WORKING PROTOCOL - TB Alliance

Global Alliance for TB Drug Development NC-001-(J-M-Pa-Z) Working Protocol 02; 06 December 2010

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CONFIDENTIAL

WORKING PROTOCOL

WORKING PROTOCOL NUMBER: 02 WORKING PROTOCOL DATE: 06 DECEMBER 2010

COMBINATION OF THE FOLLOWING APPROVED FINAL DOCUMENTS:

PROTOCOL 27 APRIL 2010 PROTOCOL ADMINISTRATIVE CHANGE NUMBER 01; 09 SEPTEMBER 2010

PROTOCOL AMENDMENT 01, 06 DECEMBER 2010

Note: This document does not require formal approval as it is a working document containing a combination of the above two documents, which comprise the formal approved documents.

Protocol Title: A Phase II Trial to Evaluate the Early Bactericidal Activity, Safety and Tolerability of the following: TMC207 alone, TMC207 plus pyrazinamide,

TMC207 plus PA-824, PA-824 plus pyrazinamide and PA-824 plus pyrazinamide and moxifloxacin, in Adult Patients with Newly Diagnosed, Smear-Positive

Pulmonary Tuberculosis.

Protocol Number: NC-001-(J-M-Pa-Z)


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Development Phase: II Sponsor: Global Alliance for TB Drug Development

40 Wall Street, 24th Floor New York, NY 10005 United States of America

Clinical Director/Medical Director Christo van Niekerk; MD, FCPaed

Senior Director, Clinical Development Global Alliance for TB Drug Development Enterprise Building, 1st Floor The Innovation Hub Pretoria 0087 South Africa

Immediately Reportable Events Christo van Niekerk; MD, FCPaed

Senior Director, Clinical Development Global Alliance for TB Drug Development Enterprise Building, 1st Floor The Innovation Hub Pretoria 0087 South Africa Telephone: +27 (0)12 844 0955 Mobile: +27 (0)82 550 3856 Facsimile: + 27 (0)12 844 0959


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Table of Contents

1. PROTOCOL SYNOPSIS .................................................................................................................... 11

1.1. Synopsis ................................................................................................................................. 11

1.2. Study Flow Chart ................................................................................................................... 14

1.3. PK and ECG Chart .................................................................................................................. 17

1.3.1. TMC207 (excluding TMC207 plus PA-824) and Rifafour e275® Containing Treatment

Arms 17

1.3.2. PA-824 (excluding TMC207 plus PA-824) Containing Treatment Arms ........................ 18

1.3.3. TMC207 (J) plus PA-824 (Pa) Containing Treatment Arms ............................................ 19

2. INTRODUCTION ............................................................................................................................ 20

2.1. Background Information ....................................................................................................... 20

2.2. Preclinical Studies .................................................................................................................. 24

2.2.1. TMC207 .......................................................................................................................... 24

2.2.2. PA-824 ............................................................................................................................ 26

2.2.3. Moxifloxacin ................................................................................................................... 29

2.3. Clinical Trials .......................................................................................................................... 29

2.3.1. TMC207 .......................................................................................................................... 29

2.3.2. PA-824 ............................................................................................................................ 35

2.3.3. Moxifloxacin ................................................................................................................... 44

2.4. Known and Potential Risks and Benefits of the Investigational Medicinal Product (IMP)

used in the Study .............................................................................................................................. 47

2.4.1. TMC207 .......................................................................................................................... 47

2.4.2. PA-824 ............................................................................................................................ 47

2.4.3. Moxifloxacin ................................................................................................................... 47

2.4.4. Pyrazinamide .................................................................................................................. 48

2.4.5. Standard, first-line TB treatment ................................................................................... 48

3. TRIAL RATIONALE AND OBJECTIVES ............................................................................................. 48

3.1. Trial Rationale ....................................................................................................................... 48

3.2. Trial Objectives ...................................................................................................................... 50

3.3. Trial Endpoints ....................................................................................................................... 50

3.3.1. Primary Endpoint ........................................................................................................... 50


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3.3.2. Secondary Endpoints ..................................................................................................... 51

3.3.2.1. Efficacy ....................................................................................................................... 51

3.3.2.2. Safety and Tolerability................................................................................................ 51

3.3.2.3. Pharmacokinetics ....................................................................................................... 51

3.3.2.4. Pharmacokinetics-Pharmacodynamics (PK-PD) ......................................................... 52

3.3.2.5. Extent of QT Prolongation .......................................................................................... 52

3.4. Mycobacteriological Characterization .................................................................................. 52

3.5. Participant Inclusion/Exclusion Criteria ................................................................................ 53

3.5.1. Inclusion Criteria ............................................................................................................ 53

3.5.2. Exclusion Criteria............................................................................................................ 54

4. STUDY DESIGN AND DURATION ................................................................................................... 58

4.1. Summary of Study Design ..................................................................................................... 58

4.2. Treatment Plan ...................................................................................................................... 59

4.2.1. Pre-treatment Visits 1 to 4 (Days -9 to -1) ..................................................................... 59

4.2.2. Treatment Period (Visits 5 to 19 [Days 1 to 15]) ........................................................... 62

4.2.3. Follow-Up Period ........................................................................................................... 68

4.2.4. Early Withdrawal ............................................................................................................ 69

4.3. Participant Withdrawal Criteria ............................................................................................ 71

4.4. Trial Treatment Discontinuation ........................................................................................... 71

4.5. Stopping Rules ....................................................................................................................... 72

4.6. Participant Progress Definitions ............................................................................................ 72

4.6.1. Screening Failure ............................................................................................................ 72

4.6.2. Completed Treatment.................................................................................................... 72

4.6.3. Early Withdrawal ............................................................................................................ 72

4.6.4. Completed Trial .............................................................................................................. 72

4.6.5. Lost to Follow-up ........................................................................................................... 72

4.7. Restrictions ............................................................................................................................ 72

4.7.1. Foods and Beverages ..................................................................................................... 72

4.7.2. Prior and Concomitant Medications .............................................................................. 73

4.7.3. Activity ........................................................................................................................... 74

5. INVESTIGATIONAL MEDICINAL PRODUCT .................................................................................... 74

5.1. Trial Treatments .................................................................................................................... 75


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5.2. Methods of Assigning Participants to Treatment Groups .................................................... 75

5.3. IMP Administration ............................................................................................................... 76

5.3.1. TMC207 and PA-824 Treatment Groups ....................................................................... 76

5.3.2. First-line standard TB treatment per SA national guidelines (Rifafour e-275 tablets)

Treatment Group .......................................................................................................................... 77

5.3.3. Participant Compliance .................................................................................................. 77

5.4. Blinding and Procedures for Breaking the Blind ................................................................... 77

5.5. IMP Packaging and Labeling .................................................................................................. 78

5.5.1. PA-824 and TMC207 Containing Treatment Arms ........................................................ 80

5.5.2. Standard, first line TB treatment ................................................................................... 81

5.6. Storage .................................................................................................................................. 81

5.7. Dispensing and Accountability .............................................................................................. 81

5.8. Returns and Destruction ....................................................................................................... 82

6. TRIAL VARIABLES .......................................................................................................................... 82

6.1. Demographic and Background Variables .............................................................................. 82

6.2. Efficacy Variables................................................................................................................... 83

6.3. Pharmacokinetic Variables .................................................................................................... 83

6.4. Safety Variables ..................................................................................................................... 83

6.5. Mycobacterial Characterization ............................................................................................ 84

7. TRIAL PROCEDURES ...................................................................................................................... 84

7.1. Sputum Sampling .................................................................................................................. 84

7.1.1. Spot Sputum ................................................................................................................... 84

7.1.2. Overnight Sputum .......................................................................................................... 85

7.2. Clinical Laboratory Tests ....................................................................................................... 86

7.2.1. Safety Laboratory Tests ................................................................................................. 86

7.3. Plasma Pharmacokinetics (PK) .............................................................................................. 88

7.4. Electrocardiography (ECG) .................................................................................................... 89

7.5. Ophthalmology Examinations ............................................................................................... 90

7.6. Physical Examinations and Vital Signs ................................................................................... 91

7.7. Chest X-ray ............................................................................................................................ 91

7.8. Retention Sample Collection ................................................................................................. 92

7.8.1. Plasma and Serum ......................................................................................................... 92


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7.8.2. Sputum ........................................................................................................................... 92

7.8.3. Urine ............................................................................................................................... 92

8. ADVERSE EVENTS .......................................................................................................................... 93

8.1. Definitions ............................................................................................................................. 93

8.1.1. Adverse Event (AE) ......................................................................................................... 93

8.1.2. Serious Adverse Event (SAE) .......................................................................................... 93

8.1.3. Unlisted (Unexpected) Adverse Event ........................................................................... 94

8.1.4. Life Threatening ............................................................................................................. 94

8.1.5. Associated With the Use of the Drug............................................................................. 94

8.2. Attribution Definitions .......................................................................................................... 94

8.3. Reporting ............................................................................................................................... 95

8.3.1. Adverse Event Reporting ............................................................................................... 95

8.3.2. Serious Adverse Event Reporting................................................................................... 95

8.3.3. Follow-up of Adverse Events ......................................................................................... 96

8.3.4. Follow-up of Post Trial Adverse Events ......................................................................... 96

8.3.5. Clinical Laboratory Adverse Events ................................................................................ 97

8.3.6. Pregnancy ....................................................................................................................... 97

8.3.7. Disease Under Study ...................................................................................................... 98

9. MONITORING AND SAFETY FOR SPECIFIC TOXICITIES .................................................................. 98

9.1. ALT and AST ........................................................................................................................... 98

9.2. Amylase elevation ................................................................................................................. 99

9.3. Pancreatic amylase and/or lipase elevation ......................................................................... 99

9.4. Trypsin-like immunoreactivity ≥ 1.5 times ULN .................................................................... 99

9.5. Musculo-skeletal System and Cardiac Muscle .................................................................... 100

9.6. LDH and LDH-isoenzymes .................................................................................................... 100

9.7. Cardiac Rhythm Disturbances ............................................................................................. 100

9.8. Gastrointestinal System ...................................................................................................... 101

9.9. Other toxicities .................................................................................................................... 101

10. STATISTICAL ANALYSIS ................................................................................................................ 101

10.1. Sample Size ...................................................................................................................... 101

10.2. Primary Efficacy Analysis ................................................................................................. 102

10.3. Secondary Efficacy Analysis ............................................................................................. 102


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10.4. Pharmacokinetic Analysis ................................................................................................ 103

10.5. Pharmacokinetic and Pharmacodynamic Statistical Analysis ......................................... 104

10.6. Safety and Tolerability Analyses ...................................................................................... 104

10.7. Mycobacteriology Characterization ................................................................................ 105

11. RECORDS MANAGEMENT ........................................................................................................... 106

11.1. Data Collection ................................................................................................................ 106

11.2. Source Documents ........................................................................................................... 106

11.3. File Management at the Trial Center .............................................................................. 106

11.4. Records Retention at the Trial Center ............................................................................. 106

12. QUALITY CONTROL AND QUALITY ASSURANCE ......................................................................... 107

12.1. Site Procedures ................................................................................................................ 107

12.2. Monitoring ....................................................................................................................... 107

12.3. Auditing............................................................................................................................ 108

13. ETHICS AND RESPONSIBILITY ...................................................................................................... 108

13.1. Basic Principles ................................................................................................................ 108

13.2. Independent Ethics Committee/Institutional Review Board (IEC/IRB) Review .............. 109

13.3. Regulatory Authorities ..................................................................................................... 109

13.4. Informed Consent ............................................................................................................ 109

13.5. Confidentiality ................................................................................................................. 110

13.6. Publication Policy ............................................................................................................. 110

13.7. Protocol Amendment Policy ............................................................................................ 111

13.8. Financial Aspects, Insurance and Indemnity ................................................................... 111

14. REFERENCES ................................................................................................................................ 113

APPENDIX 1: PROTOCOL SIGNATURE PAGES ..................................................................................... 116

APPENDIX 2: RIFAFOUR E-275 PACKAGE INSERT............................................................................ 117

APPENDIX 3: THE IUATLD SCALE ........................................................................................................ 120

APPENDIX 4: DIVISION OF MICROBIOLOGY AND INFECTIOUS DISEASES (DMID) ADULT TOXICITY

TABLE ................................................................................................................................................. 121

APPENDIX 5: CARDIOVASCULAR SAFETY ........................................................................................... 132

APPENDIX 6: PYRAZINAMIDE PACKAGE INSERT ................................................................................ 133

APPENDIX 7: MOXIFLOXACIN PACKAGE INSERT ................................................................................ 134


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Table 1: Overview of the TMC207 Clinical Program ............................................................................ 30

Table 2: Overview of PA-824 Clinical Program .................................................................................... 36

Table 3 Summary of Phase IIb studies in which moxifloxacin was administered as part of a four-drug regimen during the intensive phase of treatment (total treatment duration: 2 months) .................. 45

Table 4 : Investigational Medicinal Product Details ............................................................................ 79

Table 5: Pyrazinamide dosing per weight ............................................................................................ 80

Table 6: Expected Standard Errors of Group mean log CFU and confidence intervals ..................... 102

Figure 1: PA-824-CL-007 Mean Group logCFU Over Time ................................................................... 39


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS

AE Adverse Event AFB acid fast bacilli AIDS acquired immune deficiency syndrome ALP alkaline phosphatase ALT alanine aminotransferase APTT activated partial thromboplastin time ART antiretroviral therapy AST aspartate aminotransferase AUC area under the plasma concentration time curve AUC(0-24) area under the plasma concentration time curve from zero to end of dosing

interval AV Atrioventricular BMI body mass index CFU colony forming units Cmax maximum observed plasma concentration

Cmin minimum observed plasma concentration at the end of the dosing interval CPK creatine phosphokinase CPK-MB creatine phosphokinase of myocardial band CRF case report form CRO Contract Research Organization

CYP3A4 cytochrome P450 3A4 DBP diastolic blood pressure DMID Division of Microbiology and Infectious Diseases DOTS Internationally agreed strategy for TB control E Ethambutol EBA early bactericidal activity ECG Electrocardiogram GGT gamma-glutamyltransferase H isoniazid HDL high density lipoprotein HIV Human Immunodeficiency Virus

IB Investigator Brochure

ICF informed consent form ICH GCP International Conference on Harmonization Good Clinical Practice IMP Investigational Medicinal Product INR international normalized ratio IUATLD International Union Against Tuberculosis and Lung Disease J TMC207 Kel terminal elimination rate constant LDH lactate dehydrogenase m Meters M2 N-monodesmethyl metabolite of TMC207

MBD minimum bactericidal dose MDR-TB multidrug resistant-tuberculosis


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MED minimum effective dose MIC minimum inhibitory concentration MGIT mycobacterial growth indicator tube MTB Mycobacterium tuberculosis PCR polymerase chain reaction PD pharmacodynamic PK Pharmacokinetic PT prothrombin time PTT partial thromboplastin time QRS electrocardiographic QRS interval QT electrocardiographic QT interval

QTc corrected QT interval QTcB QT interval corrected by Bazett’s method QTcF QT interval corrected by Fridericia’s method R Rifampicin R Pearson’s correlation coefficient SAE Serious Adverse Event SA GCP Guidelines for Good Practice in the Conduct of Clinical Trials in Human Patients

in South Africa 2006 SAP Statistical Analysis Plan SBP systolic blood pressure T Time

t½ apparent terminal elimination phase half-life TB Tuberculosis TEAEs treatment-emergent adverse events Tmax time at which Cmax is observed TTP time to sputum culture positivity ULN upper limit of normal WBA whole blood assay

WHO World Health Organization Z Pyrazinamide


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1. PROTOCOL SYNOPSIS

1.1. Synopsis

Name of Sponsor/Company: Global Alliance for TB Drug Development For National Authority Use Only

Name of Finished Products: TMC207 tablets; PA-824 tablets; pyrazinamide tablets; moxifloxacin tablets.

Protocol Title: A Phase II Trial to Evaluate the Early Bactericidal Activity, Safety and Tolerability of the following: TMC207 alone, TMC207 plus pyrazinamide, TMC207 plus PA-824, PA-824 plus pyrazinamide and PA-824 plus pyrazinamide and moxifloxacin, in Adult Participants with Newly Diagnosed, Smear-Positive Pulmonary Tuberculosis.

Treatment Indication: Pulmonary tuberculosis (TB).

Trial Objective: To evaluate the early bactericidal activity (EBA), safety, tolerability and pharmacokinetics of TMC207 alone, TMC207 plus pyrazinamide (Z), TMC207 plus PA-824, PA-824 plus pyrazinamide and PA-824 plus pyrazinamide and moxifloxacin, administered orally as once daily doses for 14 consecutive days, in adult participants with newly diagnosed, smear positive pulmonary tuberculosis, in order to help select appropriate combination therapies for later stage clinical development.

Trial Design: A two-center, partially double-blinded, randomized clinical trial in six parallel groups. The first five treatment arms are: TMC207 alone, TMC207 plus pyrazinamide, TMC207 plus PA-824, PA-824 plus pyrazinamide and PA-824 plus pyrazinamide plus moxifloxacin. The sixth arm will receive standard first line TB treatment as per the

South African TB guidelines (Rifafour e-275) and is included as a control for the EBA quantitative mycobacteriology. The following blinding will occur:

TMC207 alone treatment arm blinded against TMC207 plus pyrazinamide treatment arm;

PA-824 plus pyrazinamide treatment arm blinded against PA-824 plus pyrazinamide plus moxifloxacin treatment arm;

TMC207 plus PA-824 treatment arm and Rifafour e-275 treatment arm will be open-label.

Patient Population: A total of 85 male or female participants (5 groups of 15 participants receiving a TMC207 and/or PA-824 containing treatment arm and one group of 10 participants

receiving Rifafour e275) aged between 18 and 65 years (inclusive) with newly diagnosed, smear-positive, pulmonary TB.

Test Product, Dose and Mode of Administration:

TMC207 will be supplied as 100-mg tablets and PA-824 will be supplied as 200-mg tablets. Pyrazinamide will be supplied as 500-mg tablets or placebo. Moxifloxacin will be supplied as 400-mg tablets or placebo. Treatment will be administered orally once daily for 14 consecutive days in the following dosing schemes:

1. TMC207 700 mg Day 1; 500 mg Day 2; 400 mg Days 3-14; + pyrazinamide placebo (dosed by weight) Days 1-14;

2. TMC207 700 mg Day 1; 500mg Day 2; 400 mg Days 3-14 + pyrazinamide (dosed by weight) Days 1-14;

3. TMC207 700 mg Day 1; 500 mg Day 2; 400 mg Days 3-14 + PA-824 200 mg Days 1-14;

4. PA-824 200 mg + pyrazinamide (dosed by weight) + moxifloxacin 400 mg placebo Days 1-14;

5. PA-824 200 mg + pyrazinamide (dosed by weight) + moxifloxacin 400 mg Days 1-14.

Pyrazinamide and pyrazinamide placebo will be dosed based on the participant’s weight as follows: <55 kg: 1000 mg; >55kg – 75 kg: 1500 mg; > 75 kg: 2000 mg.


