

Days 64-65

(Days 64-65) [ S ]

Days 70-71

(Days 70-71) [ S ]

Days 85-86

(Days 85-86) [ S ]

Day 127

(Day 127) [ S ]

Day 169 (FU1)

(Day 169 (FU1)) [ S ]

Day 197 (FU2)

(Day 197 (FU2)) [ S ]

End of Study

(EOS) [ S ]

Logs/Repeats

(Logs/Rpts) [ U ]

PGx

(PGx) [ S ]

Liver Event

(LE) [ U/D ]

Conflict

(Conflict) [ U/R/D ]

1 DATE OF VISIT DoV 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

2 DEMOGRAPHY Demog 2

3 12-LEAD ECG ECG 3

4 VITAL SIGNS VS 4

5 ELECTRONICALLY TRANSFERRED SAFETY LAB DATA Lab 5 4 5 5 5 5 5 5 5 5

6 ELIGIBILITY QUESTION ELIG 6

7 SUBJECT IDENTIFICATION Subj ID 7

8 MEDICAL CONDITIONS MEDHX 8

9 MULTIPLE SCLEROSIS MEDICAL HISTORY MSHIST 9

10 ELECTRONICALLY TRANSFERRED CRANIAL MRI DATA CRAN_MRI 10 5 13 12 13 13 12 13

11 Neurological Exam NeurExam 11 6 14 13 13 14 14 13 14

12 ELECTRONICALLY TRANSFERRED BIOMARKER DATA BIOMARK 12 7 7 6 6

13 COLUMBIA SUICIDE SEVERITY RATING SCALE - V4BL CSSRS 13

14 COLUMBIA SUICIDE SEVERITY RATING SCALE - V4BL CSSRS1 14-DF








22 COLUMBIA SUICIDE SEVERITY RATING SCALE - V4BL CSSRS4 22



25 Expanded Disability Status Scale (Neurostatus) EDSS 25 7 15 14 14 15 15

26 Expanded Disability Status Scale (Visual) EDSS Visual 26-DF 8-DF 9-DF 16-DF 5-DF 15-DF 5-DF 15-DF 16-DF 16-DF

27 Expanded Disability Status Scale (Brainstem) EDSS Brainstem 27-DF 9-DF 10-DF 17-DF 6-DF 16-DF 6-DF 16-DF 17-DF 17-DF

28 Expanded Disability Status Scale (Pyramidal) EDSS Pyramidal 28-DF 10-DF 11-DF 18-DF 7-DF 17-DF 7-DF 17-DF 18-DF 18-DF

29 Expanded Disability Status Scale (Cerebellar) EDSS Cerebellar 29-DF 11-DF 12-DF 19-DF 8-DF 18-DF 8-DF 18-DF 19-DF 19-DF

30 Expanded Disability Status Scale (Sensory) EDSS Sensory 30-DF 12-DF 13-DF 20-DF 9-DF 19-DF 9-DF 19-DF 20-DF 20-DF

31 Expanded Disability Status Scale (Bowel/Bladder) EDSS Bowel/Bladder 31-DF 13-DF 14-DF 21-DF 10-DF 20-DF 10-DF 20-DF 21-DF 21-DF

32 Expanded Disability Status Scale (Cerebral) EDSS Cerebral 32-DF 14-DF 15-DF 22-DF 11-DF 21-DF 11-DF 21-DF 22-DF 22-DF

33 Expanded Disability Status Scale (Ambulation) EDSS Ambulation 33-DF 15-DF 16-DF 23-DF 12-DF 22-DF 12-DF 22-DF 23-DF 23-DF

34 12-LEAD ECG ECG 2 3 3 3 3 3 3 3 3 2 2

35 Weight Weight 3

36 Confirm Eligibility Confirm Eligibility 16

37 RANDOMISATION NUMBER Rand 2

38 COHORT Cohort 3

39 STRATA STRATA 4-DF

40 STRATA STRATA 5-DF

41 CSF SAMPLE TAKEN? CSF SAMPLE TAKEN? 6-DF 2-DF 2-DF 2-DF 2-DF 2-DF 2-DF 2-DF 2-DF 2-DF 2-DF

42 Neurological Exam NeurExam 7 3 3

43 Expanded Disability Status Scale (Neurostatus) EDSS 8 4 4

44 COLUMBIA SUICIDE SEVERITY RATING SCALE - V4LV CSSRS1 17 7 8 13 7 7 13 7 8 8 8 7 8

45 COLUMBIA SUICIDE SEVERITY RATING SCALE - V4LV CSSRS2 18-DF 8-DF 9-DF 14-DF 8-DF 8-DF 14-DF 8-DF 9-DF 9-DF 9-DF 8-DF 9-DF


47 COLUMBIA SUICIDE SEVERITY RATING SCALE - V4LV CSSRS4 20 10 11 16 10 10 16 10 11 11 11 10 11


49 INVESTIGATIONAL PRODUCT - IV DOSING IP IV 22 18 18

50 PRE DOSE 12-LEAD ECG PRE DOSE ECG 23 19 19

51 2H 12-LEAD ECG 2H ECG 24

52 3H 12-LEAD ECG 3H ECG 25

53 12H 12-LEAD ECG 12H ECG 26 20 20

54 24H 12-LEAD ECG 24H ECG 27 21 21

55 TELEMETRY OR BEDSIDE CARDIAC MONITORING Cardiac Monitoring 28 22 22

56 SUMMARY TELEMETRY ABNORMALITIES Telemetry Ab 29-DF 23-DF 23-DF

57 VITAL SIGNS VS 30 24 24

58 ELECTRONICALLY TRANSFERRED SAFETY LAB DATA Lab 31 25 25

59 PHARMACOKINETICS BLOOD - [GSK1223249] PK 32 26 26

60 IMMUNOGENICITY SAMPLING IMGLINK 33

61 CEREBROSPINAL FLUID SAMPLING CSFLINK 34-DF 12-DF 24-DF 27-DF 12-DF 23-DF 27-DF 12-DF 23-DF 24-DF 24-DF

62 VITAL SIGNS VS 4 4 4 4 4 4 4

63 PHARMACOKINETICS BLOOD - [GSK1223249] PK 6 6 6 6 6 6 6 6 5 5

64 VITAL SIGNS VS 4 3 3

65 IMMUNOGENICITY SAMPLING IMGLINK 7 7 7

66 ELECTRONICALLY TRANSFERRED LAB DATA Lab 4 4

67 STATUS OF TREATMENT BLIND Blind 2

68 STUDY CONCLUSION Conclusion 3

69 PREGNANCY INFORMATION Preg F 4-DF

70 PREGNANCY INFORMATION Preg M 5-DF

71 LOGS AND REPEATS Logs/Rpts 1

72 NON-SERIOUS ADVERSE EVENT AE 2-RF-DF

73 SERIOUS ADVERSE EVENTS SAE 3-RF-DF

74 POSSIBLE SUICIDALITY-RELATED ADVERSE EVENT PSRAE 4-RF-DF

75 RELAPSES RELAPSES 5-RF-DF

76 CONCOMITANT MEDICATIONS Con Meds 6-RF-DF

77 ELECTRONICALLY TRANSFERRED LAB DATA Lab Rpt 7-RF-DF


78 VITAL SIGNS VS Rpt 8-RF-DF

79 12-LEAD ECG ECG Rpt 9-RF-DF

80 ECG ABNORMALITIES ECG Abn 10-RF-DF

81 REPEAT PHARMACOKINETICS BLOOD - [GSK1223249] PK Rpt 11-RF-DF

82 IMMUNOGENICITY SAMPLING IMGLINK 12-RF-DF

83 ELECTRONICALLY TRANSFERRED BIOMARKER DATA BIOMARK 13-RF-DF

84 ELECTRONICALLY TRANSFERRED CRANIAL MRI DATA CRAN_MRI 14-RF-DF

85 Neurological Exam NeurExam 15-RF-DF

86 Expanded Disability Status Scale (Neurostatus) EDSS RPT 16-RF-DF

87 Expanded Disability Status Scale (Visual) EDSS Visual 17-RF-DF

88 Expanded Disability Status Scale (Brainstem) EDSS Brainstem 18-RF-DF

89 Expanded Disability Status Scale (Pyramidal) EDSS Pyramidal 19-RF-DF

90 Expanded Disability Status Scale (Cerebellar) EDSS Cerebellar 20-RF-DF

91 Expanded Disability Status Scale (Sensory) EDSS Sensory 21-RF-DF

92 Expanded Disability Status Scale (Bowel/Bladder) EDSS Bowel/Bladder 22-RF-DF

93 Expanded Disability Status Scale (Cerebral) EDSS Cerebral 23-RF-DF

94 Expanded Disability Status Scale (Ambulation) EDSS Ambulation 24-RF-DF

95 REPEAT CARDIAC MONITORING Cardiac Monitoring Rpt 25-RF-DF

96 REPEAT TELEMETRY ABNORMALITIES Telemetry Abn Rpt 26-RF-DF

97 PGx-PHARMACOGENETIC RESEARCH CONSENT PGx Consent 2

98 PHARMACOGENETIC (PGx) RESEARCH WITHDRAWAL OF CONSENT PGx Withdraw 3-DF

99 Reg Docs REG

100 LIVER EVENTS LIVER EVENTS 2

101 PHARMACOKINETICS LIVER PK 3

102 MEDICAL CONDITIONS AT ONSET OF LIVER EVENT LIVER MEDHX 4

103 ALCOHOL INTAKE AT ONSET OF LIVER EVENT LIVER ALCOHOL 5

104 LIVER IMAGING IMAGING 6-RF-DF

105 LIVER BIOPSY BIOPSY 7-RF-DF

Key: [S] = Scheduled Visit [O] = Optional Visit [D] = Dynamic Visit [U] = Unscheduled Visit [R] = Repeating Visit

C = Common Form DF = Dynamic Form RF = Repeating Form


NGM114840_mjo : INFORM SCREENING (SCREEN)

INFORM SCREENING

1.* Subject initials [hidden] A3 (MAPPINGS1:t_SCREEN.txtScrSINIT)

2. Date of birth Enter subject’s date of birth, if you are unable to provide a full date of birth, enter a partial date of birth.

Req/Unk / Req/Unk / Req (1951-1997) (MAPPINGS1:t_SCREEN.DOBDT)

* Item is not required

Form Design Note:

Trial designers must use this form as specified here. Allowed changes are mentioned in the particular item level notes.

Item Design Notes:

Item No. Design Note

1. This item is hidden to all users and will be autopopulated by the system as "---"

2. Will mapped from SCREEN form to DEMO form.

CDD: MAPPINGS1 Table: t_SCREEN Key Type: PATIENTVISIT

Column Name Column Data Type Design Note

txtScrSINIT STRING(3) - A3

DOBDT DATE - DDMONYYYY


NGM114840_mjo : INFORM ENROLMENT (ENROL)

SUBJECT NUMBER

1. Subject number A6 (MAPPINGS1:t_ENROL.mtxtSubjectNumber)

CDD: MAPPINGS1 Table: t_ENROL Key Type: PATIENTVISIT


mtxtSubjectNumber STRING(6) - A6


NGM114840_mjo : DATE OF VISIT (DoV)

Adverse Events/Concomitant Medications » Record details of any new serious adverse event or any changes to ongoing serious adverse events in the SAE form in the Logs/Rpts visit. » From Day 1 onwards, record details of any new non-serious adverse event or any changes to ongoing non-serious adverse events in the appropriate AE form in the Logs/Rpts visit » Record any changes to the subject's concomitant medication or any new medication taken since the last visit in the Con Meds form in the Logs/Rpts visit.

DATE OF VISIT/ASSESSMENT

1. Date of visit/assessment Req / Req / Req (2011-2013) (MAPPINGS1:t_VISIT.DOV)

CDD: MAPPINGS1 Table: t_VISIT Key Type: PATIENTVISIT


DOV DATE - DDMONYYYY


NGM114840_mjo : DEMOGRAPHY (Demog)

DEMOGRAPHY

1. Date of birth Enter subject’s date of birth, if you are unable to provide a full date of birth, enter a partial date of birth.

Req/Unk / Req/Unk / Req (1951-1997) (MAPPINGS1:t_DEMO.DOBDT)

2.* Date of birth - Imputed [hidden] Req / Req / Req (1951-1997) (MAPPINGS1:t_DEMO.BIRTHDT)

3. Sex (MAPPINGS1:t_DEMO.SEX)

[M] Male

[F] (MAPPINGS1:t_DEMO.CHDPOTCD)

Female : Record child-bearing potential

[2] Post-menopausal

[3] Sterile (of child-bearing age)

[4] Potentially able to bear children

4. Ethnicity (MAPPINGS1:t_DEMO.ETHNICCD)

[1] Hispanic or Latino

[2] Not Hispanic or Latino

5. Geographic ancestry Check all that apply

(MAPPINGS1:t_DEMO.RACECCD11)

[11] African American/African Heritage


[12] American Indian or Alaskan Native


[13] Asian - Central/South Asian Heritage


[14] Asian - East Asian Heritage


[15] Asian - Japanese Heritage


[16] Asian - South East Asian Heritage


[17] Native Hawaiian or Other Pacific Islander


[18] White - Arabic/North African Heritage


[19] White - White/Caucasian/European Heritage


Item Design Notes:


1. Will map from SCREEN form to DEMO form.

2. Will be imputed if a partial date is entered based on the following conditions: If partial date of birth of UNK/MMM/YYYY = 15/MMM/YYYY If partial date of birth of UNK/UNK/YYYY = 30/JUN/YYYY

CDD: MAPPINGS1 Table: t_DEMO Key Type: PATIENTVISIT


DOBDT DATE - DDMONYYYY

BIRTHDT DATE - DDMONYYYY

SEX STRING(1)

CHDPOTCD STRING(1)

ETHNICCD STRING(1)

RACECCD11 STRING(255)










NGM114840_mjo : 12-LEAD ECG (ECG)

1. Date and Time of ECG Hr:Min (00:00-23:59)

Req / Req / Req (2011-2013)

Req : Req 24-hour clock

(MAPPINGS1:t_ECG_A_SCR.EGDTTM)

2. Heart rate xxx ( n >= 0 ) beats/min (MAPPINGS1:t_ECG_A_SCR.EGHR)

3. PR Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_A_SCR.PR)

4. QRS Duration xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_A_SCR.QRS)

5. Uncorrected QT Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_A_SCR.QT)

6. Method of QTc Calculation (MAPPINGS1:t_ECG_A_SCR.EGMTCLCD)

[1] Machine; record QTc value(s) generated by the machine

(MAPPINGS1:t_ECG_A_SCR.chkQTCB)

[B] QTcB (Bazett) xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_A_SCR.QTCB)

(MAPPINGS1:t_ECG_A_SCR.chkQTCF)

[F] QTcF (Fridericia) xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_A_SCR.QTCF)

(MAPPINGS1:t_ECG_A_SCR.chkQTC)

[U] QTc (Unspecified method of correction) xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_A_SCR.QTC)

[2] (MAPPINGS1:t_ECG_A_SCR.rdcRR)

Manual; record the RR interval that precedes the measured QT interval

[RR] RR interval xxxxxx ( n >= 0 ) msec (MAPPINGS1:t_ECG_A_SCR.RR)

[NA] RR interval not available

7. Result of the ECG (MAPPINGS1:t_ECG_A_SCR.EGINTPCD)

[1] Normal

[2] Abnormal - Not clinically significant

[3] Abnormal - Clinically significant (complete the ECG abnormality form for all clinically significant abnormalities, and additionally complete the AE form if the abnormality meets the protocol definition for an AE)

[4] No result (not available)

Form Design Note:

Screening ECG

CDD: MAPPINGS1 Table: t_ECG_A_SCR Key Type: PATIENTVISIT


EGDTTM DATE - DDMONYYYY HHMM

EGHR NUMERIC - N3

PR FLOAT - F6.0

QRS FLOAT - F6.0

QT FLOAT - F6.0

EGMTCLCD NUMERIC

chkQTCB STRING(255)

QTCB FLOAT - F6.0

chkQTCF STRING(255)

QTCF FLOAT - F6.0

chkQTC STRING(255)

QTC FLOAT - F6.0

rdcRR STRING(2)

RR NUMERIC - N6

EGINTPCD STRING(1)


NGM114840_mjo : VITAL SIGNS (VS)

1. Actual date/time Hr:Min (00:00-23:59)

Req / Req / Req (2011-2013)


(MAPPINGS1:t_VITALS_A_SCR.VSACTDTTM)

2. Height xxx ( n >= 0 ) cm (MAPPINGS1:t_VITALS_A_SCR.HEIGHT)

3. Weight xxx.x ( n >= 0.0 ) kg (MAPPINGS1:t_VITALS_A_SCR.WEIGHT)

Body mass index (MAPPINGS1:t_VITALS_A_SCR.VSBMI)

4. Blood pressure xxx ( n >= 0 ) / (MAPPINGS1:t_VITALS_A_SCR.SYSBP) xxx ( n >= 0 ) mmHg (MAPPINGS1:t_VITALS_A_SCR.DIABP)

(systolic/diastolic)

5. Heart rate xxx ( n >= 0 ) beats/min (MAPPINGS1:t_VITALS_A_SCR.HEART)

Form Design Note:

Screening vital signs

Item Design Notes:


itmVSBMI Item to be calculated as: Weight in kilograms divided by the square of height in meters

CDD: MAPPINGS1 Table: t_VITALS_A_SCR Key Type: PATIENTVISIT


VSACTDTTM DATE - DDMONYYYY HHMM

HEIGHT NUMERIC - N3

WEIGHT FLOAT - F5.1

VSBMI STRING(255)

SYSBP NUMERIC - N3

DIABP NUMERIC - N3

HEART NUMERIC - N3


NGM114840_mjo : ELECTRONICALLY TRANSFERRED SAFETY LAB DATA (Lab)

1. Haematology Date and time sample taken Hr:Min (00:00-23:59)

(MAPPINGS1:t_LABLINK_X1_A.rdcLABDTTM)

[-99]

Date Req / Req / Req (2011-2013)


(MAPPINGS1:t_LABLINK_X1_A.LBDTTM1)

[ND] Not Done

2. Clinical Chemistry Date and time sample taken Hr:Min (00:00-23:59)

(MAPPINGS1:t_LABLINK_X1_A.rdcLABDTTM1)

[-

98]

Same as the Haematology sample

[-

99]




[ND] Not Done

3. Urinalysis Date and time sample taken Hr:Min (00:00-23:59)

(MAPPINGS1:t_LABLINK_X1_A.rdcLABDTTM)

[-

99]




[ND] Not Done

Form Design Note:

Bench Lablink form (x1) Clone A.

Section Design Notes:

Title Design Note

sctLABLINK_X1_A_1 If only one sample date and time is needed for all lab tests performed remove the last two items and modify the text of the first item

Item Design Notes:


1. Time is optional. Use this item as the first item on this form. For additional tests, use the second item.

2. Time is optional. Use this item for all other samples on the form


CDD: MAPPINGS1 Table: t_LABLINK_X1_A Key Type: PATIENTTOITEM


rdcLABDTTM STRING(3)

LBDTTM1 DATE - DDMONYYYY HHMM

rdcLABDTTM1 STRING(3)


NGM114840_mjo : ELIGIBILITY QUESTION (ELIG)

ELIGIBILITY QUESTION

1. Did the subject meet all the entry criteria? (MAPPINGS1:t_ELIG.IEELIG)

[Y] Yes

[N] No, please select all boxes corresponding to violations of any inclusion/exclusion criteria

Inclusion Criteria

(MAPPINGS1:t_ELIG.IECRTNUMI01)

[I01] 1. Suitable as determined by the Principal Investigator, based on his/her overall evaluation. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the Investigator and the GlaxoSmithKline Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.


[I02] 2. Diagnosed with a relapsing form of MS defined as either

a. RRMS according to revised McDonald Criteria [McDonald, 2001; Polman, 2005] and a history of brain MRI lesions consistent with MS, OR b. SPMS with relapses and a history of brain MRI lesions


[I03] 3. Using one of the following ongoing MS treatment strategies, defined as

a. Currently receiving Beta-interferon/Copaxone for treatment of MS and have been receiving the current course of therapy for 3 or more months prior to screening, OR b. Not currently receiving disease modifying therapies for treatment of MS, and has not received such therapies for at least 3 months prior to screening.


[I04] 4. Have demonstrated clinical activity in 2 years prior to screening, whilst receiving current/previous treatment regimen or prior to any treatment regimen, by either:

a. One or more documented relapses, or b. One or more documented Gd enhancing lesions in the brain or spinal cord, or c. Confirmed disease progression on EDSS by greater than or equal to 0.5 points.


[I05] 5. Expanded Disability Status Scale (EDSS) score ≤6.0 at either the screening or baseline visit.


[I06] 6. Male or female between 18 and 60 years of age inclusive, at the time of signing the informed consent.


[I07] 7. A female subject is eligible to participate as follows:


b. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods described in Section 7.1.1 if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status prior to study enrollment. For most forms of HRT, at least two to four weeks must elapse between the cessation of therapy and the blood draw; this interval depends on the type and dose of HRT. Following confirmation of their post-menopausal status, subjects may resume use of HRT during the study without use of a contraceptive method.

c. Women of childbearing potential should have used one of the contraception methods listed in Section 7.1 for at least 1 month prior to the start of dosing to sufficiently minimize the risk of pregnancy. Women of childbearing potential must agree to continue to use contraception throughout the study and for an additional 6 months after dosing. Their male partners should also use contraception.


[I08] 8. Male subjects must agree to use one of the contraception methods listed in Section 7.1.2, even if they have had a vasectomy. This criterion must be followed from the time of the first dose of study medication, during the study, and for 6 months after dosing.


[I09] 9. Body weight ≥ 50 kg .


[I10] 10. On ECG, QTcB interval < 450 msec; or QTc < 480 msec in subjects with bundle branch block.


[I11] 11. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form, and authorisation of the release and use of protected health information (PHI).

Exclusion Criteria

(MAPPINGS1:t_ELIG.IECRTNUME01)

[E01] 1. History of, or laboratory findings indicative of any clinically significant (as determined by the Investigator) cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal, and/or other major disease or of known drug sensitivity that would preclude the administration of a recombinant humanized antibody or the use of systemic steroids during the course of the study.


[E02] 2. Abnormal baseline blood tests exceeding any of the limits defined below:

� Alanine transaminase (ALT) or aspartate transaminase (AST) >1.5 x the upper limit of normal (ULN) � Alkaline phosphatase (AP) and bilirubin >1.5X ULN (isolated bilirubin >1.5x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). � Total white blood cell count < 2,500/mm3 � Platelet count < 95,000/mm3 � Creatinine > 2 x ULN � Calculated creatinine clearance < 60 ml/min (per Cockcroft & Gault) at Screening � International Normalised Ratio (INR) larger than upper limit of the normal reference range (0.9 - 1.3)


[E03] 3. Treatment with methylprednisolone or any other systemic steroid, for a relapse or otherwise, within 30 days of screening


[E04] 4. Treatment within the past 12 months or currently with any of the following agents: cyclosporine, cladribine, natalizumab (Tysabri) or other monoclonal antibodies, murine protein, T-cell vaccination, plasmapheresis, IV IgG, stem cell transplantation.


[E05] 5. Treatment in the past 6 months with any of the following agents: Fingolimod (Gilenya), methotrexate, mitoxantrone, azathioprine, or other small molecule immunosuppressants.


[E06] 6. History of intolerance to acetominophen, ibuprofen, naproxen or any other nonsteroidal anti-inflammatory agent which would preclude use of at least one of these during the study.


[E07] 7. Previous history of anaphylaxis, severe allergic reaction, generation of neutralizing antibodies, or hypersensitivity to albumin or a protein-based therapeutic, including natalizumab (Tysabri) or any other monoclonal antibody. History of hypersensitivity to any of the components of the formulation.


[E08] 8. History of alcohol or drug abuse (as defined by DSM-IVR criteria) within 2 years prior to randomization


[E09] 9. A positive pre-study hepatitis B surface antigen or positive hepatitis C antibody result.


[E10] 10. Subjects with evidence of dementia or psychiatric illness which, in the Investigator's opinion, is likely to prevent them from a full understanding of and/or compliance with the study requirements and procedures.


[E11] 11. Known diagnosis or history consistent with human immunodeficiency virus (HIV) positivity.


[E12] 12. Blood donation (1 unit or more) within 3 months prior to investigational drug administration.


[E13] 13. History of regular alcohol consumption within 6 months of the study defined as: Average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 g of alcohol: a half-pint (~240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.


[E14] 14. Subjects who have received vaccinations 3 weeks prior to administration of study drug.


[E15] 15. Contraindications to MRI scanning including but not limited to:

� Intracranial aneurysm clips (except Sugita clips) with an appropriate operative conformation; � History of intra-orbital metal fragments that have not been removed by an MD; � Documented: � Pacemakers and non-MRI compatible heart valves � Inner ear implants � History of severe claustrophobia or inability to lie still on the back for a period of approximately one (1) hour in the MRI scanner.


[E16] 16. Contraindications for administration of Gd-contrast agents ie. any history of severe renal insufficiency if not already mentioned above.


[E17] 17. Greater than 10 Gadolinium-enhancing lesions present at screening MRI.


[E18] 18. Unwillingness or inability to follow the procedures outlined in the protocol.


[E19] 19. Subjects with a medical history of significant infections (such as tuberculosis, opportunistic or atypical infections) or any congenital or acquired immunodeficiency


[E20] 20. Active or latent tuberculosis (TB) infection: All subjects will be tested with QuantiFERON TB Gold test and those with positive test result will be excluded. [Note: Subjects with an indeterminate test result may undergo one re-test; a subsequent indeterminate or positive result excludes participation]. Chest radiographs may be performed if the investigator determines that it is clinically indicated and any abnormal findings suggestive of active or latent TB will exclude thes patient



[E21] 21. Subjects, who in the investigator's judgement, pose a significant suicide risk. Evidence of serious suicide risk may include any history of suicidal behavior in the last 6 months and/or any suicidal ideation of type 4 or 5 on the C-SSRS in the last 2 months.

Form Design Note:

IDSL Version 02.00A - 22 NOV 06

CDD: MAPPINGS1 Table: t_ELIG Key Type: PATIENTVISIT


IEELIG STRING(1)

IECRTNUMI01 STRING(255)











IECRTNUME01 STRING(255)






















NGM114840_mjo : SUBJECT IDENTIFICATION (Subj ID)

SUBJECT NUMBER

1. Subject number A6 (MAPPINGS1:t_SUBID.mtxtSubjectNumber)

CDD: MAPPINGS1 Table: t_SUBID Key Type: PATIENTVISIT


mtxtSubjectNumber STRING(6) - A6


NGM114840_mjo : MEDICAL CONDITIONS (MEDHX)

MEDICAL CONDITIONS

Check only one response for each MedDRA System Organ Class

1. Blood and lymphatic system disorders (MAPPINGS1:t_MEDHIST_C.MHSTATCD)

[1] Current, specify:

A200

(MAPPINGS1:t_MEDHIST_C.MHTERMCurrent)

[2] Past, specify:

A200

(MAPPINGS1:t_MEDHIST_C.MHTERMPast)

[3] No Medical History

2. Cardiac disorders (MAPPINGS1:t_MEDHIST_C.MHSTATCD)


A200


[2] Past, specify:

A200



3. Ear and labyrinth disorders (MAPPINGS1:t_MEDHIST_C.MHSTATCD)


A200


[2] Past, specify:

A200



4. Endocrine disorders (MAPPINGS1:t_MEDHIST_C.MHSTATCD)


A200


[2] Past, specify:

A200



5. Eye disorders (MAPPINGS1:t_MEDHIST_C.MHSTATCD)


A200


[2] Past, specify:

A200



6. Gastrointestinal disorders (MAPPINGS1:t_MEDHIST_C.MHSTATCD)


A200


[2] Past, specify:

A200



7. Hepatobiliary disorders (MAPPINGS1:t_MEDHIST_C.MHSTATCD)


A200


[2] Past, specify:

A200



8. Immune system disorders (MAPPINGS1:t_MEDHIST_C.MHSTATCD)


A200


[2] Past, specify:

A200



9. Metabolism and nutrition disorders (MAPPINGS1:t_MEDHIST_C.MHSTATCD)


A200


[2] Past, specify:

A200




10. Musculoskeletal and connective tissue disorders (MAPPINGS1:t_MEDHIST_C.MHSTATCD)


A200


[2] Past, specify:

A200



11. Neoplasms benign, malignant and unspecified (including cysts and polyps) (MAPPINGS1:t_MEDHIST_C.MHSTATCD)


A200


[2] Past, specify:

A200



12. Nervous system disorders (MAPPINGS1:t_MEDHIST_C.MHSTATCD)


A200


[2] Past, specify:

A200



13. Psychiatric disorders (MAPPINGS1:t_MEDHIST_C.MHSTATCD)


A200


[2] Past, specify:

A200



14. Renal and urinary disorders (MAPPINGS1:t_MEDHIST_C.MHSTATCD)


A200


[2] Past, specify:

A200



15. Reproductive system and breast disorders (MAPPINGS1:t_MEDHIST_C.MHSTATCD)


A200


[2] Past, specify:

A200



16. Respiratory, thoracic and mediastinal disorders (MAPPINGS1:t_MEDHIST_C.MHSTATCD)


A200


[2] Past, specify:

A200



17. Skin and subcutaneous tissue disorders (MAPPINGS1:t_MEDHIST_C.MHSTATCD)


A200


[2] Past, specify:

A200



18. Vascular disorders (MAPPINGS1:t_MEDHIST_C.MHSTATCD)


A200


[2] Past, specify:

A200



19. Infections and infestations (MAPPINGS1:t_MEDHIST_C.MHSTATCD)



A200


[2] Past, specify:

A200



20. Congenital, familial and genetic disorders (MAPPINGS1:t_MEDHIST_C.MHSTATCD)


A200


[2] Past, specify:

A200



21. General disorders and administration site conditions (MAPPINGS1:t_MEDHIST_C.MHSTATCD)


A200


[2] Past, specify:

A200



22. Injury, poisoning and procedural complications (MAPPINGS1:t_MEDHIST_C.MHSTATCD)


A200


[2] Past, specify:

A200



23. Investigations (MAPPINGS1:t_MEDHIST_C.MHSTATCD)


A200


[2] Past, specify:

A200



Form Design Note:

IDSL Version 02.00A - 21 APR 05 This form is optional


Title Design Note

MEDICAL CONDITIONS The following combinations are acceptable: 1. Current+No Medical Condition;2. Current+Past+No Medical Condition;3. Past+No Medical History. Not Assessed is optional for all combinations. Combinations must be consistent for all terms specified

CDD: MAPPINGS1 Table: t_MEDHIST_C Key Type: PATIENTTOITEM


MHSTATCD STRING(1)

MHTERMCurrent STRING(200) - A200

MHTERMPast STRING(200) - A200


NGM114840_mjo : MULTIPLE SCLEROSIS MEDICAL HISTORY (MSHIST)

MULTIPLE SCLEROSIS MEDICAL HISTORY

1. Date of onset of initial MS symptoms Req/Unk / Req/Unk / Req/Unk (1951-2013) (MAPPINGS1:t_MSHIST.MSONSDT)

2. Date of MS diagnosis Req / Req / Req (1951-2013) (MAPPINGS1:t_MSHIST.MSDIAGDT)

3. Total Number of Relapses xx (MAPPINGS1:t_MSHIST.RELAPTOT)

4. Number of relapses in the last 12 months xx (MAPPINGS1:t_MSHIST.RELAP12)

5. Number of relapses in the last 24 months xx (MAPPINGS1:t_MSHIST.RELAP24)

6. Date of last relapse Req/Unk / Req/Unk / Req/Unk (1951-2013) (MAPPINGS1:t_MSHIST.RELAPDT)

SEQ Date symptoms started Date

seen in

clinic

Was the

subject admitted

to hospital?