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Positive Control Product, Dose, and Mode of Administration:

Rifafour e-275 will be supplied as tablets and administered orally once daily for 14

days as per South African National TB Treatment Guidelines. The daily dose is dependent on the participants’ weight as follows: 30-37kg: 2 tablets; 38-54kg: 3 tablets; 55 – 70kg: 4 tablets; 71kg and over: 5 tablets.

Criteria for evaluation: Primary Endpoints: The EBA (EBA0-14) as determined by the rate of change in logCFU per ml sputum over the period Day 0 to Day 14 which may be described with linear, bi-linear or non-linear regression of logCFU on time. These data will be presented as descriptive analyses, and no inferential tests will be carried out. Secondary Endpoints: Efficacy: The secondary efficacy endpoints are as follows:

The EBA (EBA0-2, EBA2-14 and EBA7-14) as determined by the rate of change of logCFU in sputum over the period Day 0 to Day 2, Day 2 to Day 14 and Day 7 to 14 which may be described with linear, bi-linear or non-linear regression of logCFU on time.

The time to sputum culture positivity (TTP) (TTP0-2, TTP0-14, TTP2-14, and TTP7-14) in the Mycobacterial Growth Indicator Tube (Bactec MGIT960) system as determined by the rate of change in TTP in sputum over the periods Day 0 to Day 2, Day 0 to Day 14, Day 2 to Day 14 and Day 7 to Day 14 in participants, which may be described with linear, bi-linear or non-linear regression of TTP on time.

These data will be presented as descriptive analyses, and no inferential tests will be carried out. Safety and Tolerability: Proportion of participants with adverse events and proportion of participants who discontinue due to an adverse event in each experimental arm. These data will be presented as descriptive analyses, and no inferential tests will be carried out. Pharmacokinetics (PK): For TMC207 (excluding TMC207 plus PA-824 containing treatment arm) containing study arms: The following PK parameters will be estimated for TMC207, TMC207 metabolite M2 and pyrazinamide on Day 14 only: the maximum observed plasma concentration (Cmax), time to reach Cmax (Tmax), the minimum observed plasma concentration (Cmin) 24 hours following the last dose, area under the plasma concentration time (t) curve from zero to 24 hours (AUC(0-24)). These data will be presented as descriptive analyses, and no inferential tests will be carried out. For PA-824 (excluding TMC207 plus PA-824 containing treatment arm) containing study arms: The following PK parameters will be estimated for PA-824, pyrazinamide and moxifloxacin on Days 1, 8 and 14: the maximum observed plasma concentration (Cmax), time to reach Cmax (Tmax), the minimum observed plasma concentration (Cmin) 24 hours following the last dose, area under the plasma concentration time (t) curve from zero to 24 hours (AUC(0-24)). These data will be presented as descriptive analyses, and no inferential tests will be carried out. For TMC207 plus PA-824 containing study arm: The following PK parameters will be estimated for PA-824, TMC207 and TMC207 metabolite M2 on Day 14 only: the maximum observed plasma concentration (Cmax), time to reach Cmax (Tmax), the minimum observed plasma concentration (Cmin) 24 hours following the last dose, area under the plasma concentration time (t) curve from zero to 24 hours (AUC(0-24)). These data will be presented as descriptive analyses, and no inferential tests will be carried out. Pharmacokinetics-Pharmacodynamics (PK-PD): For TMC207 and PA-824 containing treatment arms, the following will be estimated for TMC207, PA-824, pyrazinamide and moxifloxacin as appropriate per the above PK analyses performed: The EBAs vs. the following PK variables (Day 14 only) will be presented:

Cmax;

AUC(0-24);

Time over Minimum inhibitory concentrations (MIC) (for TMC207, PA-824 and moxifloxacin). These data will be presented as descriptive analyses, and no inferential tests will be carried out.


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Criteria for evaluation (cont): Extent of QT prolongation For TMC207 and PA-824 containing treatment arms, administered for 14 days, the potential correlations between the plasma concentration of IMP and the change from baseline of QT interval corrected by Fridericia’s method (QTcF) and change from baseline of QT interval corrected by Bazett’s method (QTcB) with respect to time for the different treatment groups will be explored. These data will be presented as descriptive analyses, and no inferential tests will be carried out.

Mycobacteriology Characterization: Cultures grown from the overnight sputum collections from Day -2 and Day 14 will be assessed as follows:

MIC of TMC207, PA-824 and moxifloxacin;

Drug susceptibility testing of the M. tuberculosis isolates with the MGIT system for sensitivity to isoniazid, rifampicin, ethambutol and pyrazinamide;

Speciation of the infecting organism by polymerase chain reaction (PCR).

Statistical Methods: This is a descriptive study with no inferential statistics or hypothesis testing. The planned sample size of 15 participants per treatment group is in keeping with other Phase II trials of this type and accounts for the possibility of up to 3 drop-outs per arm, which, based on previous studies of this type conducted at these sites, represents a conservative estimate of the expected drop-out rate. It will allow estimation of the study endpoints with good accuracy and low variability. The Statistical Analysis Plan (SAP) will be developed before the database is locked.

Trial Duration: Estimated date of first participant enrolled: Quarter 3 2010 Estimated date of last participant enrolled: Quarter 1 2011 Estimated date of last participant completed: Quarter 3 2011 Duration of study: 41 Weeks (25-week enrolment period plus 1-week pre-treatment plus 2-week treatment period plus 13 weeks of post-treatment follow-up).


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1.2. Study Flow Chart

Period Pre-Treatment Treatment Follow-Up

Visit 1 2 3 4 5 6 to 11 12 13 to

17 18 19 Early

with-drawal

20 21 22

Day (-9 to -4) A

-3B -2 -1 1 2 to 7C 8 9 to 13C

14 15 28D 42D 104D

Positive TB smear (TB clinic/site of initial

diagnosis) X

Written informed consent

X

Spot sputum (study lab – confirm TB &

adequate bacterial load)

X

Demography X

Medical & Treatment History

X

Hospital Admission XB XB

Inclusion/Exclusion /Eligibility assessment

X X

X

(pre-dose)

Chest X-ray X

Visual Acuity and Slit Lamp ExaminationE

X

X

FundoscopyF X X X X

Physical ExaminationG and Vital signs H X X X X

X (pre-dose)

X X X X X X X X

12-Lead ECG I X X X X X X X X X X

Laboratory Assessments J

X X

(pre-dose)

X

(pre-dose)

X X X

Serum EndocrinologyK X

Retention SamplesL X X X X X X X X X X

Urine Drug Screen M X

Urine IsoniazidM X

β-HCG Serum Pregnancy (women of child bearing potential

only)

X

HIV test and CD4 count X

Overnight Sputum N X X X X X X X X

RandomizationO X

IMP administration and Compliance Check

X X X X X

PK P X X X X X X X

Isoniazid and Rifampicin Resistance

Test (rapid)Q X

Mycobacteriology AssessmentsR

X X

Hospital Discharge X X

Concomitant medication

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

Adverse EventsS X X X X X X X X X X X X X


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A: The Visit 1 (Day -9 to -4) time period will be up to a maximum of 6 days. Should a site’s ethics committee request that this be modified, the agreed upon time period will be implemented for that site.

B: Participants can proceed with the Visit 2 (Day -3) assessments as soon as their Visit 1 (Day -9 to -4) assessments have been completed i.e. visits 1 and 2 may occur on the same day as long as the screening results are available in time for randomization. Participants may be hospitalized during the entire pre-treatment period if the investigator considers it advisable.

C: Except for ECGs, retention sample, and PK collection (as noted below), all events listed as occurring on Visit 6 (Day 2) to Visit 11 (Day 7) and Visit 13 (Day 9) to Visit 17 (Day 13) will be conducted each day during these times.

D: Follow-up visits will be performed at the site: (1) for participants in TMC207 containing arms (excluding TMC207 plus PA-824 containing treatment arm) at: Visit 20

(Day 28)(± 1 day) and Visit 21 (Day 42)(± 3 days); (2) for participants in PA-824 containing arms (excluding TMC207 plus PA-824 containing treatment arm) at Visit 20 (Day 28)(± 1 day) and Visit 22 (Day 104)(±14 days); (3) for participants in the TMC207 plus PA-824 and Rifafour e275® containing arms at Visit 20 (Day 28)(± 1 day), Visit 21 (Day 42)(± 3 days) and Visit 22 (Day 104)(±14 days).

E: Ophthalmologic Medical History will be obtained; Visual Acuity and Slit Lamp examination will be performed on all participants at Visit 1 (Day -9 to -4)(anytime during the pre-treatment period, however it must be performed before randomization on Visit 3 (Day -2). Visit 22 (Day 104): Visual Acuity and Slit Lamp examinations done on the PA-824 (including TMC207 plus PA-824) containing and the Rifafour e275® treatment arms.

F: Fundoscopy will be performed on all participants at Visit 1 (Day -9 to -4)(anytime during the pre-treatment period, however it must be performed before randomization on Visit 3 (Day -2). Visit 19 (Day 15) or early withdrawal and Visit 21 (Day 42): Eye exam with fundoscopy done on the TMC207 (including TMC207 plus PA-824) containing and the Rifafour e275® treatment arms.

G: Includes weight and height (m). Height (m) will only be collected once at Visit 1 (Day -9 to -4). To be performed within 2 hours before dosing on Days 1 through 14 and within 2 hours before the time dosing would have occurred on Day 15. For the TMC207 plus PA-824 treatment arm these are to be performed within 2 hours before the PA-824 dose.

H: Systolic blood pressure (SBP) and diastolic blood pressure (DBP) (mmHg), heart rate (beats per minute [bpm]), and body temperature (°C; axillary). To be performed within 2 hours before dosing on Days 1 through 14 and within 2 hours before the time dosing would have occurred on Day 15. For the TMC207 plus PA-824 treatment arm these are to be performed within 2 hours before the PA-824 dose.

I: 12-lead ECGs will be performed as noted in the ECG/PK flow charts. J: Laboratory Assessments: Hematology (hemoglobin, hematocrit, red blood cell count, white blood cell count with

differential), platelet count, Coagulation (activated partial thromboplastin time (APTT), prothrombin time (PT), international normalized ratio (INR)). Clinical Chemistry (albumin, urea, creatinine, direct, indirect and total bilirubin, uric acid, cholesterol (total), triglycerides, total protein, lipase, total amylase, alkaline phosphatase, creatine phosphokinase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), lactic dehydrogenase (LDH), phosphate, sodium, potassium, calcium (corrected for albumin), chloride, random/fasting glucose, bicarbonate/CO2). Urinalysis (pH, specific gravity, protein, glucose, micro-albumin, ketones, bilirubin, creatinine, nitrite, sodium, urobilinogen, blood, leukocytes, microscopy). If total amylase results are Grade 3 or higher, further testing of pancreatic amylase and trypsin like immunoreactivity should be considered after consultation with the Sponsor Medical Monitor. For the TMC207 plus PA-824 treatment arm at Visit 5/Day 1 and Visit 12/Day 8 these are to be performed pre the PA-824 dose.

K: Serum Endocrinology: testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH). These will be performed on male participants only. The serum endocrinology sampling (in males, only) may be repeated in the morning (ideally 8 am) if the original results show an isolated abnormal value (i.e., only 1 of the 3 hormones is abnormal). Only the item which was abnormal in the original testing needs to be repeated.

L: Retention Sample collection: Plasma samples will be collected for: (1) all participants in parallel with the pre-dose blood draws planned for Visit 5 (Day 1), Visit 12 (Day 8) and with the laboratory samples at the Hour 0 draws on Visit 19 (Day 15) or early withdrawal. For the TMC207 plus PA-824 treatment arm at Visit 5/Day 1 ), Visit 12 (Day 8) and with the lab samples at the hour 0 draw scheduled for Visit 19 (Day 15), these are to be performed pre the PA-824 dose/dosing time; (2) for the TMC207(including TMC207 plus PA-824) and Rifafour e275® containing treatment arms, Visit 21 (Day 42) samples will also be collected. Serum samples (males only) will be collected for the PA-824 (including TMC207 plus PA-824) and Rifafour e275® containing treatment arms, in parallel from the pre-dose blood draws scheduled for Visit 5 (Day 1), Visit 12 (Day 8) and with the lab samples at the hour 0 draw scheduled for Visit 19 (Day 15) or early withdrawal. For the TMC207 plus PA-

http://activate.lww.com/semdweb/internetsomd/ASP/1520420.asp


Page 16 of 142

824 treatment arm at Visit 5/Day 1 ), Visit 12 (Day 8) and with the lab samples at the hour 0 draw scheduled for Visit 19 (Day 15), these are to be performed pre the PA-824 dose/dosing time. Urine samples will be collected for all participants in parallel with urinalysis samples collected on Visit 5 (Day 1), Visit 12 (Day 8) and Visit 19 (Day 15) or early withdrawal. For the TMC207 plus PA-824 treatment arm at Visit 5/Day 1), Visit 12 (Day 8) and Visit 19 (Day 15), these are to be performed pre the PA-824 dose/dosing time. Sputum samples will be taken from the overnight sputum samples collected from all participants at Visit 3 (Day-2), Visit 4 (Day -1), Visit 5 (Day 1), Visit 6 (Day 2), Visit 7 (Day 3), Visit 8 (Day 4), Visit 10 (Day 6), Visit 12 (Day 8), Visit 14 (Day 10), Visit 16 (Day 12) and Visit 18 (Day 14).

M: Urine drug screen: cannabinoids, cocaine, amphetamines, opiates, benzodiazepines, barbiturates. Urine Drug screen and Urine Isoniazid test should be repeated at Visit 2 (Day -3) for patients who were not hospitalized at Visit 1 (Day -9 to -4).

N: On-study overnight sputum sampling will start on Visit 2 (Day -3) and will be collected from the afternoon and for 16 hours overnight. The 16-hour sputum sampling for each of the sampling days must be finished prior to the administration of the next day’s IMP. Sputum will be sampled starting on Visit 2 (Day –3) and will continue daily until Visit 18 (Day 14). Sputum sampling will stop on the morning of Visit 19 (Day 15). Overnight sputum collection will start at the latest on Visit 2 (Day -3), however may be collected for a number of more days if the screening results are delayed, or the mycobacterial testing on the first spot sputum shows an indeterminate result in which case the test may be repeated on a freshly collected spot sputum or an overnight sputum and that result used. It will not be collected for more than the pre-treatment time period. Visit 2 (Day -3) overnight sputum sampling will be used to ensure adequate volume and is not required for efficacy variable tests, retention sample collection and mycobacterial characterization testing

O: Randomization by the pharmacist/registered dispenser may occur once all the screening results are available and the investigator has determined that the participant is eligible for the trial. Randomization must occur prior to the Visit 4 (Day -1) ECGs.

P: Pharmacokinetics details are provided in the ECG/PK Flow charts. Q: Isoniazid and Rifampicin Resistance Test: Susceptibility testing for rifampicin and isoniazid, (rapid, sputum-based,

screening test). If the first spot sputum shows an indeterminate result, the test may be repeated on freshly collected spot sputum or overnight sputum and that result used.

R: The Mycobacterium tuberculosis (MTB) isolates from the Visit 3 (Day -2) and Visit 18 (Day 14) overnight sputum samples will be kept and later be batched and processed for (1) MIC against TMC207, PA-824 and moxifloxacin, (2) drug susceptibility testing for rifampicin, isoniazid, ethambutol and pyrazinamide with the MGIT system, (3) speciation of the infecting organism by polymerase chain reaction (PCR). If no Visit 18 (Day 14) pooled sputum sample is available these tests will be done on the last available sample. If the participant was treated with IMP for less than 9 days, mycobacteriology testing will be performed on the Visit 3 (Day -2) isolate only for these participants.

S: Adverse events will be collected by the Investigator from the time a participant signs the Informed Consent Form through to: (1) for TMC207 containing treatment arms (excluding TMC207 plus PA-824 containing treatment arm): - all AEs and SAEs – through to the end of Visit 21 (Day 42); (2) for PA-824 containing treatment arms (excluding TMC207 plus PA-824 containing treatment arm): - all AEs and SAEs – through to the end of Visit 20 (Day 28); - only ophthalmologic related adverse events and all serious adverse events - from Visit 20 (Day 28) through to the

end of Visit 22 (Day 104); (3) for TMC207 plus PA-824 and Rifafour e275® treatment arm: - all AEs and SAEs - through to the end of Visit 21 (Day 42); - only ophthalmologic related adverse events and all serious adverse events - from Visit 21 (Day 42) through to the

end of Visit 22 (Day 104).


Page 17 of 142

1.3. PK and ECG Chart

1.3.1. TMC207 (excluding TMC207 plus PA-824) and Rifafour e275® Containing Treatment Arms

† All ECGs for TMC207 and Rifafour e275® containing treatment arms to be done in single. Pre-dose ECG on Visit 5 (Day 1) to occur up to 16 hours before the dose. At Visit 7 (Day 3), Visit 12 (Day 8) and Visit 18 (Day 14) the pre-dose ECG must be performed within 1 hour before the dose. Other ECGs should be performed +/- 15 minutes of the scheduled time point, except for at Visit 1 (Day -9 to -4), early withdrawal, Visit 20 (Day 28) and Visit 21 (Day 42), when the ECG may be performed at any time. β The site staff are to immediately check the ECG readings performed by the provided ECG machine for the QT prolongation safety margins as described in section 7.5. If these safety margins are not met, the site staff will immediately notify the designated appropriately trained physician, who will manually read the ECG tracing in question to determine if the QTc prolongation criteria for patient withdrawal (see section 9.7) have been met. Prior to dosing on each treatment day, clinical assessment of the previous days ECGs are to be performed for safety monitoring (section 9.7) by the designated appropriately trained physician.

*PK performed on the TMC207 treatment arms only. PKs are to be performed at the specified time points as follows: - Pre-dose: 0-5 minutes before dose - 1-8 hours post-dose: +/- 5 minutes - 24 post-dose: +/- 15 minutes (and prior to dosing) - Day 42 no limit. On days where there is IMP dosing Hour 0 represents pre-dose. On days where there is no dosing Hour 0 should be performed pre-dose to the time dosing would have occurred. The exception to this is Visit 1 (Days -9 to -4), Visit 20 (Day 28) and Visit 21 (Day 42), when Hour 0 may be at any time.