Deficit

Type

Outcome Event

Course

Intensity

7. [hidden]

Click on the 'Add Entry' button to record details of each relapse the subject experienced in the past 12 months Entry

SEQ [hidden] (MAPPINGS1:t_MSHIST.SEQ)

7.a Date symptoms started NReq/Unk / Req / Req (2010-2013) (MAPPINGS1:t_MSHIST.SYMSTDT_MSHIST)

7.b Date seen in clinic NReq/Unk / Req / Req (2010-2013) (MAPPINGS1:t_MSHIST.CLINDT_MSHIST)

7.c Was the subject admitted to hospital? (MAPPINGS1:t_MSHIST.HADMIN_MSHIST)

[N] No

[Y] Yes. If yes, enter both dates below

Date of admission NReq/Unk / Req / Req (2010-2013) (MAPPINGS1:t_MSHIST.ADMISDT_MSHIST)

Date of discharge NReq/Unk / Req / Req (2010-2013) (MAPPINGS1:t_MSHIST.DISCHDT_MSHIST)

7.d Type of Neurological Deficit (check all that apply) (MAPPINGS1:t_MSHIST.DEFICICD_MSHIST)

[1] Visual

[2] Brainstem

[3] Pyramidal

[4] Cerebellar

[5] Sensory

[6] Bladder/Bowel

[7] Mental

7.e Outcome (MAPPINGS1:t_MSHIST.NDOUTCD_MSHIST)

[1] Ongoing

[2] Resolved, enter the End Date

NReq/Unk / Req / Req (2010-2013) (MAPPINGS1:t_MSHIST.NDENDT_MSHIST)

7.f Event Course (MAPPINGS1:t_MSHIST.NDCOURCD)

[2] Constant

[1] Intermittent

xx Number of episodes (MAPPINGS1:t_MSHIST.NDEPISOD)

7.g Maximum Intensity (MAPPINGS1:t_MSHIST.NDINTCD)

[1] Mild

[2] Moderate

[3] Severe

8. Number of scans showing new lesions in the last 12 months xx (MAPPINGS1:t_MSHIST.SCNNLES)

9. Date of last steroid use Req / Req / Req (1951-2013) (MAPPINGS1:t_MSHIST.LSTRDDT)

Form Design Note:

MS Version 01.00A - JUL 08

Item Design Notes:


4. This item is optional.

5. This item is optional.

8. This item is optional

CDD: MAPPINGS1 Table: t_MSHIST Key Type: PATIENTVISIT


MSONSDT DATE - DDMONYYYY

MSDIAGDT DATE - DDMONYYYY

RELAPTOT NUMERIC - N2

RELAP12 NUMERIC - N2

RELAP24 NUMERIC - N2

RELAPDT DATE - DDMONYYYY

SEQ STRING(255)

SYMSTDT_MSHIST DATE - DDMONYYYY

CLINDT_MSHIST DATE - DDMONYYYY

HADMIN_MSHIST STRING(1)

ADMISDT_MSHIST DATE - DDMONYYYY

DISCHDT_MSHIST DATE - DDMONYYYY

DEFICICD_MSHIST STRING(255)

NDOUTCD_MSHIST NUMERIC

NDENDT_MSHIST DATE - DDMONYYYY

NDCOURCD NUMERIC

NDEPISOD NUMERIC - N2

NDINTCD STRING(1)

SCNNLES NUMERIC - N2

LSTRDDT DATE - DDMONYYYY



NGM114840_mjo : ELECTRONICALLY TRANSFERRED CRANIAL MRI DATA (CRAN_MRI)

1. Date of Cranial MRI Date Req / Req / Req (2011-2013) (MAPPINGS1:t_CRAN_MRI.SCNSTDTTM)

CDD: MAPPINGS1 Table: t_CRAN_MRI Key Type: PATIENTVISIT


SCNSTDTTM DATE - DDMONYYYY


NGM114840_mjo : Neurological Exam (NeurExam)

Neurological Examination

1. Exam date/time Req / Req / Req (2011-2013)


(MAPPINGS1:t_NEUREXAM_X1_A.ACTDTTM)

2. Mental Status (MAPPINGS1:t_NEUREXAM_X1_A.rdcNERES)

[0] Normal

[1] Abnormal, specify

A200

(MAPPINGS1:t_NEUREXAM_X1_A.NETXT)

3. Gait (MAPPINGS1:t_NEUREXAM_X1_A.rdcNERES)

[0] Normal


A200


4. Balance (MAPPINGS1:t_NEUREXAM_X1_A.rdcNERES)

[0] Normal


A200


5. Coordination (MAPPINGS1:t_NEUREXAM_X1_A.rdcNERES)

[0] Normal


A200


6. Cranial Nerves (MAPPINGS1:t_NEUREXAM_X1_A.rdcNERES)

[0] Normal


A200


7. Motor (MAPPINGS1:t_NEUREXAM_X1_A.rdcNERES)

[0] Normal


A200


8. Reflexes (MAPPINGS1:t_NEUREXAM_X1_A.rdcNERES)

[0] Normal


A200


9. Sensory (MAPPINGS1:t_NEUREXAM_X1_A.rdcNERES)

[0] Normal


A200


CDD: MAPPINGS1 Table: t_NEUREXAM_X1_A Key Type: PATIENTTOITEM


ACTDTTM DATE - DDMONYYYY HHMM

rdcNERES STRING(1)

NETXT STRING(200) - A200


NGM114840_mjo : ELECTRONICALLY TRANSFERRED BIOMARKER DATA (BIOMARK)

1. Date/time of biomarker collection Hr:Min (00:00-23:59)



(MAPPINGS1:t_BIOMARK_X1_A.BIACTDTTM)

CDD: MAPPINGS1 Table: t_BIOMARK_X1_A Key Type: PATIENTVISIT


BIACTDTTM DATE - DDMONYYYY HHMM


NGM114840_mjo : COLUMBIA SUICIDE SEVERITY RATING SCALE - V4BL (CSSRS)

SUICIDAL IDEATION


This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by copyright laws and therefore have been excluded.

NGM114840_mjo : Expanded Disability Status Scale (Neurostatus) (EDSS)



NGM114840_mjo : 12-LEAD ECG (ECG)


Req / Req / Req (2011-2013)


(MAPPINGS1:t_ECG_X1_A.EGDTTM)

2. Heart rate xxx ( n >= 0 ) beats/min (MAPPINGS1:t_ECG_X1_A.EGHR)

3. PR Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X1_A.PR)

4. QRS Duration xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X1_A.QRS)

5. Uncorrected QT Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X1_A.QT)

6. Method of QTc Calculation (MAPPINGS1:t_ECG_X1_A.EGMTCLCD)


(MAPPINGS1:t_ECG_X1_A.chkQTCB)

[B] QTcB (Bazett) xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X1_A.QTCB)

(MAPPINGS1:t_ECG_X1_A.chkQTCF)

[F] QTcF (Fridericia) xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X1_A.QTCF)

(MAPPINGS1:t_ECG_X1_A.chkQTC)

[U] QTc (Unspecified method of correction) xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X1_A.QTC)

[2] (MAPPINGS1:t_ECG_X1_A.rdcRR)


[RR] RR interval xxxxxx ( n >= 0 ) msec (MAPPINGS1:t_ECG_X1_A.RR)


7. Result of the ECG (MAPPINGS1:t_ECG_X1_A.EGINTPCD)

[1] Normal




Form Design Note:

Bench ECG (x1) clone A

CDD: MAPPINGS1 Table: t_ECG_X1_A Key Type: PATIENTVISIT



EGHR NUMERIC - N3

PR FLOAT - F6.0

QRS FLOAT - F6.0

QT FLOAT - F6.0

EGMTCLCD NUMERIC

chkQTCB STRING(255)

QTCB FLOAT - F6.0

chkQTCF STRING(255)

QTCF FLOAT - F6.0

chkQTC STRING(255)

QTC FLOAT - F6.0

rdcRR STRING(2)

RR NUMERIC - N6

EGINTPCD STRING(1)


NGM114840_mjo : Weight (Weight)


Req / Req / Req (2011-2013)


(MAPPINGS1:t_VITALS_X1_C.VSACTDTTM)

2. Weight xxx.x ( n >= 0.0 ) kg (MAPPINGS1:t_VITALS_X1_C.WEIGHT)

Form Design Note:

Bench vitals (x1) clone C

CDD: MAPPINGS1 Table: t_VITALS_X1_C Key Type: PATIENTVISIT



WEIGHT FLOAT - F5.1


NGM114840_mjo : Confirm Eligibility (Confirm Eligibility)

1. Did the subject meet all Inclusion/Exclusion criteria on the ELIG form at Screening? (MAPPINGS1:t_ELIG_CONF.ELIG_CONF)

[Y] Yes

[N] No

CDD: MAPPINGS1 Table: t_ELIG_CONF Key Type: PATIENTVISIT


ELIG_CONF STRING(1)


NGM114840_mjo : RANDOMISATION NUMBER (Rand)

RANDOMISATION

1. Randomisation number xxxxxx (MAPPINGS1:t_RAND.RANDNUM)

2. Randomisation date Req / Req / Req (2011-2013) (MAPPINGS1:t_RAND.RANDDT)

CDD: MAPPINGS1 Table: t_RAND Key Type: PATIENTVISIT


RANDNUM NUMERIC - N6

RANDDT DATE - DDMONYYYY


NGM114840_mjo : COHORT (Cohort)

REGIMEN

1. Regimen (MAPPINGS1:t_REGIMEN.REGIMECD)

[23] Cohort 1

[24] Cohort 2

[35] Cohort 3

Form Design Note:

Bench Regimen form

CDD: MAPPINGS1 Table: t_REGIMEN Key Type: PATIENTVISIT


REGIMECD STRING(2)


NGM114840_mjo : STRATA (STRATA)

STRATA

1. Strata (MAPPINGS1:t_STRATA_COH2.STRATACD)

[1] Strata 1

[2] Strata 2

[3] Strata 3

[4] Strata 4

CDD: MAPPINGS1 Table: t_STRATA_COH2 Key Type: PATIENTVISIT


STRATACD STRING(1)


NGM114840_mjo : STRATA (STRATA)

STRATA

1. Strata (MAPPINGS1:t_STRATA_COH3.STRATACD_COH3)

[5] Strata 5

[6] Strata 6

[7] Strata 7

[8] Strata 8

CDD: MAPPINGS1 Table: t_STRATA_COH3 Key Type: PATIENTVISIT


STRATACD_COH3 STRING(1)


NGM114840_mjo : CSF SAMPLE TAKEN? (CSF SAMPLE TAKEN?)

1. Was a lumbar puncture performed at this visit to collect a CSF sample? (MAPPINGS1:t_LUMB_PUNCT_TRIG.LUMB_PUNCT_TRIG)

[Y] Yes

[N] No

CDD: MAPPINGS1 Table: t_LUMB_PUNCT_TRIG Key Type: PATIENTVISIT


LUMB_PUNCT_TRIG STRING(1)


NGM114840_mjo : Neurological Exam (NeurExam)

DOSING DATE AND TIME

1.* Dosing date/time (Start) [read-only] Req / Req / Req (2011-2013)


(MAPPINGS1:t_NEUREXAM_X1_B.CDDDOSESTDTTM)

2.* Dosing date/time (Stop) [read-only] Req / Req / Req (2011-2013)


(MAPPINGS1:t_NEUREXAM_X1_B.CDDDOSESPDTTM)

Pre-Dose Neurological Examination



(MAPPINGS1:t_NEUREXAM_X1_B.ACTDTTM)

4. Mental Status (MAPPINGS1:t_NEUREXAM_X1_B.rdcNERES)

[0] Normal


A200

(MAPPINGS1:t_NEUREXAM_X1_B.NETXT)

5. Gait (MAPPINGS1:t_NEUREXAM_X1_B.rdcNERES)

[0] Normal


A200


6. Balance (MAPPINGS1:t_NEUREXAM_X1_B.rdcNERES)

[0] Normal


A200


7. Coordination (MAPPINGS1:t_NEUREXAM_X1_B.rdcNERES)

[0] Normal


A200


8. Cranial Nerves (MAPPINGS1:t_NEUREXAM_X1_B.rdcNERES)

[0] Normal


A200


9. Motor (MAPPINGS1:t_NEUREXAM_X1_B.rdcNERES)

[0] Normal


A200


10. Reflexes (MAPPINGS1:t_NEUREXAM_X1_B.rdcNERES)

[0] Normal


A200


11. Sensory (MAPPINGS1:t_NEUREXAM_X1_B.rdcNERES)

[0] Normal


A200



CDD: MAPPINGS1 Table: t_NEUREXAM_X1_B Key Type: PATIENTTOITEM


CDDDOSESTDTTM DATE - DDMONYYYY HHMM

CDDDOSESPDTTM DATE - DDMONYYYY HHMM


rdcNERES STRING(1)



NGM114840_mjo : Expanded Disability Status Scale (Neurostatus) (EDSS)




NGM114840_mjo : COLUMBIA SUICIDE SEVERITY RATING SCALE - V4LV (CSSRS1)

SUICIDAL IDEATION



NGM114840_mjo : INVESTIGATIONAL PRODUCT - IV DOSING (IP IV)

1. Start Date and Time Hr:Min (00:00-23:59)

Req / Req / Req (2011-2013)


(MAPPINGS1:t_EXPOSURE_IV_X1_A.EXSTDTTM)

2. Stop Date and Time Hr:Min (00:00-23:59)

Req / Req / Req (2011-2013)


(MAPPINGS1:t_EXPOSURE_IV_X1_A.EXENDTTM)

3. Dose xxxx.xx (MAPPINGS1:t_EXPOSURE_IV_X1_A.DOSE)

4. Did the subject receive the correct treatment (e.g., treatment which the subject was assigned to) during this dosing interval? If the full dose was not given, please record the proportion that was administered

(MAPPINGS1:t_EXPOSURE_IV_X1_A.EXTRTCFM)

[Y] Yes

[N] No, record reason(s)

A200

(MAPPINGS1:t_EXPOSURE_IV_X1_A.EXTRTRS)

Form Design Note:

Bench IP IV (x1) Clone A

Item Design Notes:


1. Time is optional

2. Time is optional

CDD: MAPPINGS1 Table: t_EXPOSURE_IV_X1_A Key Type: PATIENTVISIT


EXSTDTTM DATE - DDMONYYYY HHMM

EXENDTTM DATE - DDMONYYYY HHMM

DOSE FLOAT - F7.2

EXTRTCFM STRING(1)

EXTRTRS STRING(200) - A200


NGM114840_mjo : PRE DOSE 12-LEAD ECG (PRE DOSE ECG)




(MAPPINGS1:t_ECG_X3_A.CDDDOSESTDTTM)



(MAPPINGS1:t_ECG_X3_A.CDDDOSESPDTTM)

PRE DOSE


Req / Req / Req (2011-2013)


(MAPPINGS1:t_ECG_X3_A.EGDTTM)

4. Heart rate xxx ( n >= 0 ) beats/min (MAPPINGS1:t_ECG_X3_A.EGHR)

5. PR Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_A.PR)

6. QRS Duration xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_A.QRS)

7. Uncorrected QT Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_A.QT)

8. Method of QTc Calculation (MAPPINGS1:t_ECG_X3_A.EGMTCLCD)


(MAPPINGS1:t_ECG_X3_A.chkQTCB)

[B] QTcB (Bazett) xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_A.QTCB)

(MAPPINGS1:t_ECG_X3_A.chkQTCF)

[F] QTcF (Fridericia) xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_A.QTCF)

(MAPPINGS1:t_ECG_X3_A.chkQTC)

[U] QTc (Unspecified method of correction) xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_A.QTC)

[2] (MAPPINGS1:t_ECG_X3_A.rdcRR)


[RR] RR interval xxxxxx ( n >= 0 ) msec (MAPPINGS1:t_ECG_X3_A.RR)


9. Result of the ECG (MAPPINGS1:t_ECG_X3_A.EGINTPCD)

[1] Normal





Form Design Note:

Bench ECG (x3) clone A

CDD: MAPPINGS1 Table: t_ECG_X3_A Key Type: PATIENTVISIT





EGHR NUMERIC - N3

PR FLOAT - F6.0

QRS FLOAT - F6.0

QT FLOAT - F6.0

EGMTCLCD NUMERIC

chkQTCB STRING(255)

QTCB FLOAT - F6.0

chkQTCF STRING(255)

QTCF FLOAT - F6.0

chkQTC STRING(255)

QTC FLOAT - F6.0

rdcRR STRING(2)

RR NUMERIC - N6

EGINTPCD STRING(1)


NGM114840_mjo : 2H 12-LEAD ECG (2H ECG)




(MAPPINGS1:t_ECG_X3_B.CDDDOSESTDTTM)



(MAPPINGS1:t_ECG_X3_B.CDDDOSESPDTTM)

2H (1 of 3)


Req / Req / Req (2011-2013)


(MAPPINGS1:t_ECG_X3_B.EGDTTM)

4. Heart rate xxx ( n >= 0 ) beats/min (MAPPINGS1:t_ECG_X3_B.EGHR)

5. PR Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_B.PR)

6. QRS Duration xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_B.QRS)

7. Uncorrected QT Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_B.QT)

8. Method of QTc Calculation (MAPPINGS1:t_ECG_X3_B.EGMTCLCD)


(MAPPINGS1:t_ECG_X3_B.chkQTCB)

[B] QTcB (Bazett) xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_B.QTCB)

(MAPPINGS1:t_ECG_X3_B.chkQTCF)

[F] QTcF (Fridericia) xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_B.QTCF)

(MAPPINGS1:t_ECG_X3_B.chkQTC)

[U] QTc (Unspecified method of correction) xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_B.QTC)

[2] (MAPPINGS1:t_ECG_X3_B.rdcRR)


[RR] RR interval xxxxxx ( n >= 0 ) msec (MAPPINGS1:t_ECG_X3_B.RR)


9. Result of the ECG (MAPPINGS1:t_ECG_X3_B.EGINTPCD)

[1] Normal




2H (2 of 3)


Req / Req / Req (2011-2013)




















[1] Normal




2H (3 of 3)


Req / Req / Req (2011-2013)




















[1] Normal






Form Design Note:

Bench ECG (x3) clone B

CDD: MAPPINGS1 Table: t_ECG_X3_B Key Type: PATIENTTOSECTION





EGHR NUMERIC - N3

PR FLOAT - F6.0

QRS FLOAT - F6.0

QT FLOAT - F6.0

EGMTCLCD NUMERIC

chkQTCB STRING(255)

QTCB FLOAT - F6.0

chkQTCF STRING(255)

QTCF FLOAT - F6.0

chkQTC STRING(255)

QTC FLOAT - F6.0

rdcRR STRING(2)

RR NUMERIC - N6

EGINTPCD STRING(1)






(MAPPINGS1:t_ECG_X3_C.CDDDOSESTDTTM)



(MAPPINGS1:t_ECG_X3_C.CDDDOSESPDTTM)

3H (1 of 3)


Req / Req / Req (2011-2013)


(MAPPINGS1:t_ECG_X3_C.EGDTTM)

4. Heart rate xxx ( n >= 0 ) beats/min (MAPPINGS1:t_ECG_X3_C.EGHR)

5. PR Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_C.PR)

6. QRS Duration xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_C.QRS)

7. Uncorrected QT Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_C.QT)

8. Method of QTc Calculation (MAPPINGS1:t_ECG_X3_C.EGMTCLCD)


(MAPPINGS1:t_ECG_X3_C.chkQTCB)

[B] QTcB (Bazett) xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_C.QTCB)

(MAPPINGS1:t_ECG_X3_C.chkQTCF)

[F] QTcF (Fridericia) xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_C.QTCF)

(MAPPINGS1:t_ECG_X3_C.chkQTC)

[U] QTc (Unspecified method of correction) xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_C.QTC)

[2] (MAPPINGS1:t_ECG_X3_C.rdcRR)


[RR] RR interval xxxxxx ( n >= 0 ) msec (MAPPINGS1:t_ECG_X3_C.RR)


9. Result of the ECG (MAPPINGS1:t_ECG_X3_C.EGINTPCD)

[1] Normal




3H (2 of 3)


Req / Req / Req (2011-2013)




















[1] Normal




3H (3 of 3)


Req / Req / Req (2011-2013)




















[1] Normal






Form Design Note:

Bench ECG (x3) clone C

CDD: MAPPINGS1 Table: t_ECG_X3_C Key Type: PATIENTTOSECTION





EGHR NUMERIC - N3

PR FLOAT - F6.0

QRS FLOAT - F6.0

QT FLOAT - F6.0

EGMTCLCD NUMERIC

chkQTCB STRING(255)

QTCB FLOAT - F6.0

chkQTCF STRING(255)

QTCF FLOAT - F6.0

chkQTC STRING(255)

QTC FLOAT - F6.0

rdcRR STRING(2)

RR NUMERIC - N6

EGINTPCD STRING(1)






(MAPPINGS1:t_ECG_X3_D.CDDDOSESTDTTM)



(MAPPINGS1:t_ECG_X3_D.CDDDOSESPDTTM)

12H (1 of 3)


Req / Req / Req (2011-2013)


(MAPPINGS1:t_ECG_X3_D.EGDTTM)

4. Heart rate xxx ( n >= 0 ) beats/min (MAPPINGS1:t_ECG_X3_D.EGHR)

5. PR Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_D.PR)

6. QRS Duration xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_D.QRS)

7. Uncorrected QT Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_D.QT)

8. Method of QTc Calculation (MAPPINGS1:t_ECG_X3_D.EGMTCLCD)


(MAPPINGS1:t_ECG_X3_D.chkQTCB)

[B] QTcB (Bazett) xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_D.QTCB)

(MAPPINGS1:t_ECG_X3_D.chkQTCF)

[F] QTcF (Fridericia) xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_D.QTCF)

(MAPPINGS1:t_ECG_X3_D.chkQTC)

[U] QTc (Unspecified method of correction) xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_D.QTC)

[2] (MAPPINGS1:t_ECG_X3_D.rdcRR)


[RR] RR interval xxxxxx ( n >= 0 ) msec (MAPPINGS1:t_ECG_X3_D.RR)


9. Result of the ECG (MAPPINGS1:t_ECG_X3_D.EGINTPCD)

[1] Normal




12H (2 of 3)


Req / Req / Req (2011-2013)




















[1] Normal




12H (3 of 3)


Req / Req / Req (2011-2013)




















[1] Normal






Form Design Note:

Bench ECG (x3) clone D

CDD: MAPPINGS1 Table: t_ECG_X3_D Key Type: PATIENTTOSECTION





EGHR NUMERIC - N3

PR FLOAT - F6.0

QRS FLOAT - F6.0

QT FLOAT - F6.0

EGMTCLCD NUMERIC

chkQTCB STRING(255)

QTCB FLOAT - F6.0

chkQTCF STRING(255)

QTCF FLOAT - F6.0

chkQTC STRING(255)

QTC FLOAT - F6.0

rdcRR STRING(2)

RR NUMERIC - N6

EGINTPCD STRING(1)






(MAPPINGS1:t_ECG_X3_E.CDDDOSESTDTTM)



(MAPPINGS1:t_ECG_X3_E.CDDDOSESPDTTM)

24H (1 of 3)


Req / Req / Req (2011-2013)


(MAPPINGS1:t_ECG_X3_E.EGDTTM)

4. Heart rate xxx ( n >= 0 ) beats/min (MAPPINGS1:t_ECG_X3_E.EGHR)

5. PR Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_E.PR)

6. QRS Duration xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_E.QRS)

7. Uncorrected QT Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_E.QT)

8. Method of QTc Calculation (MAPPINGS1:t_ECG_X3_E.EGMTCLCD)


(MAPPINGS1:t_ECG_X3_E.chkQTCB)

[B] QTcB (Bazett) xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_E.QTCB)

(MAPPINGS1:t_ECG_X3_E.chkQTCF)

[F] QTcF (Fridericia) xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_E.QTCF)

(MAPPINGS1:t_ECG_X3_E.chkQTC)

[U] QTc (Unspecified method of correction) xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_X3_E.QTC)

[2] (MAPPINGS1:t_ECG_X3_E.rdcRR)


[RR] RR interval xxxxxx ( n >= 0 ) msec (MAPPINGS1:t_ECG_X3_E.RR)


9. Result of the ECG (MAPPINGS1:t_ECG_X3_E.EGINTPCD)

[1] Normal




24H (2 of 3)


Req / Req / Req (2011-2013)




















[1] Normal




24H (3 of 3)


Req / Req / Req (2011-2013)




















[1] Normal






Form Design Note:

Bench ECG (x3) clone E

CDD: MAPPINGS1 Table: t_ECG_X3_E Key Type: PATIENTTOSECTION





EGHR NUMERIC - N3

PR FLOAT - F6.0

QRS FLOAT - F6.0

QT FLOAT - F6.0

EGMTCLCD NUMERIC

chkQTCB STRING(255)

QTCB FLOAT - F6.0

chkQTCF STRING(255)

QTCF FLOAT - F6.0

chkQTC STRING(255)

QTC FLOAT - F6.0

rdcRR STRING(2)

RR NUMERIC - N6

EGINTPCD STRING(1)


NGM114840_mjo : TELEMETRY OR BEDSIDE CARDIAC MONITORING (Cardiac Monitoring)




(MAPPINGS1:t_HMSUM_TEL_X1_A.CDDDOSESTDTTM)



(MAPPINGS1:t_HMSUM_TEL_X1_A.CDDDOSESPDTTM)

PRE-DOSE - 24 H

3. Start Date and Time of Telemetry Hr:Min (00:00-23:59)

Req / Req / Req (2011-2013)


(MAPPINGS1:t_HMSUM_TEL_X1_A.HMSTDTTM)

4. Stop Date and Time of Telemetry Hr:Min (00:00-23:59)

Req / Req / Req (2011-2013)


(MAPPINGS1:t_HMSUM_TEL_X1_A.HMENDTTM)

5. Result of telemetry or bedside cardiac monitoring (MAPPINGS1:t_HMSUM_TEL_X1_A.HMORRSCD_TEL)

[1] Normal


[3] Abnormal - Clinically significant

[4] No result

[8] Unable to evaluate


Item Design Notes:


5. No result and unable to evaluate are optional items

CDD: MAPPINGS1 Table: t_HMSUM_TEL_X1_A Key Type: PATIENTVISIT




HMSTDTTM DATE - DDMONYYYY HHMM

HMENDTTM DATE - DDMONYYYY HHMM

HMORRSCD_TEL STRING(1)


NGM114840_mjo : SUMMARY TELEMETRY ABNORMALITIES (Telemetry Ab)

RECORD CLINICALLY SIGNIFICANT ABNORMALITIES BELOW

INCLUDE ABNORMALITIES FOR TELEMETRY AT THIS VISIT ONLY

1. Check all that apply (MAPPINGS1:t_HMSUM_TEL_AB.HMORRSCD6)

[A00] No abnormalities

(MAPPINGS1:t_HMSUM_TEL_AB.HMORRSCD7)

[A01] Sinus bradycardia (50-59 beats/min)






[A04] Sinus bradycardia (<30 beats/min)


[A05] Sinus pause


[A06] Sinus tachycardia (>100 beats/min)


[A07] Ectopic supraventricular beats


[A08] Ectopic supraventricular rhythm


[A09] Wandering atrial pacemaker


[A10] Multifocal atrial tachycardia (wandering atrial pacemaker w/rate >100 beats/min)


[A11] Non-sustained supraventricular tachycardia (>100 beats/min, 3-30 beats)


[A12] Sustained supraventricular tachycardia (>100 beats/min, >30 beats)


[A13] Atrial flutter


[A14] Atrial fibrillation


[A15] Junctional rhythm (<=100 beats/min, defined by narrow QRS complex)


[A16] Junctional tachycardia (>100 beats/min)


[A17] Ventricular premature depolarisation


[A18] Ventricular couplets


[A19] Bigeminy


[A20] Trigeminy


[A21] Electrical alternans


[A22] R on T phenomenon


[A23] Ventricular fibrillation


[A24] Idioventricular rhythm (<=100 beats/min, defined by wide QRS complex)


[A25] Non-sustained ventricular tachycardia (>100 beats/min, 3-30 beats)


[A26] Sustained ventricular tachycardia (>100 beats/min, >30 beats)


[A27] Wide QRS tachycardia (diagnosis unknown)


[A28] Monomorphic non-sustained ventricular tachycardia (>100 beats/min, 3-30 beats)


[A29] Monomorphic sustained ventricular tachycardia (>100 beats/min, >30 beats)


[A30] Polymorphic non-sustained ventricular tachycardia (>100 beats/min, 3-30 beats)