STUDY VISIT » 1 5 7 12 18 19 Early Withdrawal

20 21

STUDY DAY» Day-9 to -4 Day 1 Day 3 Day 8 Day 14 Day 15 Day 28 Day 42*

STUDY HOUR » 0 0 5 0 5 0 5 0 1 2 5 8 0 0 0 0

EVENT

Dose X X X X

ECG†β X

X X X X X X X X X X X

Plasma Pharmacokinetics

for TMC207, TMC207 metabolite M2, and pyrazinamide*

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


Page 18 of 142

1.3.2. PA-824 (excluding TMC207 plus PA-824) Containing Treatment Arms

† Single 12-lead ECGs are to be done on Visit 1 (Day -9 to -4), Visits 6-11 (Days 2-7), Visits 13-17 (Days 9-13), Visit 18 (Day 14), at early withdrawal and Visit 20 (day 28). Triplicate ECGs are to be done on Visit 4 (Day -1), Visit 5 (Day 1) and Visit 12 (Day 8). The 24 hours ECGs on Visit 4(Day -1), Visit 5 (Day 1) and Visit 12 (Day 8) will serve as the pre-dose (hour 0) ECGs for the following study visit/day, and are therefore to be performed in triplicate. Pre-dose ECGs must be performed within 1 hour before the dose. Other ECGs should be performed +/- 15 minutes of the scheduled time point, except for at Visit 1 (Day -9 to -4), early withdrawal and Visit 20 (Day 28) when the ECG may be performed at any time. β The site staff are to immediately check the ECG readings performed by the provided ECG machine for the QT prolongation safety margins as described in section 7.5. If these safety margins are not met, the site staff will immediately notify the designated appropriately trained physician, who will manually read the ECG tracing in question to determine if the QTc prolongation criteria for patient withdrawal (see section 9.7) have been met. Prior to dosing on each treatment day, clinical assessment of the previous days ECGs are to be performed for safety monitoring (section 9.7) by the designated appropriately trained physician. When ECGs are obtained in triplicate, the first recorded ECG should be used for the on-site QT evaluation. *PKs are to be performed at the specified time points as follows: - Pre-dose: 0-5 minutes before dose - 1-12 hours post-dose: +/- 5 minutes - 24 post-dose: +/- 15 minutes (and prior to dosing) - Day 42 no limit. On days where there is IMP dosing Hour 0 represents pre-dose. On days where there is no dosing Hour 0 should be performed pre-dose to the time dosing would have occurred. The exception to this is Visit 1 (Days -9 to -4) and Visit 20 (Day 28), when Hour 0 may be at any time.

STUDY VISIT » 1 4 5 and 12 6-11 and

13-17 18 19 Early

Withdrawal

20

STUDY DAY»

Day-9 to -4 Day -1 Day 1 and Day 8

Days 2-7 and

Day 9-13 Day 14 Day 15

Day 28

STUDY HOUR » 0 0 1 2 3 4 6 8 12 24 0 1 2 3 4 6 8 12 24 0 2 5 0 1 2 5 8 0 0 0

EVENT

Dose X X X

ECG† X X X X X X X X X X X X X X X X X X X X X X X X X X X

On-site ECG Assessment β

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

Plasma Pharmacokinetics

PA-824, pyrazinamide and moxifloxacin*

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


Page 19 of 142

1.3.3. TMC207 (J) plus PA-824 (Pa) Containing Treatment Arms

£ PA-824 should be administered under fasting conditions in the morning at least 4 hours prior to breakfast. TMC207 should be administered within 30 minutes after breakfast. † All ECGs to be done in single. ECGs should be performed +/- 15 minutes of the scheduled time point, except for Visit 1 (Day -9 to -4), early withdrawal, Visit 20 (Day 28) and Visit 21 (Day 42) when the ECG may be performed at any time . β The site staff are to immediately check the ECG readings performed by the provided ECG machine for the QT prolongation safety margins as described in section 7.5. If these safety margins are not met, the site staff will immediately notify the designated appropriately trained physician, who will manually read the ECG tracing in question to determine if the QTc prolongation criteria for patient withdrawal (see section 9.7) have been met. Prior to dosing on each treatment day, clinical assessment of the previous days ECGs are to be performed for safety monitoring (section 9.7) by the designated appropriately trained physician. *PKs are to be performed at the specified time points as follows: - Pre-dose: 0-5 minutes before dose - 1-12 hours post-dose: +/- 5 minutes - Day 42 no limit. On days where there is IMP dosing Hour 0 represents pre-dose. On days where there is no dosing Hour 0 should be performed pre-dose to the time dosing would have occurred. The exception to this is Visit 20 (Day 28) and Visit 21(Day 42), when Hour 0 may be at any time.

STUDY VISIT » 1 5 and 12 7 6, 8-11, 13-17

18 19 Early Withdraw

al

20 21

STUDY DAY» Day-9 to -

4 Day 1 and 8 Day 3

Days 2, 4-7, 9-

13 Day 14 Day 15

Day 28

Day 42

EVENT

STUDY HOUR Pa » 0 0 4 8 9 0 4 9 0 4 0 1 2 4 5 6 8 9 12 0 0 0 0

STUDY HOUR J» 0 -4 0 4 5 -4 0 5 -4 0 -4 -3 -2 0 1 2 4 5 8 0 0 0 0

BREAKFAST » X X X X

DOSE £ » Pa J Pa J Pa J Pa J

ECG† X X X X X X X X X X X X X

On-site ECG Assessment β

X X X X X X X X X X

Plasma PK

TMC207, TMC207 metabolite M2*

X

X X X X X X X X X X X

Plasma PK

PA-824 * X X X X X X X X X X


Page 20 of 142

2. INTRODUCTION

2.1. Background Information

Although some progress has been made in recent years in controlling TB globally, TB has remained

a persistent problem in the developing countries of Africa and Asia. TB is currently one of the top

three killer infectious diseases, and there is more TB in the world today than at any other time in

history. The current first-line antituberculosis agents have been in use for over 20 years and are

relatively ineffective in controlling TB as a public health problem. Although the current regimens

and drugs have been very successful in controlled clinical trials resulting in the permanent cure of

more than 95% of trial participants, treatment takes 6 months to complete. This, plus side effects,

result in poor compliance which is particularly likely to occur after the second month of treatment.

The full application of the DOTS strategy is becoming more and more difficult in the developing

countries of the world that are also battling to control the HIV-epidemic. As a result of poor

treatment compliance, drug resistance is becoming more common and fears of an epidemic with

virtually untreatable strains of TB are growing. Since the discovery of the rifamycins (1), and their

introduction into standard antituberculosis regimens, very few new classes of drugs have been

evaluated with a view to their registration as antituberculosis agents.

Following the declaration of TB as a global emergency by the World Health Organization (WHO) in

1993, there has been a resurgence of efforts to develop improved TB therapies and several

promising new agents are presently in or approaching clinical evaluation. New combination

regimens are desperately needed for two reasons; to shorten treatment to a duration more easily

manageable by patients and public health services and to provide more efficacious, safer and better

tolerated, affordable treatment for the growing number of patients suffering from multidrug-

resistant and extensively drug-resistant tuberculosis.

The bactericidal action of antituberculosis agents alone or in combination can be quantified by

studying the fall in the number of colony forming units (CFU) of M. tuberculosis (MTB) present in

the sputum of participants with microscopy smear-positive pulmonary TB. In the first

comprehensive evaluation of this technique all of the then available antituberculosis agents were

studied both alone and in combination during the first 14 days of treatment in small groups of

approximately 4 participants(2). This study showed significant differences between the different

drugs, but these differences were most obvious during the first 2 days of treatment and this period


Page 21 of 142

of activity was consequently labeled EBA or “standard EBA”. Since this pioneering study, a number

of EBA studies have been carried out, many in the Western Cape Province of South Africa. These

studies have been carried out mainly over 2 days in view of the initial findings by Jindani et al (2).

More recently, EBA studies have been conducted over 5, 7 and 14 days and it has become apparent

that valuable additional information may be found by conducting EBA studies over a longer period

(“extended EBA”) (3-6).

TMC207 is a new agent being developed for TB treatment. As detailed in the Investigator’s

Brochure (7), TMC207 is a diarylquinoline investigational compound that offers a novel mechanism

of anti-TB action by specifically inhibiting mycobacterial adenosine triphosphate (ATP) synthase (8).

In vitro, TMC207 potently inhibits both drug-sensitive and drug-resistant MTB isolates (9, 10), and is

also bactericidal against non-replicating tubercle bacilli (11). In the murine model of TB, TMC207 was

as active as the triple combination of isoniazid (H), rifampin (R), and pyrazinamide (Z), while

addition of TMC207 to this drug regimen results in accelerated clearance of bacilli (7). There

appears to be a synergistic interaction with pyrazinamide, 100% of mice were culture negative after

8 weeks of treatment with TMC207 and pyrazinamide compared to 0% of mice treated with the

standard regimen of rifampicin, isoniazid and pyrazinamide (12). Collectively, these findings in the

mouse model have led to the suggestion that a regimen containing TMC207 and pyrazinamide

could be effective in the treatment of both drug-sensitive and multi-drug resistant (MDR) TB as well

as shorten treatment duration in patients. On the other hand, the combination of TMC207 and PA-

824 in the murine model of TB, while somewhat antagonistic relative to TMC207, alone, appeared

as active as the triple combination of HRZ (38). Thus a novel regimen with a TMC207 plus PA-824

core could be effective in the treatment of MDR-TB by providing two novel drugs for which there is

no known pre-existing resistance. Moreover, the underlying mechanism of the antagonism seen in

the mouse model is not known, and it is not clear whether it will also be seen in humans, or

whether an additive or synergistic effect might be seen instead.

TMC207 has been studied in one dose-ranging 7-day EBA trial to date (6). The results from the 7-day

EBA trial showed clinically relevant bactericidal activity only at the highest TMC207 dose (400 mg)

tested with a delay in onset of response (activity detected from Day 4 onwards). No clinically

relevant changes were seen with the lower doses of TMC207 (25 mg and 100 mg) during the 7 days

of treatment. The reason for this delayed onset of activity (400 mg) or lack of bactericidal activity

(at lower doses) is not yet clear but may be partly due to suboptimal plasma concentrations initially


Page 22 of 142

or throughout the 7-day duration of treatment. Based on mouse data, the average target plasma

concentration of TMC207 for efficacy in humans is about 600ng/ml (IB, page 27) (7). In an ongoing

14-day dose-ranging EBA study (TMC207-CL001) being conducted in South Africa, different dosing

regimens are being studied to obtain average plasma concentrations ranging from 500 to 2000

ng/ml throughout most of the dosing period. Because combination, multidrug therapy is required

for treatment of TB, it is now important to determine the safety and efficacy of TMC207 in an EBA

study in combination with other antituberculosis drugs such as pyrazinamide and PA-824, to help

determine how TMC207 might be combined with other drugs to optimize TB treatment, prior to

evaluation of such a regimen in longer-term studies.

PA-824 is also a new agent being developed for TB treatment. As detailed in the Investigator’s

Brochure (13), PA-824 is a new chemical entity and a member of a class of compounds known as

nitroimidazo-oxazines, which possess significant antituberculosis activity and a unique mechanism

of action (14). Nonclinical studies of PA-824 highlighted important properties that may result in

significant improvements in TB treatment. PA-824 demonstrated in vitro activity against both drug-

sensitive and MDR-TB(15), and in vivo activity in a mouse model of tuberculosis (15,16).

PA-824 has been studied in two dose-ranging, 14-day EBA trials to date. In these studies, PA-824

monotherapy has demonstrated significant mycobactericidal activity. The efficacy data from study

PA-824-CL-007 indicated that all doses of PA-824 (200, 600, 1000 and 1200 mg) produced an

equivalent decrease in sputum CFU counts over the 14-day treatment period; no difference could

be discerned among the PA-824 treatment groups. In study PA-824-CL-010, an EBA study with a

similar design to study PA-824-CL-007 except for the use of lower doses of PA-824 (50, 100, 150 and

200 mg/day), preliminary results indicate that PA-824 treatment resulted in a measurable dose-

dependent mycobactericidal activity. As stated above for TMC207, it is also important to determine

the safety and efficacy of PA-824 in an EBA study in combination with other antituberculosis drugs

(e.g., moxifloxacin and pyrazinamide), to help determine how PA-824 might be combined with

other drugs to optimize TB treatment, prior to evaluation of such a regimen in longer-term studies.

Moxifloxacin (M) is an 8-methoxyquinolone whose oral formulation (which will be used in this

study) has been approved in South Africa and most other countries around the world for the

treatment of acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis,

community-acquired pneumonia, skin and soft tissue infections. It has enhanced activity against

Gram-positive pathogens, and anaerobes while retaining useful activity against Gram-negative


Page 23 of 142

organisms. Moxifloxacin is not metabolized by the cytochrome P450 system, thus the risk of

clinically relevant drug interactions is reduced. It has a positive safety profile within the

fluoroquinolone class. Clinical studies have been carried out in additional indications (urinary tract

infections, pelvic infections, pharyngitis/tonsillitis, and tuberculosis).

Studies in murine models of TB and in TB patients have shown that moxifloxacin has significant

mycobactericidal activity(17-26). These include EBA studies as well as four 8-week treatment period

phase IIb studies in which moxifloxacin was substituted for either isoniazid or ethambutol in the

standard, first-line, TB treatment regimen (see Table 3). Currently, a phase III trial is enrolling in

which moxifloxacin replaces either isoniazid or ethambutol in first-line treatment and is

administered in combination with the other first-line drugs for four months, with the expectation

that total treatment duration of drug-sensitive TB can be shortened to four months. The dose of

moxifloxacin employed in these TB clinical trials is 400 mg daily, the registered dose (for other

indications as stated above) and the dose that is commonly used as second line therapy for TB

(e.g., in MDR-TB patients). This is the same dose we plan to use in the proposed study.

Pyrazinamide, the pyrazine analogue of nicotinamide, is an approved anti-tuberculosis agent.

Pyrazinamide is indicated for the initial treatment of active tubercuIosis in adults and children when

combined with other antituberculosis agents and it contributes significantly to the sterilization of

lesions and thus, treatment shortening (27).

The current study is being conducted as part of the clinical development of TMC207- and PA-824-

based combinations to treat TB. As noted above, in the mouse model of TB, 100% of mice treated

with the combination of TMC207 and pyrazinamide were culture negative after 8 weeks of

treatment compared to 0% in the group of mice treated with the first-line regimen of rifampicin,

isoniazid and pyrazinamide (12). In different studies using a similar mouse model of TB, the

combination of PA-824 and TMC207 as well as the combination of PA-824 and pyrazinamide

displayed mycobactericidal activity that was equivalent to that of the first-line regimen of

rifampicin, isoniazid and pyrazinamide (28), while the combination of PA-824, moxifloxacin and

pyrazinamide cured mice more rapidly than the first-line regimen (4 versus 6 months) (29). Thus,

these novel regimens, which contain neither isoniazid nor rifampicin, may have the potential to (1)

shorten the duration of TB chemotherapy and (2) treat both drug-sensitive and multidrug-resistant

TB.


Page 24 of 142

This study will be conducted in accordance with the Guidelines for Good Practice in the Conduct of

Clinical Trials in Human Participants in South Africa 2006 (SA GCP), International Conference on

Harmonization Good Clinical Practice (ICH GCP), the ethical principles that have their origin in the

Declaration of Helsinki and the U.S. Code of Federal Regulations, 21 CFR Parts 50, 56, and 312 (30,31).

The participant population will consist of adult males and females with newly diagnosed sputum

smear microscopy-positive pulmonary TB.

2.2. Preclinical Studies

2.2.1. TMC207

Full details of the preclinical studies are provided in the current TMC207 Investigator’s Brochure

(Pages 20-48) (7).

Microbiology

In vitro studies have demonstrated that the range of minimum inhibitory concentrations (MICs) for

M. tuberculosis H37Rv, the international reference strain, and 6 fully drug-susceptible clinical

isolates was 0.030 to 0.120 µg/ml. The activity of TMC207 appears to be specific for mycobacteria,

as the MICs for non-mycobacteria were at least 500-fold higher. The activity of the main

metabolite of TMC207, M2, was determined against M. tuberculosis H37Rv in both solid and liquid

media and its MIC was found to be 0.1 µg/ml. This MIC shows that M2 is active against M.

tuberculosis but 3-6 times less active than the parent compound TMC207 (MIC of 0.015-

0.025µg/ml). TMC207 demonstrated similar in vitro efficacy against M. tuberculosis clinical isolates

resistant to the known anti-TB drugs (isoniazid, rifampin, pyrazinamide, streptomycin, ethambutol,

or fluoroquinolones). As expected, from the lack of cross-resistance with currently used anti-TB

agents, TMC207 retained activity against MDR-TB isolates.

Nonclinical Safety Studies

The non-clinical safety evaluation of TMC207 includes pharmacology, pharmacokinetics, toxicology

and metabolism studies that were conducted in accordance with current ICH guidelines. Repeated

dose toxicity studies were performed with dosing durations up to 3 months in mice and up to 6

months in rats and in dogs. Recovery was studied in rats and dogs. For more detailed information

please refer to the IB (Pages 20-48) (7).


Page 25 of 142

Respiratory parameters were unaffected by treatment. There were no effects suggestive of

neurological impairment or delayed neurotoxicity in rats. In single dose toxicity studies there were

no mortalities following oral doses of up to 200 mg/kg in mice and rats. No mutagenicity or

clastogenic effects were seen in a series of in vitro and in vivo genotoxicity tests. TMC207 was

evaluated for possible developmental toxicity effects in the rat and the rabbit. No teratogenic

effects were found.

In vitro, TMC207 slightly to moderately inhibited the delayed rectifier potassium current (IKr) in the

human ether-à-go-go-related gene (hERG) model but this effect was not manifest as a prolongation

of repolarization in subsequent in vivo studies. There were no relevant effects on the isolated right

atrium of guinea pigs in vitro, or in the isolated Langendorff-perfused rabbit heart. In vivo, positive

chronotropic effects were seen in the anesthetized guinea pig after i.v. administration, but not in

the conscious dog. In conscious, telemetered dogs, oral TMC207 had no relevant effects on cardio-

hemodynamic and electrocardiogram (ECG) parameters.