[A31] Polymorphic sustained ventricular tachycardia (>100 beats/min, >30 beats)


[A32] Torsade de Pointes (TdP)


[A33] Pacemaker


[A34] First degree AV block (PR interval >200msec)


[A35] Short PR Interval


[A36] Second degree AV block (Mobitz type 1)




[A38] 2:1 AV block


[A39] Third degree AV block


[A40] Left axis deviation (QRS axis more negative than -30 degrees)


[A41] Right axis deviation (QRS axis more positive than +110 degrees)


[A42] Incomplete right bundle branch block


[A43] Incomplete left bundle branch block


[A44] Right bundle branch block


[A45] Left anterior hemiblock


[A46] Left posterior hemiblock


[A47] Left bundle branch block


[A48] Bifascicular block


[A49] Non-specific intraventricular conduction delay (QRS >=120 msec)


[A50] Accessory pathway (Wolff-Parkinson-White, Lown-Ganong-Levine)


[A51] QTc prolongation >=500 msec


[A52] AV dissociation


[A53] Myocardial infarction, old



[A54] Myocardial infarction, non Q-wave


[A55] Non-specific ST-T changes


[A56] J point elevation


[A57] ST elevation


[A58] ST depression


[A59] ST segment abnormality


[A60] U waves


[A61] T wave inversion


[A62] T wave peaked


[A63] T waves biphasic


[A64] T waves flat


[A65] Notched T-waves


[A66] Low QRS voltage


[A67] T wave abnormality


[A94] Other abnormal rhythm A200(MAPPINGS1:t_HMSUM_TEL_AB.HMORRSSP)


[A95] Other morphology A200(MAPPINGS1:t_HMSUM_TEL_AB.HMORRSSP1)


[A96] Other conduction A200(MAPPINGS1:t_HMSUM_TEL_AB.HMORRSSP2)


[A97] Other myocardial infarction A200(MAPPINGS1:t_HMSUM_TEL_AB.HMORRSSP3)


[A98] Other depolarisation/repolarisation A200(MAPPINGS1:t_HMSUM_TEL_AB.HMORRSSP4)


[A99] Other abnormality/Cardiologist comments A200(MAPPINGS1:t_HMSUM_TEL_AB.HMORRSSP5)

Form Design Note:

P1TT v2.6

CDD: MAPPINGS1 Table: t_HMSUM_TEL_AB Key Type: PATIENTVISIT


HMORRSCD6 STRING(255)






































































HMORRSSP STRING(200) - A200


HMORRSSP1 STRING(200) - A200














(MAPPINGS1:t_VITALS_X20_A.CDDDOSESTDTTM)



(MAPPINGS1:t_VITALS_X20_A.CDDDOSESPDTTM)

PRE-DOSE


Req / Req / Req (2011-2013)


(MAPPINGS1:t_VITALS_X20_A.VSACTDTTM)

4. Weight xxx.x ( n >= 0.0 ) kg (MAPPINGS1:t_VITALS_X20_A.WEIGHT)

5. Blood pressure xxx ( n >= 0 ) / (MAPPINGS1:t_VITALS_X20_A.SYSBP) xxx ( n >= 0 ) mmHg (MAPPINGS1:t_VITALS_X20_A.DIABP)


6. Heart rate xxx ( n >= 0 ) beats/min (MAPPINGS1:t_VITALS_X20_A.HEART)

1 H

7. Actual time Hr:Min (00:00-23:59)

Req : Req 24-hour clock (MAPPINGS1:t_VITALS_X20_A.CDDVSACTTM)




3 H

10. Actual time Hr:Min (00:00-23:59)

Req : Req 24-hour clock (MAPPINGS1:t_VITALS_X20_A.CDDVSACTTM)




12 H


Req / Req / Req (2011-2013)






24 H


Req / Req / Req (2011-2013)







Form Design Note:

Bench vitals (x20) clone A

CDD: MAPPINGS1 Table: t_VITALS_X20_A Key Type: PATIENTTOSECTION





WEIGHT FLOAT - F5.1

SYSBP NUMERIC - N3

DIABP NUMERIC - N3

HEART NUMERIC - N3

CDDVSACTTM DATE - HHMM


NGM114840_mjo : ELECTRONICALLY TRANSFERRED SAFETY LAB DATA (Lab)




(MAPPINGS1:t_LABLINK_X1_B.CDDDOSESTDTTM)



(MAPPINGS1:t_LABLINK_X1_B.CDDDOSESPDTTM)

PRE-DOSE


(MAPPINGS1:t_LABLINK_X1_B.rdcLABDTTM)

[-99]



(MAPPINGS1:t_LABLINK_X1_B.LBDTTM1)

[ND] Not Done


(MAPPINGS1:t_LABLINK_X1_B.rdcLABDTTM1)

[-

98]


[-

99]




[ND] Not Done


(MAPPINGS1:t_LABLINK_X1_B.rdcLABDTTM)

[-99]




[ND] Not Done


Form Design Note:

Bench Lablink form (x1) Clone B.


Title Design Note

PRE-DOSE If only one sample date and time is needed for all lab tests performed remove the last two items and modify the text of the first item

Item Design Notes:





CDD: MAPPINGS1 Table: t_LABLINK_X1_B Key Type: PATIENTTOITEM








NGM114840_mjo : PHARMACOKINETICS BLOOD - [GSK1223249] (PK)




(MAPPINGS1:t_PK_X20_A.CDDDOSESTDTTM)



(MAPPINGS1:t_PK_X20_A.CDDDOSESPDTTM)

PRE-DOSE

3. Actual date/time Req / Req / Req (2011-2013)


(MAPPINGS1:t_PK_X20_A.PKSTDTTM)

4. Sample identifier A17 (MAPPINGS1:t_PK_X20_A.PKSMPID)

1 H

5. Actual time Req : Req 24-hour clock (MAPPINGS1:t_PK_X20_A.CDDPKSTTM)


6 H

7. Actual time Req : Req 24-hour clock (MAPPINGS1:t_PK_X20_A.CDDPKSTTM)


12 H





24 H






Form Design Note:

Bench PK (x20) clone A

CDD: MAPPINGS1 Table: t_PK_X20_A Key Type: PATIENTTOSECTION




PKSTDTTM DATE - DDMONYYYY HHMM

PKSMPID STRING(17) - A17

CDDPKSTTM DATE - HHMM


NGM114840_mjo : IMMUNOGENICITY SAMPLING (IMGLINK)




(MAPPINGS1:t_IMGLINK_A.CDDDOSESTDTTM)



(MAPPINGS1:t_IMGLINK_A.CDDDOSESPDTTM)

3. Was a Immunogenicity sample collected? (MAPPINGS1:t_IMGLINK_A.IGSMPCOL)

[Y] Date/time of sample taken

Req / Req / Req (2011-2013)

NReq : NReq 24-hour clock

(MAPPINGS1:t_IMGLINK_A.IGDTTM)

[N] No

4.* Immunogenicity Sample ID number A17 (MAPPINGS1:t_IMGLINK_A.IGREFID)


Form Design Note:

IDSL Version 01.00A - 05 AUG 09. This form is optional

Item Design Notes:


3. Time is an optional item

4. Sample ID is an optional item

CDD: MAPPINGS1 Table: t_IMGLINK_A Key Type: PATIENTVISIT




IGSMPCOL STRING(1)

IGDTTM DATE - DDMONYYYY HHMM

IGREFID STRING(17) - A17


NGM114840_mjo : CEREBROSPINAL FLUID SAMPLING (CSFLINK)

1. Was a Cerebrospinal Fluid sample collected? (MAPPINGS1:t_CSFLINK_A.CSFSMPCOL)


Req / Req / Req (2011-2013)


(MAPPINGS1:t_CSFLINK_A.CSFDTTM)

[N] No

2.* Cerebrospinal Fluid Sample ID number A17 (MAPPINGS1:t_CSFLINK_A.CSFREFID)


Item Design Notes:




CDD: MAPPINGS1 Table: t_CSFLINK_A Key Type: PATIENTVISIT


CSFSMPCOL STRING(1)

CSFDTTM DATE - DDMONYYYY HHMM

CSFREFID STRING(17) - A17




Req / Req / Req (2011-2013)


(MAPPINGS1:t_VITALS_X1_B.VSACTDTTM)

2. Blood pressure xxx ( n >= 0 ) / (MAPPINGS1:t_VITALS_X1_B.SYSBP) xxx ( n >= 0 ) mmHg (MAPPINGS1:t_VITALS_X1_B.DIABP)


3. Heart rate xxx ( n >= 0 ) beats/min (MAPPINGS1:t_VITALS_X1_B.HEART)

Form Design Note:

Bench vitals (x1) clone B

CDD: MAPPINGS1 Table: t_VITALS_X1_B Key Type: PATIENTVISIT



SYSBP NUMERIC - N3

DIABP NUMERIC - N3

HEART NUMERIC - N3


NGM114840_mjo : PHARMACOKINETICS BLOOD - [GSK1223249] (PK)





Form Design Note:

Bench PK (x1) clone A

CDD: MAPPINGS1 Table: t_PK_X1_A Key Type: PATIENTVISIT







Req / Req / Req (2011-2013)



2. Weight xxx.x ( n >= 0.0 ) kg (MAPPINGS1:t_VITALS_X1_A.WEIGHT)




Form Design Note:

Bench vitals (x1) clone A

CDD: MAPPINGS1 Table: t_VITALS_X1_A Key Type: PATIENTVISIT



WEIGHT FLOAT - F5.1

SYSBP NUMERIC - N3

DIABP NUMERIC - N3

HEART NUMERIC - N3


NGM114840_mjo : IMMUNOGENICITY SAMPLING (IMGLINK)

1. Was a Immunogenicity sample collected? (MAPPINGS1:t_IMGLINK_B.IGSMPCOL)


Req / Req / Req (2011-2013)


(MAPPINGS1:t_IMGLINK_B.IGDTTM)

[N] No

2.* Immunogenicity Sample ID number A17 (MAPPINGS1:t_IMGLINK_B.IGREFID)


Form Design Note:

IDSL Version 01.00A - 05 AUG 09. This form is optional

Item Design Notes:




CDD: MAPPINGS1 Table: t_IMGLINK_B Key Type: PATIENTVISIT


IGSMPCOL STRING(1)




NGM114840_mjo : ELECTRONICALLY TRANSFERRED LAB DATA (Lab)


(MAPPINGS1:t_LABLINK_X1_C.rdcLABDTTM)

[-99]



(MAPPINGS1:t_LABLINK_X1_C.LBDTTM1)

[ND] Not Done


(MAPPINGS1:t_LABLINK_X1_C.rdcLABDTTM1)

[-

98]


[-

99]




[ND] Not Done


(MAPPINGS1:t_LABLINK_X1_C.rdcLABDTTM)

[-

99]




[ND] Not Done

Form Design Note:

Bench Lablink form (x1) Clone C.


Title Design Note

sctLABLINK_X1_C_1 If only one sample date and time is needed for all lab tests performed remove the last two items and modify the text of the first item

Item Design Notes:





CDD: MAPPINGS1 Table: t_LABLINK_X1_C Key Type: PATIENTTOITEM






NGM114840_mjo : STATUS OF TREATMENT BLIND (Blind)

STATUS OF TREATMENT BLIND

1. Was the treatment blind broken during the study?If yes, complete the Adverse Event form and/or Investigational Product forms as appropriate Hr:Min (00:00-23:59)

(MAPPINGS1:t_BLIND.BLBRK)

[N] No

[Y] Yes, complete the following :

Date/time blind broken

Req / Req / Req (2011-2013)


(MAPPINGS1:t_BLIND.BLDTTM)

(MAPPINGS1:t_BLIND.BLREASCD)

Reason blind broken

[1] Medical emergency requiring identification of investigational product for further treatment

[Z] Other, specify

A200

(MAPPINGS1:t_BLIND.BLRSOTH)

Item Design Notes:


1. Time blind broken is optional

CDD: MAPPINGS1 Table: t_BLIND Key Type: PATIENTVISIT


BLBRK STRING(1)

BLDTTM DATE - DDMONYYYY HHMM

BLREASCD STRING(1)

BLRSOTH STRING(200) - A200


NGM114840_mjo : STUDY CONCLUSION (Conclusion)

If the subject completed the study »Date of last contact must match the last actual contact with the subject whether or not the contact was a clinic visit. If the subject withdrew »Date of decision to withdraw must match the date of subject withdrawal. »Date of last contact must match the last actual contact with the subject whether or not the contact was a clinic visit. Do not record dates of unsuccessful attempts to contact the subject. Note: An ’actual contact’ is defined as an interaction between the subject and the investigator or investigator’s designee, where the investigator/designee has the opportunity to query the subject about the subject’s status. This would include clinic visits and telephone contacts, but normally would not include mail correspondence or third party reports.

STUDY CONCLUSION

1. Date of last contact Req / Req / Req (2011-2013) (MAPPINGS1:t_DS_CONCLUSION.DSSTDT)

2. Was the subject withdrawn from the study? (MAPPINGS1:t_DS_CONCLUSION.DSFAIL1)

[N] No

[Y] Yes; complete details : Date of decision to withdraw

Req / Req / Req (2011-2013) (MAPPINGS1:t_DS_CONCLUSION.DSSTDT)

(MAPPINGS1:t_DS_CONCLUSION.DSRSCD)

Primary reason for withdrawal

[1] Adverse Event Record details on the Non-Serious Adverse Events or Serious Adverse Events forms as appropriate.

[2] Lack of efficacy

[3] Protocol deviation

[4] Subject reached protocol defined stopping criteria

[5] Study closed/terminated

[6] Lost to Follow-up

[7] Investigator discretion, specify Select this reason if none of the other primary reasons are appropriate.

A200

(MAPPINGS1:t_DS_CONCLUSION.DSRSSP)

[8] Withdrew consent

3.* Case book ready for signature [hidden] (MAPPINGS1:t_DS_CONCLUSION.chkReadyForSig)

[Y] Yes

Data owner should check the box when data cleaning is complete

Office Use 1 [hidden] (MAPPINGS1:t_DS_CONCLUSION.COMPLETERADIO)

[N] No [Y] Yes

Office Use 2 [hidden] (MAPPINGS1:t_DS_CONCLUSION.REASONRADIO)

[?] 1 [?] 2 [?] 3 [?] 4 [?] 5 [?] 6 [?] 7 [?] 8 [?] 9


Form Design Note:

IDSL version 01.01A - 15 MAY 07 (modified for Phase 1 template)


Title Design Note

STUDY CONCLUSION Alignment of predefined sub-reasons will be rectified once eCRF Designer has replaced [?] by valid codes.

Item Design Notes:


2. Pre-defined sub-reasons are optional. The following primary reasons are optional : Lack of efficacy, Subject reached protocol-defined stopping criteria, Investigator discretion.

CDD: MAPPINGS1 Table: t_DS_CONCLUSION Key Type: PATIENTTOITEM


DSSTDT DATE - DDMONYYYY

DSFAIL1 STRING(1)

DSRSCD STRING(1)

DSRSSP STRING(200) - A200

chkReadyForSig STRING(255)

COMPLETERADIO STRING(1)

REASONRADIO STRING(42)


NGM114840_mjo : PREGNANCY INFORMATION (Preg F)

PREGNANCY INFORMATION

1. Did the subject become pregnant during the study? If Yes, complete the paper Pregnancy Notification form

(MAPPINGS1:t_STATUS_PREG_F.PGYN)

[N] No

[Y] Yes

Form Design Note:

This is an optional form but is conditional upon females in the trial; This form will be dynamically generated to appear at the End visit if Female is selected on the Demographics form

CDD: MAPPINGS1 Table: t_STATUS_PREG_F Key Type: PATIENTVISIT


PGYN STRING(1)


NGM114840_mjo : PREGNANCY INFORMATION (Preg M)

PREGNANCY INFORMATION

1. Did a female partner of the male subject become pregnant during the study? If Yes, complete the paper Pregnancy Notification form

(MAPPINGS1:t_STATUS_PREG_M.PGFPYN)

[N] No

[Y] Yes

[X] Not Applicable

Check Not Applicable if female partner not of childbearing potential or no female partner

Form Design Note:

This is an optional form, but is conditional upon males in the trial. This form will be dynamically generated if the male is selected on the Demography form

CDD: MAPPINGS1 Table: t_STATUS_PREG_M Key Type: PATIENTVISIT


PGFPYN STRING(1)


NGM114840_mjo : LOGS AND REPEATS (Logs/Rpts)

Date below is the start of the study for this subject

DATE OF VISIT/ASSESSMENT

1. Date of visit/assessment Req / Req / Req (2011-2013) (MAPPINGS1:t_STATUS_LOGS.DOV)

ADVERSE EVENT/CONCOMITANT MEDICATION/REPEAT ASSESSMENT CHECK QUESTIONS

2. Were any concomitant medications taken by the subject during the study? (MAPPINGS1:t_STATUS_LOGS.CMANY)

[Y] Yes [N] No

3. Did the subject experience any non-serious adverse events during the study? (MAPPINGS1:t_STATUS_LOGS.AEANY)

[Y] Yes [N] No

4. Did the subject experience any serious adverse events during the study? (MAPPINGS1:t_STATUS_LOGS.SAEANY)

[Y] Yes [N] No

5. Did the subject experience any possible suicidality-related adverse events during the study? (MAPPINGS1:t_STATUS_LOGS.PSRAEANY)

[Y] Yes [N] No

6. Were any MS relapses experienced? (MAPPINGS1:t_STATUS_LOGS.rdcRptTrigger)

[Y] Yes [N] No

7. Were any repeat lab samples taken during the study? (MAPPINGS1:t_STATUS_LOGS.rdcRptTrigge1)

[Y] Yes [N] No

8. Were any repeat vital signs recorded? (MAPPINGS1:t_STATUS_LOGS.rdcRptTrigge2)

[Y] Yes [N] No

9. Were any repeat ECGs performed? (MAPPINGS1:t_STATUS_LOGS.rdcRptTrigge3)

[Y] Yes [N] No

10. Were any abnormal, clinically significant ECG measurements recorded for this subject during the study? (MAPPINGS1:t_STATUS_LOGS.rdcRptTrigge4)

[Y] Yes [N] No

11. Were any repeat PK blood samples taken? (MAPPINGS1:t_STATUS_LOGS.rdcRptTrigge5)

[Y] Yes [N] No

12. Were any repeat immunogenicity samples taken? (MAPPINGS1:t_STATUS_LOGS.rdcRptTrigge6)

[Y] Yes [N] No

13. Were any repeat biomarker samples taken? (MAPPINGS1:t_STATUS_LOGS.rdcRptTrigge7)

[Y] Yes [N] No

14. Were any repeat cranial MRIs performed? (MAPPINGS1:t_STATUS_LOGS.rdcRptTrigge8)

[Y] Yes [N] No

15. Were any repeat neurological exams performed? (MAPPINGS1:t_STATUS_LOGS.rdcRptTrigge9)

[Y] Yes [N] No

16. Were any repeat Expanded Disability Status Scales (EDSS) administered? (MAPPINGS1:t_STATUS_LOGS.rdcRptTrigg10)

[Y] Yes [N] No

17. Was any repeat Telemetry performed? (MAPPINGS1:t_STATUS_LOGS.rdcRptTrigg11)

[Y] Yes [N] No

LIVER EVENT

If liver event occurred, stop investigational product, complete date stopped on Investigational Product form and contact GSK within 24 hours of occurrence of liver event by phone or fax. NOTE: If the liver event meets the definition of an SAE, the SAE form must be completed in InForm. If InForm is unavailable, the SAE form should be faxed to GSK. * Obtain tests as per protocol * An unscheduled PK sample must be obtained within < insert time interval recommended by Clinical pharmacokinetics representative > of last dose * Complete Liver Event Forms (completed Liver Event Forms do not need to be supplied to GSK within 24 hours)

18. Have liver chemistry results reached or exceeded protocol-defined investigational product stopping criteria? (MAPPINGS1:t_STATUS_LOGS.LVEVTANY)

[Y] Yes [N] No

If Yes to Liver Events, go to the LE DETAILS visit and complete the Liver Event forms

Item Design Notes:


18. If response is Yes to Liver Events, go to the LE DETAILS tab and complete the liver events forms.

CDD: MAPPINGS1 Table: t_STATUS_LOGS Key Type: PATIENTVISIT


DOV DATE - DDMONYYYY

CMANY STRING(1)

AEANY STRING(1)

SAEANY STRING(1)

PSRAEANY STRING(1)

rdcRptTrigger STRING(1)

rdcRptTrigge1 STRING(1)









rdcRptTrigg10 STRING(1)

rdcRptTrigg11 STRING(1)

LVEVTANY STRING(1)


NGM114840_mjo : NON-SERIOUS ADVERSE EVENT (AE) - Repeating Form

# Event Start Date and Time Outcome Frequency Maximum Intensity Action Taken Subject Withdrawn? Relationship

1

NON-SERIOUS ADVERSE EVENT

1.* Sequence Number [hidden] A5 (MAPPINGS1:t_AE.AESEQ)

2. Event Diagnosis Only (if known) Otherwise Sign/Symptom

A100(MAPPINGS1:t_AE.AETERM)

3.* Modified term Do not query this item, as it is not displayed for sites [hidden]

A100(AE_CODE:0.LogsRpts.AE.sctAE.0.itmAELLTCD.AELLTCD) (AE_FAILED:0.LogsRpts.AE.sctAE.0.itmAE_FAILED.calAE_FAILED) (AE_SYNONYM:0.LogsRpts.AE.sctAE.0.itmAEMEDSYN.AEMEDSYN) (MAPPINGS1:t_AE.AEMODIFY)

MedDRA synonym [hidden] (MAPPINGS1:t_AE.AEMEDSYN)

MedDRA lower level term code [hidden] (MAPPINGS1:t_AE.AELLTCD)

Failed coding [hidden] (MAPPINGS1:t_AE.calAE_FAILED)


Req / Req / Req (2011-2013)

Req/Unk : Req/Unk 24-hour clock

(MAPPINGS1:t_AE.AESTDTTM)

5. Outcome / End Date and Time Hr:Min (00:00-23:59)

(MAPPINGS1:t_AE.AEOUTCD)

[1] Recovered/Resolved, provide End Date and Time

Req / Req / Req (2011-2013)


(MAPPINGS1:t_AE.AEENDTTM1)

[2] Recovering/Resolving

[3] Not recovered/Not resolved

[4] Recovered/Resolved with sequelae, provide End Date and Time

Req / Req / Req (2011-2013)


(MAPPINGS1:t_AE.AEENDTTM2)

6. Frequency (MAPPINGS1:t_AE.AEFREQCD)

[1] Single Episode

[2] Intermittent

7. Maximum Intensity (MAPPINGS1:t_AE.AESEVCD)

[1] Mild

[2] Moderate

[3] Severe

[X] Not applicable

8.* Maximum Grade [hidden] (MAPPINGS1:t_AE.AETOXCD)

[1] Grade 1

[2] Grade 2

[3] Grade 3

[4] Grade 4

9.* Maximum Grade or Intensity [hidden] (MAPPINGS1:t_AE.AETXHVCD)

[1] Mild or Grade 1

[2] Moderate or Grade 2

[3] Severe or Grade 3

[4] Grade 4

[5] Grade 5

[X] Not applicable

10. Action Taken with Investigational Product(s) as a Result of the AE (MAPPINGS1:t_AE.AEACTRCD)

[1] Investigational product(s) withdrawn

[2] Dose reduced

[3] Dose increased

[4] Dose not changed

[5] Dose interrupted

[X] Not applicable

11. Did the subject withdraw from study as a result of this AE? (MAPPINGS1:t_AE.AEWD)

[Y] Yes

[N] No

12. Is there a reasonable possibility that the AE may have been caused by the investigational product? (MAPPINGS1:t_AE.AEREL)

[Y] Yes

[N] No

13.* Duration of AE if < 24 hours [hidden] xx ( 0 =< n <= 23 )

Hr(s)

(MAPPINGS1:t_AE.AEDURHR) xx ( 0 =< n <= 59 )

Min(s)

(MAPPINGS1:t_AE.AEDURMIN)

14.* Time to Onset Since Last Dose [hidden] xx

Hr(s)

(MAPPINGS1:t_AE.AEONLDSH) xx ( 0 =< n <= 59 )

Min(s)

(MAPPINGS1:t_AE.AEONLDSM)


Form Design Note:

IDSL Version 03.01A - 16 NOV 2005

Item Design Notes:


4. Start Time is optional

5. End Time is optional


7. Optional item: This item may be hidden if either the "Maximum Grade" or "Maximum Grade or Intensity" item has been used. Grade 5 is optional.

8. Optional item: This item may be hidden if either the "Maximum Intensity" or "Maximum Grade or Intensity" item has been used Grade 5 is optional.

9. Optional item: This item may be hidden if either the "Maximum Intensity" or "Maximum Grade" item has been used Grade 5 is optional.

13. If AE start and end time are used this item must be hidden.



CDD: MAPPINGS1 Table: t_AE Key Type: PATIENTVISIT


AESEQ STRING(5) - A5

AETERM STRING(100) - A100

AEMODIFY STRING(100) - A100

AEMEDSYN STRING(255)

AELLTCD STRING(255)

calAE_FAILED STRING(255)

AESTDTTM DATE - DDMONYYYY HHMM

AEOUTCD STRING(1)

AEENDTTM1 DATE - DDMONYYYY HHMM


AEFREQCD STRING(1)

AESEVCD STRING(1)

AETOXCD STRING(1)

AETXHVCD STRING(1)

AEACTRCD STRING(1)

AEWD STRING(1)

AEREL STRING(1)

AEDURHR NUMERIC - N2

AEDURMIN NUMERIC - N2

AEONLDSH NUMERIC - N2

AEONLDSM NUMERIC - N2


NGM114840_mjo : SERIOUS ADVERSE EVENTS (SAE) - Repeating Form

# Initial Report

Follow-Up Report

Did SAE occur after initiation of study medication?

SERIOUS ADVERSE EVENT

Serious? RELEVANT CONCOMITANT/TREATMENT MEDICATIONS

RELEVANT MEDICAL CONDITIONS/RISK FACTORS

Relevant Medical History / Risk Factors

RELEVANT DIAGNOSTIC RESULTS

Relevant diagnostic results

If Investigational product(s) stopped, did the reported event(s) recur after further investigational product(s) were administered?

General narrative comments

1

If you wish to record a new SAE please determine if the new SAE is clinically or temporally related to an SAE previously entered on this form. If yes, record the details below using the 'Add Entry' button in this form. If not clinically or temporally related, create a new SAE form for this subject by clicking on the 'New' button at the top of the page. Do not record pre and post randomization events on the same form.

TYPE OF REPORT

1.* Initial Report [read-only] (MAPPINGS1:t_AE_SER.chkSAE)

[1] Initial

2.* Follow-Up Report [read-only] (MAPPINGS1:t_AE_SER.chkFU)

[2] Follow-Up

RANDOMISATION

3. Did SAE occur after initiation of study medication? (MAPPINGS1:t_AE_SER.rdcSAERAND)

[N] No

[Y] Yes

SAE Sequence Number Event Modified term

MedDRA synonym

MedDRA lower

level term code

Failed coding

Start Date

and Time

Outcome Maximum Intensity

Maximum Grade

Maximum Grade or

Intensity

Action Taken

Subject Withdrawn?

Relationship Duration of AE if

< 24 hours

Time to Onset

Was SAE

study related?

Was the event

serious?

4. [hidden] [hidden] [hidden] [hidden] [hidden] [hidden] [hidden] [hidden] [hidden] [hidden]

SERIOUS ADVERSE EVENT Entry

4.a* SAE Sequence Number [hidden] A5 (MAPPINGS1:t_AE_SER.AESEQ)

4.b Serious Adverse Event Diagnosis Only (if known) Otherwise Sign/Symptom

A100(MAPPINGS1:t_AE_SER.AETERM)

4.c* Modified term Do not query this item, as it is not displayed for sites [hidden]

A100(AE_CODE1:0.LogsRpts.AE_SER.sctSAE.itsSAE.itmAELLTCD.AELLTCD) (AE_FAILED1:0.LogsRpts.AE_SER.sctSAE.itsSAE.itmAE_FAILED.calAE_FAILED) (AE_SYNONYM1:0.LogsRpts.AE_SER.sctSAE.itsSAE.itmAEMEDSYN.AEMEDSYN) (MAPPINGS1:t_AE_SER.AEMODIFY)

MedDRA synonym [hidden] (MAPPINGS1:t_AE_SER.AEMEDSYN)

MedDRA lower level term code [hidden] (MAPPINGS1:t_AE_SER.AELLTCD)

Failed coding [hidden] (MAPPINGS1:t_AE_SER.calAE_FAILED)

4.d Start Date and Time Hr:Min (00:00-23:59)

Req / Req / Req (2011-2013)


(MAPPINGS1:t_AE_SER.AESTDTTM)

4.e Outcome / End Date and Time Hr:Min (00:00-23:59)

(MAPPINGS1:t_AE_SER.AEOUTCD1)

[1] Recovered/Resolved, provide End Date and Time

Req / Req / Req (2011-2013)


(MAPPINGS1:t_AE_SER.AEENDTTM1)

[2] Recovering/Resolving

[3] Not recovered/Not resolved

[4] Recovered/Resolved with sequelae, provide End Date and Time

Req / Req / Req (2011-2013)



[5] Fatal, record Date and Time of Death

Req / Req / Req (2011-2013)



4.f Maximum Intensity (MAPPINGS1:t_AE_SER.AESEVCD)

[1] Mild

[2] Moderate

[3] Severe

[X] Not applicable

4.g* Maximum Grade [hidden] (MAPPINGS1:t_AE_SER.AETOXCD)

[1] Grade 1

[2] Grade 2

[3] Grade 3

[4] Grade 4

4.h* Maximum Grade or Intensity [hidden] (MAPPINGS1:t_AE_SER.AETXHVCD)

[1] Mild or Grade 1

[2] Moderate or Grade 2

[3] Severe or Grade 3

[4] Grade 4

[5] Grade 5

[X] Not applicable

4.i Action Taken with Investigational Product(s) as a Result of the AE (MAPPINGS1:t_AE_SER.AEACTRCD)

[1] Investigational product(s) withdrawn

[2] Dose reduced

[3] Dose increased

[4] Dose not changed

[5] Dose interrupted

[X] Not applicable

4.j Did the subject withdraw from study as a result of this AE? (MAPPINGS1:t_AE_SER.AEWD)

[Y] Yes

[N] No

4.k Is there a reasonable possibility that the AE may have been caused by the investigational product? (MAPPINGS1:t_AE_SER.AEREL)

[Y] Yes

[N] No

4.l* Duration of AE if < 24 hours [hidden] xx ( 0 =< n <= 23 )

Hr(s)

(MAPPINGS1:t_AE_SER.AEDURHR) xx ( 0 =< n <= 59 )

Min(s)

(MAPPINGS1:t_AE_SER.AEDURMIN)

4.m* Time to Onset Since Last Dose [hidden] xx

Hr(s)

(MAPPINGS1:t_AE_SER.AEONLDSH) xx ( 0 =< n <= 59 )

Min(s)

(MAPPINGS1:t_AE_SER.AEONLDSM)

4.n Was SAE caused by activities related to study participation (e.g. procedures)? (MAPPINGS1:t_AE_SER.rdcAESREL)

[Y] Yes

[N] No

4.o* Was the event serious? [hidden] (MAPPINGS1:t_AE_SER.AESER)

[Y] Yes

[N] No

SERIOUSNESS

Specify the reason for considering this an SAE. Check all that apply.


5. Seriousness? (MAPPINGS1:t_AE_SER.AESERDTH)

[A] Results in death

(MAPPINGS1:t_AE_SER.AESERLIF)

[B] Is life-threatening

(MAPPINGS1:t_AE_SER.AESERHOS)

[C] Requires hospitalisation or prolongation of existing hospitalisation

(MAPPINGS1:t_AE_SER.AESERDIS)

[D] Results in disability/incapacity

(MAPPINGS1:t_AE_SER.AESERCON)

[E] Congenital anomaly/birth defect

(MAPPINGS1:t_AE_SER.AESEROTH)

[F] Other, specify within general narrative comment

(MAPPINGS1:t_AE_SER.AESERPROTSP)

[G] Is associated with liver injury and impaired liver function defined as: ALT >= 3xULN, and either total bilirubin >= 2xULN or INR > 1.5

CM Sequence Number Drug Name

(Trade Name preferred)

Dose Unit Frequency Route Start

Date

Ongoing? Primary

Indication

Drug

Type

6. [hidden]

RELEVANT CONCOMITANT/TREATMENT MEDICATIONS Entry

Include details of any medication that may have contributed to the SAE or was used to treat the SAE.

6.a* CM Sequence Number [hidden] A4 (MAPPINGS1:t_AE_SER.txtSAECMSEQ)

6.b Drug Name (Trade Name preferred)

A100(MAPPINGS1:t_AE_SER.txtCMTERM)

6.c* Dose xxxxxxxxx. (MAPPINGS1:t_AE_SER.txtSAECMDOS)

6.d* Unit Pulldown List 1 (MAPPINGS1:t_AE_SER.pdcCMUNIT)

6.e* Frequency Pulldown List 2 (MAPPINGS1:t_AE_SER.pdcSAECMFRQ)

6.f* Route Pulldown List 3 (MAPPINGS1:t_AE_SER.pdcCMROUTCD)

6.g* Start Date Req/Unk / Req/Unk / Req/Unk (1951-2013) (MAPPINGS1:t_AE_SER.dtmSAECMSTD)

6.h* Ongoing? (MAPPINGS1:t_AE_SER.rdcSAECMONG)

[Y] Yes

[N] No, specify End Date

Req/Unk / Req/Unk / Req/Unk (1951-2013) (MAPPINGS1:t_AE_SER.dtmSAECMEND)

6.i* Primary Indication A50 (MAPPINGS1:t_AE_SER.txtCMIND)

6.j Drug Type Pulldown List 4 (MAPPINGS1:t_AE_SER.pdcCMDRGTYP)

MHx Sequence Number Specific Condition Name Date of onset

Continuing?

7. [hidden]

RELEVANT MEDICAL CONDITIONS/RISK FACTORS Entry

Specify past or current medical disorders, allergies, surgeries, family or social history that may help explain the SAE

7.a* MHx Sequence Number [hidden] A4 (MAPPINGS1:t_AE_SER.txtMHXSEQ)

7.b Specific Condition NameA100

(MAPPINGS1:t_AE_SER.txtSAEMHTRM)

7.c* Date of onset Req/Unk / Req/Unk / Req (1951-2013) (MAPPINGS1:t_AE_SER.dtmMHSTDTM)

7.d* Continuing? (MAPPINGS1:t_AE_SER.rdcMHCONT)

[Y] Yes

[N] No, specify date of last occurrence

Req/Unk / Req/Unk / Req (1951-2013) (MAPPINGS1:t_AE_SER.dtmMHLSTOC)

[U] Unknown

8.* Relevant Medical History / Risk Factors not noted above A1000

Lab Sequence Number Test Name Test

Date

Test Result Test Units Normal

Low Range

Normal

High Range

9. [hidden]

RELEVANT DIAGNOSTIC RESULTS Entry

Provide details of any tests or procedures carried out to diagnose the SAE.

9.a* Lab Sequence Number [hidden] A4 (MAPPINGS1:t_AE_SER.txtSAELBSEQ)

9.b Test Name Pulldown List 5 (MAPPINGS1:t_AE_SER.pdcLBTST)

9.c Test Date Req/Unk / Req/Unk / Req (2011-2013) (MAPPINGS1:t_AE_SER.dtmLABDTM)

9.d Test Result A50 (MAPPINGS1:t_AE_SER.txtLABRES)

9.e* Test Units A35 (MAPPINGS1:t_AE_SER.txtLABUNIT)

9.f* Normal Low Range xxxxxxx. (MAPPINGS1:t_AE_SER.txtLABNLR)

9.g* Normal High Range xxxxxxx. (MAPPINGS1:t_AE_SER.txtLABNHR)

10.* Relevant diagnostic results not noted above A1000

A1000

INVESTIGATIONAL PRODUCTS

11.* If Investigational product(s) stopped, did the reported event(s) recur after further investigational product(s) were administered?

(MAPPINGS1:t_AE_SER.rdcSAEIP)

[N] No

[Y] Yes

[U] Unknown at this time

[X] Not applicable

GENERAL NARRATIVE COMMENTS

Provide a brief narrative description of SAE, possible other causes of the event (e.g. lack of efficacy, withdrawal of investigational product, the disease under study or other medical conditions) and details of the treatment.

12. General narrative comments A1000


A1000

NON CLINICAL

13.* Send incomplete SAE data to GSK Safety [hidden] (MAPPINGS1:t_AE_SER.chkSAESENDI)

[3] Incomplete SAE

14.* Receipt by GSK date [hidden] Req / Req / Req (2011-2013)


(MAPPINGS1:t_AE_SER.dtmSAEDTM)

15.* Was the event serious? [hidden] (MAPPINGS1:t_AE_SER.AESE1)

[Y] Yes

[N] No

16.* SAE Sequence Number [hidden] A5 (MAPPINGS1:t_AE_SER.AESE2)

17.* Version Number [hidden] A4 (MAPPINGS1:t_AE_SER.txtSAEVERSION)

18.* Case ID [hidden] A20 (MAPPINGS1:t_AE_SER.txtSAEID)

19.* Randomisation Number [hidden] A255 (MAPPINGS1:t_AE_SER.txtSAERNDNO)

20.* OCEANS Code [hidden] A13 (MAPPINGS1:t_AE_SER.txtOCEANSCD)

Email Flag [hidden] (MAPPINGS1:t_AE_SER.calSAEEmailFlag)


Form Design Note:

Version 05.04A - 18 OCT 2006

Item Design Notes:


4.d Start Time is optional

4.e End Time is optional

4.f Optional item: This item may be hidden if either the "Maximum Grade" or "Maximum Grade or Intensity" item has been used. Grade 5 is optional.

4.g Optional item: This item may be hidden if either the "Maximum Intensity" or "Maximum Grade or Intensity" item has been used Grade 5 is optional.

4.h Optional item: This item may be hidden if either the "Maximum Intensity" or "Maximum Grade" item has been used Grade 5 is optional.

4.l If AE start and end time are used this item must be hidden.

4.m This item is optional

5. Optional Criterion G is an optional criterion and may be removed


Pulldown List 1:

RefName Display Text Value Design Note

estrSaeUnitACTU Actuation ACTU

estrSaeUnitAMP Ampoule AMP

estrSaeUnitAPP Application AP

estrSaeUnitBOT Bottle BT

estrSaeUnitCAP Capsule CAP

estrSaeUnitCC Cubic centimeter CC

estrSaeUnitGTT Drops 031

estrSaeUnitGM Gram 002

estrSaeUnitIU International units 025

estrSaeUnitIUKG International units per kilogram 028

estrSaeUnitIUML International units per millilitre IUML

estrSaeUnitL Litre 011

estrSaeUnitLPM Litre per minute LM

estrSaeUnitLOZ Lozenge LOZ

estrSaeUnitMU Megaunits (million units) MEGU

estrSaeUnitMCG Microgram (MCG) 004

estrSaeUnitUG Microgram (UG) 004

estrSaeUnitMCGKG Microgram/kilogram 008

estrSaeUnitMCGKGMIN Microgram/kilogram per minute MCG/KG/MIN

estrSaeUnitMCGMIN Micrograms per minute MCG/MIN

estrSaeUnitMCL Microlitre 013

estrSaeUnitMEQ Milliequivalent 029

estrSaeUnitMEQ24HR Milliequivalent per 24 hours MEQ24

estrSaeUnitMG Milligram 003

estrSaeUnitMGPER Milligrams percent MGPER

estrSaeUnitMGHR Milligram per hour MGH

estrSaeUnitMGKG Milligram/kilogram 007

estrSaeUnitMGKGHR Milligram/kilogram per hour MGKH

estrSaeUnitMGKGMIN Milligram/kilogram per minute MGKM

estrSaeUnitMGM2 Milligram/metre squared 009

estrSaeUnitMGML Milligram/millilitre MGML

estrSaeUnitML Millilitre 012

estrSaeUnitMLHR Millilitre per hour MLH

estrSaeUnitMLMIN Millilitre per minute MLM


estrSaeUnitMMOL Millimole 023

estrSaeUnitMIU Million international units 027

estrSaeUnitMAC Minimum alveolar concentration MAC

estrSaeUnitNEB Nebule NEB

estrSaeUnitPATCH Patch PAT

estrSaeUnitPer Percent 030

estrSaeUnitPUFF Puff PUFF

estrSaeUnitSACH Sachet SAC

estrSaeUnitSP Spray SPR

estrSaeUnitSUPP Suppository SUP

estrSaeUnitTBSP Tablespoon TBS

estrSaeUnitTAB Tablet TAB

estrSaeUnitTSP Teaspoon TSP

estrSaeUnitUNIT Units UNT

estrSaeUnitUNK Unknown U

estrSaeUnitVIAL Vial VIA

Pulldown List 2:


estrSaeFreq2XWK 2 times per week 2W



estrSaeFreq5XD 5 times per day 5D


estrSaeFreqAC AC AC

estrSaeFreqBID BID 2D

estrSaeFreqCINF Continuous infusion CO

estrSaeFreqQ2WK Every 2 weeks FO

estrSaeFreqQ3WK Every 3 weeks Q3WK

estrSaeFreqQ3M Every 3 months Q3M

estrSaeFreqQOD Every other day AD

estrSaeFreqHS At Bedtime 1N

estrSaeFreqQM Once a month MO

estrSaeFreqQWK Once a week WE

estrSaeFreqQD Once daily 1D

estrSaeFreqONE Once only 1S

estrSaeFreqPC PC PC

estrSaeFreqPRN PRN PRN

estrSaeFreqQ2H Q2H 12D

estrSaeFreqQ3D Q3D Q3D

estrSaeFreqQ4D Q4D Q4D





estrSaeFreqQAM QAM 1M

estrSaeFreqQH QH 24D

estrSaeFreqQID QID 4D

estrSaeFreqQPM QPM 1N

estrSaeFreqTID TID 3D

estrSaeFreqUNK Unknown U

Pulldown List 3:


estrSaeRouteOU Both eyes 047

estrSaeRouteEP Epidural 008

estrSaeRouteGTT Gastrostomy tube GT

estrSaeRouteIH Inhalation 055

estrSaeRouteINJ Injection INJ

estrSaeRouteIA Intra-arterial 013

estrSaeRouteIB Intra-bursa IBU

estrSaeRouteIL Intralesional 026

estrSaeRouteIM Intramuscular 030

estrSaeRouteIN Intranasal 045

estrSaeRouteIO Intraocular 031

estrSaeRouteIOS Intraosteal IOS

estrSaeRouteIP Intraperitoneal 033

estrSaeRouteIT Intrathecal 037

estrSaeRouteIU Intrauterine 015

estrSaeRouteIV Intravenous 042

estrSaeRouteNS Nasal 045

estrSaeRoutePO Oral 048

estrSaeRoutePR Rectal 054

estrSaeRouteSC Subcutaneous 058

estrSaeRouteSL Sublingual 060

estrSaeRouteTP Topical 061

estrSaeRouteTD Transdermal 062

estrSaeRouteUNK Unknown 065

estrSaeRouteVG Vaginal 067


Pulldown List 4:


estrDRUGTYPE01 Concomitant 2

estrDRUGTYPE02 Treatment T

estrDRUGTYPE03 Cause of SAE 1

Pulldown List 5:


estrSAELBTST01 Activated partial thromboplastin time Activated partial thromboplastin time

estrSAELBTST02 Albumin Albumin

estrSAELBTST03 Alkaline phosphatase Alkaline phosphatase

estrSAELBTST04 Amylase Amylase

estrSAELBTST05 Basophils Basophils

estrSAELBTST06 Bicarbonate Bicarbonate

estrSAELBTST07 Bilirubin Bilirubin

estrSAELBTST08 Bilirubin direct Bilirubin direct

estrSAELBTST09 Bilirubin total Bilirubin total

estrSAELBTST10 Blood myoglobin Blood myoglobin

estrSAELBTST11 Blood pH Blood pH

estrSAELBTST12 Blood pressure Blood pressure

estrSAELBTST13 Blood urea nitrogen Blood urea nitrogen

estrSAELBTST14 Body temperature Body temperature

estrSAELBTST15 Calcium Calcium

estrSAELBTST16 CD4 lymphocytes CD4 lymphocytes

estrSAELBTST17 CD8 lymphocytes CD8 lymphocytes

estrSAELBTST18 Chloride Chloride

estrSAELBTST19 Cholesterol total Cholesterol total

estrSAELBTST20 C-reactive protein C-reactive protein

estrSAELBTST21 Creatine Creatine

estrSAELBTST22 Creatine phosphokinase Creatine phosphokinase

estrSAELBTST23 Creatine phosphokinase MB Creatine phosphokinase MB

estrSAELBTST24 Creatinine Creatinine

estrSAELBTST25 Creatinine clearance Creatinine clearance

estrSAELBTST26 Diastolic blood pressure Diastolic blood pressure

estrSAELBTST27 Eosinophils Eosinophils

estrSAELBTST28 Erythrocyte sedimentation rate Erythrocyte sedimentation rate

estrSAELBTST29 Fasting blood glucose Fasting blood glucose

estrSAELBTST30 FEV 1 FEV 1

estrSAELBTST31 Gamma-glutamyltransferase Gamma-glutamyltransferase

estrSAELBTST32 Glutamic-oxaloacetic transferase Glutamic-oxaloacetic transferase

estrSAELBTST33 Glutamic-pyruvate transaminase Glutamic-pyruvate transaminase

estrSAELBTST34 HbA1c HbA1c

estrSAELBTST35 HBV-DNA decreased HBV-DNA decreased

estrSAELBTST36 HBV-DNA increased HBV-DNA increased

estrSAELBTST37 Heart rate Heart rate

estrSAELBTST38 Hematocrit Hematocrit

estrSAELBTST39 Hemoglobin Hemoglobin

estrSAELBTST40 High density lipoprotein High density lipoprotein

estrSAELBTST41 HIV viral load HIV viral load

estrSAELBTST42 INR INR

estrSAELBTST43 Lactic dehydrogenase Lactic dehydrogenase

estrSAELBTST44 Lipase Lipase

estrSAELBTST45 Low density lipoprotein Low density lipoprotein

estrSAELBTST46 Lymphocytes Lymphocytes

estrSAELBTST47 Magnesium Magnesium

estrSAELBTST48 Mean cell hemoglobin concentration Mean cell hemoglobin concentration

estrSAELBTST49 Mean corpuscular hemoglobin Mean corpuscular hemoglobin

estrSAELBTST50 Mean corpuscular volume Mean corpuscular volume

estrSAELBTST51 Monocytes Monocytes

estrSAELBTST52 Neutrophils Neutrophils

estrSAELBTST53 Oxygen saturation Oxygen saturation

estrSAELBTST54 pCO2 pCO2

estrSAELBTST55 pH pH

estrSAELBTST56 Phosphate Phosphate

estrSAELBTST57 Platelet count Platelet count

estrSAELBTST58 pO2 pO2

estrSAELBTST59 Potassium Potassium

estrSAELBTST60 Protein total Protein total

estrSAELBTST61 Prothrombin time Prothrombin time

estrSAELBTST62 Red blood cell count Red blood cell count

estrSAELBTST63 Respiratory rate Respiratory rate

estrSAELBTST64 Reticulocyte count Reticulocyte count

estrSAELBTST65 Serum glucose Serum glucose

estrSAELBTST66 Serum uric acid Serum uric acid

estrSAELBTST67 Sodium Sodium

estrSAELBTST68 Systolic blood pressure Systolic blood pressure

estrSAELBTST69 Thrombin time Thrombin time

estrSAELBTST70 Total lung capacity Total lung capacity

estrSAELBTST71 Triglycerides Triglycerides

estrSAELBTST72 Troponin Troponin


estrSAELBTST73 Troponin I Troponin I

estrSAELBTST74 Troponin T Troponin T

estrSAELBTST75 Urine myoglobin Urine myoglobin

estrSAELBTST76 Urine pH Urine pH

estrSAELBTST77 Vital capacity Vital capacity

estrSAELBTST78 White blood cell count White blood cell count

CDD: MAPPINGS1 Table: t_AE_SER Key Type: PATIENTVISIT


chkSAE STRING(255)

chkFU STRING(255)

rdcSAERAND STRING(1)

AESEQ STRING(5) - A5

AETERM STRING(100) - A100

AEMODIFY STRING(100) - A100

AEMEDSYN STRING(255)

AELLTCD STRING(255)

calAE_FAILED STRING(255)

AESTDTTM DATE - DDMONYYYY HHMM

AEOUTCD1 STRING(1)




AESEVCD STRING(1)

AETOXCD STRING(1)

AETXHVCD STRING(1)

AEACTRCD STRING(1)

AEWD STRING(1)

AEREL STRING(1)

AEDURHR NUMERIC - N2

AEDURMIN NUMERIC - N2

AEONLDSH NUMERIC - N2

AEONLDSM NUMERIC - N2

rdcAESREL STRING(1)

AESER STRING(1)

AESERDTH STRING(255)

AESERLIF STRING(255)

AESERHOS STRING(255)

AESERDIS STRING(255)

AESERCON STRING(255)

AESEROTH STRING(255)

AESERPROTSP STRING(255)

txtSAECMSEQ STRING(4) - A4

txtCMTERM STRING(100) - A100

txtSAECMDOS FLOAT - F10.0

pdcCMUNIT STRING(255) - ACTU, AMP, AP, BT, CAP, CC, 031, 002, 025, 028, IUML, 011, LM, LOZ, MEGU, 004, 004, 008, MCG/KG/MIN, MCG/MIN, 013, 029, MEQ24, 003, MGPER, MGH, 007, MGKH, MGKM, 009, MGML, 012, MLH, MLM, 023, 027, MAC, NEB, PAT, 030, PUFF, SAC, SPR, SUP, TBS, TAB, TSP, UNT, U, VIA

pdcSAECMFRQ STRING(255) - 2W, 3W, 4W, 5D, 5W, AC, 2D, CO, FO, Q3WK, Q3M, AD, 1N, MO, WE, 1D, 1S, PC, PRN, 12D, Q3D, Q4D, 6D, 4D, 3D, 2D, 1M, 24D, 4D, 1N, 3D, U

pdcCMROUTCD STRING(255) - 047, 008, GT, 055, INJ, 013, IBU, 026, 030, 045, 031, IOS, 033, 037, 015, 042, 045, 048, 054, 058, 060, 061, 062, 065, 067

dtmSAECMSTD DATE - DDMONYYYY

rdcSAECMONG STRING(1)

dtmSAECMEND DATE - DDMONYYYY

txtCMIND STRING(50) - A50

pdcCMDRGTYP STRING(255) - 2, T, 1

txtMHXSEQ STRING(4) - A4

txtSAEMHTRM STRING(100) - A100

dtmMHSTDTM DATE - DDMONYYYY

rdcMHCONT STRING(1)

dtmMHLSTOC DATE - DDMONYYYY

txtSAELBSEQ STRING(4) - A4

pdcLBTST STRING(255) - Activated partial thromboplastin time, Albumin, Alkaline phosphatase, Amylase, Basophils, Bicarbonate, Bilirubin, Bilirubin direct, Bilirubin total, Blood myoglobin, Blood pH, Blood pressure, Blood urea nitrogen, Body temperature, Calcium, CD4 lymphocytes, CD8 lymphocytes, Chloride, Cholesterol total, C-reactive protein, Creatine, Creatine phosphokinase, Creatine phosphokinase MB, Creatinine, Creatinine clearance, Diastolic blood pressure, Eosinophils, Erythrocyte sedimentation rate, Fasting blood glucose, FEV 1, Gamma-glutamyltransferase, Glutamic-oxaloacetic transferase, Glutamic-pyruvate transaminase, HbA1c, HBV-DNA decreased, HBV-DNA increased, Heart rate, Hematocrit, Hemoglobin, High density lipoprotein, HIV viral load, INR, Lactic dehydrogenase, Lipase, Low density lipoprotein, Lymphocytes, Magnesium, Mean cell hemoglobin concentration, Mean corpuscular hemoglobin, Mean corpuscular volume, Monocytes, Neutrophils, Oxygen saturation, pCO2, pH, Phosphate, Platelet count, pO2, Potassium, Protein total, Prothrombin time, Red blood cell count, Respiratory rate, Reticulocyte count, Serum glucose, Serum uric acid, Sodium, Systolic blood pressure, Thrombin time, Total lung capacity, Triglycerides, Troponin, Troponin I, Troponin T, Urine myoglobin, Urine pH, Vital capacity, White blood cell count

dtmLABDTM DATE - DDMONYYYY

txtLABRES STRING(50) - A50

txtLABUNIT STRING(35) - A35

txtLABNLR FLOAT - F8.0

txtLABNHR FLOAT - F8.0

rdcSAEIP STRING(1)

chkSAESENDI STRING(255)

dtmSAEDTM DATE - DDMONYYYY HHMM

AESE1 STRING(1)

AESE2 STRING(5) - A5

txtSAEVERSION STRING(4) - A4

txtSAEID STRING(20) - A20

txtSAERNDNO STRING(255) - A255

txtOCEANSCD STRING(13) - A13

calSAEEmailFlag STRING(255)


NGM114840_mjo : POSSIBLE SUICIDALITY-RELATED ADVERSE EVENT (PSRAE) - Repeating Form

# Possible suicidality related AE

Start Date

Brief description of possible suicidality-

related AE

Disease under study

Concomitant medication(s)

Comorbid psychiatric condition(s)

Medical condition(s)

Psycho-social stressors

Withdrawal of investigational product(s)

Investigational product dose change

Lack of efficacy

Investigational product(s)

Other Has the subject had any psychiatric

conditions in the past?

Has the subject had any suicidal

ideation, behaviour

or self-harm in the past?

Subject\'s current use of illicit drugs?

Subject\'s current use of alcohol?

Family history of suicidality?

Family history of psychiatric disorders?

Information on subject\'s current psycho-social

stressors.

Relevant/recent suicidal ideation

Suicide behaviour present

during study

Comments on medical/psych treatment

1

SECTION 1.

If the subject experienced a possible suicidality-related adverse event as assessed by the investigator during the study, provide information below. Note: The event must also be reported on the Adverse Events CRF Form (Non-serious or Serious Adverse Events form as applicable) using the same terminology.

Record only 1 event per form.

1. Possible suicidality related AE A200 (MAPPINGS1:t_PSRAE.PSRAE)

2. Start Date Req / Req / Req (2011-2013) (MAPPINGS1:t_PSRAE.PSRSTDT)

SECTION 2. BRIEF DESCRIPTION OF POSSIBLE SUICIDALITY-RELATED ADVERSE EVENT

Provide a Brief Description of the Possible Suicidality-Related Adverse Event:

3. Brief description of possible suicidality-related AE A200 (MAPPINGS1:t_PSRAE.PSRAETX)

A200 (MAPPINGS1:t_PSRAE.PSRAETX2)

A200 (MAPPINGS1:t_PSRAE.PSRAETX3)

SECTION 3. POSSIBLE CAUSE(S) OF POSSIBLE SUICIDALITY-RELATED ADVERSE EVENT:

4. Disease under study (MAPPINGS1:t_PSRAE.PCAEDUST)

[Y] Yes

[N] No

5. Concomitant medication(s) Record in Section 8

(MAPPINGS1:t_PSRAE.PCAECMED)

[Y] Yes

[N] No

6. Comorbid psychiatric condition(s) Record in Section 8

(MAPPINGS1:t_PSRAE.PCAEPSC)

[Y] Yes

[N] No

7. Medical condition(s) Record in Section 8

(MAPPINGS1:t_PSRAE.PCAEMEDC)

[Y] Yes

[N] No

8. Psycho-social stressors Record in Section 5

(MAPPINGS1:t_PSRAE.PCAEPSST)

[Y] Yes

[N] No

9. Withdrawal of investigational product(s) (MAPPINGS1:t_PSRAE.PCAEWDIP)

[Y] Yes

[N] No

10. Investigational product dose change (MAPPINGS1:t_PSRAE.PCAEIPCH)

[Y] Yes

[N] No

11. Lack of efficacy (MAPPINGS1:t_PSRAE.PCAELKEF)

[Y] Yes

[N] No

12. Investigational product(s) (MAPPINGS1:t_PSRAE.PCAEIP)

[Y] Yes

[N] No

13. Other (MAPPINGS1:t_PSRAE.PCAEOTH)

[N] No

[Y] Yes, specify:

A200

(MAPPINGS1:t_PSRAE.PCAEOTTX)

SECTION 4. PROVIDE INFORMATION

Provide this information, including timeframe(s) where possible:

14. Has the subject had any psychiatric conditions in the past? (MAPPINGS1:t_PSRAE.PSP)

[Y] Yes

[N] No

15. Has the subject had any suicidal ideation, behaviour or self-harm in the past? (MAPPINGS1:t_PSRAE.SUIID)

[Y] Yes

[N] No

16. Subject's current use of illicit drugs? (MAPPINGS1:t_PSRAE.CURDR)

[Y] Yes

[N] No

17. Subject's current use of alcohol? (MAPPINGS1:t_PSRAE.CURAL)

[Y] Yes

[N] No

18. Family history of suicidality? (MAPPINGS1:t_PSRAE.FSUI)

[Y] Yes

[N] No

[U] Unknown

19. Family history of psychiatric disorders? (MAPPINGS1:t_PSRAE.FPSD)

[Y] Yes

[N] No

[U] Unknown

SECTION 5. PROVIDE INFORMATION ON THE SUBJECT'S CURRENT PSYCHO-SOCIAL STRESSORS.

Provide information on the subject's current psycho-social stressors. For example, isolation, problems with family, relationships, work, finances, stress, etc.

20. Information on subject's current psycho-social stressors. A200 (MAPPINGS1:t_PSRAE.CPSSLTX)

A200 (MAPPINGS1:t_PSRAE.CPSSLTX2)

A200 (MAPPINGS1:t_PSRAE.CPSSLTX3)

SECTION 6. RELEVANT AND/OR RECENT SUICIDAL IDEATION

Provide information on any relevant and/or recent suicidal ideation, not associated with suicidal behavior, as assessed by the investigator, for this index event i.e., provide details, including any suicidal thoughts, and associated frequency, severity and duration, as well as likelihood of the subject acting upon these thoughts.

21. Relevant/recent suicidal ideation A200 (MAPPINGS1:t_PSRAE.RSUIDTX)

A200 (MAPPINGS1:t_PSRAE.RSUIDTX2)

A200 (MAPPINGS1:t_PSRAE.RSUIDTX3)

SECTION 7. SUICIDAL BEHAVIOUR PRESENT DURING STUDY

Provide information on any suicidal behaviour present during the study, as assessed by the investigator, for this index event, i.e.

Details of any suicidal behaviour, including any plan, preparations, and/or attempt Description of the associated frequency, severity and duration of these behaviours


Likelihood of the subject acting upon plans and preparations If possible, description of the subject's intent (or evidence of attention seeking behaviour) Description of the degree of impulsivity or premeditation

Description of the subject's mood and thoughts before and after the behaviour

22. Suicide behaviour present during study A200 (MAPPINGS1:t_PSRAE.SUIBTX)

A200 (MAPPINGS1:t_PSRAE.SUIBTX2)

A200 (MAPPINGS1:t_PSRAE.SUIBTX3)

SECTION 8. COMMENTS ON MEDICAL AND PSYCHIATRIC TREATMENT

Provide any additional comments or explanation, including, but not limited to, both medical and psychiatric treatment, outcome and follow-up.