Prior to the use of PA-824 in combination with TMC207 in this clinical study, a preclinical

cardiovascular safety pharmacology study was conducted in unrestrained beagle dogs with both

drugs to explore the potential for additive effects on QT prolongation induced by the combination.

TMC207 was administered at 100 mg/kg, PO, for 7 days in order to allow for the accumulation of

TMC207 and its metabolites, M2 and M3. On Day 7, these animals were also given PA-824 at 100

mg/kg, SC. The dose and route of PA-824 chosen, 100 mg/kg, SC, was shown in preliminary PK

studies to achieve a Cmax ~3-4-fold higher than the clinical exposure at the 200-mg dose. To assess

the impact of PA-824 administered to dogs receiving TMC207, the QT interval for this group of

animals was compared on Day 6 (following 6 daily doses of TMC207) vs Day 7 (following 7 daily

doses of TMC207 and a single dose of PA-824). To assess the effect of TMC207 administration to

dogs receiving PA-824, the QT interval for the group of animals described above, on Day 7, was

compared to a separate group of animals receiving PA-824 only. A third group of animals receiving

both vehicles acted as control. The cardiovascular parameters recorded were systolic, diastolic, and

mean arterial pressures, heart rate and ECG (including QRS duration; PR, RR, and QT intervals; and

height of R wave). Monitoring periods were baseline prior to study start (Day -1), Day 6, and Day 7

for a full 24 hours each day. Preliminary results indicate that administration of 100 mg/kg TMC207

daily for 7 days causes a small increase in QTc interval by Day 6 in some animals that is not

influenced by the addition of 100 mg/kg PA-824 on Day 7. The effect of PA-824 dosing alone on QT


Page 26 of 142

interval appeared to be due to discomfort related to the SC route of administration and not related

to the plasma exposure. Given these limited findings in this preclinical study, participants will not

be exposed to undue risk in the study, during which they will be closely monitored in the hospital

throughout the treatment period, including extensive ECG monitoring.

2.2.2. PA-824

Full details of the preclinical studies are provided in the current Investigator’s Brochure (Pages 34-

57) (13).

Microbiology

In vitro studies have demonstrated that the minimum inhibitory concentration (MIC) of PA-824

against a variety of drug-sensitive MTB isolates is similar to the MIC of isoniazid (MIC of PA-824,

0.015 to 0.25 g/mL; MIC of isoniazid, 0.03 to 0.06 g/mL). PA-824 was efficacious in vitro against

drug-resistant clinical isolates of MTB, with MIC values ranging from 0.03 to 0.53 µg/mL. The

minimum effective dose (MED) of PA-824 was 12.5 mg/kg/day in a mouse model of TB. The MED is

defined as the lowest dose able to prevent the development of macroscopic lung lesions and

splenomegaly. The minimum bactericidal dose (MBD) was 100 mg/kg/day in the same mouse

model. The MBD is defined as the lowest dose able to reduce the lung TB colony forming unit (CFU)

counts by 99%. The magnitude of CFU reduction by PA-824 at this dose is similar to that seen with

the highest dose of isoniazid tested in the same study (25 mg/kg/day).

Nonclinical Safety Studies

The non-clinical safety evaluation of PA-824 includes pharmacology, pharmacokinetics, toxicology

and metabolism studies that were conducted in accordance with current ICH guidelines.

Metabolite analyses in rats, monkeys, and humans indicate an overall similar metabolic profile in

these species with some differences among minor metabolites. These studies have confirmed that

rats and monkeys are appropriate species for the toxicology program.

PA-824 was negative in all genotoxicology studies performed. One of its metabolites (M50) that is

found in rat, monkey and human plasma was positive in a screening Ames assay. M50 is not a major

metabolite in humans and the exposure relative to parent drug is higher in the rat (24%) and

monkey (18%) than in humans (6%).

PA-824-induced effects in respiratory, CNS, and cardiovascular safety pharmacology studies were

generally mild and reversible; effects were most prominent at 450 mg/kg/day. PA-824 is a weak


Page 27 of 142

inhibitor (IC50=20uM) of the hERG channel. In a telemetry monkey study, in the dose range 50-450

mg/kg, there was no or minor prolongation of the QT interval, depending on the method of

correction. The weight of evidence suggests that there should be no effect on QT in the

concentration range being explored in the clinical studies.

Prior to the use of PA-824 in combination with moxifloxacin in the planned clinical study, a

preclinical cardiovascular safety study was conducted in unrestrained cynomolgus monkeys with

both drugs to explore the potential for PA-824 to alter the QT prolongation induced by

moxifloxacin. The doses of moxifloxacin chosen for this monkey study, 30 mg/kg and 100 mg/kg,

have been shown in the literature and historically by the research lab performing the study, to

induce at least a 20-msec increase in QTc (32). The dose of PA-824 chosen, 50 mg/kg, has been

shown in previous monkey studies to result in a free plasma concentration ~10-fold higher than the

clinical exposure at the 200 mg dose. This study design included 2 Latin squares with 4 animals in

each; the first group of animals receiving vehicle, low-dose moxifloxacin, PA-824, and PA-824

together with moxifloxacin. The second group followed a similar design with the high dose of

moxifloxacin. All animals received a 1-week washout period between doses. The cardiovascular

parameters recorded were systolic, diastolic, and mean arterial pressures, heart rate and ECG

(including QRS duration; PR, RR, and QT intervals; and height of R wave). Monitoring periods were

baseline prior to study start, 24 hours pre-dose and 24 hours post dose. Statistical evaluations will

be made comparing all dose intervals to vehicle as well as comparing the combination PA-

824/moxifloxacin dose to the moxifloxacin-alone dose. Preliminary results indicate that

administration of 50 mg/kg PA-824 in combination with 100 mg/kg moxifloxacin resulted in

increases in QT and QTc intervals in 1 animal (out of 4 animals tested) that were ~10% higher than

administration of 100 mg/kg moxifloxacin alone. Given this limited finding with the relatively high

doses of PA-824 and moxifloxacin employed in the preclinical study, participants will not be

exposed to undue risk in the proposed clinical study, during which they will be closely monitored in

the hospital throughout the treatment period, including extensive ECG monitoring.

Repeat-dose toxicology studies with PA-824 have been conducted in male and female rats (14 days

to 6 months) and in male and female monkeys (7 days to 3 months). In all studies, dose-dependent

reduced food consumption and reduced weight gain or weight loss were noted. In addition,

testicular atrophy was observed in rats while cataracts were observed by indirect ophthalmoscopy

in both rats and monkeys. In general, toxicity in both rat and monkey was significantly greater when


Page 28 of 142

exposures exceeded approximately 300 μg·hr/mL in the 14-day studies and approximately

200 μg·hr/mL in the 3-month studies.

Reproductive toxicology studies show that PA-824 is not teratogenic in rats or rabbits. In the rat

fertility study, dose-dependent reduced fertility rates, due to decreased sperm numbers and

decreased motility, were observed at doses of 30 mg/kg and greater. This effect was partially

reversible. As in the 3-month rat toxicology study, irreversible testicular lesions were not observed

at 30 mg/kg, only at 100 and 300 mg/kg.

To more fully characterize the cataract and male reproductive system findings, a 3-month monkey

study in sexually mature males (0, 50, 150, 300 mg/kg/day) and a 6-month rat study (0, 30, 100,

300 mg/kg) in males and females were conducted. Ocular assessments were conducted in a much

more careful and systematic manner than in the initial 3-month toxicology studies described above.

In each of the later studies, all ophthalmologic examinations were conducted by a single

ophthalmologist, using both indirect ophthalmoscopy and slit-lamp biomicroscopy. Animals were

screened before dosing to ensure no animal had cataracts at baseline, and then monthly during

dosing and recovery. In this monkey study, although similar drug exposures were attained as in

the original 3-month monkey study, no cataracts or testes effects (semenology, organ weights,

histopathology, or hormones [testosterone, follicle-stimulating hormone, Inhibin-B]) were observed

at any point during dosing or during a 20-week recovery period. PA-824 does not appear to cause

cataracts or testicular toxicity in monkeys. In the 6-month rat study, PA-824 caused irreversible

cataracts at 100 mg/kg from Day 118 of the study in males and females. In contrast to the original

3-month rat report, rats in this more carefully conducted study developed cataracts while on drug

but not during recovery. The NOAEL was 30 mg/kg for cataracts and 10 mg/kg for testicular

toxicity. Rats that developed cataract and testicular toxicity also experienced marked decreases in

body weight gain and food consumption. The AUC safety multiples (relative to the exposures

obtained at the anticipated clinical dose of 200 mg/day) for cataract are ~1.5x in the rat; in the

monkey at the highest dose tolerated, where there were no cataracts in the second well conducted

study, the multiple is at least 3.7x.

To summarize, cataracts have been detected in multiple animals from two similar rat studies at

mid-to-high doses. In contrast, the finding of cataracts in one monkey study could not be

confirmed in a follow-up study. Thus, both cataracts and the testicular effects appear to be

species-limited.


Page 29 of 142

Refer to the TMC207 preclinical section for details on the PA-824 TMC207 combination preclinical

cardiovascular study. Given these limited findings in this preclinical study, participants will not be

exposed to undue risk in the proposed clinical amendment, during which they will be closely

monitored in the hospital throughout the treatment period, including extensive ECG monitoring.

2.2.3. Moxifloxacin

Moxifloxacin has been approved in South Africa and most other countries around the world for the


community-acquired pneumonia, skin and soft tissue infections. An extensive preclinical program

supports the safety and efficacy of 400 mg moxifloxacin given once daily for 5 to 21 days in adults

for the above specified indications. For more detailed information, please refer to the IB for

Moxifloxacin (34).

2.3. Clinical Trials

2.3.1. TMC207

Six Phase I trials in healthy patients and 1 short-term Phase II trial in treatment-naïve patients with

sputum smear-positive pulmonary TB have been conducted. One long-term double-blind Phase II

trial consisting of 2 different stages and one long-term open label trial in patients infected with

newly diagnosed sputum smear-positive pulmonary MDR-TB are ongoing. In the former, Stage 1

has completed dosing with TMC207. The principal findings of these trials are summarized below

(Table 1). For more detailed information, please refer to the IB for TMC207 (Pages 53-83) (7).

A second short-term (14 days) Phase II trial in treatment-naïve patients with sputum smear-positive

pulmonary TB is being conducted in South Africa (Study Protocol TMC207-CL001). Preliminary

results indicate that all dosing regimens were well tolerated and produced measurable

mycobactericidal activity with a statistically significant linear trend over the dose groups. Thus, the

regimen chosen for this study (700mg on day 1, 500mg on day 2 and 400mg days 3-14) is

appropriate.


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Table 1: Overview of the TMC207 Clinical Program

Study Design Dose Levels (mg) Enrolled

(active and control) Key Safety/Efficacy Findings

Phase I

R207910-CDE-101 Part 1

Single ascending dose 10, 30, 100, 300, 450, 700

55

Median Tmax 5 hrs.

T1/2 for TMC207 and M2, 132 days and 112 days, respectively.

Safe and well tolerated

R207910-CDE-101 Part 2

Fed-Fasted, single dose, 2 way cross-over

300 12

T1/2=101-120 in fasted and fed;

Tmax =6 hr in fasted, 5 hr in fed.

Exposures higher in fed than fasted state (by 32%)

R207910BAC1003

Single-dose, Rifampicin interaction

300, Rifampicin 600 mg (7 days)

16

Exposure (AUC336h) to TMC207 and M2 decreased by 52% and 25% respectively)

Most common AE = chromaturia

TMC207-108 Bioavailability, single-dose, 3-way crossover, fed/fasted.

100 capsule, 100 tablet, 100 oral solution

24

PK comparable after admin of 3 formulations with food.

With food AUC240h for capsule and tablet increased by 31% and 95%.

R207910-CDE-102

Multiple ascending dose 50, 100, 400 (14 days) 27

Median Tmax=5hr.

Mean T1/2 range from 167 to 173 hr.

Variability in exposure to TMC207 at 14 days =20-25% across doses

TMC207-C104 Multiple-dose, 1-way crossover Isoniazid/pyrazinamide interaction trial

400 (15 days), Isoniazid 300, pyrazinamide 2000

24

Reduction in exposure (AUC24h) to TMC207

(-13%) after 5 days of co administration and increase in exposure to M2 (+30%).

TMC207 increased exposure to both H and Z (±8%);

10 subjects had G3and G4 hyperuricemia

TMC207-C109 Multiple-dose Ketoconazole interaction trial

400mg 14 days Ketoconazole 400mg

16

Increased exposure to TMC207 by 22%

No effect on M2 (+1%);

1 grade 3 increase in lipase (normalized after treatment stopped)


Page 31 of 142

Study Design Dose Levels (mg) Enrolled

(active and control) Key Safety/Efficacy Findings

Phase II

C-202 Open-label, randomized Evaluate the early bactericidal activity, safety, tolerability and PK

TMC207: 50, 100, 400mg Rifampicin 600mg Isoniazid 300 mg

60

Bactericidal activity only at 400mg starting at Day 4.

Generally safe and well- tolerated.

Slight QTc prolongation.

Most common AE: hemoptysis.

C208 Part 1 Placebo-controlled, double-blind, randomized Evaluate the anti-bacterial activity, PK, safety and tolerability

400mg x14 days, followed by 200mg tiw vs. placebo (plus background regimen) for 6 wks

47

Sputum culture negativity at 8 wks: 47.5% (TMC) vs. 8.7% (pbo)

AEs: nausea, unilateral deafness, arthralgia, hyperuricemia, hemoptysis, pain in extremities, rash and chest pain

C208 Part 2 Placebo-controlled, double-blind, randomized Demonstrate superiority of the anti-bacterial activity of TMC207 compared to PBO for 24 weeks on BR

400mg x14 days, followed by 200mg tiw vs. placebo (plus background regimen) for 22 wks

150

Ongoing.

C209 Open-label safety trial Evaluate safety, tolerability and efficacy of TMC207 as part of multi-drug regimen

400mg x14 days, followed by 200mg tiw vs. placebo for 22 wks in combination with an individualized BR

225

Ongoing.

CL-001 Partially double-blind, randomized Evaluate the early bactericidal activity, safety, tolerability and PK

G1:700, 500, 400 G2:500, 400, 300 G3:400,300,200 G4:200, 100 mg Rifafour (control) For 14 days

60 Preliminary results indicate that all dosing regimens were well tolerated and produced measurable mycobactericidal activity with a statistically significant linear trend over the dose groups


Page 32 of 142

Phase I

The Phase I trials have provided a basic understanding of TMC207’s pharmacokinetic

characteristics, drug-drug interaction potential, and short-term safety/tolerability profile in 173

healthy patients.

TMC207 was well absorbed with a median time to reach the maximum plasma concentration (tmax)

of about 5 hours after dosing. The maximum plasma concentration (Cmax) and area under the

plasma concentration-time curve (AUC) increased proportionally up to the highest doses studied

(700 mg single dose and 400 mg multiple q.d. doses). Accumulation from Day 1 to Day 14 was

approximately 2-fold expressed as increase in AUC, while trough concentrations increased up to 3.5

fold. The pharmacokinetics of TMC207 in patients with pulmonary TB were comparable to those in

healthy patients. The average terminal elimination half-life (t1/2,term) of TMC207 and its N-

monodesmethyl metabolite (M2) was about 132 and 112 days, respectively. The latter was found

to be active against M. tuberculosis, although less potent than TMC207 (7).

Administration of TMC207 as the tablet formulation with food increased the relative bioavailability

(by 95%) as compared to administration without food.

Drug-drug interaction studies confirmed the role of cytochrome P450 3A4 (CYP3A4) in the

metabolism of TMC207 to M2. A study with rifampicin (a CYP3A4 inducer) showed that the

exposure (AUC336h) to TMC207 as well as M2 was significantly reduced (by 52 and 25%,

respectively). Furthermore, co-administration of ketoconazole (a CYP3A4 inhibitor) increased

exposure (AUC24h) to TMC207 by 22%, without a significant effect on M2 (+1%). A drug-drug

interaction study with the combination of isoniazid/pyrazinamide showed a reduction in the

exposure (AUC24h) to TMC207 (-13%) after 5 days of co-administration, while exposure to M2

increased (+30%). TMC207 increased exposure (AUC24h) to both isoniazid and pyrazinamide (≤8%)

which is not considered clinically relevant. Thus, no significant drug-drug interaction between

TMC207 and pyrazinamide is anticipated in the proposed clinical study.

Phase II

In a Phase IIa study (6), efficacy (bactericidal activity) was measured by change in the amount of

bacilli in the sputum, estimated by changes in the number of CFU. The log10 of the CFU counts, the

changes from baseline in log10 sputum CFU counts (log10 fall) as well as the average daily change

in log10 sputum CFU counts (Early Bactericidal Activity [EBA]), over a period of 7 days, were


Page 33 of 142

derived. Over a period of 7 days, mean values for extended EBA (eEBA) were -0.01, -0.04 and -0.11

log10 CFU/day for the TMC207 25 mg, 100 mg and 400 mg group, respectively. Corresponding

values for the control treatments were -0.24 log10 CFU/day for the rifampin group and -0.27 log10

CFU/day for the isoniazid group.

Over a period of 2 days, mean values for EBA were 0.01, -0.10 and 0.02 log10 CFU/day for the

TMC207 25 mg, 100 mg and 400 mg group, respectively. Corresponding values for the control

treatments were -0.44 log10 CFU/day for the rifampin group and -0.28 log10 CFU/day for the

isoniazid group.

On Day 7, changes from baseline in log10 sputum CFU count were -0.04, -0.26 and -0.77 for the

TMC207 25 mg, 100 mg and 400 mg groups, respectively. For the control treatments, the changes

versus baseline on Day 7 were -1.70 and -1.88 for the rifampin and isoniazid groups, respectively.

For the control treatments, the changes versus baseline on Day 2 were -0.88 and -0.57 for the

rifampin and isoniazid groups, respectively. Note that the Day 2 changes for the isoniazid group

were influenced by 2 outliers. All patients started standard TB therapy after collection of the

overnight sputum specimen on the morning of Day 7. All TMC207 dose groups had an additional

log10 fall of approximately 0.40 log10 CFU on Day 8.

The addition of TMC207 to a 5-drug MDR-TB treatment regimen in an ongoing Phase IIB trial

resulted in significantly shorter time to culture conversion compared to placebo. During the 8-

week treatment in Stage 1, 10 of 21 (47.6%) patients in the TMC207 group became sputum culture

negative in the Mycobacteria Growth Indicator Tube (MGIT) compared to 2 of 23 (8.7%) patients in

the placebo group. No differences in exposure to TMC207 and M2 in plasma or sputum between

patients with or without culture conversion were observed. The selected dosing regimen (400 mg

q.d. for the first 2 weeks and 200 mg t.i.w. for the following 6 weeks) successfully controlled

accumulation of TMC207 and M2 in plasma, with most patients achieving average concentrations

above the targeted 600 ng/mL throughout the dosing period. The results of Stage 1 supported the

extension of this dosing regimen up to 24 weeks of treatment in Stage 2 of the trial (33) which is

currently ongoing.