23. Comments on medical/psych treatment A200 (MAPPINGS1:t_PSRAE.COMTRTX)

A200 (MAPPINGS1:t_PSRAE.COMTRTX2)

A200 (MAPPINGS1:t_PSRAE.COMTRTX3)

Form Design Note:

PSY Version 01.00A - MAY 08

CDD: MAPPINGS1 Table: t_PSRAE Key Type: PATIENTVISIT


PSRAE STRING(200) - A200

PSRSTDT DATE - DDMONYYYY

PSRAETX STRING(200) - A200

PSRAETX2 STRING(200) - A200

PSRAETX3 STRING(200) - A200

PCAEDUST STRING(1)

PCAECMED STRING(1)

PCAEPSC STRING(1)

PCAEMEDC STRING(1)

PCAEPSST STRING(1)

PCAEWDIP STRING(1)

PCAEIPCH STRING(1)

PCAELKEF STRING(1)

PCAEIP STRING(1)

PCAEOTH STRING(1)

PCAEOTTX STRING(200) - A200

PSP STRING(1)

SUIID STRING(1)

CURDR STRING(1)

CURAL STRING(1)

FSUI STRING(1)

FPSD STRING(1)

CPSSLTX STRING(200) - A200

CPSSLTX2 STRING(200) - A200

CPSSLTX3 STRING(200) - A200

RSUIDTX STRING(200) - A200

RSUIDTX2 STRING(200) - A200

RSUIDTX3 STRING(200) - A200

SUIBTX STRING(200) - A200

SUIBTX2 STRING(200) - A200

SUIBTX3 STRING(200) - A200

COMTRTX STRING(200) - A200

COMTRTX2 STRING(200) - A200

COMTRTX3 STRING(200) - A200


NGM114840_mjo : RELAPSES (RELAPSES) - Repeating Form

# Date symptoms started Date seen in clinic Was the subject admitted to hospital? Click on the Add Entry button to record details of each type of neurological deficit the subject developed

1

RELAPSES (Create a new repeat of the form for each new relapse)

1. Date symptoms started NReq / Req / Req (2011-2013) (MAPPINGS1:t_RELAPSE.SYMSTDT)

2. Date seen in clinic NReq / Req / Req (2011-2013) (MAPPINGS1:t_RELAPSE.CLINDT)

3. Was the subject admitted to hospital? (MAPPINGS1:t_RELAPSE.HADMIN)

[N] No

[Y] Yes, If yes, enter both dates below

Date of admission NReq / Req / Req (2011-2013) (MAPPINGS1:t_RELAPSE.ADMISDT)

Date of discharge NReq / Req / Req (2011-2013) (MAPPINGS1:t_RELAPSE.DISCHDT)

SEQ Deficit Type Onset

Date

Outcome Event

Course

Intensity Concomitant

Medication Taken

4. [hidden]

Click on the Add Entry button to record details of each type of neurological deficit the subject developed Entry

SEQ [hidden] (MAPPINGS1:t_RELAPSE.SEQ)

4.a Type of Neurological Deficit (MAPPINGS1:t_RELAPSE.DEFICICD)

[1] Visual

[2] Brainstem

[3] Pyramidal

[4] Cerebellar

[5] Sensory

[6] Bladder/Bowel

[7] Mental

4.b Onset Date NReq / Req / Req (2011-2013) (MAPPINGS1:t_RELAPSE.NDSTDT)

4.c Outcome (MAPPINGS1:t_RELAPSE.NDOUTCD)

[1] Ongoing

[2] Resolved, enter the End Date

NReq / Req / Req (2011-2013) (MAPPINGS1:t_RELAPSE.NDENDT)

4.d Event Course (MAPPINGS1:t_RELAPSE.NDCOURCD)

[2] Constant

[1] Intermittent

xx Number of episodes (MAPPINGS1:t_RELAPSE.NDEPISOD)

4.e Maximum Intensity (MAPPINGS1:t_RELAPSE.NDINTCD)

[1] Mild

[2] Moderate

[3] Severe

4.f Was Concomitant Medication Taken? (MAPPINGS1:t_RELAPSE.NDCM)

[Y] Yes

[N] No

CDD: MAPPINGS1 Table: t_RELAPSE Key Type: PATIENTVISIT


SYMSTDT DATE - DDMONYYYY

CLINDT DATE - DDMONYYYY

HADMIN STRING(1)

ADMISDT DATE - DDMONYYYY

DISCHDT DATE - DDMONYYYY

SEQ STRING(255)

DEFICICD NUMERIC

NDSTDT DATE - DDMONYYYY

NDOUTCD NUMERIC

NDENDT DATE - DDMONYYYY

NDCOURCD NUMERIC

NDEPISOD NUMERIC - N2

NDINTCD STRING(1)

NDCM STRING(1)


NGM114840_mjo : CONCOMITANT MEDICATIONS (Con Meds) - Repeating Form

# Sequence Number Drug Name

(Trade Name preferred)

Unit Dose Units Frequency Route Reason for Medication Start Date and Time Taken Prior to Study? Ongoing?

1

CONCOMITANT MEDICATIONS

Sequence Number (MAPPINGS1:t_CONMEDS.CMSEQ)

1. Drug Name (Trade Name preferred)

A100(MAPPINGS1:t_CONMEDS.CMTERM)

2.* Modified reported term Do not query this item, as it is not displayed for sites [hidden]

A100(CM_CODE:0.LogsRpts.CONMEDS.sctCM.0.itmCMDRGCOL.CMDRGCOL) (CM_FAILED:0.LogsRpts.CONMEDS.sctCM.0.itmCM_FAILED.calCM_FAILED) (CM_SYNONYM:0.LogsRpts.CONMEDS.sctCM.0.itmCMDRGSYN.CMDRGSYN) (MAPPINGS1:t_CONMEDS.CMMODIFY)

GSK Drug synonym [hidden] (MAPPINGS1:t_CONMEDS.CMDRGSYN)

GSK Drug Collection code [hidden] (MAPPINGS1:t_CONMEDS.CMDRGCOL)

Failed coding [hidden] (MAPPINGS1:t_CONMEDS.calCM_FAILED)

3. Unit Dose A10 (MAPPINGS1:t_CONMEDS.CMUDOS)

4. Units Pulldown List 1 (MAPPINGS1:t_CONMEDS.CMUNIT)

5. Frequency Pulldown List 2 (MAPPINGS1:t_CONMEDS.CMFREQ)

6. Route Pulldown List 3 (MAPPINGS1:t_CONMEDS.CMROUTCD)

7. Reason for MedicationA70

(MAPPINGS1:t_CONMEDS.CMREAS)


Req/Unk / Req/Unk / Req/Unk (1951-2013)


(MAPPINGS1:t_CONMEDS.CMSTDTTM)

9. Taken Prior to Study? (MAPPINGS1:t_CONMEDS.CMPRIOR)

[Y] Yes

[N] No

10. Ongoing? Hr:Min (00:00-23:59)

(MAPPINGS1:t_CONMEDS.CMONGO)

[Y] Yes

[N] No, specify End Date and Time

Req/Unk / Req/Unk / Req/Unk (2011-2013)


(MAPPINGS1:t_CONMEDS.CMENDTTM)


Item Design Notes:


3. This item is conditional

Pulldown List 1:


mestrUnitACTU Actuation ACTU

mestrUnitAMP Ampoule AMP

mestrUnitAPP Application APP

mestrUnitAUC Area under curve AUC

mestrUnitBOT Bottle BOT

mestrUnitCAP Capsule CAP

mestrUnitCC Cubic centimeter CC

mestrUnitCUP Cup CUP

mestrUnitGAKGM Gamma per kilogram per minute GA/KG/MIN

mestrUnitGM Gram G

mestrUnitGTT Drops GTT

mestrUnitHIUML 100 International units/ml 100IU/ML

mestrUnitINH Inhalation INH

mestrUnitIU International units IU

mestrUnitIUKG International units per kilogram IU/KG

mestrUnitIUKGH International units per kilogram per hour IU/KG/HR

mestrUnitIUML International units per millilitre IU/ML

mestrUnitL Litre L

mestrUnitLOZ Lozenge LOZ

mestrUnitLPM Litre per minute L/MIN

mestrUnitMAC Minimum alveolar concentration MAC

mestrUnitMBQ Mega becquerels (MBq) MBQ

mestrUnitMCG Microgram (MCG) MCG

mestrUnitMCGH Micrograms per hour MCG/HR

mestrUnitMCGKG Microgram/kilogram MCG/KG

mestrUnitMCGKGMIN Microgram/kilogram per minute MCG/KG/MIN

mestrUnitMCGMIN Micrograms per minute MCG/MIN

mestrUnitMCGML Micrograms per millitre MCG/ML

mestrUnitMCL Microlitre MCL

mestrUnitMEQ Milliequivalent MEQ

mestrUnitMEQ24HR Milliequivalent per 24 hours MEQ/24HR

mestrUnitMG Milligram MG

mestrUnitMGD Milligram per day MG/DAY

mestrUnitMGHR Milligram per hour MG/HR

mestrUnitMGKG Milligram/kilogram MG/KG

mestrUnitMGKGHR Milligram/kilogram per hour MG/KG/HR

mestrUnitMGKGMIN Milligram/kilogram per minute MG/KG/MIN


mestrUnitMGM2 Milligram/metre squared MG/M2

mestrUnitMGML Milligram/millilitre MG/ML

mestrUnitMGPER Milligrams percent MG%

mestrUnitMIU Million international units MIU

mestrUnitML Millilitre ML

mestrUnitMLHR Millilitre per hour ML/HR

mestrUnitMLMIN Millilitre per minute ML/MIN

mestrUnitMMOL Millimole MMOL

mestrUnitMU Megaunits (million units) MU

mestrUnitNEB Nebule NEB

mestrUnitOZ Ounce OZ

mestrUnitPATCH Patch PATCH

mestrUnitPer Percent %

mestrUnitPUFF Puff PUFF

mestrUnitSACH Sachet SACH

mestrUnitSP Spray SPR

mestrUnitSUPP Suppository SUPP

mestrUnitTAB Tablet TAB

mestrUnitTBSP Tablespoon TBLSP

mestrUnitTSP Teaspoon TSP

mestrUnitUG Microgram (UG) UG

mestrUnitUHR Units per hour U/HR

mestrUnitUKGM Units per kilogram per minute U/KG/MIN

mestrUnitUMN Units per minute U/MIN

mestrUnitUNIT Units U

mestrUnitUNK Unknown UNK

mestrUnitVIAL Vial VIAL

Pulldown List 2:


mestrFreq2XWK 2 times per week 2XWK



mestrFreq5XD 5 times per day 5XD


mestrFreqAC AC AC

mestrFreqBID BID BID

mestrFreqCINF Continuous infusion CINF

mestrFreqHS HS HS

mestrFreqOD Once daily OD

mestrFreqONE Once only ONE

mestrFreqPC PC PC

mestrFreqPRN PRN PRN

mestrFreqQ12H Q12H Q12H


mestrFreqQ2WK Every 2 weeks Q2WK

mestrFreqQ3D Q3D Q3D

mestrFreqQ3M Every 3 months Q3M

mestrFreqQ3WK Every 3 weeks Q3WK

mestrFreqQ4D Q4D Q4D




mestrFreqQAM QAM QAM

mestrFreqQH QH QH

mestrFreqQID QID QID

mestrFreqQM Once a month QM

mestrFreqQOD Every other day QOD

mestrFreqQPM QPM QPM

mestrFreqQWK Once a week QWK

mestrFreqTID TID TID

mestrFreqUNK Unknown UNK

Pulldown List 3:


mestrRouteEP Epidural EP

mestrRouteGTT Gastrostomy tube GTT

mestrRouteIA Intra-arterial IA

mestrRouteIART Intra-articular IART

mestrRouteIB Intra-bursa IB

mestrRouteID Intradermal ID

mestrRouteIH Inhalation IH

mestrRouteIL Intralesional ILES

mestrRouteIM Intramuscular IM

mestrRouteIN Intranasal IN

mestrRouteINJ Injection INJ

mestrRouteIO Intraocular IO

mestrRouteIOS Intraosteal IOS

mestrRouteIP Intraperitoneal IP

mestrRouteIT Intrathecal IT


mestrRouteIU Intrauterine IU

mestrRouteIV Intravenous IV

mestrRouteNG Nasogastric NG

mestrRouteNS Nasal NS

mestrRouteOD Right eye OD

mestrRouteOP Ophthalmic OP

mestrRouteOS Left eye OS

mestrRouteOT Otic OT

mestrRouteOTH Other OTH

mestrRouteOU Both eyes OU

mestrRoutePO Oral PO

mestrRoutePR Rectal PR

mestrRouteSC Subcutaneous SC

mestrRouteSL Sublingual SL

mestrRouteTD Transdermal TD

mestrRouteTP Topical TP

mestrRouteUNK Unknown UNK

mestrRouteVG Vaginal VG

CDD: MAPPINGS1 Table: t_CONMEDS Key Type: PATIENTVISIT


CMSEQ STRING(255)

CMTERM STRING(100) - A100

CMMODIFY STRING(100) - A100

CMDRGSYN STRING(255)

CMDRGCOL STRING(255)

calCM_FAILED STRING(255)

CMUDOS STRING(10) - A10

CMUNIT STRING(255) - ACTU, AMP, APP, AUC, BOT, CAP, CC, CUP, GA/KG/MIN, G, GTT, 100IU/ML, INH, IU, IU/KG, IU/KG/HR, IU/ML, L, LOZ, L/MIN, MAC, MBQ, MCG, MCG/HR, MCG/KG, MCG/KG/MIN, MCG/MIN, MCG/ML, MCL, MEQ, MEQ/24HR, MG, MG/DAY, MG/HR, MG/KG, MG/KG/HR, MG/KG/MIN, MG/M2, MG/ML, MG%, MIU, ML, ML/HR, ML/MIN, MMOL, MU, NEB, OZ, PATCH, %, PUFF, SACH, SPR, SUPP, TAB, TBLSP, TSP, UG, U/HR, U/KG/MIN, U/MIN, U, UNK, VIAL

CMFREQ STRING(255) - 2XWK, 3XWK, 4XWK, 5XD, 5XWK, AC, BID, CINF, HS, OD, ONE, PC, PRN, Q12H, Q2H, Q2WK, Q3D, Q3M, Q3WK, Q4D, Q4H, Q6H, Q8H, QAM, QH, QID, QM, QOD, QPM, QWK, TID, UNK

CMROUTCD STRING(255) - EP, GTT, IA, IART, IB, ID, IH, ILES, IM, IN, INJ, IO, IOS, IP, IT, IU, IV, NG, NS, OD, OP, OS, OT, OTH, OU, PO, PR, SC, SL, TD, TP, UNK, VG

CMREAS STRING(70) - A70

CMSTDTTM DATE - DDMONYYYY HHMM

CMPRIOR STRING(1)

CMONGO STRING(1)

CMENDTTM DATE - DDMONYYYY HHMM


NGM114840_mjo : ELECTRONICALLY TRANSFERRED LAB DATA (Lab Rpt) - Repeating Form

# Laboratory Test Type Date

1

ELECTRONICALLY TRANSFERRED LAB DATA

Record each repeat lab in a separate record

1. Laboratory Test Type (MAPPINGS1:t_LABLINK_RPT.rdcLBType)

[H] Haematology

[C] Clinical Chemistry

[U] Urinalysis

2. Date and time sample taken Hr:Min (00:00-23:59)

Req / Req / Req (2011-2013)


(MAPPINGS1:t_LABLINK_RPT.LBDTTM)

Form Design Note:

Repeat Lablink

Item Design Notes:


1. Study team can add additional test types if needed for their protocol

CDD: MAPPINGS1 Table: t_LABLINK_RPT Key Type: PATIENTVISIT


rdcLBType STRING(1)

LBDTTM DATE - DDMONYYYY HHMM


NGM114840_mjo : VITAL SIGNS (VS Rpt) - Repeating Form

# Actual Weight BP HR

1

VITAL SIGNS


Req / Req / Req (2011-2013)


(MAPPINGS1:t_VITALS_RPT.VSACTDTTM)

2. Weight (MAPPINGS1:t_VITALS_RPT.rdcWEIGHT)

[ND] Not Done

[Y] xxx.x ( n >= 0.0 ) kg (MAPPINGS1:t_VITALS_RPT.WEIGHT)

3. Blood pressure (MAPPINGS1:t_VITALS_RPT.rdcBPRpt)

[ND] Not Done

[Y] xxx ( n >= 0 ) / (MAPPINGS1:t_VITALS_RPT.SYSBP) xxx ( n >= 0 ) mmHg (MAPPINGS1:t_VITALS_RPT.DIABP)


4. Heart rate (MAPPINGS1:t_VITALS_RPT.rdcHEART)

[ND] Not Done

[Y] xxx ( n >= 0 ) beats/min (MAPPINGS1:t_VITALS_RPT.HEART)

Form Design Note:

Repeat vital signs

CDD: MAPPINGS1 Table: t_VITALS_RPT Key Type: PATIENTVISIT



rdcWEIGHT STRING(2)

WEIGHT FLOAT - F5.1

rdcBPRpt STRING(2)

SYSBP NUMERIC - N3

DIABP NUMERIC - N3

rdcHEART STRING(2)

HEART NUMERIC - N3


NGM114840_mjo : 12-LEAD ECG (ECG Rpt) - Repeating Form

# Date HR PR QRS QT Method QTc Calc Result

1

12-LEAD ECG


Req / Req / Req (2011-2013)


(MAPPINGS1:t_ECG_RPT.EGDTTM)

2. Heart rate xxx ( n >= 0 ) beats/min (MAPPINGS1:t_ECG_RPT.EGHR)

3. PR Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_RPT.PR)

4. QRS Duration xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_RPT.QRS)

5. Uncorrected QT Interval xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_RPT.QT)

6. Method of QTc Calculation

(MAPPINGS1:t_ECG_RPT.EGMTCLCD)


(MAPPINGS1:t_ECG_RPT.chkQTCB)

[B] QTcB (Bazett) xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_RPT.QTCB)

(MAPPINGS1:t_ECG_RPT.chkQTCF)

[F] QTcF (Fridericia) xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_RPT.QTCF)

(MAPPINGS1:t_ECG_RPT.chkQTC)

[U] QTc (Unspecified method of correction) xxxxx. ( n >= 0.0 ) msec (MAPPINGS1:t_ECG_RPT.QTC)

[2] (MAPPINGS1:t_ECG_RPT.rdcRR)


[RR] RR interval

xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx ( n >= 0 ) msec (MAPPINGS1:t_ECG_RPT.RR)


7. Result of the ECG (MAPPINGS1:t_ECG_RPT.EGINTPCD)

[1] Normal




Form Design Note:

Repeat ECG

CDD: MAPPINGS1 Table: t_ECG_RPT Key Type: PATIENTVISIT



EGHR NUMERIC - N3

PR FLOAT - F6.0

QRS FLOAT - F6.0

QT FLOAT - F6.0

EGMTCLCD NUMERIC

chkQTCB STRING(255)

QTCB FLOAT - F6.0

chkQTCF STRING(255)

QTCF FLOAT - F6.0

chkQTC STRING(255)

QTC FLOAT - F6.0

rdcRR STRING(2)

RR NUMERIC - N255

EGINTPCD STRING(1)


NGM114840_mjo : ECG ABNORMALITIES (ECG Abn) - Repeating Form

# Date Result

1

12-LEAD ECG ABNORMALITIES


Req / Req / Req (2011-2013)


(MAPPINGS1:t_ECG_ABNORM.EGDTTM)

2. Record clinically significant abnormalities (check all that apply)

A. Rhythm

(MAPPINGS1:t_ECG_ABNORM.RHYTHM1_AAA)

[A1] Sinus bradycardia

(MAPPINGS1:t_ECG_ABNORM.RHYTHM1_BBB)

[A21] Sinus bradycardia (heart rate 40-50 beats/min)

(MAPPINGS1:t_ECG_ABNORM.RHYTHM1_CCC)

[A22] Sinus bradycardia (heart rate 30-39 beats/min)

(MAPPINGS1:t_ECG_ABNORM.RHYTHM1_DDD)

[A23] Sinus bradycardia (heart rate <30 beats/min)

(MAPPINGS1:t_ECG_ABNORM.RHYTHM1_EEE)

[A3] Sinus pause

(MAPPINGS1:t_ECG_ABNORM.RHYTHM1_FFF)

[A2] Sinus tachycardia (heart rate > 100 beats/min)

(MAPPINGS1:t_ECG_ABNORM.RHYTHM1_GGG)


(MAPPINGS1:t_ECG_ABNORM.RHYTHM1_HHH)


(MAPPINGS1:t_ECG_ABNORM.RHYTHM1_III)


(MAPPINGS1:t_ECG_ABNORM.RHYTHM1_JJJ)


(MAPPINGS1:t_ECG_ABNORM.RHYTHM1_KKK)

[A6] Supraventricular tachycardia (heart rate>100 beats/min)

(MAPPINGS1:t_ECG_ABNORM.RHYTHM1_LLL)

[A7] Atrial flutter

(MAPPINGS1:t_ECG_ABNORM.RHYTHM1_MMM)


(MAPPINGS1:t_ECG_ABNORM.RHYTHM1_NNN)

[A5] Junctional rhythm (heart rate<=100 beats/min)

(MAPPINGS1:t_ECG_ABNORM.RHYTHM1_OOO)

[A25] Junctional rhythm

(MAPPINGS1:t_ECG_ABNORM.RHYTHM1_PPP)

[A24] Junctional tachycardia (heart rate>100 beats/min)

(MAPPINGS1:t_ECG_ABNORM.RHYTHM1_QQQ)

[A9] Ectopic ventricular beats

(MAPPINGS1:t_ECG_ABNORM.RHYTHM1_RRR)


(MAPPINGS1:t_ECG_ABNORM.RHYTHM1_SSS)

[A13] Bigeminy

(MAPPINGS1:t_ECG_ABNORM.RHYTHM1_TTT)

[A28] Trigeminy

(MAPPINGS1:t_ECG_ABNORM.RHYTHM1_UUU)


(MAPPINGS1:t_ECG_ABNORM.RHYTHM1_VVV)


(MAPPINGS1:t_ECG_ABNORM.RHYTHM1_WWW)


(MAPPINGS1:t_ECG_ABNORM.RHYTHM1_XXX)

[A19] Idioventricular rhythm

(MAPPINGS1:t_ECG_ABNORM.RHYTHM1_YYY)

[A10] Sustained ventricular tachycardia

(MAPPINGS1:t_ECG_ABNORM.RHYTHM1_ZZZ)

[A11] Non-sustained ventricular tachycardia

(MAPPINGS1:t_ECG_ABNORM.RHYTHM2_GGG)


(MAPPINGS1:t_ECG_ABNORM.RHYTHM2_AAA)

[A27] Ventricular tachycardia

(MAPPINGS1:t_ECG_ABNORM.RHYTHM2_BBB)

[A30] Monomorphic ventricular tachycardia

(MAPPINGS1:t_ECG_ABNORM.RHYTHM2_CCC)

[A15] Torsades de Pointes (Polymorphic ventricular tachycardia with prolonged QT)

(MAPPINGS1:t_ECG_ABNORM.RHYTHM2_DDD)

[A31] Polymorphic (sustained and non-sustained) ventricular tachycardia

(MAPPINGS1:t_ECG_ABNORM.RHYTHM2_EEE)

[A16] Artificial Pacemaker

(MAPPINGS1:t_ECG_ABNORM.RHYTHM2_FFF)

[A99] Other abnormal rhythm, enter comment

A200

(MAPPINGS1:t_ECG_ABNORM.EGFOTHA)

B. P-Wave Morphology

(MAPPINGS1:t_ECG_ABNORM.MORPHOLOGY_AAA)

[B1] Left atrial abnormality (P mitrale)

(MAPPINGS1:t_ECG_ABNORM.MORPHOLOGY_BBB)

[B2] Right atrial abnormality (P pulmonale)

(MAPPINGS1:t_ECG_ABNORM.MORPHOLOGY_CCC)

[B3] Right ventricular hypertrophy

(MAPPINGS1:t_ECG_ABNORM.MORPHOLOGY_DDD)

[B5] Intraatrial conduction delay

(MAPPINGS1:t_ECG_ABNORM.MORPHOLOGY_EEE)

[D14] Increased voltage consistent with left ventricular hypertrophy

(MAPPINGS1:t_ECG_ABNORM.MORPHOLOGY_FFF)

[B99] Other morphology, enter comment

A200

(MAPPINGS1:t_ECG_ABNORM.EGFOTHB)

C. Conduction

(MAPPINGS1:t_ECG_ABNORM.CONDUCTION_AAA)

[C1] First degree AV block (PR interval > 200msec)

(MAPPINGS1:t_ECG_ABNORM.CONDUCTION_TTT)

[C20] Short PR interval

(MAPPINGS1:t_ECG_ABNORM.CONDUCTION_BBB)

[C2] Second degree AV block (Mobitz type 1)

(MAPPINGS1:t_ECG_ABNORM.CONDUCTION_CCC)

[C3] Second degree AV block (Mobitz type 2)

(MAPPINGS1:t_ECG_ABNORM.CONDUCTION_DDD)

[C16] 2:1 AV block

(MAPPINGS1:t_ECG_ABNORM.CONDUCTION_EEE)


[C4] Third degree AV block

(MAPPINGS1:t_ECG_ABNORM.CONDUCTION_FFF)

[C5] Left axis deviation (QRS axis more negative than -30 degrees)

(MAPPINGS1:t_ECG_ABNORM.CONDUCTION_GGG)

[C6] Right axis deviation (QRS axis more positive than +110 degrees)

(MAPPINGS1:t_ECG_ABNORM.CONDUCTION_HHH)

[C7] Incomplete right bundle branch block

(MAPPINGS1:t_ECG_ABNORM.CONDUCTION_III)

[C13] Incomplete left bundle branch block

(MAPPINGS1:t_ECG_ABNORM.CONDUCTION_JJJ)

[C8] Right bundle branch block

(MAPPINGS1:t_ECG_ABNORM.CONDUCTION_KKK)

[C14] Left anterior hemiblock (synonymous to left anterior fascicular block)

(MAPPINGS1:t_ECG_ABNORM.CONDUCTION_LLL)

[C15] Left posterior hemiblock (synonymous to left posterior fascicular block)

(MAPPINGS1:t_ECG_ABNORM.CONDUCTION_MMM)

[C9] Left bundle branch block

(MAPPINGS1:t_ECG_ABNORM.CONDUCTION_NNN)

[C17] Bifascicular block

(MAPPINGS1:t_ECG_ABNORM.CONDUCTION_OOO)

[C10] Non-specific intraventricular conduction delay (QRS > 120 msec)

(MAPPINGS1:t_ECG_ABNORM.CONDUCTION_PPP)

[C11] Accessory pathway (Wolff-Parkinson White, Lown-Ganong-Levine)

(MAPPINGS1:t_ECG_ABNORM.CONDUCTION_UUU)

[C19] Prolonged QT interval

(MAPPINGS1:t_ECG_ABNORM.CONDUCTION_QQQ)

[C12] QT/QTc prolongation > 500 msec

(MAPPINGS1:t_ECG_ABNORM.CONDUCTION_RRR)

[C18] AV dissociation

(MAPPINGS1:t_ECG_ABNORM.CONDUCTION_SSS)

[C99] Other conduction, enter comment

A200

(MAPPINGS1:t_ECG_ABNORM.EGFOTHC)

D. Myocardial Infarction

(MAPPINGS1:t_ECG_ABNORM.MI_AAA)

[D1] Myocardial infarction, old

(MAPPINGS1:t_ECG_ABNORM.MI_BBB)

[D2] Myocardial infarction, anterior

(MAPPINGS1:t_ECG_ABNORM.MI_CCC)

[D3] Myocardial infarction, lateral

(MAPPINGS1:t_ECG_ABNORM.MI_DDD)

[D4] Myocardial infarction, posterior

(MAPPINGS1:t_ECG_ABNORM.MI_EEE)

[D5] Myocardial infarction, inferior

(MAPPINGS1:t_ECG_ABNORM.MI_FFF)

[D6] Myocardial infarction, septal

(MAPPINGS1:t_ECG_ABNORM.MI_GGG)

[D20] Myocardial infarction, Non Q-wave

(MAPPINGS1:t_ECG_ABNORM.MI_HHH)

[D98] Other myocardial infarction, enter comment

A200

(MAPPINGS1:t_ECG_ABNORM.EGFOTHD)

E. Depolarisation/Repolarisation (QRS-T)

(MAPPINGS1:t_ECG_ABNORM.DEPO_AAA)

[D7] Non-specific ST-T changes

(MAPPINGS1:t_ECG_ABNORM.DEPO_BBB)

[D19] J point elevation

(MAPPINGS1:t_ECG_ABNORM.DEPO_CCC)

[D8] ST elevation

(MAPPINGS1:t_ECG_ABNORM.DEPO_DDD)

[D21] ST-elevation - pericarditis

(MAPPINGS1:t_ECG_ABNORM.DEPO_EEE)

[D9] ST depression

(MAPPINGS1:t_ECG_ABNORM.DEPO_FFF)

[D10] U waves abnormal

(MAPPINGS1:t_ECG_ABNORM.DEPO_GGG)

[D11] T wave inversion

(MAPPINGS1:t_ECG_ABNORM.DEPO_HHH)

[D12] T wave peaked

(MAPPINGS1:t_ECG_ABNORM.DEPO_III)

[D15] T waves flat

(MAPPINGS1:t_ECG_ABNORM.DEPO_JJJ)

[D16] T waves biphasic

(MAPPINGS1:t_ECG_ABNORM.DEPO_KKK)

[D18] Notched T-waves

(MAPPINGS1:t_ECG_ABNORM.DEPO_LLL)

[D13] Low QRS voltage

(MAPPINGS1:t_ECG_ABNORM.DEPO_MMM)

[D17] T-wave flattening/inversion

(MAPPINGS1:t_ECG_ABNORM.DEPO_NNN)

[D99] Other depolarisation/repolarisation, enter comment

A200

(MAPPINGS1:t_ECG_ABNORM.EGFOTHE)

Other abnormalities

(MAPPINGS1:t_ECG_ABNORM.OTHER_AAA)

[E99] Enter comment

A200

(MAPPINGS1:t_ECG_ABNORM.EGFOTHO)

CDD: MAPPINGS1 Table: t_ECG_ABNORM Key Type: PATIENTVISIT



RHYTHM1_AAA STRING(255)

RHYTHM1_BBB STRING(255)

RHYTHM1_CCC STRING(255)

RHYTHM1_DDD STRING(255)

RHYTHM1_EEE STRING(255)

RHYTHM1_FFF STRING(255)

RHYTHM1_GGG STRING(255)


RHYTHM1_HHH STRING(255)

RHYTHM1_III STRING(255)

RHYTHM1_JJJ STRING(255)

RHYTHM1_KKK STRING(255)