Clinical Safety

In the Phase I trials, TMC207 was generally safe and well tolerated. The most common adverse

events (AEs) were headache, nasopharyngitis, postural dizziness, and hyperuricemia.


Page 34 of 142

Hyperuricemia is a known side effect of pyrazinamide. There were no deaths or serious adverse

events (SAEs) reported.

In the short-term, 7-day Phase IIa EBA trial in 75 treatment-naïve TB-infected patients, the most

commonly reported AE was hemoptysis, a common complication of pulmonary TB (6). The most

commonly reported AE during treatment phases including TMC207 was hemoptysis, reported by 1

(6%) subject in the 100 mg group and 3 (21%) patients in the 400 mg group. All AEs were

considered not or doubtfully related to the trial medication, except for 2 AEs (diarrhea and rash) in

the 100 mg TMC207 group and 1 AE (somnolence) in the 400 mg TMC207 group, which were

considered possibly related to the study medication. All AEs were grade 1 or 2 in severity, except

for 1 subject in the isoniazid group, with a grade 4 hemoptysis. This event was serious and

considered not related to the study medication, but related to TB and led to premature

discontinuation. One additional subject in the isoniazid group prematurely discontinued treatment

due to an AE (hemoptysis; grade 3 in severity) that had already started during the screening period.

Two patients in the TMC207 400 mg group died during the follow-up period. These were a 25-year

old female who died due to retroviral infection and pulmonary TB, and a 41-year old male who was

prematurely withdrawn after 3 days of treatment, started standard TB therapy and eventually died

due to massive hemoptysis.

Changes in QTcF were seen in both the TMC207 and control groups. Average increases of more

than 10 ms in QTcF were seen on Day 7 for the TMC207 400 mg group and for both control groups.

On Day 7, effects were larger 5 hours post-dose compared to pre-dose for all treatment groups.

Increases by 30-60 ms in QTcF were observed for 1 and 6 subjects of the TMC207 100 and 400 mg

groups, respectively, and for 4 and 2 subjects of the rifampin and isoniazid groups, respectively. In

addition, 1 patient in the rifampin group had an increase >60 ms in QTcF.

In Stage 1 of the ongoing Phase IIb trial in 47 patients with newly diagnosed sputum smear-positive

pulmonary MDR-TB infection, the most common AEs (reported in more than 10% of patients in the

TMC207 group) were nausea, arthralgia, hyperuricemia, unilateral deafness, hemoptysis, dizziness,

and diarrhea (16). Except for nausea (26.1% versus 4.2%), the incidences of AEs in the TMC207

group were similar or lower than the incidences of AEs in the placebo group. Mean QTcF and QTcB

increased in both treatment groups but the increases were more pronounced in the TMC207 group.

With respect to mean QTcF, the difference from placebo fluctuated between 1.0 and 10.8 ms and


Page 35 of 142

did not change over time. There were 2 patients who reported an SAE, of which 1 patient was

randomized to the TMC207 group (a grade 4 diabetic ketoacidosis in a diabetic patient 42 days after

first intake of drug). The SAE was not considered related to study medication and the adverse

event resolved after treatment for ketoacidosis.

2.3.2. PA-824

Seven Phase I and one Phase II clinical trials with PA-824 have been completed. Both a Phase I

midazolam drug-drug interaction study and a Phase II EBA trial using lower doses than an earlier

study have completed the treatment phase and are in the follow-up phase. Table 1 provides a high-

level summary of the completed and ongoing studies. Full details of the clinical studies are

provided in the current Investigator’s Brochure (pages 68-103) (13).


Page 36 of 142

Table 2: Overview of PA-824 Clinical Program

Study Design Dose Levels (mg) Enrolled (active

and control) Key Safety/Efficacy Findings

Phase I

CL-001 Double-blind, placebo-controlled, single-dose, dose-escalating, PK and safety study

0, 50, 250, 500, 750, 1000, 1250, 1500

53

Well tolerated; no dose-limiting AEs or abnormal laboratory results; no effects on ECG, vital signs, or PE.

CL-002 Double-blind, placebo-controlled 7-day multidose, escalating, PK and safety study

0, 200, 600, 1000 24

Well tolerated; no effects on ECG, vital signs, or PE.

After 5 days’ dosing at 1000 mg/d, progressive moderate creatinine elevation: reversed during 7-day washout period.

No consistent effect on BUN.

A planned 1400-mg cohort not enrolled.

CL-003 Open-label, single-dose, food effects

1000 16


Treatment-emergent AEs affecting more than one subject occurred more frequently after dosing in the fed condition than the fasted condition, and more frequently among women than men.

Bioavailability is 3.5-to-4.5-fold higher when PA-824 is administered within 30 minutes of a high-fat, high-calorie meal than when it is administered after an overnight fast.


Page 37 of 142



Phase 1 continued

CL-004 Open-label, single-dose, ADME

~860, oral suspension [benzyl-14

C]PA-824

6


No significant radioactivity captured as [benzyl-14

C]CO2.

~91% of dose recovered (~65% in urine; ~26% in feces) Plasma: parent drug and one major metabolite. Urine: little or no parent drug; multiple major metabolites. Feces: minimal unchanged parent drug; numerous low-abundance metabolites.

CL-005 Double-blind, 8-day multidose, renal effects

0, 800, 1000 47

Well tolerated; no dose-limiting AEs or abnormal laboratory results; no effects on ECG, vital signs, or PE

As anticipated, serum/plasma creatinine levels increased significantly (up to ~ 40%) during treatment; reversed during 7-day washout period.

No effect during treatment on GFR, ERPF, FF, BUN or UA

CL-006 Open-label, multidose, DDI

400 14

Based on Preliminary results:

Well tolerated; no dose-limiting AEs

For midazolam, the geometric mean ratio of Day 17 (midazolam+Pa-824) vs. Day 1 (midazolam alone) for Cmax was 0.84 and AUC(0-infinity) was 0.85

For the 1-hydroxy midazolam metabolite, the corresponding geometric mean ratio for Cmax was 1.05 and AUC(0-infinity) was 1.11

CL-008 Open-label, single-dose, ADME

~1100, oral suspension [imidazooxazine-

14C]

PA-824

6


No significant radioactivity captured as [imidazooxazine-14

C]CO2.

~91% of dose recovered (~53% in urine; ~38% in feces) Plasma: parent drug. Urine: little or no parent drug; multiple major metabolites. Feces: unchanged parent drug and numerous low-abundance metabolites.

CL-009 Open-label, single-dose, food effects

50 and 200 32

Based on Preliminary results:

Well tolerated; no dose-limiting AEs

In the presence of high fat, high calorie diet, Cmax and AUC of the 50-mg dose increased 1.40-fold and 1.45-fold respectively, whereas for the 200-mg dose, Cmax increased 1.76-fold and AUC increased 1.88-fold.


Page 38 of 142



Phase II

CL-007 Partially double-blinded (blinded as to PA-824 dose), 14-day multidose, extended early bactericidal activity

200, 600, 1000, 1200 69 Overall well tolerated with relatively few AEs and no dose-limiting AEs or laboratory findings. No clinically significant effects on ECG, vitals, or PE noted.

Two SAEs occurred during study, both were considered possibly related to TB disease (hemoptysis).

PA-824 treatment produced a measurable decrease in log CFU, with the magnitude of effect equivalent for all doses.

CL-010 Partially double-blinded (blinded as to PA-824 dose), 14-day multidose, extended early bactericidal activity

50, 100, 150, 200 69 Based on Preliminary results:

Well tolerated.

PA-824 treatment produced a measurable decrease in log CFU with some evidence of dose dependence.

ADME = absorption, distribution, metabolism, excretion; AE = adverse events; BUN = blood urea nitrogen; ECG = electrocardiogram; ERPF = effective renal plasma flow; F = female; FF = filtration fraction; GFR = glomerular filtration rate; hr = hour; M = male; PD = pharmacodynamics; PE = physical exam; SAE = serious adverse event; UA = uric acid.


Page 39 of 142

Phase I

In these trials, PA-824 has been administered in doses ranging from 50 to 1500 mg as 50 or 200 mg

tablets or as an oral suspension. PK parameters have largely been consistent in each study and can

be summarized as follows:

PA-824 is moderately rapidly absorbed, with median Tmax values across subjects and dose

levels ranging from 4 to 7 hours.

The mean half-life for elimination (t½) across subjects and dose levels was approximately 16

- 25 hours.

Exposure increased approximately linearly but less than dose-proportionally, with increasing

doses up to approximately 600 – 1000 mg, while higher doses achieved minimal additional

increases in either Cmax or AUC.

Two studies using radiolabeled PA-824 in an oral-suspension formulation have been conducted to

investigate the metabolism and excretion patterns of PA-824 in humans: Study PA-824-CL-004,

which used [benzyl-14C] PA-824 and Study PA-824-CL-008, which used [imidazooxazine-14C]PA-824.

The mass balance results from the two studies were very similar. In each study, the majority (53-

65%) of radioactivity was excreted in the urine; an additional 26-38% was collected in the feces

such that approximately 91% of the administered dose was ultimately recovered in the excreta.

Radioprofiling and metabolite ID work have been completed on samples from the two human

studies as well as from analogous work in rat and monkey using both radiolabeled PA-824

preparations. The metabolism of PA-824 proceeds via a combination of reductive metabolism (~20

– 25% of the dose) and oxidative metabolism (remainder of the characterized metabolites). The

metabolic profile of PA-824 in vivo was qualitatively similar in the three species, with quantitative

differences being minor. No human unique metabolites were detected and there is no one single

metabolic path that can be considered major. Furthermore, there are no major metabolites in

human plasma.

Study PA-824-CL-006, a drug-drug interaction study with midazolam to assess the extent of CYP3A

inhibition by PA-824, also recently completed and a complete analysis is pending. Preliminary

results indicate that dosing of PA-824 400 mg once daily for 14 days did not have a major effect on

the exposure of midazolam or its major metabolite 1-hydroxy midazolam. For midazolam, the

geometric mean ratio of Day 17 (midazolam+PA-824) vs. Day 1 (midazolam alone) for Cmax was


Page 40 of 142

0.84 and AUC was 0.85. For the 1-hydroxy midazolam metabolite, the corresponding geometric

mean ratio for Cmax was 1.05 and AUC was 1.11. The data suggests that PA-824 should not cause

clinically significant drugs interactions with drugs metabolized by CYP3A. No drug-drug interaction

is anticipated between PA-824 and TMC207 or pyrazinamide or moxifloxacin.

Study PA-824-CL-009, a food effects study using lower doses of PA-824 (200 mg and 50 mg),

recently completed and a complete analysis is pending. Preliminary results indicate that the food

effect observed is dependent on the PA-824 dose administered. When a single dose of PA-824 was

administered with a high fat, high calorie meal, Cmax and AUC of the 50 mg dose increased 1.40-

fold and 1.45-fold respectively, whereas for the 200 mg dose, Cmax increased 1.76-fold and AUC

increased 1.88-fold.

Phase II

Study PA-824-CL-007 examined the effects of 14 days’ treatment with PA-824 monotherapy at

doses ranging from 200 to 1200 mg/day on TB participants’ lung bacterial load measured as logCFU

(log of Colony Forming Units) in the sputum. Four groups of approximately 15 men and women

received 200, 600, 1000, or 1200 mg/day PA-824. An additional group of eight participants

received the standard South African 4-drug combination TB treatment (Rifafour® e-275, comprised

of a fixed-dose combination of isoniazid, rifampin, pyrazinamide and ethambutol). This group was

included to provide control for the microbiological techniques used to measure lung TB bacterial

burden. The efficacy data from this study indicated that all doses of PA-824 including the lowest

dose, 200 mg, produced a measureable and equivalent decrease in sputum CFU counts over the 14-

day treatment period; no difference could be discerned among the PA-824 treatment groups

(Figure 1).


Page 41 of 142

Figure 1 PA-824-CL-007 Mean Group logCFU Values Over Time

Study PA-824-CL-010, an EBA study with a similar design to study PA-824-CL-007 except for the use

of lower doses of PA-824 (50, 100, 150 or 200 mg/day), is in the post-treatment follow-up phase.

Preliminary results indicate that PA-824 treatment resulted in a measurable dose-dependent

mycobactericidal activity.

Clinical Safety

The overall safety profile determined from the clinical studies indicates PA-824 is well tolerated in

both healthy adults and TB patients. Single doses ranging from 50 to 1500 mg in men and daily

doses in men and women up to 1200 mg for up to 14 days were well tolerated and resulted in

generally minor adverse events (AEs). Approximately 80% of AEs were mild, with most of the

remainder as moderate. Among healthy volunteers dosed to date, one severe AE and no serious

adverse events (SAEs) have been observed. Among TB patients dosed with PA-824, one severe AE

and one SAE were observed.

Across the Phase I studies, headache was the most common AE recorded, occurring at least once

during study confinement in up to 80% of PA-824 subjects, as compared with up to 30% of placebo

subjects. Headache occurrence was typically higher in studies with longer confinement periods.


Page 42 of 142

Other common AEs associated with PA-824 treatment include elevated serum creatinine and

stomach discomfort (including nausea and other gastrointestinal symptoms such as flatulence

and/or diarrhea). Stomach discomfort AEs were the most commonly reported AEs in the PA-824-

CL-007 Phase IIa study of TB patients. For the multidose, placebo-controlled Studies PA-824-CL-

002, PA-824-CL-005 and PA-824-CL-007, overall AE frequency tended to be greater among PA-824

subjects than among placebo subjects, and tended to be higher in higher PA-824 dose groups.

Study PA-824-CL-005 was undertaken to determine the mechanism responsible for the elevation in

serum creatinine seen with PA-824 dosing in studies PA-824-CL-001 and PA-824-CL-002. This study

explored the effects of PA-824 on kidney function by measuring glomerular filtration rate (GFR),

effective renal plasma flow (ERPF), filtration fraction (FF, calculated as GFR/ERPF), and creatinine

clearance. Subjects were dosed in blinded fashion with placebo, 800 mg PA-824, or 1000 mg

PA-824 for 8 days. Serum creatinine levels rose in both the 800- and 1000-mg/day PA-824 groups,

by an average of 0.18 mg/dL (19%) and 0.25 mg/dL (27%) in the two groups respectively by Day 8;

the largest individual increase was approximately 40% over baseline. In this study, although serum

creatinine levels rose, no meaningful effects were noted during the dosing period on GFR, ERPF,

BUN, uric acid or FF. As expected, creatinine clearance was reduced concomitantly with maximally

elevated serum creatinine levels relative to baseline. Taken together, these results indicate that

PA-824 does not negatively affect renal function. Instead, the drug can be assumed to cause its

effects on serum creatinine by inhibiting tubular creatinine secretion; such an effect has been

reported with other approved drugs (e.g. cimetidine) and is not considered clinically significant.

Across all studies, the great majority (>~95%) of AEs resolved without sequelae. In Study PA-824-

CL-003, one subject concluded the study with blurry/double vision that may have been related to

childhood strabismus, while another subject had ongoing swollen fingers on both hands at the end

of the study. In Study PA-824-CL-007, two patients exited the study with an ongoing AE (anemia

[mild, unrelated] and rash [mild, related]) and the outcomes for three AEs in one patient each

(anemia [mild, possibly related], elevated LFT [moderate, unrelated], and Wolff-Parkinson-White

syndrome [mild, unrelated] were not known due to loss to follow-up. In Study PA-824-CL-005, one

subject treated with 800 mg PA-824 was discharged with three ongoing AEs (proteinuria [nephrotic

range during the study, but non-nephrotic range in follow-up], hypoalbuminemia, and iron

deficiency). The proteinuria and hypoalbuminemia were moderate in severity and the iron

deficiency was mild. This subject has substantially improved, and the subject is being seen


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periodically by a nephrologist and by trial site staff. A renal biopsy performed 20 months post-

study revealed focal segmental glomerulosclerosis likely secondary type, although the subject

remains fundamentally healthy with normal renal function indices and no signs of peripheral edema

or hypertension. A complete review of her screening and check-in lab values suggests in the

opinion of the Sponsor that she might have had a preexisting undiagnosed clinical condition

including atypical lipid profile, BUN below the lower limit of the normal range, and ALT and AST

above the upper limit of normal range. Furthermore, her eosinophil count was above-normal at

Screening at 6.7% and progressively rose during the study to 8.9% by Day 15 and she reported a

personal and family history of allergies and rhinorrea. The PI considered this individual normal and

meeting the protocol entry criteria, and enrolled this subject.

Among the healthy volunteers tested, any concomitant therapy for AEs was generally palliative in

nature. Occasionally, pains such as headaches, sore throat, and muscle ache were treated with

analgesics. One instance of iron deficiency (deemed not related to study drug) was treated with an

iron supplement. In Study PA-824-CL-007, multiple AEs, most of which were associated with

ongoing TB disease, were treated with medications or other interventions including hospitalization

(e.g., to treat hemoptysis).

In most of the completed Phase I studies, no subjects discontinued from the study as a result of

AEs. In Study PA-824-CL-002, dosing for all subjects in the 1000 mg dose group was discontinued

on Day 5 in response to rising serum creatinine levels. In Study PA-824-CL-005, one subject was

discontinued for safety reasons in relation to a severe rash that developed approximately 32 hours

after the 8th and last dose of PA-824 (1000 mg). The rash symptoms were treated with

diphenhydramine, prednisone, and hydroxyzine at various points during the ensuing approximately

9 days until the symptoms completely resolved. In Study PA-824-CL-007, two patients (one in the

200 mg/day PA-824 group and one in the control arm) were discontinued as a result of disease-

related hemoptysis. Each of these events was classified as an SAE, both resolved with treatment in

hospital and neither was considered possibly related to the study drugs.

Post-study follow-up ophthalmic examinations have been performed on subjects and patients

enrolled in two studies where participants received the highest doses of PA-824 for the longest

duration among the clinical studies conducted to date. Male and female healthy volunteers were


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treated at doses up to 1000 mg/day for 8 days in Study PA-824-CL-005, and male and female TB

patients were treated at doses up to 1200 mg/day for 14 days in Study PA-824-CL-007.