RHYTHM1_LLL STRING(255)

RHYTHM1_MMM STRING(255)

RHYTHM1_NNN STRING(255)

RHYTHM1_OOO STRING(255)

RHYTHM1_PPP STRING(255)

RHYTHM1_QQQ STRING(255)

RHYTHM1_RRR STRING(255)

RHYTHM1_SSS STRING(255)

RHYTHM1_TTT STRING(255)

RHYTHM1_UUU STRING(255)

RHYTHM1_VVV STRING(255)

RHYTHM1_WWW STRING(255)

RHYTHM1_XXX STRING(255)

RHYTHM1_YYY STRING(255)

RHYTHM1_ZZZ STRING(255)

RHYTHM2_GGG STRING(255)

RHYTHM2_AAA STRING(255)

RHYTHM2_BBB STRING(255)

RHYTHM2_CCC STRING(255)

RHYTHM2_DDD STRING(255)

RHYTHM2_EEE STRING(255)

RHYTHM2_FFF STRING(255)

EGFOTHA STRING(200) - A200

MORPHOLOGY_AAA STRING(255)

MORPHOLOGY_BBB STRING(255)

MORPHOLOGY_CCC STRING(255)

MORPHOLOGY_DDD STRING(255)

MORPHOLOGY_EEE STRING(255)

MORPHOLOGY_FFF STRING(255)

EGFOTHB STRING(200) - A200

CONDUCTION_AAA STRING(255)

CONDUCTION_TTT STRING(255)

CONDUCTION_BBB STRING(255)

CONDUCTION_CCC STRING(255)

CONDUCTION_DDD STRING(255)

CONDUCTION_EEE STRING(255)

CONDUCTION_FFF STRING(255)

CONDUCTION_GGG STRING(255)

CONDUCTION_HHH STRING(255)

CONDUCTION_III STRING(255)

CONDUCTION_JJJ STRING(255)

CONDUCTION_KKK STRING(255)

CONDUCTION_LLL STRING(255)

CONDUCTION_MMM STRING(255)

CONDUCTION_NNN STRING(255)

CONDUCTION_OOO STRING(255)

CONDUCTION_PPP STRING(255)

CONDUCTION_UUU STRING(255)

CONDUCTION_QQQ STRING(255)

CONDUCTION_RRR STRING(255)

CONDUCTION_SSS STRING(255)

EGFOTHC STRING(200) - A200

MI_AAA STRING(255)

MI_BBB STRING(255)

MI_CCC STRING(255)

MI_DDD STRING(255)

MI_EEE STRING(255)

MI_FFF STRING(255)

MI_GGG STRING(255)

MI_HHH STRING(255)

EGFOTHD STRING(200) - A200

DEPO_AAA STRING(255)

DEPO_BBB STRING(255)

DEPO_CCC STRING(255)

DEPO_DDD STRING(255)

DEPO_EEE STRING(255)

DEPO_FFF STRING(255)

DEPO_GGG STRING(255)

DEPO_HHH STRING(255)

DEPO_III STRING(255)

DEPO_JJJ STRING(255)

DEPO_KKK STRING(255)

DEPO_LLL STRING(255)

DEPO_MMM STRING(255)

DEPO_NNN STRING(255)

EGFOTHE STRING(200) - A200


OTHER_AAA STRING(255)

EGFOTHO STRING(200) - A200


NGM114840_mjo : REPEAT PHARMACOKINETICS BLOOD - [GSK1223249] (PK Rpt) - Repeating Form

# Actual date/time Sample identifier Sample number (3 digit)

1

REPEAT PHARMACOKINETICS BLOOD



(MAPPINGS1:t_PK_RPT.PKSTDTTM)

2. Sample identifier A17 (MAPPINGS1:t_PK_RPT.PKSMPID)

3. Sample number (3 digit) xxx ( n > 0 ) (MAPPINGS1:t_PK_RPT.PKSMPNUM)

Form Design Note:

Repeat PK

CDD: MAPPINGS1 Table: t_PK_RPT Key Type: PATIENTVISIT




PKSMPNUM NUMERIC - N3


NGM114840_mjo : IMMUNOGENICITY SAMPLING (IMGLINK) - Repeating Form

# Was a Immunogenicity sample collected? Immunogenicity Sample ID number

1

1. Was a Immunogenicity sample collected? (MAPPINGS1:t_IMGLINK_RPT.IGSMPCOL)


Req / Req / Req (2011-2013)


(MAPPINGS1:t_IMGLINK_RPT.IGDTTM)

[N] No

2.* Immunogenicity Sample ID number A17 (MAPPINGS1:t_IMGLINK_RPT.IGREFID)


Item Design Notes:




CDD: MAPPINGS1 Table: t_IMGLINK_RPT Key Type: PATIENTVISIT


IGSMPCOL STRING(1)




NGM114840_mjo : ELECTRONICALLY TRANSFERRED BIOMARKER DATA (BIOMARK) - Repeating Form

# Date/time of biomarker collection Hr:Min (00:00-23:59)

1

1. Date/time of biomarker collection Hr:Min (00:00-23:59)



(MAPPINGS1:t_BIOMARK_RPT.BIACTDTTM)

CDD: MAPPINGS1 Table: t_BIOMARK_RPT Key Type: PATIENTVISIT


BIACTDTTM DATE - DDMONYYYY HHMM


NGM114840_mjo : ELECTRONICALLY TRANSFERRED CRANIAL MRI DATA (CRAN_MRI) - Repeating Form

# Date of Cranial MRI

1

1. Date of Cranial MRI Date Req / Req / Req (2011-2013) (MAPPINGS1:t_CRAN_MRI_RPT.SCNSTDTTM)

CDD: MAPPINGS1 Table: t_CRAN_MRI_RPT Key Type: PATIENTVISIT


SCNSTDTTM DATE - DDMONYYYY


NGM114840_mjo : Neurological Exam (NeurExam) - Repeating Form

# Exam date/time ITEM1_I ITEM1_I ITEM1_I ITEM1_I ITEM1_I ITEM1_I ITEM1_I ITEM1_I

1

Neurological Examination



(MAPPINGS1:t_NEUREXAM_RPT.ACTDTTM)

2. Mental Status (MAPPINGS1:t_NEUREXAM_RPT.rdcNERES)

[0] Normal


A200

(MAPPINGS1:t_NEUREXAM_RPT.NETXT)

3. Gait (MAPPINGS1:t_NEUREXAM_RPT.rdcNERES)

[0] Normal


A200


4. Balance (MAPPINGS1:t_NEUREXAM_RPT.rdcNERES)

[0] Normal


A200


5. Coordination (MAPPINGS1:t_NEUREXAM_RPT.rdcNERES)

[0] Normal


A200


6. Cranial Nerves (MAPPINGS1:t_NEUREXAM_RPT.rdcNERES)

[0] Normal


A200


7. Motor (MAPPINGS1:t_NEUREXAM_RPT.rdcNERES)

[0] Normal


A200


8. Reflexes (MAPPINGS1:t_NEUREXAM_RPT.rdcNERES)

[0] Normal


A200


9. Sensory (MAPPINGS1:t_NEUREXAM_RPT.rdcNERES)

[0] Normal


A200


CDD: MAPPINGS1 Table: t_NEUREXAM_RPT Key Type: PATIENTTOITEM



rdcNERES STRING(1)



NGM114840_mjo : Expanded Disability Status Scale (Neurostatus) (EDSS RPT) - Repeating Form



NGM114840_mjo : REPEAT CARDIAC MONITORING (Cardiac Monitoring Rpt) - Repeating Form

# Start Date/Time Stop Date/Time Result of telemetry or bedside cardiac monitoring

1

TELEMETRY

1. Start Date and Time of Telemetry Hr:Min (00:00-23:59)

Req / Req / Req (2011-2013)


(MAPPINGS1:t_HMSUM_TEL_RPT.HMSTDTTM)

2. Stop Date and Time of Telemetry Hr:Min (00:00-23:59)

Req / Req / Req (2011-2013)


(MAPPINGS1:t_HMSUM_TEL_RPT.HMENDTTM)

3. Result of telemetry or bedside cardiac monitoring (MAPPINGS1:t_HMSUM_TEL_RPT.HMORRSCD_TEL)

[1] Normal


[3] Abnormal - Clinically significant

[4] No result

[8] Unable to evaluate

Item Design Notes:


3. No result and unable to evaluate are optional items

CDD: MAPPINGS1 Table: t_HMSUM_TEL_RPT Key Type: PATIENTVISIT




HMORRSCD_TEL STRING(1)


NGM114840_mjo : REPEAT TELEMETRY ABNORMALITIES (Telemetry Abn Rpt) - Repeating Form

# Start Date/Time Stop Date/Time Abnormalities

1

RECORD CLINICALLY SIGNIFICANT ABNORMALITIES BELOW

1.* Start Date and Time of Telemetry Hr:Min (00:00-23:59)

Req / Req / Req (2011-2013)


(MAPPINGS1:t_HMSUM_TEL_AB_RPT.HMSTDTTM)

2.* Stop Date and Time of Holter Hr:Min (00:00-23:59)

Req / Req / Req (2011-2013)


(MAPPINGS1:t_HMSUM_TEL_AB_RPT.HMENDTTM)

3. Check all that apply (MAPPINGS1:t_HMSUM_TEL_AB_RPT.HMORRSCD6)

[A00] No abnormalities

(MAPPINGS1:t_HMSUM_TEL_AB_RPT.HMORRSCD7)







[A04] Sinus bradycardia (<30 beats/min)


[A05] Sinus pause


[A06] Sinus tachycardia (>100 beats/min)










[A11] Non-sustained supraventricular tachycardia (>100 beats/min, 3-30 beats)


[A12] Sustained supraventricular tachycardia (>100 beats/min, >30 beats)


[A13] Atrial flutter




[A15] Junctional rhythm (<=100 beats/min, defined by narrow QRS complex)


[A16] Junctional tachycardia (>100 beats/min)


[A17] Ventricular premature depolarisation




[A19] Bigeminy


[A20] Trigeminy








[A24] Idioventricular rhythm (<=100 beats/min, defined by wide QRS complex)


[A25] Non-sustained ventricular tachycardia (>100 beats/min, 3-30 beats)


[A26] Sustained ventricular tachycardia (>100 beats/min, >30 beats)




[A28] Monomorphic non-sustained ventricular tachycardia (>100 beats/min, 3-30 beats)


[A29] Monomorphic sustained ventricular tachycardia (>100 beats/min, >30 beats)


[A30] Polymorphic non-sustained ventricular tachycardia (>100 beats/min, 3-30 beats)


[A31] Polymorphic sustained ventricular tachycardia (>100 beats/min, >30 beats)


[A32] Torsade de Pointes (TdP)


[A33] Pacemaker


[A34] First degree AV block (PR interval >200msec)


[A35] Short PR Interval






[A38] 2:1 AV block


[A39] Third degree AV block


[A40] Left axis deviation (QRS axis more negative than -30 degrees)


[A41] Right axis deviation (QRS axis more positive than +110 degrees)


[A42] Incomplete right bundle branch block


[A43] Incomplete left bundle branch block


[A44] Right bundle branch block


[A45] Left anterior hemiblock


[A46] Left posterior hemiblock


[A47] Left bundle branch block



[A48] Bifascicular block


[A49] Non-specific intraventricular conduction delay (QRS >=120 msec)


[A50] Accessory pathway (Wolff-Parkinson-White, Lown-Ganong-Levine)


[A51] QTc prolongation >=500 msec


[A52] AV dissociation


[A53] Myocardial infarction, old


[A54] Myocardial infarction, non Q-wave


[A55] Non-specific ST-T changes


[A56] J point elevation


[A57] ST elevation


[A58] ST depression


[A59] ST segment abnormality


[A60] U waves


[A61] T wave inversion


[A62] T wave peaked


[A63] T waves biphasic


[A64] T waves flat


[A65] Notched T-waves


[A66] Low QRS voltage


[A67] T wave abnormality


[A94] Other abnormal rhythm A200(MAPPINGS1:t_HMSUM_TEL_AB_RPT.HMORRSSP)


[A95] Other morphology A200(MAPPINGS1:t_HMSUM_TEL_AB_RPT.HMORRSSP1)


[A96] Other conduction A200(MAPPINGS1:t_HMSUM_TEL_AB_RPT.HMORRSSP2)


[A97] Other myocardial infarction A200(MAPPINGS1:t_HMSUM_TEL_AB_RPT.HMORRSSP3)


[A98] Other depolarisation/repolarisation A200(MAPPINGS1:t_HMSUM_TEL_AB_RPT.HMORRSSP4)


[A99] Other abnormality/Cardiologist comments A200(MAPPINGS1:t_HMSUM_TEL_AB_RPT.HMORRSSP5)


Form Design Note:

P1TT v2.6

CDD: MAPPINGS1 Table: t_HMSUM_TEL_AB_RPT Key Type: PATIENTVISIT










































































HMORRSSP STRING(200) - A200












NGM114840_mjo : PGx-PHARMACOGENETIC RESEARCH CONSENT (PGx Consent)

PGx-PHARMACOGENETIC RESEARCH CONSENT

1. Has informed consent been obtained for PGx-Pharmacogenetic research? (MAPPINGS1:t_GENPRO_CONSENT.GPCNS)

[Y] Yes, record:

Date informed consent obtained for PGx-Pharmacogenetic research

Req / Req / Req (2011-2013) (MAPPINGS1:t_GENPRO_CONSENT.GPCNSDT)

(MAPPINGS1:t_GENPRO_CONSENT.GPSMPCOL)

Has a blood sample been collected for PGx-pharmacogenetic (DNA) research?

[N] No

[Y] Yes, record date sample taken

Req / Req / Req (2011-2013) (MAPPINGS1:t_GENPRO_CONSENT.GPSMPDT)

[N] (MAPPINGS1:t_GENPRO_CONSENT.GPCNRSCD)

No, check reason

[1] Subject declined

[2] Subject not asked by Investigator

[Z] Other, specify

A100

(MAPPINGS1:t_GENPRO_CONSENT.GPCNSOTH)

Form Design Note:

This form should only exist once in the study and is conditional upon inclusion of Pharmacogenetics in the protocol.

CDD: MAPPINGS1 Table: t_GENPRO_CONSENT Key Type: PATIENTVISIT


GPCNS STRING(1)

GPCNSDT DATE - DDMONYYYY

GPSMPCOL STRING(1)

GPSMPDT DATE - DDMONYYYY

GPCNRSCD STRING(1)

GPCNSOTH STRING(100) - A100


NGM114840_mjo : PHARMACOGENETIC (PGx) RESEARCH WITHDRAWAL OF CONSENT (PGx Withdraw)

WITHDRAWAL OF CONSENT FOR PGx (DNA) SAMPLE DESTRUCTION

1. Has subject withdrawn consent for PGx research? (MAPPINGS1:t_GENPRO_WD.GPCNSWD)

[N] No

[Y] Yes, date informed consent withdrawn

NReq / NReq / NReq (2011-2013) (MAPPINGS1:t_GENPRO_WD.GPCNSWDT)

2. Has a request been made for sample destruction? (MAPPINGS1:t_GENPRO_WD.GPDSREQ)

[N] No

[Y] (MAPPINGS1:t_GENPRO_WD.GPDSRSCD)

Yes, check reason

[3] Subject withdrew consent for PGx

[2] Screen failure

[Z] Other, specify

A100

(MAPPINGS1:t_GENPRO_WD.GPDSOTH)

Form Design Note:

IDSL Version 02.00A - 05 OCT 06. This form will be dynamically created when Q1, Has a blood sample been collected is Yes. Form is conditional upon inclusion of Pharmacogenetics in protocol. DNA in section title can be removed. Sample type to be stated.


Title Design Note

WITHDRAWAL OF CONSENT FOR PGx (DNA) SAMPLE DESTRUCTION FOR PGx (DNA) is optional

Item Design Notes:


2. Screen failure is an optional choice. Please replace 'insert sample type' with the appropriate sample type as specified in the protocol.

CDD: MAPPINGS1 Table: t_GENPRO_WD Key Type: PATIENTVISIT


GPCNSWD STRING(1)

GPCNSWDT DATE - DDMONYYYY

GPDSREQ STRING(1)

GPDSRSCD STRING(1)

GPDSOTH STRING(100) - A100


NGM114840_mjo : VISIT REPORTS (VRP)

VISIT REPORTS

1.* This section is not implemented for your study (MAPPINGS1:t_VISITREPORT.NOTAVAIL_CC)


CDD: MAPPINGS1 Table: t_VISITREPORT Key Type: PATIENTVISIT


NOTAVAIL_CC STRING(255)


NGM114840_mjo : Reg Docs (REG)

Reg Docs

1. This section is not implemented for your study (MAPPINGS1:t_REGDOCS.NOTAVAIL_CC)

CDD: MAPPINGS1 Table: t_REGDOCS Key Type: PATIENTVISIT


NOTAVAIL_CC STRING(255)


NGM114840_mjo : LIVER EVENTS (LIVER EVENTS)

1. Is this liver event a serious adverse event? (MAPPINGS1:t_RUCAM.LVSAE)

[Y] Yes, Please complete liver event forms and serious adverse event form immediately.

[N] No

2.* Notification Sent [read-only] Last Email Sent to Medical Monitor:

Req / Req / Req (2011-2013)


(MAPPINGS1:t_RUCAM.dtcLEMDMNCUR)

Initial Email Sent to Medical Monitor:

Req / Req / Req (2011-2013)


(MAPPINGS1:t_RUCAM.dtcLEMDMNINI)

Last Email Sent to GCSP:

Req / Req / Req (2011-2013)


(MAPPINGS1:t_RUCAM.dtcLEGCSPCUR)

Initial Email Sent to GCSP:

Req / Req / Req (2011-2013)


(MAPPINGS1:t_RUCAM.dtcLEGCSPINI)

Changed to Non Serious on:

Req / Req / Req (2011-2013)


(MAPPINGS1:t_RUCAM.dtcLESRTONSR)

3. Which liver chemistry result reached or exceeded protocol-defined investigational product stopping/interruption criteria? Check all that apply

(MAPPINGS1:t_RUCAM.RUORRSCD1A)

[1] ALT (alanine aminotransferase)


[2] AST (aspartate aminotransferase)


[3] Total bilirubin


[4] Alkaline phosphatase


[5] 5` nucleotidase


[6] Gammaglutamyltranspeptidase

(MAPPINGS1:t_RUCAM.RUORRSCDOT1)

[OT] Other

Record the details of any Adverse Events or exacerbations of Adverse Events on the Non-Serious Adverse Event Form or the Serious Adverse Event form. Exacerbations of Adverse Events include increases in frequency and severity.

It is particularly important to record any significant hypotension immediately prior to or concomitant with ALT elevation. It is particularly important to record any gallbladder or biliary disease, or pancreatitis, that occurred during the study.

4. Is the subject age 55 or older? (MAPPINGS1:t_RUCAM.RUORRSCD2)

[Y] Yes

[N] No

5. If female, is the subject pregnant? (MAPPINGS1:t_RUCAM.RUORRSCD3)

[Y] Yes

[N] No

[X] Not applicable

If yes, ensure Pregnancy Notification Form has been completed.

6. Were any diagnostic imaging tests of the liver or hepatobiliary system performed (such as liver ultrasound, computerised tomography or CAT scan, magnetic resonance imaging or MRI, or endoscopic retrograde cholangiopancreatography, or other)?

(MAPPINGS1:t_RUCAM.RUORRSCD4)

[Y] Yes. If Yes, were the results normal? (MAPPINGS1:t_RUCAM.RUORRSCD5)

[Y] Yes

[N] No

If No, record the details on the Imaging form. Please ensure the overall diagnosis indicated by imaging is captured on the Non-serious Adverse Event form or Serious Adverse Event form.

[N] No

7. Were any liver biopsies performed? (MAPPINGS1:t_RUCAM.RUORRSCD6)

[Y] Yes

[N] No

complete Liver Biopsy form.

8. Does the subject use herbals, complementary or alternative medicines, food supplements (vitamins) or illicit drugs? (MAPPINGS1:t_RUCAM.RUORRSCD7)

[Y] Yes

[N] No

record on the appropriate Concomitant Medication form.

9. Did the subject fast or undergo significant dietary change in the past week? (MAPPINGS1:t_RUCAM.RUORRSCD8)

[Y] Yes

[N] No

Evaluation interval code [hidden] (MAPPINGS1:t_RUCAM.EVLINTCD)

INVESTIGATIONAL PRODUCT (LIVER)

10. When did the liver event occur? (MAPPINGS1:t_RUCAM.LVEVOC)

[D] During the treatment period: If the liver event occurred during treatment period record start and stop date of investigational product for that treatment period.

Start Date Investigational Product

Req/Unk / Req/Unk / Req/Unk (2011-2013) (MAPPINGS1:t_RUCAM.EXSTDT4)

End Date Investigational Product

Req/Unk / Req/Unk / Req/Unk (2011-2013) (MAPPINGS1:t_RUCAM.EXENDT4)

[A] After the treatment period: If the liver event occurred after treatment period record start and stop date of investigational product for the most recent period prior to the liver event.

Start Date Investigational Product

Req/Unk / Req/Unk / Req/Unk (2011-2013) (MAPPINGS1:t_RUCAM.EXSTDT5)

End Date Investigational Product

Req/Unk / Req/Unk / Req/Unk (2011-2013) (MAPPINGS1:t_RUCAM.EXENDT5)


Form Design Note:

IDSL Version 03.01A 25 MAR 09 [Ex. 900]

Item Design Notes:


3. Codes 5 and 6 are conditional. Interruption may be removed if stopping/monitoring study only

itmEVLINTCD1L Item will be calculated by InForm.

CDD: MAPPINGS1 Table: t_RUCAM Key Type: PATIENTVISIT


LVSAE STRING(1)

dtcLEMDMNCUR DATE - DDMONYYYY HHMM

dtcLEMDMNINI DATE - DDMONYYYY HHMM

dtcLEGCSPCUR DATE - DDMONYYYY HHMM

dtcLEGCSPINI DATE - DDMONYYYY HHMM

dtcLESRTONSR DATE - DDMONYYYY HHMM

RUORRSCD1A STRING(255)







RUORRSCDOT1 STRING(255)

RUORRSCD2 STRING(1)

RUORRSCD3 STRING(1)

RUORRSCD4 STRING(1)

RUORRSCD5 STRING(1)

RUORRSCD6 STRING(1)

RUORRSCD7 STRING(1)

RUORRSCD8 STRING(1)

EVLINTCD STRING(255)

LVEVOC STRING(1)

EXSTDT4 DATE - DDMONYYYY

EXENDT4 DATE - DDMONYYYY

EXSTDT5 DATE - DDMONYYYY

EXENDT5 DATE - DDMONYYYY


NGM114840_mjo : PHARMACOKINETICS (LIVER PK)

An unscheduled PK sample must be obtained within 24 hours of last dose

1. Was a pharmacokinetic blood sample obtained? Hr:Min (00:00-23:59)

(MAPPINGS1:t_PK_LIVER.rdcPKLIVER)

[Y] Yes, date and time sample taken

Req / Req / Req (2011-2013)


(MAPPINGS1:t_PK_LIVER.PKSTDTTM3)

If Yes, date and time of last investigational product dose prior to PK sample Req / Req / Req (2011-2013)


(MAPPINGS1:t_PK_LIVER.EXSTDTTM1)

[N] No

Form Design Note:

IDSL Version 05.00A - 06APR09


Title Design Note

An unscheduled PK sample must be obtained within 24 hours of last dose The following text 'protocol specified longer value to be inserted' is a prompt for the eCRF designer and should be replaced with the relevant text from the protocol.

CDD: MAPPINGS1 Table: t_PK_LIVER Key Type: PATIENTVISIT


rdcPKLIVER STRING(1)

PKSTDTTM3 DATE - DDMONYYYY HHMM

EXSTDTTM1 DATE - DDMONYYYY HHMM


NGM114840_mjo : MEDICAL CONDITIONS AT ONSET OF LIVER EVENT (LIVER MEDHX)

LIVER DISEASE MEDICAL CONDITIONS

1. Acute Viral Hepatitis A (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATCD2)

[1] Current

[2] Past

[5] No Medical Condition

2. Chronic Hepatitis B (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATCD1)

[1] Current

[2] Past


3. Chronic Hepatitis C (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATCD3)

[1] Current

[2] Past


4. Cytomegalovirus Hepatitis (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATCD4)

[1] Current

[2] Past


5. Epstein Barr Virus Infectious Mononucleosis (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATCD5)

[1] Current

[2] Past


6. Herpes Simplex Hepatitis (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATCD6)

[1] Current

[2] Past


7. Alcoholic Liver Disease (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATCD7)

[1] Current

[2] Past


8. Non-alcoholic Steatohepatitis (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATCD8)

[1] Current

[2] Past


9. Fatty Liver (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATCD9)

[1] Current

[2] Past


10. Hepatic Cirrhosis (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATC10)

[1] Current

[2] Past


11. Hemochromatosis (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATC11)

[1] Current

[2] Past


12. Autoimmune Hepatitis (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATC12)

[1] Current

[2] Past


13. Gallbladder disease (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATC13)

[1] Current

[2] Past


DRUG RELATED LIVER DISEASE CONDITIONS (All drugs including Investigational Product)

14. Drug related liver disease (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATC14)

[1] Current

[2] Past


Sequence Number Specific Condition Modified Term

MedDRA Synonym

MedDRA lower

level term

code

Failed coding

Status

15. [hidden] [hidden] [hidden] [hidden] [hidden]

OTHER LIVER DISEASE CONDITIONS Entry

15.a* Sequence Number [hidden] xxxx (MAPPINGS1:t_MEDHIST_A_LIVER.MHSEQ)

15.b Specific ConditionA100

(MAPPINGS1:t_MEDHIST_A_LIVER.MHTERM)

15.c* Modified Term [hidden]A100

(MAPPINGS1:t_MEDHIST_A_LIVER.MHMODIFY)

MedDRA Synonym [hidden] (MAPPINGS1:t_MEDHIST_A_LIVER.MHMEDSYN)

MedDRA lower level term code [hidden] (MAPPINGS1:t_MEDHIST_A_LIVER.MHLLTCD)

Failed coding [hidden] (MAPPINGS1:t_MEDHIST_A_LIVER.calMH_FAILED)

15.d Status (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATC15)

[1] Current

[2] Past

OTHER MEDICAL CONDITIONS

16. Drug Allergies (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATC16)

[1] Current

[2] Past


17. Rheumatoid Arthritis (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATC17)

[1] Current

[2] Past


18. Psoriasis (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATC18)

[1] Current

[2] Past


19. Thyroid Disease (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATC19)


[1] Current

[2] Past


20. Inflammatory Bowel Disease (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATC20)

[1] Current

[2] Past


21. Lupus (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATC21)

[1] Current

[2] Past


22. Sjogren's Syndrome (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATC22)

[1] Current

[2] Past


23. Vitiligo (MAPPINGS1:t_MEDHIST_A_LIVER.MHSTATC23)

[1] Current

[2] Past



Form Design Note:

IDSL Version 01.03B 13 OCT 08


Title Design Note

OTHER LIVER DISEASE CONDITIONS Item 15 relates to Other Liver Disease Conditions (as in itemset below it) and not to Drug Related Liver Disease Conditions.

Item Design Notes:


15.d This item is optional

CDD: MAPPINGS1 Table: t_MEDHIST_A_LIVER Key Type: PATIENTVISIT


MHSTATCD2 STRING(1)

MHSTATCD1 STRING(1)

MHSTATCD3 STRING(1)

MHSTATCD4 STRING(1)

MHSTATCD5 STRING(1)

MHSTATCD6 STRING(1)

MHSTATCD7 STRING(1)

MHSTATCD8 STRING(1)

MHSTATCD9 STRING(1)

MHSTATC10 STRING(1)

MHSTATC11 STRING(1)

MHSTATC12 STRING(1)

MHSTATC13 STRING(1)

MHSTATC14 STRING(1)

MHSEQ NUMERIC - N4

MHTERM STRING(100) - A100

MHMODIFY STRING(100) - A100

MHMEDSYN STRING(255)

MHLLTCD STRING(255)

calMH_FAILED STRING(255)

MHSTATC15 STRING(1)

MHSTATC16 STRING(1)

MHSTATC17 STRING(1)

MHSTATC18 STRING(1)

MHSTATC19 STRING(1)

MHSTATC20 STRING(1)

MHSTATC21 STRING(1)

MHSTATC22 STRING(1)

MHSTATC23 STRING(1)


NGM114840_mjo : ALCOHOL INTAKE AT ONSET OF LIVER EVENT (LIVER ALCOHOL)

ALCOHOL INTAKE AT ONSET OF LIVER EVENT

1. Does the subject consume alcohol? (MAPPINGS1:t_SUBUSE_AL_LIVER.SUAL1)

[N] No

[Y] Yes, record the average number of units of alcohol consumed per week

xxx.xx

(MAPPINGS1:t_SUBUSE_AL_LIVER.SUALUNWK1)

Substance Use Type [hidden] (MAPPINGS1:t_SUBUSE_AL_LIVER.SUTYPCD1)

Form Design Note:

IDSL Version 01.03B 13 OCT 08

Item Design Notes:


1. For the SUALUNWK textbox the 2 decimal point section is optional. Study teams are allowed to capture whole numbers if required.

itmSUTYPCD1 This item will be calculated by InForm.

CDD: MAPPINGS1 Table: t_SUBUSE_AL_LIVER Key Type: PATIENTVISIT


SUAL1 STRING(1)

SUALUNWK1 FLOAT - F6.2

SUTYPCD1 STRING(255)


NGM114840_mjo : LIVER IMAGING (IMAGING) - Repeating Form

# Date of hepatic or liver imaging test

What method was used for this imaging test?

Are images technically adequate?

Indicate the liver size

Indicate the liver texture

Grade the diffuse and/or geographic fatty infiltrate of the liver

Ascites present

Are Focal Hepatic Lesions characterisable?

Gallstones or gallbladder lesions?

Biliary ductal lesions?

Portal/Hepatic vein abnormalities?

1

Date of hepatic or liver imaging test

1. Date of hepatic or liver imaging test Req / Req / Req (2011-2013) (MAPPINGS1:t_LIMAGING.LIDT)

What method was used for this imaging test?