For Study PA-824-CL-005, 30 of the randomized 47 subjects have been examined with no cataracts

being detected in any subject. For Study PA-824-CL-007, 46 of the 69 randomized patients received

post-study ophthalmic examinations and two were found with single, asymptomatic, unilateral

cataracts. One of these was among the 12 patients from the 1200 mg group who returned for the

eye examination; the other was from among the 5 patients from the control TB regimen (Rifafour®)

group who returned for the eye examination. For the PA-824 patient, the cataract was judged by

an external, independent ophthalmology review board (ORB) to be most consistent with an age-

related cataract based on the patient’s age (52 years at time of ophthalmologic examination) and

the unilateral nature of the cataract. Furthermore, the ORB has determined that there is no

evidence of an association between PA-824 exposure and cataracts in humans when PA-824 is

administered at the doses used and in the populations studied in the clinical studies completed to

date. The ORB recommended that slit-lamp eye exams (including at baseline) be incorporated into

future studies of PA-824. An additional expert clinical ophthalmologist also recommended for

future studies that ocular examinations be performed at baseline, and 3 to 6 months after dosing

for studies less than 12 weeks in duration. For studies of 12 or more weeks in duration, this

evaluation should be conducted at baseline, end of dosing and 3 to 6 months after dosing. The TB

Alliance intends to follow these guidelines in this study.

2.3.3. Moxifloxacin

Moxifloxacin has been approved in South Africa and most other countries around the world for the


community-acquired pneumonia, skin and soft tissue infections. An extensive clinical program

supports the safety and efficacy of 400 mg moxifloxacin given once daily for 5 to 21 days in adults

for the above specified indications. For more detailed information, please refer to the IB for

Moxifloxacin (34).

Moxifloxacin is commonly used as second line therapy for TB in patients (e.g., MDR- TB), and has

also been evaluated in several clinical studies of patients with TB, including four 8-week treatment

period phase IIb studies (see Table 3 below).


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Table 3 Summary of Phase IIb studies in which moxifloxacin was administered as part of a four-drug regimen during the intensive phase of treatment (total treatment duration: 2 months)

Study Sponsor Design Objectivea Patients

N Countries Status

Study 27 Tuberculosis Trials

Consortium (TBTC)

Randomized, double-blind,

controlled

To compare the sputum culture-conversion rate at the end of the 4-drug (intensive) phase of therapy using the standard 4-drug regimen

HRZE with a standard regimen with M replacing E.

336 USA, Canada, Uganda,

South Africa

Completed

OFLOTUB Study

South African Medical

Research Council

Randomized, Open label,

Controlled

To compare the bactericidal activities of regimens where gatifloxacin, M, and ofloxacin

were substituted for E in the 2-month initial phase of standard

TB treatment with HRZE.

217 South Africa

Completed

Johns Hopkins (FDA orphan drug) Study

Johns Hopkins

University & FDA orphan

drugs program


Controlled

To compare the sputum culture conversion rate at the end of the 4-drug (intensive)

phase of therapy using a standard 4-drug regimen

(HRZE) with a regimen with M replacing E (HRZM).

170 Brazil Completed

Study 28 Tuberculosis Trials

Consortium (TBTC) /CDC


Controlled

To compare the culture-conversion rate at the end of

the 4-drug (intensive) phase of therapy using a standard 4-drug regimen (HRZE 5 days

per week) with a regimen with M replacing H (MRZE 5 days

per week).

433 USA, Canada, Brazil, Spain,

Uganda, South Africa

Completed

aH = isoniazid; R = rifampin; E = ethambutol; Z = pyrazinamide; M = moxifloxacin

In Study 27 (23), the moxifloxacin-containing TB regimens (HRZM) were shown to be safe and well

tolerated. There was no difference in SAEs between the HRZM and HRZE treatment arms, and most

SAEs were hospitalizations thought to be unrelated to the study treatment. Patients treated with

moxifloxacin-containing regimen were more likely to report nausea (22% vs. 9%, p = 0.002), but this

was generally mild and did not lead to treatment discontinuation as similar proportions of patients

in both groups completed study drug treatment (88% HRZM-treated vs. 89% HRZE-treated). The

one death during the first 2 months of treatment was thought to be caused by pulmonary

embolism, unrelated to tuberculosis therapy.

In the OFLOTUB study (24), AEs and SAEs occurred with equal frequency in the four treatment arms.

The most frequent AEs were raised amylase (in 41% of patients due to HIV infection), raised

transaminase (10%), arthralgia (9%), anemia (7%), hypokalaemia (6%) and vomiting (5%). No

patient was withdrawn from the study due to an adverse event. There were 4 deaths in the study:

2 in the control group, 1 each in the moxifloxacin and ofloxacin arms. Importantly, patients in this


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study who received moxifloxacin and pyrazinamide in addition to isoniazid and rifampin had more

rapid sputum clearance than patients on the four standard first line drugs (isoniazid, rifampin,

pyrazinamide and ethambutol). This difference was evident 14 days after initiation of treatment.

In the JHU Study (25), AEs did not differ by treatment group. There were 16 SAEs (8 in each group) in

12 patients. Only 1 event was judged related to study drug (grade 3 cutaneous reaction in the

ethambutol group). Eight patients died during the study, including 1 in each group still receiving

study phase treatment. No death was attributed to study treatment. Only 5 patients discontinued

treatment because of toxic effects; 2 patients in the moxifloxacin group stopped because of grade 2

nausea and vomiting and 1 because of grade 2 paraesthesias and ataxia. Two patients in the E

group stopped because of grade 2 rash and pruritis and 1 because of grade 3 peripheral

neuropathy. There was no change in the QTc interval on serial electrocardiograms taken during the

trial.

In Study 28 (26), the proportions of patients with SAEs during intensive phase treatment were similar

between arms (isoniazid 3.9% vs. moxifloxacin 4.2%; P = 0.88). Three SAEs attributed to study

treatment during the first 2 months occurred among the moxifloxacin group and two in the

isoniazid group. Seven patients died during the study including 3 patients receiving the

moxifloxacin treatment regimen and 4 patients receiving the isoniazid treatment regimen. All 3

moxifloxacin patients died during intensive phase TB treatment. Two patients died from advanced

pulmonary TB judged not related to study treatment and 1 subject (who developed diabetic

ketoacidosis considered possibly related to study treatment) died from possible acute pulmonary

embolus unrelated to study treatment. The 4 isoniazid deaths occurred during continuation phase,

and all 4 were considered unrelated to study treatment. Nausea was more common among

patients in the moxifloxacin arm than in the isoniazid arm (19.6% vs. 11.7%, respectively; P = 0.03)

although similar proportions reported vomiting. However, the proportions of patients with

hepatitis, defined as serum AST 3 times or greater than the upper limit of normal, were similar

between treatment arms during intensive phase (isoniazid 3.4% vs. moxifloxacin 3.3%; P = 0.93).

For additional information on moxifloxacin, refer to the IB(34) and the manufacturer’s package insert

(Appendix 7).


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2.4. Known and Potential Risks and Benefits of the Investigational Medicinal Product (IMP) used

in the Study

2.4.1. TMC207

In the clinical studies conducted to date, a total of 173 healthy volunteers and 68 TB patients have

taken TMC207. Multiple dosing has extended for as long as 8 weeks. The most common side

effects or AEs observed across these studies are described above (Section 2.3.1), and most of them

were considered to be not or doubtfully related to TMC207.

2.4.2. PA-824

In the nine clinical studies completed to date, a total of 149 healthy volunteers and 61 TB

participants have taken PA-824. Multiple dosing has extended for as long as 14 days. As described

above (section 2.3.2), the most common side effects or AEs associated with PA-824 exposure

include:

Headache

Benign, isolated and reversible elevations of serum creatinine

Stomach discomfort (nausea, vomiting, flatulence, and/or diarrhea)

Post-study follow-up ophthalmic examinations have been performed on subjects and patients

treated at doses up to 1000 mg/day for 8 days in Study PA-824-CL-005, and male and female TB

participants treated at doses up to 1200 mg/day for 14 days in Study PA-824-CL-007. An

independent Ophthalmology Review Board concluded there was no evidence from these two

studies that PA-824 caused cataracts in humans. In addition, because exposures at the dose

planned for this study (200 mg/day) are anticipated to be lower than those associated with cataract

formation in rats (and substantially lower than exposures associated with cataracts in one monkey

study - a finding that could not be repeated in a more carefully conducted repeat monkey

toxicology study), the TB Alliance believes that the dose selected for the present study (200 mg/day

PA-824) does not represent a significant risk of cataract formation for participants enrolled into the

present study. For additional information, please refer to pages 40-47 and 133-134 in the PA-824 IB

(13).

2.4.3. Moxifloxacin

In the usual daily doses of 400 mg/day, moxifloxacin is well tolerated. As stated in the IB (34) (Table

5-41, pp 136-142), the most frequent individual drug related AEs observed in clinical studies with


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400 mg oral moxifloxacin therapy were nausea and vomiting (8.2%) and diarrhea (4.9%). In

addition, moxifloxacin has been shown to prolong the QT interval of the electrocardiogram in some

patients. It should be used with caution in patients being treated concomitantly with other drugs

where an additive effect on the QT interval cannot be excluded.

2.4.4. Pyrazinamide

The doses of pyrazinamide that will be used in this study are those approved for the treatment of

TB *manufacturer’s package insert (Appendix 6)+. Pyrazinamide is mostly metabolized by the liver

and 3 to 4% of the administered dose is excreted unchanged by the kidneys.

The most serious side-effect is hepatotoxicity and its frequency appears to be dose-related.

Hyperuricemia commonly occurs, occasionally accompanied by arthralgia and may lead to attacks

of gout. Photosensitivity and skin rash have been reported less frequently. Other side-effects that

have been reported are anorexia, nausea and vomiting, malaise, fever, sideroblastic anemia and

dysuria. Pyrazinamide may decrease the efficacy of gout therapy (e.g. allopurinol, colchicine,

probenecid or sulphinpyrazone) and dosage adjustments of these medications may be necessary.

For additional information on pyrazinamide, refer to the manufacturer’s package insert (Appendix

6).

2.4.5. Standard, first-line TB treatment

Patients in the control group (control for Mycobacteriology laboratory methodology) will receive

standard, intensive phase pulmonary TB treatment as recommended in the SA National TB

Treatment Guidelines, which is RHZE 150/75/400/275 mg oral daily (Rifafour e-275) (R=rifampicin:

H=isoniazid: Z=pyrazinamide: E=ethambutol).

Please see the Rifafour e-275 Package Insert for its known and potential risks and benefits

(Appendix 2).

3. TRIAL RATIONALE AND OBJECTIVES

3.1. Trial Rationale

TMC207 and PA-824, new chemical entities with significant promise for shortening treatment of

active TB, have been under development for several years, and entered clinical trials in 2005. This

study will be the third study of each of these compounds in drug sensitive TB patients. As described

above, several studies of TMC207 and PA-824 have also been conducted previously in healthy

volunteers. Collectively, these studies in patients and healthy subjects have defined the efficacy,


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safety and pharmacokinetic features of the drugs. Overall, TMC207 and PA-824 have

mycobactericidal activity in participants and are well tolerated and bioavailable after oral dosing.

Moxifloxacin is an approved drug for several indications and while not approved for TB, it is

regularly used in second line TB treatment. In addition, it is currently in late stage clinical

development for first-line TB treatment in combination with other TB drugs, including

pyrazinamide.

As previously stated, data from preclinical studies suggest that a regimen consisting of TMC207 and

pyrazinamide, TMC207 and PA-824, PA-824 and pyrazinamide or PA-824, pyrazinamide and

moxifloxacin may not only be appropriate for treating both drug-sensitive and MDR-TB but may

also shorten duration of therapy. The main purpose of this study is to determine whether these

combinations are as bactericidal in man as has been demonstrated in the mouse model of TB

(12,28,29). The dose of TMC207 for the current EBA study was selected to provide an average target

plasma concentration of ~2000 ng/mL to maximize TMC207’s mycobactericidal activity; the dose of

PA-824 selected for this study is based on data from two dose-ranging EBA studies; the currently

approved dose of pyrazinamide will be used, as will the approved dose of moxifloxacin (for other

indications; 400 mg per day), which is also the dose being evaluated in the ongoing Phase III clinical

TB trial.

EBA studies measure the time- and dose-dependent decline of viable bacteria in the patient's

expectorated sputum. Measuring the extended EBA of a new agent or regimen in TB patients is an

accepted method of determining mycobactericidal activity. In addition, these studies allow the

opportunity to characterize safety and tolerability profile in patients prior to evaluation in longer-

term studies.

Participants will not be exposed to undue risk in the proposed study. TMC207 has been used in TB

patients for up to 14 days at the 400-mg dose. (33) The proposed dosing regimen for this study is

being used in an ongoing 14-day EBA study in South Africa and preliminary results indicate that it is

well tolerated and produced significant mycobactericidal activity with no TMC-related SAEs. PA-

824 has been used in TB patients for up to 14 days at doses (up to 1200 mg) much higher than what

is being proposed (200 mg); 400 mg moxifloxacin per day has been used in TB patients for up to

four months, while pyrazinamide is approved for TB treatment and is used for 8 or more weeks

depending on whether drug-sensitive or drug-resistant TB patients are being treated. Moxifloxacin

and pyrazinamide are being co-administered to TB patients for 4 months in the phase III TB

moxifloxacin trial and are often co-administered to MDR-TB patients in clinical practice for even


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longer periods. This will be the first clinical study where PA-824 will be used in combination with

moxifloxacin or TMC207. Although preliminary results from the preclinical safety pharmacology

study conducted with PA-824 plus moxifloxacin in monkeys and PA-824 plus TMC207 in dogs do not

suggest the potential for a marked QT prolongation in humans (see pages 24-26), there will be daily

ECG safety monitoring of all study participants timed to approximate the Cmax for moxifloxacin,

TMC207 and PA-824 (Flow chart, page 18). In addition, study participants on PA-824 containing

treatment arms (PA-824 + Z and PA-824 + Z + M) will have intensive ECG monitoring on Day 1 (first

day of dosing) and Day 8 (midway through the study ensuring attainment of steady state for PA-

824) as well as time matched baseline ECGs on Day -1. Finally, specific discontinuation criteria

based on QT prolongation are listed in section 9.7 (page 96).

All participants will remain under constant medical attention and will be housed and monitored in

hospital from check-in through the duration of the treatment period; this will allow a continuous

monitoring of the health conditions of each participant, any of whom can be withdrawn at any

stage of the trial and removed from study treatment should his/her condition suggest to the

Investigator that this would be in his/her best interest. Upon discharge, the participants will be

given initial doses of standard TB treatment and immediately referred to the national TB treatment

program local TB clinic. The Investigators’ primary responsibility is to ensure participant safety.

Information gained in this study will provide critical insight into the efficacy, safety and

pharmacokinetic profile of the indicated drug combinations, as well as their suitability for further

evaluation in longer-term clinical trials.

3.2. Trial Objectives

To evaluate the early bactericidal activity (EBA), safety, tolerability and pharmacokinetics of

TMC207 alone, TMC207 plus pyrazinamide, TMC207 plus PA-824, PA-824 plus pyrazinamide and

PA-824 plus pyrazinamide and moxifloxacin, administered orally as once daily doses for 14

consecutive days, in adult patients with newly diagnosed, smear positive pulmonary tuberculosis, in

order to help select appropriate combination therapies for later stage clinical development.

3.3. Trial Endpoints

3.3.1. Primary Endpoint


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The EBA (EBA0-14) as determined by the rate of change in logCFU per ml sputum over the period

Day 0 to Day 14 which may be described with linear, bi-linear or non-linear regression of logCFU on

time.

3.3.2. Secondary Endpoints

3.3.2.1. Efficacy

S econdary Efficacy Endpoints:

The EBA (EBA0-2, EBA2-14 and EBA7-14) as determined by the rate of change of logCFU in

sputum over the period Day 0 to Day 2, Day 2 to Day 14 and Day 7 to Day 14, in participants,

which may be described with linear, bi-linear or non-linear regression of logCFU on time.

The time to sputum culture positivity (TTP) (TTP0-2, TTP0-14, TTP2-14, and TTP7-14) in the

Mycobacterial Growth Indicator Tube (Bactec MGIT960) system as determined by the rate of

change in TTP in sputum over the periods Day 0 to Day 2, Day 0 to Day 14, Day 2 to Day 14 and

Day 7 to Day 14 in participants, which may be described with linear, bi-linear or non-linear

regression of TTP on time.

3.3.2.2. Safety and Tolerability

The proportion of participants with adverse events and proportion of participants who discontinue

due to an adverse event in each experimental arm. These data will be presented as descriptive

analyses, and no inferential tests will be carried out.

3.3.2.3. Pharmacokinetics

For participants in the TMC207 (excluding TMC207 plus PA-824 containing treatment

arm)containing treatment arms:

The following PK parameters will be estimated for TMC207, TMC207 metabolite M2 and

pyrazinamide on Day 14 only: the maximum observed plasma concentration (Cmax), the minimum

observed plasma concentration 24 hours following the last dose (Cmin), time to reach Cmax (Tmax),

area under the plasma concentration time (t) curve from zero to 24 hours (AUC(0-24). These data

will be presented as descriptive analyses, and no inferential tests will be carried out.

For participants in the PA-824 (excluding TMC207 plus PA-824 containing treatment arm)

containing treatment arms:


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The following PK parameters will be estimated for PA-824, pyrazinamide and moxifloxacin on Days

1, 8 and 14: the maximum observed plasma concentration (Cmax), the minimum observed plasma

concentration 24 hours following the last dose (Cmin), time to reach Cmax (Tmax), area under the

plasma concentration time (t) curve from zero to 24 hours (AUC(0-24)). These data will be

presented as descriptive analyses, and no inferential tests will be carried out.

For participants in the TMC207 plus PA-824 containing treatment arms:

The following PK parameters will be estimated for PA-824, TMC207 and TMC207 metabolite M2 on

Day 14 only: the maximum observed plasma concentration (Cmax), time to reach Cmax (Tmax), the

minimum observed plasma concentration (Cmin) 24 hours following the last dose, area under the

plasma concentration time (t) curve from zero to 24 hours (AUC(0-24)). These data will be

presented as descriptive analyses, and no inferential tests will be carried out.

No pharmacokinetic sampling is planned on participants receiving Rifafour e275®.

3.3.2.4. Pharmacokinetics-Pharmacodynamics (PK-PD)

For TMC207 and PA-824 containing treatment arms, the following will be estimated for TMC207,

PA-824, pyrazinamide and moxifloxacin, as appropriate per the above PK analyses performed:

The EBAs vs. the following PK variables (Day 14 only) will be presented:

Cmax;

AUC(0-24);

Time over Minimum inhibitory concentrations (MIC) (for TMC207, PA-824 and moxifloxacin).