2. What method was used for this imaging test? (MAPPINGS1:t_LIMAGING.LIMETHCD1)

[1] Ultrasound - transabdominal

[2] Ultrasound - endoscopic

[3] Magnetic Resonance Imaging (MRI)

[4] Computerised Tomography (CT)

[5] Endoscopic Retrograde Cholangiopancreatography (ERCP)

[6] Positron Emission Tomography (PET)

[7] Positron Emission Tomography/Computerised Tomography (PET/CT)

[OT] Other, specify: A200 (MAPPINGS1:t_LIMAGING.LIMETHSP)

Are images technically adequate?

3. Are images technically adequate? (MAPPINGS1:t_LIMAGING.IMGADQCD1)

[1] Optimal

[2] Readable, but not optimal

[3] Not readable

[OT] Other, specify: A200 (MAPPINGS1:t_LIMAGING.IMGADQSP)

Indicate the liver size

4. Indicate the liver size (MAPPINGS1:t_LIMAGING.LIORRSCDA1)

[A1] Normal size

[A2] Hypertrophy (or enlarged)

[A3] Atrophy (or smaller than normal)

[A4] Segmental hypertrophy

[A99] Other, specify: A200 (MAPPINGS1:t_LIMAGING.LIORRSSPA99)

Indicate the liver texture

5. Indicate the liver texture (MAPPINGS1:t_LIMAGING.LIORRSCDB1)

[B1] Normal

[B2] Heterogenous

[B3] Suggestive of fibrosis

[B4] Nodular or suggestive of cirrhosis

[B99] Other, specify: A200 (MAPPINGS1:t_LIMAGING.LIORRSSPB99)

Grade the diffuse and/or geographic fatty infiltrate of the liver

6. Grade the diffuse and/or geographic fatty infiltrate of the liver (MAPPINGS1:t_LIMAGING.LIORRSCDC1)

[C1] Not applicable - no fatty infiltration

[C2] Mild (<=25%)

[C3] Moderate (>25% to <75%)

[C4] Severe (>=75%)

[C99] Other, specify: A200 (MAPPINGS1:t_LIMAGING.LIORRSSPC99)

Ascites present

7. Ascites present (MAPPINGS1:t_LIMAGING.LIORRSCDD1)

[D1] None present

[D2] Yes - small amount

[D3] Yes - moderate or severe amount

[D99] Other, specify: A200 (MAPPINGS1:t_LIMAGING.LIORRSSPD99)

Are Focal Hepatic Lesions characterisable?

8. Are Focal Hepatic Lesions characterisable? (MAPPINGS1:t_LIMAGING.LIORRSCDE0)

[E0] Not applicable - no hepatic lesions

[E] Check all that apply

(MAPPINGS1:t_LIMAGING.LIORRSCDE1)

[E1] Solid


[E2] Cystic


[E3] Hemangioma


[E4] Focal Nodular Hyperplasia


[E99] Other, specify: A200 (MAPPINGS1:t_LIMAGING.LIORRSSPE99)

Gallstones or gallbladder lesions?

9. Gallstones or gallbladder lesions? (MAPPINGS1:t_LIMAGING.LIORRSCDF0)

[F0] None

[F] Check all that apply

(MAPPINGS1:t_LIMAGING.LIORRSCDF1)

[F1] Gallstones


[F2] Gallbladder polyp(s)


[F3] Sludge


[F4] Gallbladder wall thickening/oedema


[F5] Gallbladder wall gas


[F6] Cholecystitis


[F7] Gallbladder wall calcification


[F8] Gallbladder mass


[F99] Other, specify: A200 (MAPPINGS1:t_LIMAGING.LIORRSSPF99)

Biliary ductal lesions?

10. Biliary ductal lesions? (MAPPINGS1:t_LIMAGING.LIORRSCDG0)

[G0] None

[G] Check all that apply

(MAPPINGS1:t_LIMAGING.LIORRSCDG1)

[G1] Intrahepatic ductal dilation (focal involving the right hepatic lobe)



[G2] Intrahepatic ductal dilation (focal involving the left hepatic lobe)


[G3] Intrahepatic ductal dilation (involving both right and left hepatic lobes)


[G4] Extrahepatic ductal dilation


[G5] Diffuse ductal dilation (involving both intrahepatic and extrahepatic ducts)


[G6] Acute Cholangitis


[G7] Primary sclerosing cholangitis


[G8] Choledocholithiasis (gallstone in duct)


[G9] Ductal filling defect(s), other than gallstone


[G10] Ductal wall thickening or oedema


[G11] Choledochal cyst


[G12] Ductal mass


[G13] Extrinsic mass compressing bile duct(s)


[G99] Other, specify: A200 (MAPPINGS1:t_LIMAGING.LIORRSSPG99)

Portal/Hepatic vein abnormalities?

11. Portal/Hepatic vein abnormalities? (MAPPINGS1:t_LIMAGING.LIORRSCDH0)

[H0] None

[H] Check all that apply

(MAPPINGS1:t_LIMAGING.LIORRSCDH1)

[H1] Portal vein enlargement


[H2] Hepatic vein enlargement


[H3] Nonocclusive portal vein thrombosis


[H4] Occlusive portal vein thrombosis - bland


[H5] Hepatic vein thrombosis - bland


[H6] Occlusive portal vein thrombosis - malignant


[H7] Hepatic vein thrombosis - malignant


[H8] Involvement of the main portal vein


[H9] Involvement of the right portal vein


[H10] Involvement of the left portal vein


[H11] Budd-Chiari syndrome


[H99] Other, specify: A200 (MAPPINGS1:t_LIMAGING.LIORRSSPH99)

Form Design Note:

IDSL Version 01.03A 03 JUL 08

CDD: MAPPINGS1 Table: t_LIMAGING Key Type: PATIENTVISIT


LIDT DATE - DDMONYYYY

LIMETHCD1 STRING(2)

LIMETHSP STRING(200) - A200

IMGADQCD1 STRING(2)

IMGADQSP STRING(200) - A200

LIORRSCDA1 STRING(3)

LIORRSSPA99 STRING(200) - A200

LIORRSCDB1 STRING(3)

LIORRSSPB99 STRING(200) - A200

LIORRSCDC1 STRING(3)

LIORRSSPC99 STRING(200) - A200

LIORRSCDD1 STRING(3)

LIORRSSPD99 STRING(200) - A200

LIORRSCDE0 STRING(2)






LIORRSSPE99 STRING(200) - A200

LIORRSCDF0 STRING(2)










LIORRSSPF99 STRING(200) - A200

LIORRSCDG0 STRING(2)
















LIORRSSPG99 STRING(200) - A200

LIORRSCDH0 STRING(2)













LIORRSSPH99 STRING(200) - A200


NGM114840_mjo : LIVER BIOPSY (BIOPSY) - Repeating Form

# Date of liver biopsy

Biopsy size

Final Diagnosis

Liver Architecture

Description of Liver Cells or Hepatocytes

Liver Cell or Hepatocyte Inclusions or Vacuoles

Hepatocyte or Liver Cell Nuclear Abnormalities

Liver or Lobular Infiltrates

Portal Tract Inflammation

Bile Ducts

Portal Veins

Liver Infections

Parasites or Ova

Histologic Staining or Additional Studies Obtained

1

Date of liver biopsy

1. Date of liver biopsy Req / Req / Req (2011-2013) (MAPPINGS1:t_LBIOPSY.LPDT)

Biopsy size

2. Approximate size of liver biopsy xx mm (MAPPINGS1:t_LBIOPSY.BIOPSZ)

3.* Biopsy size unit [hidden] MM

Final Diagnosis

4. Final Diagnosis (MAPPINGS1:t_LBIOPSY.LPORRSCDA0NOR)

[A0] Normal

[AAA] Check all that apply

(MAPPINGS1:t_LBIOPSY.LPORRSCDA1)

[A1] Acute hepatitis


[A2] Chronic hepatitis


[A3] Cholestatic hepatitis


[A4] Drug-induced cholestasis


[A5] Acute viral hepatitis


[A6] Chronic viral hepatitis


[A7] Drug-induced hepatitis


[A8] Autoimmune hepatitis


[A9] Bridging necrosis


[A10] Submassive hepatic necrosis


[A11] Massive hepatic necrosis


[A12] Steatosis - microvesicular


[A13] Steatosis - macrovesicular


[A14] Steatosis - mixed


[A15] Non-alcoholic steatohepatitis


[A16] Alcoholic hepatitis


[A17] Hepatic granulomas


[A18] Sarcoidosis


[A19] Fibrosis


[A20] Cirrhosis


[A21] Primary biliary cirrhosis


[A22] Primary sclerosing cholangitis


[A23] Autoimmune overlap syndrome


[A24] Hemochromatosis


[A25] Alpha-1-antitrypsin deficiency


[A26] Wilson's disease


[A27] Veno-occlusive disease


[A28] Budd-Chiari syndrome


[A29] Neoplasia


[A99] Other, specify: A200 (MAPPINGS1:t_LBIOPSY.LPORRSSPA99)

Liver Architecture

5. Liver Architecture (MAPPINGS1:t_LBIOPSY.LPORRSCDB1NORM)

[B1] Normal

[BBB] Check all that apply

(MAPPINGS1:t_LBIOPSY.LPORRSCDB2)

[B2] Bridging fibrosis


[B3] Diffuse fibrosis


[B4] Nodular regenerative hyperplasia


[B5] Congenital hepatic fibrosis


[B6] Cirrhosis


[B7] Centrilobular congestion


[B8] Endophlebitis


[B9] Veno-occlusive disease


[B10] Canalicular cholestasis


[B11] Apoptosis


[B12] Focal (or spotty or mild) hepatocellular necrosis


[B13] Interface hepatitis (periportal hepatitis or piecemeal necrosis)


[B14] Ischaemic necrosis



[B15] Centrolobular (Zone 3) necrosis


[B16] Focal coagulative necrosis


[B17] Centrolobular (Zone 3) coagulative necrosis


[B18] Bridging hepatocellular necrosis


[B19] Massive or panlobular hepatocellular necrosis


[B20] Dysplasia


[B21] Neoplasia


[B99] Other, specify: A200 (MAPPINGS1:t_LBIOPSY.LPORRSSPB99)

Description of Liver Cells or Hepatocytes

6. Description of Liver Cells or Hepatocytes (MAPPINGS1:t_LBIOPSY.LPORRSCDC0NOR)

[C0] Normal

[CCC] Check all that apply

(MAPPINGS1:t_LBIOPSY.LPORRSCDC1)

[C1] Ballooning


[C2] Acidophilic


[C3] Pseudoxanthomatous


[C4] Multinucleated giant hepatocytes


[C99] Other, specify: A200 (MAPPINGS1:t_LBIOPSY.LPORRSSPC99)

Liver Cell or Hepatocyte Inclusions or Vacuoles

7. Liver Cell or Hepatocyte Inclusions or Vacuoles (MAPPINGS1:t_LBIOPSY.LPORRSCDDONOINC)

[D0] No inclusions

[DDD] Check all that apply

(MAPPINGS1:t_LBIOPSY.LPORRSCDD1)

[D1] Macrovesicular steatosis


[D2] Microvesicular steatosis


[D3] Bile accumulation


[D4] Diastase-resistant, PAS-positive cytoplasmic inclusions


[D5] Alpha-1-antitrypsin inclusions


[D6] Megamitochondria


[D7] Mallory bodies


[D8] "Ground Glass" inclusions


[D9] Lipofuscin pigment


[D10] Hemosiderin granules


[D11] Orcein-positive cytoplasmin granules


[D12] Protoporphyrin crystals (birefringent under polarised light)


[D13] Uroporphyrin crystals (red fluorescence under ultraviolet light)


[D99] Other, specify: A200 (MAPPINGS1:t_LBIOPSY.LPORRSSPD99)

Hepatocyte or Liver Cell Nuclear Abnormalities

8. Hepatocyte or Liver Cell Nuclear Abnormalities (MAPPINGS1:t_LBIOPSY.LPORRSCDE0NONE)

[E0] None

[EEE] Check all that apply

(MAPPINGS1:t_LBIOPSY.LPORRSCDE1)

[E1] Hepatocellular mitosis


[E2] Binucleated or multinucleated hepatocytes


[E3] CMV inclusion bodies


[E4] HSV inclusions


[E5] Varicella inclusions


[E99] Other, specify: A200 (MAPPINGS1:t_LBIOPSY.LPORRSSPE99)

Liver or Lobular Infiltrates

9. Liver or Lobular Infiltrates (MAPPINGS1:t_LBIOPSY.LPORRSCDF0NONE)

[F0] None

[FFF] Check all that apply

(MAPPINGS1:t_LBIOPSY.LPORRSCDF1)

[F1] Eosinophils


[F2] Lymphocytes


[F3] Plasma cells


[F4] Neutrophils


[F5] Macrophages and proliferating Kupffer cells


[F6] Granulomas


[F99] Other, specify: A200 (MAPPINGS1:t_LBIOPSY.LPORRSSPF99)

Portal Tract Inflammation

10. Portal Tract Inflammation (MAPPINGS1:t_LBIOPSY.LPORRSCDG0NONE)

[G0] None

[GGG] Check all that apply

(MAPPINGS1:t_LBIOPSY.LPORRSCDG1)

[G1] Eosinophils



[G2] Lymphoid aggregates and/or follicles


[G3] Plasma cells


[G4] Neutrophils


[G5] Histocytes and macrophages


[G99] Other, specify A200 (MAPPINGS1:t_LBIOPSY.LPORRSSPG99)

Bile Ducts

11. Bile Ducts (MAPPINGS1:t_LBIOPSY.LPORRSCDH0NOR)

[H0] Normal

[HHH] Check all that apply

(MAPPINGS1:t_LBIOPSY.LPORRSCDH1)

[H1] Proliferation of bile ducts (bile ductular reaction)


[H2] Dilation, degeneration or disruption of portal bile ducts


[H3] Paucity of bile ducts


[H4] Periductal fibrosis


[H99] Other, specify: A200 (MAPPINGS1:t_LBIOPSY.LPORRSSPH99)

Portal Veins

12. Portal Veins (MAPPINGS1:t_LBIOPSY.LPORRSCDI0NOR)

[I0] Normal

[III] Check all that apply

(MAPPINGS1:t_LBIOPSY.LPORRSCDI1)

[I1] Pyelophlebitis


[I2] Thrombosis, sclerosis or occlusion of portal vein


[I3] Neoplastic invasion of portal vein


[I4] Granulomatous compression of portal vein


[I99] Other, specify: A200 (MAPPINGS1:t_LBIOPSY.LPORRSSPI99)

Liver Infections

13. Liver Infections (MAPPINGS1:t_LBIOPSY.LPORRSCDJ0NOR)

[J0] Normal

[JJJ] Check all that apply

(MAPPINGS1:t_LBIOPSY.LPORRSCDJ1)

[J1] Leishmaniasis donovani


[J2] Plasmodium falciparum


[J3] Toxoplasmosis


[J4] Cryptococcus neoformans


[J5] Histoplasma capsulatum


[J6] Mycobacterium tuberculois


[J7] Other mycobacterial species


[J99] Other, specify: A200 (MAPPINGS1:t_LBIOPSY.LPORRSSPJ99)

Parasites or Ova

14. Parasites or Ova (MAPPINGS1:t_LBIOPSY.LPORRSCDK0NONE)

[K0] None

[KKK] Check all that apply

(MAPPINGS1:t_LBIOPSY.LPORRSCDK1)

[K1] Schistosome and/or ova


[K2] Ascaris and/or ova


[K3] Toxocara and/or ova


[K4] Echinococcus cysts


[K5] Hepatic capillariasis worms and/or ova


[K99] Other, specify: A200 (MAPPINGS1:t_LBIOPSY.LPORRSSPK99)

Histologic Staining or Additional Studies Obtained

15. Histologic Staining or Additional Studies Obtained (MAPPINGS1:t_LBIOPSY.LPORRSCDL1)

[L1] Haematoxylin and eosin (or H & E)

(MAPPINGS1:t_LBIOPSY.LPORRSCDL2)

[L2] Masson


[L3] Toluidine blue or Giemsa


[L4] Prussian blue


[L5] Periodic Acidic Schiff (PAS), with or without diastase


[L6] Oil red O


[L7] Congo red


[L8] Hall's stain


[L9] Gridley's stain


[L10] Rhodanine (copper)


[L11] Rubeanic acid (copper)


[L12] Orcein, aldehyde fuchsin or Victoria blue


[L13] Electron microscopy


[L14] Hepatitis A immunostains positive



[L15] Hepatitis B core antigen or hepatitis B surface antibody immunostains positive


[L16] Hepatitis D immunostains


[L17] Other immunostains


[L99] Other, specify: A200 (MAPPINGS1:t_LBIOPSY.LPORRSSPL99)


Form Design Note:

IDSL Version 01.02A 05 OCT 06

CDD: MAPPINGS1 Table: t_LBIOPSY Key Type: PATIENTVISIT


LPDT DATE - DDMONYYYY

BIOPSZ NUMERIC - N2

LPORRSCDA0NOR STRING(3)

LPORRSCDA1 STRING(255)






























LPORRSSPA99 STRING(200) - A200

LPORRSCDB1NORM STRING(3)

LPORRSCDB2 STRING(255)





















LPORRSSPB99 STRING(200) - A200

LPORRSCDC0NOR STRING(3)

LPORRSCDC1 STRING(255)





LPORRSSPC99 STRING(200) - A200

LPORRSCDDONOINC STRING(3)

LPORRSCDD1 STRING(255)















LPORRSSPD99 STRING(200) - A200

LPORRSCDE0NONE STRING(3)

LPORRSCDE1 STRING(255)






LPORRSSPE99 STRING(200) - A200

LPORRSCDF0NONE STRING(3)

LPORRSCDF1 STRING(255)







LPORRSSPF99 STRING(200) - A200

LPORRSCDG0NONE STRING(3)

LPORRSCDG1 STRING(255)






LPORRSSPG99 STRING(200) - A200

LPORRSCDH0NOR STRING(3)

LPORRSCDH1 STRING(255)





LPORRSSPH99 STRING(200) - A200

LPORRSCDI0NOR STRING(3)

LPORRSCDI1 STRING(255)





LPORRSSPI99 STRING(200) - A200

LPORRSCDJ0NOR STRING(3)

LPORRSCDJ1 STRING(255)








LPORRSSPJ99 STRING(200) - A200

LPORRSCDK0NONE STRING(3)

LPORRSCDK1 STRING(255)






LPORRSSPK99 STRING(200) - A200

LPORRSCDL1 STRING(255)



















LPORRSSPL99 STRING(200) - A200


CRB Electronic Signature Affidavit

By my dated signature below, I, [First Name] [Last Name], verify that all case report form pages accurately display the results of the examinations, tests, evaluations and treatments performed on this patient. Pursuant to Section 11.100 of Title 21 of the Code of Federal Regulations, this is to certify that I intend that this electronic signature is to be the legally binding equivalent of my handwritten signature. To this I do attest by supplying my user name and password and clicking the button marked Submit below.

CRF Electronic Signature Affidavit

By my dated signature below, I, [First Name] [Last Name], verify that this case report form accurately displays the results of the examinations, tests, evaluations and treatments noted within. Pursuant to Section 11.100 of Title 21 of the Code of Federal Regulations, this is to certify that I intend that this electronic signature is to be the legally binding equivalent of my handwritten signature. To this I do attest by supplying my user name and password and clicking the button marked Submit below.


CONFIDENTIAL

1

LIST OF INVESTIGATORS AND IECS/IRBS FOR NGM114840

Investigator Sub-Investigator Investigator no./Center no.

Description of Research Facility, Hospital/ Institution, and Address

Name of IEC/IRB Committee, Address, Committee Chair

Germany MD*

Germany Germany

Chairperson: MD*

(FPI) Germany Germany

Chairperson:

MD* Germany Germany

Chairperson:

2012N137712_00NGM114840

CONFIDENTIAL

2

Investigator Sub-Investigator Investigator no./Center no.

Description of Research Facility, Hospital/ Institution, and Address

Name of IEC/IRB Committee, Address, Committee Chair

Italy

PhD

Italy

Italy

Chairperson:

Norway

MD, PhD*

Norway

Norway

Chairperson:

*No Patients Randomized

2012N137712_00NGM114840

This section contained Principal Investigator’s Curriculum Vitae and has been excluded to

protect Principal Investigator privacy.

Version 02, 11 May 2011

PARTICIPANT INFORMATION AND CONSENT FORM NGM114840

Page 1 of 25 Volunteer number: ____________

Study Title A randomized, single blind, placebo-controlled, single ascending dose/repeat dose cohort study to assess safety, tolerability, pharmacokinetics and immunogenicity of GSK1223249 in patients with relapsing forms of multiple sclerosis

Study Identifier NGM114840

Sponsor Company GlaxoSmithKline (GSK)

A Study of a New Monoclonal Antibody to Treat Relapsing Forms of Multiple Sclerosis

Study doctor: [NAME] Institution name: [Hospital or CRO name] Site address: Phone number: This consent form describes a clinical trial, a type of research study. The main purpose of this clinical trial is to see how safe it is to give people with Multiple Sclerosis (MS) three doses of a possible new treatment for this disease. In addition to the information contained in this form, we, the study staff, will explain the whole study to you. You are being asked to take part in this study because you have MS. The study is only for people with MS. It also only includes people who choose to take part, meaning participation is completely voluntary. Whether you decide to be in this study or not, will not affect your ability to receive medical care. Being in this trial does not take the place of your regular medical care. Some of the information in this form is required by law. This form has been reviewed and approved by an Independent Ethics Committee. This committee reviews research studies to protect the rights and well-being of the people taking part. What is “consent”? It is completely up to you to decide if you want to take part in this study. If you decide to take part, you must sign the pages at the end of this form to say that you understand what is expected of you and the study staff, what

1





the risks and benefits are to you, and to say that you agree to be part of the study. This is called “giving consent”. You should make your decision only after: 1. A study doctor at your site has explained the study to you in a way that

you understand. 2. You know the purpose of the study and any risks to you, and 3. You are willing and able to do what is asked of you in the study. Talk with your family, friends, and your regular doctor to help make your decision. You may ask questions of the study staff until you are sure that you understand the purpose of the study, your role and the risks to you. You may take as much time as you like. If you decide to take part in the study, you will let us know that you agree by signing this form. If you are physically unable to sign and date this form, you may have a witness to the consent process sign for you. We will give you a copy to keep for your records. You may change your mind and leave the study at any time, even if you have signed this form. You do not have to give a reason. Who should I call if I have any questions? You can talk with the study doctor about any questions or concerns you have about this study. Contact the study doctor, Associate [name] at [number] and / or study staff at [number] or [alternative number]. Call the study doctor if you change your mind and decide that you no longer want to take part. If you have any questions about the rights you have while taking part in this study, call the [name] Human Research Ethics Committee at [number], or contact them at [Address] , fax [number] , or email [email address] If you think you have been injured from taking part in this study, or have any questions about side effects, call the CRO/Institution at [number]. What is the treatment being tested in this study? The treatment being tested is called GSK1223249. GSK1223249 is a new

2





monoclonal antibody made by the company GlaxoSmithKline (GSK). Antibodies are proteins that are generated by white blood cells. They are part of your immune system: a network of cells, tissues and organs and the proteins and chemicals they make that protect you from infections and help keep you healthy. They travel in your blood and attach (bind) to foreign proteins called antigens. Once attached, they may block the antigen from having an effect or help the body to get rid of it. Your body naturally makes millions of antibodies every day. A monoclonal antibody is a man-made type of antibody produced in the laboratory. It can be designed to locate and bind to one antigen in the body. For example, it might be designed to bind to an antigen that causes inflammation (a reaction that causes damage to tissue) or other kinds of damage. It is known that inflammation and damage occur in the brain and spinal cord in MS. GSK1223249 is a monoclonal antibody made against a protein called Nogo-A. In MS, the protein Nogo-A is found in damaged areas of the brain - near nerves (axons) and myelin (the covering that acts like an insulator of axons) in brain and spinal cord. Nogo-A does not seem to be widely present outside the nervous system. In MS, it is thought that Nogo-A may make the brain less able to protect or repair itself. This means that blocking Nogo-A with GSK1223249, may help protect or repair the brain. The treatment will be given (administered) via the intra venous (IV) route, that is to say that the drug will be injected into a vein in one arm, and infused (given gradually) over approximately 30-60 minutes. Why is this study being done? GSK1223249 is an investigational (experimental) treatment, or study drug. It has not been approved yet by the government for doctors to prescribe for the treatment of MS. One of the first steps in testing a new treatment for a disease is seeing how safe it is. GSK1223249 has been tested in animals and has been found to be safe. It is also being tested in a clinical study in people with amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease) and this is also showing

3





GSK1223249 to be safe and well-tolerated, There is only data on how safe GSK1223249 is in patients with MS at a very low dose. Therefore, the main purpose of the study is to find out if GSK1223249 is safe and well-tolerated (meaning that it doesn’t cause a lot of unwanted effects, like headache or achiness or weakness) in patients with MS. We also want to make sure that it doesn’t make people’s MS worse instead of better. Other reasons for this study are that we want to determine how levels of GSK1223249 change in the blood over time (pharmacokinetics) and whether your body will develop it’s own antibodies to GSK1223249. We also want to know how much GSK1223249 gets into the brain. About four different doses of GSK1223249 will be studied. The current planned doses are 1, 5, 15 and 30 mg/kg. The doses of GSK1223249 studied will increase ONLY if the information regarding safety and blood levels at lower dose levels have been shown to be satisfactory. Doses of 15 mg/kg have been well tolerated in ALS patients. The planned doses may change based on the real time analysis and review of data obtained from the previous lower dose levels. GSK1223249 is being compared to a placebo (salt solution that does not contain any active drug.). Both GSK1223249 and the placebo are called “study treatment” or “medication”. If you take part in this study, you will receive three doses of study treatment/medication. That means you could receive three doses of GSK1223249 or you might receive three doses of placebo – one or the other, but not both. You will not know which study treatment you receive. The placebo is included to help make sure that information about GSK1223249 is unbiased and balanced. In this study, you will have a one in four, or 25% chance of receiving placebo. You cannot ask to receive GSK1223249 or placebo – a computer will decide this in a way similar to chance or rolling dice. Neither you nor your study staff will know whether you are receiving GSK1223249. This means that the study is “blinded”. Unless there is an emergency that requires a doctor to know whether you received GSK1223249, you will not be able to know this until the entire study is completed (which could be up to about two years from now). If it turns out that you received placebo, you will not be able to receive GSK1223249 at the end of this study. However, if there is another study with GSK1223249, you may also be able to participate in that study,

4





as long as you meet the requirements for entry into the new study (which could be different from the requirements for this study). In total, about 40 people at sites in [local country] and possibly other countries will take part in this study. Once about 40 people have completed this study, it will be finished and we will not ask for more volunteers. Do I have other treatment choices? This study allows you to continue on your current MS treatment If you choose not to take part in this study, you may choose to

continue with your regular MS care from your usual doctor. see if you qualify for a completely different study.

Please take your time to understand what choices are available to you and to make the decision that you feel is right for you. What information is being gathered in this study? The main purpose of this study is to determine if the experimental treatment, GSK1223249, is safe and tolerable (without unwanted side effects) in patients who have MS. Other reasons for this study include understanding

How long GSK1223249 stays in your blood. This is called pharmacokinetics (PK).

How much GSK1223249 gets from your blood into and around your brain tissue

Whether the body develops antibodies to GSK1223249. We will assess how safe the doses of GSK1223249 have been by asking how you and your MS symptoms have been, physical examination (similar to the one you would have every year at a doctor’s office), neurologic examination (similar to the one your neurologist does), blood and urine tests, taking one sample of spinal fluid, and taking pictures of your brain using magnetic resonance imaging (MRI). How long GSK1223249 stays in your blood is determined by taking blood samples often (about 4 times) over the first 24 hours after it is given and

5





then about 10 times between and after the doses. How much GSK1223249 gets from your blood into and around your brain tissue is looked at by taking 1 sample of fluid from your spinal cord (the fluid is called cerebrospinal fluid, or CSF for short). The procedure is called a lumbar puncture. You will only have 1 sample of CSF taken during the entire study. You will be informed of the timing of the sample by the study staff by the time you receive your first dose of study medication. For patients that will receive the lowest 2 doses of study medication, there will NOT be a lumbar puncture. Your blood and urine samples (and CSF samples, if applicable) may also be analysed for drug response, other markers of MS disease that may help in developing other drugs for MS, or for further scientific understanding of MS. Whether your body develops antibodies to GSK1223249 is also looked at by taking blood samples (about 5 times) over the duration of the study. What am I expected to do in this study? If you decide to take part, you will be involved for about 7 months. Your study staff will explain to you all the visits, tests and options in this study. Being in this study means that you would have to use part or all of a total of 15 days for visits - more if you have to travel a long distance for part of the study. It is important to understand that for this study, you will need to stay a minimum of one and (if necessary because of long travel distances), two nights in the [Hospital/CRO name] (a hospital-like unit where study staff can watch you closely), at some of the visits. For the rest of the visits, most of these can be done similar to the way you would have your regular MS clinic visits. During the seven months, you will need to get tests, come to the clinic for scheduled visits and pictures of your brain, and tell us about any changes to your health or medicines. Blood samples will be taken at each visit, so you should not eat past midnight (have no food or drink except water) the night before.

6





The following table is only a guide as to which visits will be required. Extra blood samples or procedures may be needed for safety reasons or to measure the amount of study drug in your blood. A member of staff will inform you when you will be required to attend the unit for extra blood sampling. Visit 1: Screening Visit (About 2.5-3 hours)

Informed consent, medical history, physical and neurological examination, vital signs (incl. height & weight), ECG, alcohol breath test, fasting blood and urine samples (drug screen), pregnancy test (women), hormone levels (post-menopausal women), MRI

Visit 2: Baseline Visit (Within 7 days +/- 2 days prior to dosing) (About 2 hours)

MRI, physical and neurological exam, blood sample.