These data will be presented as descriptive analyses, and no inferential tests will be carried out.

3.3.2.5. Extent of QT Prolongation

For TMC207 and PA-824 containing treatment arms, the potential correlations between the plasma

concentration of IMP and the change from baseline of QT interval corrected by Fridericia’s method

(QTcF) and change from baseline of QT interval corrected by Bazett’s method (QTcB) with respect

to time for the different treatment groups will be explored. These data will be presented as

descriptive analyses, and no inferential tests will be carried out.

3.4. Mycobacteriological Characterization


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In order to characterize the participants’ infecting mycobacterium, with respect to species and TB

drug-sensitivity, and to determine the in vitro potency of each infecting strain with respect to each

treatment and Rifafour e-275® once daily, for 14 days, the overnight sputum collections from

Day -2 and Day 14 will be assessed as follows:

MIC of TMC207, PA-824 and moxifloxacin;

Drug susceptibility testing of the M. tuberculosis isolates with the MGIT system for sensitivity to

isoniazid, rifampicin, ethambutol and pyrazinamide;

Speciation of the infecting organism by polymerase chain reaction (PCR).

3.5. Participant Inclusion/Exclusion Criteria

3.5.1. Inclusion Criteria

Participants are required to meet all of the following inclusion criteria in order to be randomized.

1. Provide written, informed consent prior to all trial-related procedures including HIV testing.

2. Male or female, aged between 18 and 65 years inclusive.

3. Body weight (in light clothing and with no shoes) between 40 and 90 kg, inclusive.

4. Newly diagnosed, previously untreated, sputum smear-positive pulmonary TB.

5. A chest X-ray picture which in the opinion of the Investigator is compatible with TB.

6. Sputum positive on direct microscopy for acid-fast bacilli (at least 1+ on the IUATLD/WHO

scale (Appendix 3)).

7. Ability to produce an adequate volume of sputum as estimated from a spot assessment

(estimated 10 ml or more overnight production).

8. Females may participate if they are: 1) of non-childbearing potential (have had a bilateral

oophorectomy and/or hysterectomy or have been postmenopausal for at least 12

consecutive months), 2) if they are using effective birth control methods and are willing to

continue practicing birth control methods throughout treatment or 3) be non-

heterosexually active, practice sexual abstinence or have a vasectomized partner (confirmed

sterile). Therefore to be eligible for this study women of childbearing potential should

either: 1) use a double barrier method to prevent pregnancy (i.e. use a condom with either

diaphragm or cervical cap) or 2) use hormonal based contraceptives in combination with a

barrier contraceptive, or 3) use an intrauterine device in combination with a barrier

contraceptive. They must also be willing to continue these contraceptive measures until 6


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months after the last dose of study medication or 6 months after discontinuation from study

medication in case of premature discontinuation. (Note: Hormone-based contraception

alone may not be reliable when taking IMP; therefore, hormone-based contraceptives alone

cannot be used by female participants to prevent pregnancy).

9. Male participants who are having heterosexual intercourse with females of child-bearing

potential are required to use one of the following birth control methods during their

participation in the trial and for 12 weeks after their last dose of study medication to

prevent pregnancy:

- a double barrier method which can include a male condom, diaphragm, cervical cap,

or female condom; or

-a barrier method combined with hormone-based contraceptives or an intra-uterine

device for the female partner.

The use of the above mentioned birth control method does not apply if the male participant

has been vasectomised or has had a bilateral orchidectomy minimally one month prior to

screening, or is not heterosexually active, or practice sexual abstinence or if the female

sexual partner has had a bilateral oophorectomy and/or hysterectomy or has been

postmenopausal for at least 12 consecutive months.

3.5.2. Exclusion Criteria

Participants will be excluded from participation if they meet any of the following criteria.

Medical History

1. Evidence of clinically significant (as judged by the investigator), metabolic, gastrointestinal,

cardiovascular, musculoskeletal, ophthalmological, pulmonary, neurological, psychiatric or

endocrine diseases, malignancy, or other abnormalities (other than the indication being

studied).

2. Poor general condition where any delay in treatment cannot be tolerated per discretion of

the Investigator.

3. A history of previous TB.

4. Clinically significant evidence of extrathoracic TB (miliary TB, abdominal TB, urogenital TB,

osteoarthritic TB, TB meningitis), as judged by the Investigator.


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5. History of allergy to the IMP or related substances, including a known allergy to any

fluoroquinolone antibiotic, history of tendinopathy associated with quinolones or suspected

hypersensitivity to any rifamycin antibiotics.

6. Isoniazid-resistant and/or Rifampicin-resistant bacteria detected with a sputum specimen

collected within the pre-treatment period and tested at the study laboratory.

7. Known or suspected, current or history of within the past 2 years, alcohol or drug abuse,

that is, in the opinion of the Investigator, sufficient to compromise the safety or cooperation

of the participant.

8. HIV infected participants:

a. having a CD4+ count <300 cells/µL;

b. or having received antiretroviral therapy medication within the last 90 days;

c. or having received oral or intravenous antifungal medication within the last 90 days;

d. or with an AIDS-defining opportunistic infection or malignancies (except pulmonary TB).

9. Having participated in other clinical studies with investigational agents within 8 weeks prior

to trial start.

10. Significant cardiac arrhythmia requiring medication.

11. Participants with the following at screening. Where applicable to ECGs, the central

cardiologists reading must be used:

a. Marked prolongation of QT/QTc interval, e.g., confirmed demonstration of QTcF (Fridericia

correction) or QTcB (Bazett correction) interval >450 ms at screening;

b. History of additional risk factors for Torsade de Pointes, e.g., heart failure, hypokalemia,

family history of Long QT Syndrome;

c. Use of concomitant medications that prolong the QT/QTc interval (see exclusion criterion

22 as well as list of disallowed medication in Section 4.7.2);

d. Pathological Q waves (defined as >40ms or depth >0.4-0.5mV);

e. ECG evidence of ventricular pre-excitation;

f. ECG evidence of complete or incomplete left bundle branch block or right bundle branch

block;

g. ECG evidence of second or third degree heart block;

h. Intraventricular conduction delay with QRS duration >120ms;

i. Bradycardia as defined by sinus rate <50bpm.


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12. Females who are pregnant, breast-feeding, or planning to conceive a child within 6 months

of cessation of treatment.

13. Males planning to conceive a child within twelve weeks of cessation of treatment.

14. History and/or presence (or evidence) of neuropathy or epilepsy.

15. Diabetes Mellitus requiring insulin.

16. History of lens opacity or evidence of lens opacity on slit lamp ophthalmologic examination.

17. For males, any evidence or history of a clinically significant abnormality in the reproductive

system, including but not limited to the following: serum testosterone, luteinizing hormone

(LH), and/or follicle-stimulating hormone (FSH) levels outside the laboratory reference

range. An evaluation resulting in an isolated abnormal value (i.e., only 1 of the 3 hormones

is abnormal) may be repeated using a morning (ideally, 8am) serum specimen. If the

laboratory value on the repeat specimen is outside the laboratory reference range, unless

the result is deemed not clinically significant by the Investigator in consultation with the

Sponsor Medical Monitor, the participant should be excluded.

Specific Treatments

18. Previously received treatment with TMC207 or PA-824 as part of a clinical trial.

19. Treatment received with any drug active against MTB within the 3 months prior to Visit 1

(e.g. isoniazid, ethambutol, amikacin, cycloserine, rifabutin, rifampicin, streptomycin,

kanamycin, para-aminosalicylic acid, rifapentine, pyrazinamide, thioacetazone,

capreomycin, fluoroquinolones, thioamides, metronidazole).

20. Any diseases or conditions in which the use of the standard TB drugs or any of their

components is contra-indicated, including but not limited to allergy to any TB drug, their

component or to the IMP.

21. Any disease or conditions in which any of the medicinal products listed in the section

pertaining to prohibited medications is used.

22. Concomitant use of any drug known to prolong QTc interval (including amiodarone, bepridil,

chloroquine, chlorpromazine, cisapride, clarithromycin, disopyramide dofetilide,

domperidone, droperidol, erythromycin, halofantrine, haloperidol, ibutilide, levomethadyl,

mesoridazine, methadone, pentamidine, pimozide, procainamide, quinidine, sotalol,

sparfloxacin, thioridazine). The exception is moxifloxacin which is one of the drugs being

evaluated in this study, with extensive ECG monitoring to help ensure patient safety.




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23. Use of any drugs or substances within 30 days prior to dosing known to be strong inhibitors

or inducers of cytochrome P450 enzymes (such as quinidine, tyramine, ketoconazole,

testosterone, quinine, gestodene, metyrapone, phenelzine, doxorubicin, troleandomycin,

cyclobenzaprine, erythromycin, cocaine, furafylline, cimetidine, dextromethorphan).

Exceptions may be made for participants that have received 3 days or less of one of these

drugs or substances, if there has been a wash-out period before administration of IMP

equivalent to at least 5 half-lives of that drug or substance.

24. Use of any therapeutic agents known to alter any major organ function (e.g., barbiturates,

opiates, phenothiazines, cimetidine) within 30 days prior to dosing.

25. Use of systemic glucocorticoids within one year prior to dosing.

Based on Laboratory Abnormalities

26. Participants with the following toxicities at screening as defined by the enhanced Division of

Microbiology and Infectious Disease (DMID) adult toxicity table (November 2007) (Appendix

4):

a. creatinine grade 2 or greater (>1.5 times upper limit of normal [ULN]);

b. lipase grade 3 or greater (>2.0 x ULN);

c. hemoglobin grade 4 (<6.5 g/dL);

d. platelets grade 2 or greater (under 50x109 cells/L);

e. serum potassium grade 2 or greater (<3.5 mEq/L);

f. aspartate aminotransferase (AST) grade 3 (≥3.0 x ULN) to be excluded;

g. alanine aminotransferase (ALT) grade 3 (≥3.0 x ULN) to be excluded;

h. alkaline phosphatase (ALP) grade 4 (>8.0 x ULN) to be excluded, grade 3 (≥3.0 x ULN)

must be discussed with the sponsor Medical Monitor;

i. total bilirubin grade 3 or greater (>2.0 x ULN, or >1.50 x ULN when accompanied by any

increase in other liver function test) to be excluded, grade 2 (>1.50 x ULN, or >1.25 x ULN

when accompanied by any increase in other liver function test) must be discussed with

the sponsor Medical Monitor.

All inclusion and no exclusion criteria must be met. If no single variable/value is outside of the

ranges of acceptability, but when multiple values are close to the limits and/or whenever the

Investigator has reason to suspect that there might be a health problem (other than TB), enrolment

should only be considered after discussing the case with the sponsor medical monitor.


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4. STUDY DESIGN AND DURATION

4.1. Summary of Study Design

This is a Phase II, two-center, partially double-blinded, randomized clinical trial conducted in six

parallel groups. Participants, study investigators and staff, including laboratory staff, will be

partially blinded. All will know whether participants are on a TMC207, PA-824 or Rifafour e-275

containing treatment arm. However, the following blinding will occur:


PA-824 plus pyrazinamide treatment arm blinded against PA-824 plus pyrazinamide plus

moxifloxacintreatment arm;

TMC207 plus PA-824 and Rifafour e-275 treatment arms will be open-label.

The trial will be performed at two centers located in Cape Town, South Africa. A total of 85 eligible

adult participants (including males and females) who meet all of the inclusion criteria and none of

the exclusion criteria, aged between 18 and 65 years (inclusive), with newly diagnosed, smear-

positive pulmonary TB will be randomized to one of 6 treatment groups:

1. TMC207 700 mg Day 1; 500 mg Day 2; 400 mg Days 3-14; + pyrazinamide placebo (dosed by

weight) Days 1-14;

2. TMC207 700 mg Day 1; 500 mg Day 2; 400 mg Days 3-14 + pyrazinamide (dosed by weight)

Days 1-14;

3. TMC207 700 mg Day 1; 500 mg Day 2; 400 mg Days 3-14 + PA-824 200 mg Days 1-14


5. PA-824 200 mg + pyrazinamide (dosed by weight) + moxifloxacin 400 mg Days 1-14;

6. Rifafour e-275 which is the standard, first-line TB treatment group (isoniazid, rifampicin,

pyrazinamide and ethambutol per South African National TB Control Programme

requirements) Days 1-14.

Each of the TMC207 and PA-824 containing treatment groups will comprise 15 male or female adult

participants and the Rifafour e-275 treatment group will comprise 10 male or female adult

participants with newly diagnosed, smear-positive pulmonary TB. The Rifafour e-275 treatment

group is included as a control for the EBA quantitative mycobacteriology. With the exception of the


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PK variables, the same variables as with the investigational medicinal product groups will be

measured for the Rifafour e-275 group.

4.2. Treatment Plan

See the Study Flow Chart (Section 1.2) for the timing of all procedures and laboratory samples to

done at each visit. For details regarding specific laboratory tests or procedures see Sections 7.2.

The trial will comprise three periods:

Pre-Treatment: Visits 1 to 4 (Days -9 to -1);

Treatment: Visits 5 to 19 (Days 1 to 15);

Follow-Up:

TMC207 containing treatment arms (excluding TMC207 plus PA-824 containing treatment

arm), Visit 20 (Day 28 ± 1 day or 14 days after last dose of IMP) and Visit 21 (Day 42 ± 3 days

or 28 days after last dose of IMP);

PA-824 containing treatment arms (excluding TMC207 plus PA-824 containing treatment

arm), Visit 20 (Day 28 ± 1 day or 14 days after last dose of IMP) and Visit 22 (Day 104 ±14

days or 90 days after last dose of IMP);

TMC207 plus PA-824 containing treatment arm and Rifafour e275® treatment arm, Visit 20

(Day 28 ± 1 day or 14 days after last dose of IMP), Visit 21 (Day 42 ± 3 days or 28 days after

last dose of IMP) and Visit 22 (Day 104 ±14 days or 90 days after last dose of IMP).

4.2.1. Pre-treatment Visits 1 to 4 (Days -9 to -1)

During the pre-treatment period, participants are not receiving treatment for TB whilst results are

being obtained and baseline sputum is collected. This time period will be kept to a minimum to the

greatest extent possible and will be up to a maximum of 9 days, consisting of up to a maximum of 6

days screening followed by 3 days of baseline sputum collection. If the investigator considers it

advisable for the participant to remain at the study site during the entire pre-treatment period, the

participant will be hospitalized. Hospital admission will occur at the latest at Visit 2 (Day -3). Should

a site’s ethics committee request that this period be shortened, the agreed upon maximum pre-

treatment period will be implemented for that site, and documented in the sponsor and site trial

files. This does not affect the data collected, as all sites may shorten this time period to meet their

specific sites’ needs, as long as baseline sputum collection starts on day -3.

Visit 1 (Days -9 to -4):


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Prior to Visit 1, participants must have a positive TB sputum smear microscopy result from their TB

clinic or site of initial diagnosis.

The following information will be collected and procedures performed:

o Written informed consent obtained from the participant.

o Hospital admission (on advice of investigator).

o Demographic data: Date of birth, race, and gender.

o Inclusion and exclusion criteria will be verified.

o Spot sputum for confirmation of TB diagnosis and adequacy of bacterial count.

o Clinically significant medical and treatment history.

o Chest X-ray for confirmation of radiological picture compatible with TB.

o Physical examination including weight, height and history of menstrual cycle (e.g. possible

irregularities, missed cycles) for women.

o Ophthalmologic examination with visual acuity, and slit lamp examination of the lens.

o Fundoscopy.

o Vital signs.

o 12-lead ECG (single).

o Clinical laboratory tests: See Section 7.2 for list of tests.

o Urine drug screen (should be repeated at Visit 2 (Day -3) if participant not hospitalized at

screening visit).

o Urine test for isoniazid (should be repeated at Visit 2 (Day -3) if participant not hospitalized

at screening visit).

o Serum pregnancy test (women of child bearing potential only, whether they are sexually

active or not).

o Serum endocrinology (males only).

o HIV test and CD4 count.

o Isoniazid and Rifampicin -resistance test: sputum-based rapid test.


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o Concomitant medication/s.

Participants may proceed with the Visit 2 (Day -3) assessments as soon as their Visit 1 (Days -9

to -4) assessments have been completed. Visits 1 and 2 may occur on the same day if the

screening results are available in time for randomization. Overnight sputum collection will start

not later than Day -3, however may be collected for a number of more days if the screening

results are delayed, or the mycobacterial testing on the first spot sputum shows an

indeterminate result in which case the test may be repeated on a freshly collected spot sputum

or an overnight sputum and that result used.

Visit 2 (Day -3):


o Eligibility assessment.

o Hospital admission (if not already admitted at Visit 1(Days -9 to -4)).

o Physical examination including weight.

o Vital signs.

o Overnight sputum collection (sputum sample will be used to ensure adequate volume and is

not required for efficacy variable tests, retention sample collection or mycobacterial

characterization testing).


o Adverse events.

Visit 3 (Day -2):



o Vital signs.

o Overnight sputum (includes sputum required for efficacy variable tests, retention sample

collection and mycobacterial characterization testing).


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o Randomization by the pharmacist/registered dispenser may occur once all the screening

results are available and the investigator has determined that the participant is eligible for

the trial. Randomization must occur prior to the Visit 4 (Day -1) ECGs.


o Adverse events.

Visit 4 (Day-1)



o Vital signs.

o Overnight sputum (includes sputum required for efficacy variable tests and retention

sample collection).

o 12-lead ECG: For PA-824 (excluding TMC207 plus PA-824) containing treatment arms only.

To be performed in triplicate at 0, 1, 2, 3, 4, 6, 8, 12 and 24 hours. The hour 0 ECG should be

performed at the time it is anticipated that dosing will occur on Visit 5 (Day 1). The 24 hour

ECGs on Visit 4 (Day -1), will serve as the pre-dose (hour 0) ECGs for Visit 5 (Day 1).


o Adverse events.

4.2.2. Treatment Period (Visits 5 to 19 [Days 1 to 15])

Visit 5 (Day 1):


o Pre-dosing (for TMC207 plus PA-824 treatment arm pre-PA-824 dose):

Eligibility assessment.

Physical examination including weight.

Vital signs.

Clinical laboratory tests: See Section 7.2 for list of tests.