Visit 3, 6 & 9: In-house Period

Day 1 , Day 29, Day 57

Admitted to Unit, fasting blood and urine samples (drug screen), pregnancy test (women), ECG, vital signs (incl. weight), neurological exam, alcohol breath test. Dosed with study drug, blood samples, vital signs, continuous ECG monitoring, possible lumbar puncture

Day 2, Day 30, Day 58

Blood and urine sample, possible lumbar puncture, Discharge when all procedures have been completed.

Visits 4, 5, 7, 8, 10, 11, 12, 13, 14 & 15: Outpatient Visits

Days 7, 13, 36, 42, 64, 70, 85, 127, 169 & 197

Various assessments such as fasting blood and urine samples, pregnancy test (women), ECG, vital signs, physical and neurological examination. Possible lumbar puncture.

If applicable for you, the lumbar puncture will be carried out during the course of the treatment period and your doctor will inform you of the time and date prior to the first dose of study treatment/medication. All study procedures, examinations and tests that will be performed are outlined in greater detail below. Visit 1 (Screening): Before you actually begin the study, you will have to undergo a “screening” visit. At this visit, the following exams, tests or procedures will be carried out to find out if you can be in the study. Some of these tests are part of regular medical care, but in this case they are being done only for the purposes of the study. It is important to understand that these tests are not being used as part of your regular medical care and are not routinely provided to your regular doctor.

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Medical history: We will ask about your health, alcohol use, and any illnesses or medicines you are taking (including over-the-counter medicine, vitamins or herbal treatments). You will be asked to provide as many details as you can about your MS, such as what your first symptoms were, how old you were when you feel the disease began, where and when you were first diagnosed with MS, how many relapses you have had, whether you are still working, etc.

Physical examination and neurologic examinations: A brief standard general physical exam of your head, eyes, ears, nose, throat, skin, thyroid, lungs, cardiovascular, abdomen, lymph nodes and extremities will be carried out as they normally would in a doctors’office. A neurological examination will be given, which consists of some tests that will assess your MS symptoms. This is similar to the EDSS exam, an exam used worldwide to assess MS, and one which you may have had before.

Vital signs: We will check your weight, height, blood pressure, and pulse.

Electrocardiogram (ECG): This will record the electrical activity of your heart.

Blood tests: We will draw blood from a vein for lab tests. These will include tests for hepatitis B, hepatitis C, and HIV. Prior to having this sample taken you will be told about the significance of testing for hepatitis B, C and HIV. Appropriate counselling and referral will be arranged in the event of an abnormal result. Women will have a pregnancy test. Post-menopausal women will have a blood test for female hormone levels to confirm menopause status.

Urine sample: a urine test will check for certain conditions such as infection, and a drug screen.

Alcohol breath test: to check if you have had alcohol recently. Magnetic Resonance Imaging (MRI scan): This test may take 1 -

1½hrs. A machine is used to provide pictures of your brain. These pictures can provide some information about how active your MS is. A total of eight scans will be carried out in this study.

The results of these tests will decide if you can join the study. If you qualify for the study and wish to join you will asked to return to the clinic within 24-32 days for the baseline visit.

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Visit 2 (Baseline): You will undergo a “baseline” visit (about 2 hours) within 7 days +/- 2 days before planned study drug dosing. The results from Visit 1 will be reviewed with you in detail. If no reason is found that makes you unable to be in the study, you will be asked if you would like to continue. If you agree, then the following will be done:

Physical and neurologic examinations MRI scan Blood sample for routine safety laboratory tests ECG

Visit 3, 6 & 9 (admission to the Unit for Day 1): Day 1 On Day 1 (before you receive study drug) you will have the following tests and assessments repeated to make sure that it is safe for you to receive the study drug. You will be able to relax and get comfortable in the Unit.

Medicine and health review Body weight Neurological examination Blood samples for routine safety laboratory tests Urine sample, for routine laboratory tests and drug screen, and

pregnancy test (women) Vital signs ECG

Day 1 is also the day that you receive the one dose of study treatment in the Unit. In order to minimise your discomfort, an intravenous cannula (also known as an “IV”) will be used. This is a tiny plastic tube inserted into a vein in your forearm. You will have 2 cannulas inserted into the veins one in each arm.

One intravenous cannula will be used to give the study drug. The study treatment will be given to you through the cannula over about 30 to 60 minutes. The cannula will be removed once the study drug has been given.

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The second cannula will be used to draw blood during the day. It will

be removed after all the blood samples have been taken. However, if the cannula becomes blocked or causes you any discomfort, it will be removed earlier and may be replaced, or the subsequent blood samples will be taken with a standard needle. Up to 5 blood samples will be drawn throughout the visit.

The following tests and procedures will also be done during Day 1:

Blood samples to measure GSK1223249 in your blood and to see whether your body has made antibodies to GSK1223249 (as described above from the second cannula).

Blood and urine samples for routine safety laboratory tests Vital signs Continuous ECG monitoring: You will have a small device, about the

size of a large iPod , with five wires attached to tabs placed on your chest. This will provide ongoing heart readings from just before dosing until 24 hours after dosing.

You will be asked how you are feeling

All tests and procedures will end the next morning (Day 2). Once the last blood sample has been taken the cannula will be removed and you will go home. Visits 4, 5, 7, 8, 10- 15 (out-patient visits – ranging from about 1 hour up to 4 hours per visit) These are visits for blood samples to determine the level of study treatment remaining in your blood and sometimes whether you have antibodies to study treatment. You will be asked to report how you are feeling. Depending on where you live, the study staff may be able to arrange for a visiting nurse to come to your home to do these visits. Visits 5, 8, 10, - 15 will take about half a day, depending on how long it takes to complete an MRI. During these visits you will have some, but not all of the following tests and procedures done:

Medicine and health review Vital signs

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ECG Physical and neurological examination Urine and blood samples for routine laboratory tests, to measure the

amount of study drug in your body, and for study drug antibody levels Expanded disability status scale (EDSS) MRI scan Pregnancy test (women)

On average, about 4 teaspoons (22mL) of blood will be drawn for laboratory tests at each visit. The maximum amount of blood drawn during the outpatient visits will be about 15 tablespoons (75mL). The total amount of blood collected from you over the study will be about 1 & 1/4 cups (250mL). After Visit 15 After this visit is finished, you will not have to come back any more, unless the study doctor specifically asks you to and tells you why (this would most likely be for an extra blood sample only). If you were to leave the study early for any reason, you would be asked to try to still complete the same tests and assessments that are done at Visit 11 for safety. However, they would be done as soon as possible.. Additional Outpatient Visits: You may be asked to return to the clinic for an unscheduled outpatient visit. This may be necessary for additional safety evaluation or for the following:

Within 72 hours of the onset of any new neurologic symptom(s), for the evaluation of a suspected MS clinical relapse.

Because you are no longer going to be in the study (your decision, the study staff, or the Sponsor’s decision).

Any of the study tests or procedures already mentioned may be repeated at an unscheduled visit. The study staff will inform you of any additional unscheduled tests procedures and why they need to be done. How will being part of this study affect my lifestyle? When deciding whether to take part in this study, consider how the tests and visits listed above will affect your work and family schedules. You may find that these tests and visits are inconvenient and require too much effort. In addition, some tests may be uncomfortable. Ask the study

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doctors or nurses if you have any questions about the tests and procedures for the study. There are some medicines you should not be currently treated with or have taken within the past number of months or days. The study staff will review each of these with you:

Within the past 12 months or currently: cyclosporine, cladribine, natalizumab (Tysabri) or other monoclonal antibodies, murine protein, T-cell vaccination, plasmapheresis, IV IgG, stem cell transplantation.

Treatment in the past 6 months with any of the following agents:

Fingolimod (Gilenya), methotrexate, mitoxantrone, azathioprine, or other small molecule immunosuppressants.

Treatment with methylprednisolone or any other systemic steroids,

within 30 days of dosing Your study doctor will tell you more about what medicines you can and cannot take. It is very important that you talk with the study doctor before you receive any vaccinations, start anything you can buy without a prescription in a pharmacy (such as cold or allergy medications, large doses of vitamins, etc) or start any new prescription medications. You should not use any recreational drugs during the study. Also, as part of the study, you:

• Must not smoke or use other tobacco products while in the Unit. • Must not drink alcohol for 72 hours before dosing, until discharge

from the Unit. Must not drink caffeine or other xanthine containing products such as

tea, coffee, cola, chocolate for 24 hours before dosing, until discharge from the Unit.

Must not do strenuous exercise for 48 hours before visits. Do I have to stay in the study? You may choose to stop being in the study at any time, without giving a reason. Your decision will not affect the future medical care you receive.

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Call the study doctor if you change your mind and decide that you no longer want to take part. We will share with you any new information about GSK1223249 that might affect your choice to participate or to stay in the study. We may ask you to leave the study if:

The results of certain tests show that you are not right for this study You cannot follow instructions for treatment or follow-up visits You develop new health problems during the study that mean you

should not continue You become pregnant or decide that you want to become pregnant The study doctor thinks it is in your best interest to stop.

GSK (the study sponsor), regulatory authorities, or the study doctor may choose to stop the study at any time. We will give you the reason at that time, if this happens. What happens if I leave the study? If you leave the study, you may be asked to return for a final follow-up visit. If you need to leave the study due to side effects or abnormal test results, the study doctor may ask you to return for additional study visits and tests until the side effect or abnormal test improves or resolves. If you leave the study, no more information about you will be collected for the study. But, all the information you gave us before you left the study will still be used for the study. What side effects or risks can I expect from this study? It is possible that you will have side effects from the study drug. Everyone in the study will be watched carefully for any side effects. Side effects may be mild, moderate or serious. If you experience a side effect, the study staff may give you medicines to help lessen these effects. Some side effects may go away shortly after taking the drug. In some cases, side effects can be serious, long-lasting or may never go away.

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Safety testing in animals showed that GSK1223249 should be safe in doses to be studied in this trial. The highest dose in animals with no effects is 500 times greater than the starting dose to be given to the first group of patients in this trial. The highest dose given to animals with no effects is 17 times greater than the highest dose to be given in the final group. Experience with GSK1223249 in humans as of November 2010 is as follows: 51 patients (3 patients with MS and 48 patients with ALS) had received a single dose of GSK1223249 or placebo in clinical studies. Most adverse events were reported as mild or moderate. MS is a disease where patients normally have periods where they are good and periods where they are not so good (relapses). During relapses, problems that you had before can come back, problems that you have can get worse, or new problems can appear. The problems can be milder, worse, or just different than what you experienced before. You have been asked to take part in this study because it is known that you have had relapses. Therefore, there is a chance that you will experience a relapse during this study. This is a normal part of MS. Even though no effects were seen in healthy animals, it is not known for certain what effect GSK1223249 will have on the symptoms of MS. From what we know, we believe that GSK1223249 may improve symptoms of MS. In this study, 3 doses of GSK1223249 are given and it may not be enough for you to feel better. If you get a relapse, the study staff and your regular MS doctor will help you decide how best to treat it. This may include not doing anything and letting you recover naturally, giving you medication by mouth or by bloodstream like steroids, or starting you on a medicine for MS or your symptoms. The study staff will discuss these options with you. There is a chance that antibodies to GSK1223249 may be developed by volunteers following a single dose. This will be checked over the six months after you first have GSK1223249 by taking a sample of your blood. If this happens, it usually does not cause any problems, but it could mean that in the future you may not respond (in either a good way or a bad way) to GSK1223249. The antibodies usually go away, but if you get GSK1223249 again at some point in the future, they may stay away or they may come back. We cannot predict which will happen.

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Your study doctor will test your blood to look for liver or kidney damage and other effects such as changes in the number of white cells or red cells. These are checks that are always included in early studies. At present, changes are not expected. If there are any unexpected changes, your study doctor may ask you to come back for more tests and will explain why. These tests may be done until the results are better. There is a chance that any treatment causes an allergic reaction. These reactions can be dangerous if not treated quickly. You will be watched for allergic reactions while you receive the drug. Symptoms of an allergic reaction may include:

a rash having a hard time breathing wheezing when you breathe sudden drop in blood pressure swelling around the mouth, throat, or eyes fast pulse sweating

If you have any of these symptoms you must tell the study staff right away. There may be other side effects that may happen that are not known or expected. You may feel discomfort from some of the procedures during this study. For example, when you give blood or have a cannula inserted in your arm, you may feel faint, or experience mild pain, bruising or bleeding, irritation or redness at the site. In rare cases, you may get an infection or damage to nerves. When you have your heart monitored, you may have itching or get a rash on your skin where the tabs are placed. An MRI (magnetic resonance imaging) scan is a non-invasive way to make pictures of your body, using a strong magnetic field and radio waves. The MRI machine could move iron-containing objects in the MRI room during your scan, which could in the process possibly harm you. Precautions will be taken to prevent such an event from happening - loose metal objects like pocket knives or key chains, are not allowed in the MRI room. If you have a

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piece of metal in your body, such as a fragment in your eye, aneurysm clips, ear implants, spinal nerve stimulators, or a pacemaker, you will not be allowed into the MRI room and cannot have an MRI. The study doctor or nurse will ask you questions about any metal in your body, right at the beginning of the study, and also review your medical history. If there are any reasons (contraindications) that you can’t have an MRI, then you will not be able to take part in the study. Being able to have an MRI is an entry requirement of the study. For an MRI scan, you will lie down on a narrow bed which will then be placed in a tunnel about 140 by 70 centimetres wide and open at each end. You will lie there quietly for about 30-40 minutes, during which time you will hear a loud noise. You may feel warm during this procedure, or you may be bothered by feelings of claustrophobia, or by the loud banging noise. People have had temporary hearing loss from the loud noise, so you will be asked to wear earplugs. Ask your study doctor if you have any questions about side effects. Reproductive Risks For women: There is no information on the use of GSK1223249 in pregnant women. Therefore, it is very important that women do not become pregnant during this study. In order to take part in this study, if you are a woman:

you must have gone through menopause (at least 1 year without periods) OR

be physically unable to become pregnant because you have had your tubes tied or have had a hysterectomy OR

if you are still able to become pregnant, both you and your partner(s) must be willing to strictly use contraception throughout the course of the study and for at least six months afterwards

If you think that you may want to become pregnant over the next ten months, you should not take part in this study. If you are not sure if you can still become pregnant, you need to discuss this with the study staff and you will still need to use recommended contraception.

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Women who are still able to become pregnant, who wish to participate in this study, should carefully consider in advance, what they would do if they become pregnant, despite using contraception. This point should be discussed with your partner, doctor and the study staff. Acceptable methods of birth control include abstinence, oral contraception, injectable progestogen, implants of levonorgestrel, estrogenic vaginal ring, intrauterine device (IUD), interuterine system (IUS), male partner sterilization (vasectomy), double barrier method (condom and occlusive cap). For men: If your partner becomes pregnant while you are in this study, there may be risks to the unborn baby because of changes that are not yet known to your sperm. You should not have sex with a woman, or you should use one of the following methods of birth control (even if you have had a vasectomy) - abstinence, condoms, condoms and occlusive cap (diaphragm or cervical/vault caps) - that are acceptable to you, the study doctor, and the study sponsor (GSK) during this study. You must agree to continue to use contraception for an additional 6 months after dosing. You must tell the study doctor right away if you think that your partner has become pregnant after you have received study drug. If your partner gets pregnant while you are in the study, you may be asked questions about the pregnancy and you may be required to continue to provide information until the baby has been delivered. Both men and women should check with the study doctor about what kind of birth control methods to use and how long to use them. Some methods may not be approved for use during this study. What benefits can I expect from this study? Because this drug has not been tested in MS patients at the planned dose levels, it is difficult to predict if there will be any benefit from participating in this study. In addition to the dose of GSK1223249, an important factor is the duration (how long or length of time) treatment is given for. In this study, the length of time of treatment and total dose will probably not be enough to provide benefit.

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Will I receive payment for being part of this study? At the end of the study, you will receive xxxxx by cheque for your part in the study. If you are withdrawn for medical or non-medical reasons then you will receive full-payment for this study. Your payment might be reduced or forfeited if you do not follow the restrictions specified in this Information and Consent Form or the “Rules & Requirements for Participation in Clinical Trials” (a copy of this will be provided to you). Will I have to pay anything to be part of this study? As part of the study, you will receive the study drug and all the study tests and procedures at no cost to you. What happens if I get hurt taking part in this study If you are injured as a result of your participation in this trial you have a legal right to seek compensation. Sponsors of clinical trials in [local country] have agreed that the guidelines developed by their industry body, name of competent authority, will govern the way in which compensation claims from injured participants are managed by sponsors. These guidelines are available for your inspection at: local country website. However, as guidelines, they do NOT in any way dictate the pathway you should follow to seek compensation. The sponsor is obliged to follow these guidelines. It is the recommendation of the independent ethics committee responsible for the review of this trial that you seek independent legal advice before taking any steps towards compensation for injury. Who is GlaxoSmithKline and what does it do? GlaxoSmithKline is a company that creates and makes medicines and other health products. It is also called “GSK”.

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GSK is paying for this study. GSK pays the study doctor, study staff and the [study site unit/clinic/hospital] to run this study. Information about this study is confidential – meaning that it must not be shared with others outside this study. You can discuss the study in private with your regular doctor or family when you are deciding about taking part in this study. However, once you have decided to take part, you must not talk about it with friends or other people unrelated to the study, unless you have a specific concern. In that case, the contact information is on pages 2 and 3. Will my information be kept private? If you decide to take part in the study, you give us permission to use information about you and share it with GSK and others. This permission continues until the study is over, including the length of time that we must keep records about the study (current record retention policy requires that records be kept for 30 years). Personal and medical information about you will be kept confidential. It will be kept in a secured file. At any time, you may ask to see your personal information (such as name and address) and correct it if necessary. However, you will not be able to see your study data until the study has been fully completed. This could be up to two or more years from when you were in the study. Once you have entered into the study, you will be assigned a code. All information about you will be collected and stored under this code, not under your name. So, no one other than the study staff can easily know which information belongs to you. Your study information will be used in two ways. 1. Study management Information collected in the study about you will be checked to make sure that the study is being run properly. People who work for or with GSK, and others (like the ethics board or government officials who approve new drugs) will check how the study is run. They will keep all information confidential. 2. Study findings Medical information about you will be combined with information about

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other people in the study. This study information will be used to learn about the study drug. Information will be labelled with a code number, and will not include your name or other information that directly identifies you. During the study, we may find new medical information about you. We will share this with you right away if it is important to your health. We may advise you to get other tests to check this new information. Once the study is over, you can see any medical information about yourself. Study information about you that is not helpful to your health care (like most genetic research information) will not be given to you or others (unless it is required by a government agency or other legal authority). This means that no one (not you, your family, your doctor, your insurance company, or your employer) will have access to this information during the study. If you do get genetic research information and share it with others, there is a chance it may affect your insurance or employment. When you sign this consent form, you agree to have your personal and medical information used as described here. As part of the consent for this study you will be asked to agree to the exchange of information between your GP and/or medical specialists and the study doctor for the purposes of this study. This is to ensure that your doctors are aware of the treatment you are receiving and that information regarding your health history can be confirmed by your doctors if required. If you consent to participate in the study, some or all of the study information collected on you will be entered into a computer database at the

If you do not consent to participate in this study, your consent to keep your details on this database may be requested. You are not obliged to consent to this, and if you do not, none of your personal details will be kept by the What does GSK do with the study information? Your study doctor will send coded information to GSK. GSK may use study information in such ways as:

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• Keep it and analyse it by computer to find out what this study is telling us

• Share it with regulatory authorities who approve new drugs, or with groups that check that studies are done properly

• Write up the study results for medical journals by 12 months after the drug is approved by regulatory authorities in any country or within 18 months of a decision to stop development of this drug. (this will not include any information that directly identifies you)

• Place a summary of the results on GlaxoSmithKline’s Clinical Trial Register website at the time that the drug is approved by regulatory authorities or within 18 months of a decision to stop development of this drug (this will not include any information that directly identifies you).

• Share parts of the study with other companies or universities to better understand bacterial infections or to further develop the study drug or other drugs

• Share parts of the study with other GSK offices here and in other countries. If the information is sent to another country anywhere in the world, GSK will apply the same level of protection to your information, to the extent permitted by local law.

• Use it to plan new studies to further develop the study drug or other drugs. Your name will not appear in any of these reports.

GSK will be the owner of the study results. GSK plans to use the results, and may get patents, or sell the drug in the future, or make profits other ways. You will not be paid any part of this. If you would like any more information about GSK’s personal information management practices, you can contact GSK’s Privacy Officer at: ATTN: GSK Privacy Officer LOC address

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The [local] Research Ethics Committee has reviewed this study. Should you wish to discuss the study or view a copy of the Complaint procedure with someone not directly involved, particularly in relation to matters concerning policies, information or complaints about the conduct of the study or your rights as a participant, you may contact the Committee chair, [local] Research Ethics Committee on [telephone number].

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What happens to my blood, CSF and urine samples? As mentioned earlier, if you take part in the study, you will be asked to give blood and urine samples to check your health, to measure the amount of study drug in your blood, and to measure other markers in your blood that will tell us about the effect of the study drugs or about your disease, which may help development of other drugs for MS. Similar to information, samples may be used by GSK or shared by GSK with other companies or universities to better understand or to further develop the study drug or other drugs. Your blood, CSF (if applicable) and urine samples will be given the same code as your other study information and kept in secure storage. Anyone who works with your samples will hold the information and results in confidence. The samples will be stored for up to 15 years, during which time they may be analysed further for drug response, other markers of MS disease and/or for further scientific understanding in MS, but not for any other purpose. You may withdraw consent, at any time, for these samples to be held, at which point any remaining samples will be destroyed.

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CONSENT for GSK1223249 Study AGREEMENT TO BE IN THE STUDY This information and consent form contains important information to help you decide if you want to be in the study. If you have any questions that have not been answered in this form, ask one of the study staff. By myself (or a witness) signing below, I show that: 1) The information in this information and consent form is clear to me. 2) I have been given enough time to ask questions and talk about the study. 3) I know there are risks in taking the study drug and that there may be

side effects. 4) I have had the opportunity to discuss other choices available to me where

they are appropriate. 5) I have discussed the study and asked questions. I am satisfied with the

answers. 6) I agree to take part in the study described in this consent form. 7) I agree that GSK, study staff, and others can have access to my medical

and personal information, as described in this form 8) I know I can leave the study at any time without giving a reason. 9) I know that I cannot be in another study while I am taking part in this

study. 10) I agree that the study doctor will tell my doctor that I am taking part

in this study, and I agree to an exchange of information between my GP and/or my medical specialists and the study doctor for the purposes of this study.

11) I understand that I have not waived my legal rights by signing this document and that I have received a copy of this signed document to take with me.

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I agree to participate in this study.

Signature Printed name Date and Time (e.g. 01 JAN 2008 13:45) If participant unable to sign above, this consent process has been witnessed by:

Signature Printed name Date and Time (e.g. 01 JAN 2008 13:45)

I wish to be contacted about studies in the future for which I may be eligible. Signature Printed name Date and Time (e.g. 01 JAN 2008 13:45)

Signature of study staff conducting consent Printed name of study staff Date and Time (e.g. 01 JAN 2008 13:45)

Revocation of Consent for study

I hereby wish to WITHDRAW my consent to participate in the research proposal described above and

understand that such withdrawal WILL NOT make any difference to my medical care or my

relationship with the Hospital or my medical attendants. Signature Printed name Date and Time (e.g. 01 JAN 2008 13:45)

The Revocation of Consent for the study should be forwarded to:

.

:

:

:

:

:

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Protocol: NGM114840 Page 1 of 1Population: All Subjects Listing 1.05 Listing of Randomised and Actual Treatments

Country/Centre/Investigator: Italy Randomisation Randomisation Randomised Actual Cohort Subject ID Number Date Treatment Treatment Deviation --------------- --------------------------------------------------------------------------- 1 20OCT2011 Pbo/ Pbo/ Pbo Pbo/ Pbo/ Pbo 26OCT2011 GSK1223249 1/ 5/ 5 GSK1223249 1/ 5/ 5 mg/kg mg/kg 15NOV2011 GSK1223249 1/ 5/ 5 GSK1223249 1/ 5/ 5 mg/kg mg/kg

1


1


2


3


4


ICH Data Listings Page

Listing 1.01 Listing of Demographic Characteristics (All Subjects Population) ....... Listing 1.02 Listing of Race (All Subjects Population) ............................................. Listing 1.03 Listing of Subjects with Inclusion/Exclusion Criteria Deviations (All

Subjects Population) .................................................................................... Listing 1.04 Listing of Study Population (All Subjects Population) .......................... Listing 1.05 Listing of Randomised and Actual Treatments (All Subjects

Population) ................................................................................................... Listing 1.06 Listing of Reasons for Withdrawal (All Subjects Population) ............... Listing 1.07 Listing of Exposure Data (All Subjects Population) ............................. Listing 1.08 Listing of Concomitant Medications by Generic Term (All Subjects

Population) ................................................................................................... Listing 1.09 Listing of All Adverse Events (All Subjects Population) ....................... Listing 1.10 Listing of Serious Adverse Events (All Subjects Population) ............... Listing 1.11 Listing of Subject Numbers for Individual Adverse Events (All

Subjects Population) .................................................................................... Listing 1.12 Listing of Adverse Events leading to Permanent Discontinuation of

Study Drug or Withdrawal from Study (All Subjects Population) .................. Listing 1.13 Listing of Adverse Events leading to Permanent Discontinuation of

Study Drug or Withdrawal from Study (Safety Population) .......................... Listing 1.14 Listing of Clinical Chemistry Abnormalities of Potential Clinical

Importance (All Subjects Population) ........................................................... Listing 1.15 Listing of All Clinical Chemistry Laboratory Data (All Subjects

Population) ................................................................................................... Listing 1.16 Listing of Haematology Abnormalities of Potential Clinical Importance

(All Subjects Population) .............................................................................. Listing 1.17 Listing of All Haematology Laboratory Data (All Subjects Population) Listing 1.18 Listing of Urinalysis Data for all Subjects (All Subjects Population) ..... Listing 1.19 Listing of Subjects for Whom the Treatment Blind was Broken During

the Study (All Subjects Population) ..............................................................

23

45

678

101619

20

21

22

23

24

7172

124

146

1


This section contained data from each individual patient, rather than in aggregate. They have

been excluded to protect patient privacy. Anonymized data from each patient may be made

available subject to an approved research proposal. For further information please see the

Patient Level Data section of the GSK Clinical Study Register.

Other Data Listings Page

Listing 2.01 Listing of Medical Conditions (All Subjects Population) ....................... Listing 2.02 Listing of MS Medical History (All Subjects Population) ...................... Listing 2.03 Listing of MS Medical History-Relapses in last 12 months (All

Subjects Population) .................................................................................... Listing 2.04 Listing of Abnormal Findings from Neurological Examinations (All

Subjects Population) .................................................................................... Listing 2.05 Listing of Vital Signs (All Subjects Population) .................................... Listing 2.06 Listing of Vital Signs of Potential Clinical Importance (All Subjects

Population) ................................................................................................... Listing 2.07 Listing of ECG Values (All Subjects Population) ................................. Listing 2.08 Listing of All ECG Values for Subjects with a Value of Potential

Clinical Importance (All Subjects Population) .............................................. Listing 2.09 Listing of Abnormal ECG findings (All Subjects Population) ................ Listing 2.10 Listing of Telemetry Findings (All Subjects Population) ....................... Listing 2.11 Listing of Suicide Attempts (All Subjects Population) .......................... Listing 2.12 Listing of CSSRS Suicidal Ideation and Behavior Data (All Subjects

Population) ................................................................................................... Listing 2.13 Listing of All Possible Suicidality-Related Adverse Events (PSRAE)

(Sections 1-2) (All Subjects Population) ....................................................... Listing 2.14 Listing of All Possible Suicidality-Related Adverse Events (PSRAE)

(Section 3) (All Subjects Population) ............................................................ Listing 2.15 Listing of All Possible Suicidality-Related Adverse Events (PSRAE)

(Section 4) (All Subjects Population) ............................................................ Listing 2.16 Listing of All Possible Suicidality-Related Adverse Events (PSRAE)

(Sections 5-8) (All Subjects Population) ....................................................... Listing 2.17 Listing of Subjects Who Became Pregnant During the Study (All

Subjects Population) .................................................................................... Listing 2.18 Listing of Male Subjects with Female Partners Who Became

Pregnant During the Study (All Subjects Population) .................................. Listing 2.19 Listing of Liver Event Results and Time of Event Relative to

Treatment (All Subjects Population) ............................................................. Listing 2.20 Listing of Liver Events Information for RUCAM Score (All Subjects

Population) ................................................................................................... Listing 2.21 Listing of Liver Biopsy Details (All Subjects Population) ...................... Listing 2.22 Listing of Liver Imaging Details (All Subjects Population) .................... Listing 2.23 Listing of Patients with Relapses during the study (All Subjects

Population) ................................................................................................... Listing 2.24 Listing of Details of Relapses (Neurological Deficits) (All Subjects

Population) ................................................................................................... Listing 2.25 Listing of Expanded Disability Status Scale (EDSS) (All Subjects

Population) ................................................................................................... Listing 2.26 Listing of Gd-enhancing Lesion Counts (All Subjects Population) .......

35

6

712

2021

36374547

48

49

50

51

52

53

54

55

565758

59

60

6164

1


Listing 2.27 Listing of Gd-enhancing Lesion Volume (All Subjects Population) ...... Listing 2.28 Listing of T2- and T1-weighted Lesion Volume (All Subjects

Population) ................................................................................................... Listing 2.29 Listing of Cerebral NAWM MTR and Cerebral mean diffusivity (All

Subjects Population) .................................................................................... Listing 2.30 Listing of GSK1223249 Pharmacokinetic Concentration-Time Data

(Pharmacokinetic Population) ...................................................................... Listing 2.31 Listing of Derived Plasma GSK1223249 Primary and Secondary

Pharmacokinetic Parameters (Pharmacokinetic Population) .......................

66

68

70

72

77

2


This section contained data from each individual patient, rather than in aggregate. They have

been excluded to protect patient privacy. Anonymized data from each patient may be made

available subject to an approved research proposal. For further information please see the

Patient Level Data section of the GSK Clinical Study Register.

1

1

In February 2013, GlaxoSmithKline (GSK) announced a ...€¦ · Table 2.08 Listing of All ECG Values for Subjects with a Value of Potential Clinical Importance (All Subjects Population)

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