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Retention sample collection: plasma in parallel with the pre-dose blood draw sample for

all participants; urine in parallel with the pre-dose urinalysis sample for all participants;

serum (males only) in parallel with the pre-dose blood draw sample for PA-824

(including TMC207 plus PA-824) and Rifafour e275® containing treatment arms.

o 12 lead ECG:

TMC207 (excluding TMC207 plus PA-824) and Rifafour e275® containing treatment

arms: (single) performed pre-dose (up to approximately 16 hours before the dose) and 5

hours post-dose.

PA-824 (excluding TMC207 plus PA-824) containing treatment arms: to be performed in

triplicate pre-dose and 1, 2, 3, 4, 6, 8, 12 and 24 hours post-dose. The 24 hour Visit 4

(Day -1) ECG will serve as the Visit 5 (Day 1) pre-dose ECG. The 24 hour Visit 5 (Day 1)

ECG will serve as the Visit 6 (Day 2) pre-dose ECG and will therefore be performed in

triplicate.

TMC207 plus PA-824 treatment arm to be performed in single pre-PA-824 dose, 4 hours

post-PA-824/pre-TMC207 dose and 9 hours post-PA-824/5-hours post TMC207 dose.

o Overnight sputum collection (includes sputum required for efficacy variable tests and

retention sample collection).

o PK sampling:

TMC207 containing treatment arms: performed pre-dose and 5 hours post-TMC207

dose.

PA-824 (excluding TMC207 plus PA-824) containing treatment arms: performed pre-

dose and 1, 2, 3, 4, 6, 8, 12 and 24 hours post-dose. The 24 hour sample is to be

collected pre-dose on Visit 6 (Day 2). For TMC207 plus PA-824 containing treatment

arm: performed pre-PA-824 dose and 4 and 8 hours post-PA-824 dose

o -IMP administration.

o Compliance check (‘hand-and-mouth’).


o Adverse events.


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Visits 6 to 17 (Days 2 to 13)


o Daily:

Physical examination including weight.

Vital signs.

Overnight sputum collection (includes sputum required for efficacy variable tests and at

Visit 6 (Day 2), Visit 7 (Day 3), Visit 8 (Day 4), Visit 10 (Day 6), Visit 12 (Day 8), Visit 14

(Day 10) and Visit 16 (Day 12) includes retention sample collection).

IMP administration.

Compliance check (‘hand-and-mouth’).

Concomitant medication/s.

Adverse events.

o On Day 2:

PA-824 (excluding TMC207 plus PA-824) containing treatment arms:

12-lead ECG (triplicate) performed pre-dose as the Visit 5 (Day 1) 24 hour ECG will be

considered the pre-dose ECG for Visit 6 (Day 2).

12 lead ECG (single) performed 2 and 5 hours post-dose.

o On Day 3:

12 lead ECG (single):


arms; performed pre-dose and 5 hours post-dose.


dose, 2 and 5 hours post dose.

TMC207 plus PA-824 treatment arm to be performed pre-PA-824 dose, 4 hours post-

PA-824/pre-TMC207 dose and 9 hours post-PA-824/5-hours post TMC207 dose.


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PK sampling:

TMC207 containing treatment arms; performed pre-dose and 5 hours post-TMC207 dose.

o On Days 4 to 7:

12 lead ECG (single): PA-824 (excluding TMC207 plus PA-824) containing treatment

arms; performed pre-dose, 2 and 5 hours post-dose.

o On Day 8:

12 lead ECG:


arms; (single) performed pre-dose and 5 hours post-dose.

PA-824 (excluding TMC207 plus PA-824) containing treatment arms; (triplicate)

performed pre-dose and 1, 2, 3, 4, 6, 8, 12 and 24 hours post-dose. The 24 hour Visit

12 (Day 8) ECG will serve as the Visit 13 (Day 9) pre-dose ECG and will therefore be

performed in triplicate.

TMC207 plus PA-824 treatment arm to be performed in single pre-PA-824 dose, 4

hours post-PA-824/pre-TMC207 dose and 9 hours post-PA-824/5-hours post TMC207

dose.

PK sampling:

TMC207 containing treatment arms: performed pre-dose and 5 hours post-TMC207

dose.


dose, 1, 2, 3, 4, 6, 8, 12 and 24 hours post-dose Sampling. The 24 hour sample is to

be collected pre-dose on Visit 13 (Day 9). For TMC207 plus PA-824 containing

treatment arm:

TMC207 plus PA-824 treatment arm: performed pre-PA-824 dose and 4 and 8 hours

post-PA-824 dose.

Retention sample collection: plasma in parallel with the Hour 0 PK blood draw sample

for all participants; urine in parallel with the pre-dose urinalysis sample for all

participants; serum (males only) in parallel with the Hour 0 PK blood draw sample for


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PA-824 (including TMC207 plus PA-824) and Rifafour e275® containing treatment arms.

For the TMC207 plus PA-824 treatment arm these are to be collected pre the PA-824

dose.

Clinical laboratory tests (pre-dose, for TMC207 plus PA-824 treatment arm pre-PA-824

dose): See Section 7.2 for list of tests.

o On Day 9:

PA-824 (excluding TMC207 plus PA-824) containing treatment arms:

12-lead ECG (triplicate) performed pre-dose as the Visit 12 (Day 8) 24 hour ECG will

be considered the pre-dose ECG for Visit 13 (Day 9).

12 lead ECG (single) performed 2 and 5 hours post-dose.

o On Days 10 to 13:

12 lead ECG (single) – PA-824 (excluding TMC207 plus PA-824) containing treatment

arms; performed pre-dose, 2 and 5 hours post-dose.

Visit 18 (Day 14):



o Vital signs.

o PK sampling:

TMC207 and PA-824 (excluding TMC207 plus PA-824) containing treatment arms

performed pre-dose and 1, 2, 5 and 8 hours post-dose.

TMC207 plus PA-824 treatment arm:

For TMC207 PK analyses - performed pre-TMC207 dose and 1, 2, 5 and 8 hours

post-TMC207 dose.

For PA-824 PK analyses - performed pre-PA-824 dose and 1, 2, 5 and 8 hours

post-PA-824 dose.

o 12 lead ECG –


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arms; (single) performed pre-dose (prior to PK sampling) and 5 hours post-dose.

PA-824 (excluding TMC207 plus PA-824) containing treatment arms; (single) performed

pre-dose (prior to PK sampling) and at 2 and 5 hours post-dose.

TMC207 plus PA-824 treatment arm; performed in single pre-PA-824 dose, 4 hours post-

PA-824/pre-TMC207 dose and 9 hours post-PA-824/5-hours post TMC207 dose.

o Overnight sputum collection (includes sputum required for efficacy variable tests, retention

sample collection and mycobacterial characterization testing. If the participant was treated

with study drug for less than 9 days, mycobacteriology testing will be performed on the 32

(Day-2) isolate only for these participants).

o IMP administration.

o Compliance check (‘hand-and-mouth’).


o Adverse events.

Visit 19 (Day 15):



o Vital signs.

o Fundoscopy (TMC207 (including TMC207 plus PA-824) and Rifafour e275® containing

treatment arms).

o PK sampling (TMC207 and PA-824 containing treatment arms (including TMC207 plus PA-

824 arm, for whom two samples will be collected, one for TMC207 and one for PA-824

analyses) ) performed 24 hours after Day 14 dosing.


o Retention sample collection: plasma in parallel with the Hour 0 PK blood draw sample for all

participants; urine in parallel with the pre-dose urinalysis sample for all participants; serum

(males only) in parallel with the Hour 0 PK blood draw sample for PA-824 (including TMC207

plus PA-824) and Rifafour e275® containing treatment arms.


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o Discharge from hospital with referral letter to National TB treatment programme. The

participants on the investigational medicinal product arms will receive the first dose (s) of

standard TB therapy per SA national TB treatment guidelines. The participants in the group

receiving standard TB treatment will receive an additional dose(s) to continue on this

treatment. All participants will be referred to the local community TB clinics for a full course

of standard antituberculosis chemotherapy according to National Guidelines. The

participants will be provided with a referral letter to take with them to the TB Clinic. A

follow-up call will be made by the study site staff to the clinic to determine if the participant

attended the clinic on the date as arranged. Participants will be provided with sufficient TB

medication (Rifafour e-275®) to cover the period from attending their last visit at the study

clinic until their scheduled visit at the TB clinic.


o Adverse events.

4.2.3. Follow-Up Period

Visit 20 (Day 28 [± 1 day window period][14 day ± 1 days after the last dose of IMP]):

All participants.

A safety follow-up assessment will be conducted at the hospital 14 days ± 1 day after the last IMP

dose. The following information will be collected and procedures performed:


o Vital signs.

o 12 lead ECG (single)


o Concomitant medication.

o Adverse events.

o Document in the Case Report Form (CRF) and in the source documents whether the

participant is attending the local TB clinic and included into the National TB Programme.

Visit 21 (Day 42 [± 3 days window period][28 days ± 3 days after the last dose of IMP]):


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Only for participants in the TMC207 (including TMC207 plus PA-824) and Rifafour e275®

containing treatment arms.

A safety follow-up assessment will be conducted at the hospital 28 days ± 3 days after the last IMP



o Fundoscopy.

o Vital signs.

o PK sampling (TMC207 (including TMC207 plus PA-824) containing treatment arms).

o 12-lead ECG (single).

o Retention sample collection: plasma in parallel with PK blood draw sample (TMC207

(including TMC207 plus PA-824) and Rifafour e275® containing treatment arms).

o Concomitant medications.

o Adverse events.

Visit 22 (Day 104 [± 14 day window period][90 days ± 14 day after the last dose of IMP])

Only for participants in PA-824 (including TMC207 plus PA-824) and Rifafour e275® containing

treatment arms.

A safety follow-up assessment will be conducted at the hospital 90 days ± 14 day after the last IMP


o Ophthalmologic examination with visual acuity and slit lamp examination of the lens.

o Concomitant medications.

o Adverse events - For the period from Visit 20 (Day 28) to Visit 22 (Day 104) for participants

on the PA-824 (excluding TMC207 plus PA-824) treatment arms and Visit 21 (Day 42) to Visit

22 (Day 104) for participants on the TMC207 plus PA-824 and Rifafour e275® treatment arm,

only ophthalmologic related adverse events, and all serious adverse events, will be

collected.

4.2.4. Early Withdrawal


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In case of early withdrawal during the treatment period of the study, all efforts shall be made to

complete the Early Withdrawal assessments. At the early withdrawal visit the following

information will be collected and procedures performed:


o Vital signs.

o Fundoscopy

o PK sampling (TMC207 and PA-824 containing treatment arms).

o Retention sample collection: plasma in parallel with the PK blood draw sample for all

participants; urine in parallel with the pre-dose urinalysis sample for all participants; serum

(males only) in parallel with the Hour 0 PK blood draw sample for PA-824 (including

TMC207 plus PA-824) and Rifafour e275® containing treatment arms.

o 12-lead ECG (single)


o Concomitant medication.

o Adverse events.

o Discharge from hospital with referral letter to National TB treatment programme. The

participants on the investigational medicinal product arms will receive the first dose(s) of

standard TB therapy per SA national TB treatment guidelines. The participants in the group

receiving standard TB treatment will receive an additional dose to continue on this

treatment. All participants will be referred to the local community TB clinics for a full course

of standard antituberculosis chemotherapy according to National Guidelines. The

participants will be provided with a referral letter to take with them to the TB Clinic. A

follow-up call will be made by the study site staff to the clinic to determine if the participant

attended the clinic on the date as arranged. Participants will be provided with sufficient TB

medication (Rifafour e-275®) to cover the period from attending their last visit at the study

clinic until their scheduled visit at the TB clinic.

All participants who received at least one dose of IMP will be requested to return for the safety

follow up visits, Visit 20 (14 days ± 1 day after their early withdrawal visit), Visit 21 (28 days ± 3

days after their early withdrawal visit for all TMC207 (including TMC207 plus PA-824) and


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Rifafour e275®participants) and Visit 22 (90 days ± 14 days after their early withdrawal visit for

all PA-824 (including TMC207 plus PA-824) and Rifafour e275® participants).

4.3. Participant Withdrawal Criteria

A participant can be prematurely withdrawn from the trial as a result of the following:

At their own request or at the request of their legally acceptable representative.

If, in the investigator’s opinion, continuation in the trial would be detrimental to the well-being

of the participant.

At the specific request of the sponsor.

QTc prolongation as described in section 9.7.

A serious adverse event occurs.

Fails to comply with the protocol.

Participants who withdraw from the trial after having received IMP will not be replaced. The

exception is those participants who are discontinued due to QT prolongation on Day 1, who will be

replaced. Any participant who received at least one dose of IMP and is withdrawn or withdraws

early from the study during the treatment phase will undergo an early withdrawal visit and will be

requested to return for the applicable follow up visits.

4.4. Trial Treatment Discontinuation

Trial treatment must be immediately discontinued for the following reasons:

Withdrawal of informed consent.

Investigator considers it for safety reasons in the best interest of the participant that he/she be

withdrawn.

QTc prolongation as described in section 9.7.

Participant experiences specific toxicities as outlined in Section 0.

Pregnancy.

Termination of the study by the sponsor.


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exception is those participants who are discontinued due to QT prolongation on Day 1, who will be

replaced.

4.5. Stopping Rules

There are no stopping rules in this trial.

4.6. Participant Progress Definitions

4.6.1. Screening Failure

A screen failure participant is one from whom informed consent is obtained and is documented in

writing (that is, participant signs an informed consent form), but who’s not randomized.

4.6.2. Completed Treatment

Participants who complete their treatment will be defined as completed treatment.

4.6.3. Early Withdrawal

Participants who withdraw from the study prior to the completion of their treatment will be

defined as early withdrawal.

4.6.4. Completed Trial

Participants who complete the treatment period and attend the follow-up visit: Visit 21 (Day 42) for

TMC207 (excluding TMC207 plus PA-824) containing treatment arms and Visit 22 (Day 104) for PA-

824 (including TMC207 plus PA-824) and Rifafour e275® containing treatment arms, will be defined

as completed trial.

4.6.5. Lost to Follow-up

Participants who cannot be contacted on or before Visit 21 (Day 42) for TMC207 (excluding

TMC207 plus PA-824) participants or Visit 22 (Day 104) for PA-824 (including TMC207 plus PA-824)

and Rifafour e275® treatment participants and who do not have a known reason for

discontinuation (for example, withdrew consent or adverse event) will be defined as lost to follow-

up.

4.7. Restrictions

4.7.1. Foods and Beverages


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Consumption of foods and beverages containing the following substances will be prohibited as

indicated:

Methyl-xanthines/caffeine: From 48 hours prior to Visit 5 (Day 1) until after Visit 19 (Day 15) or

early withdrawal visit i.e. until discharge from the study clinic. Decaffeinated drinks are allowed.

Poppy seeds: 7 days prior to Visit 1 (Days -9 to -4) until after Visit 19 (Day 15) or early

withdrawal visit i.e. until discharge from the study clinic.

Alcohol: 72 hours prior to Visit 5 (Day 1) until after Visit 19 (Day 15) or early withdrawal visit i.e.

until discharge from the study clinic.

Grapefruit or grapefruit juice: 10 days prior to prior to Visit 5 (Day 1) until after Visit 19 (Day 15)

or early withdrawal visit i.e. until discharge from the study clinic.

4.7.2. Prior and Concomitant Medications

Any medication taken within 30 days prior to IMP administration or during the trial until visit 21

(Day 42) for TMC207 (excluding TMC207 plus PA-824) participants and until Visit 22 (Day 104) for

PA-824 (including TMC207 plus PA-824) and Rifafour e275® participants is defined as concomitant

medication and is to be reported on the Concomitant Therapy page of the CRF. Reported

information will include a description of the type of the drug, treatment period, dosing regimen,

route of administration, and its indication. Any changes in the dosage of concomitant medication

must also be reported on the Concomitant Therapy page of the CRF. Data on concomitant

medication will be collected up to the last follow-up visit, even after early withdrawal of a subject.

Concomitant treatments should be kept to a minimum during the trial. However, if concomitant

treatments are considered to be necessary for the participant’s welfare and are unlikely to interfere

with the investigational medication, they must be given at the discretion of the Investigator. For

any concomitant therapy given as a treatment for a new condition or a worsening of an existing

condition occurring after signing of the informed consent form (ICF), the condition must be

documented on the Adverse Event pages of the CRF.

The prescribing information for all concomitant medication should be consulted and reviewed

carefully. The determinations listed in the respective contraindicated, warning, and precaution

sections must be respected in order to prevent any potentially serious and/or life-threatening drug

interactions.


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The following medications are disallowed during administration of IMP and up to 1 month after the

last dose of IMP:

the systemic use of CYP3A4 inhibitors (e.g., azole antifungals: ketoconazole, voriconazole,

itraconazole, fluconazole; ketolides such as telithromycin; and macrolide antibiotics other

than azithromycin) for more than 3 consecutive days;

the systemic use of CYP3A4 inducers (e.g., phenytoin, carbamazepine, phenobarbital, St.

John’s wort);

The following medicinal products are prohibited from Visit 1 (Days -9 to -4) until after Visit 19 (Day

15) or early withdrawal visit i.e. until discharge from the study clinic (unless part of study

treatment):

Medications of the statin class of compounds;

Tricylic antidepressants, including amtriptyline, doxepin, desipramine, imipramine,

clomipramine;

Nonsedating antihistamines astemizole and terfenadine

The neuroleptics-phenothiazines thioridazine, haloperidol, chlorpromazine, trifluoperazine,

percyline, prochlorperazine, fluphenazine, sertindole and pimozide;

The prokinetic cisapride;

Quinoline antimalarials (e.g., chloroquine and quinacrine);

Diuretics that deplete potassium;

Systemic glucocorticoids;

Medicinal products used to treat pulmonary TB: moxifloxacin, gatifloxacin, isoniazid,

ethambutol, amikacin, cycloserine, rifabutin, rifampicin, streptomycin, kanamycin, para-

aminosalicylic acid, rifapentine, thioacetazone, capreomycin, quinolones, thioamides, and

metronidazole.

4.7.3. Activity

Participants will be requested not to undertake vigorous exercise during the period from Visit 1

(Days -9 to -4) until after the final laboratory safety tests at follow up Visit 20 (Day 28 or 14 days + 1

day post last dose of IMP).

Participants will not engage in strenuous activity at any time during the in-hospitalization period.

5. INVESTIGATIONAL MEDICINAL PRODUCT


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5.1. Trial Treatments

Participants will receive oral once-daily dosing. They will be randomized to one of the following

arms:

1. TMC207 700 mg Day 1; 500 mg Day 2; 400 mg Days 3-14; + pyrazinamide placebo (dosed by

weight) Days 1-14;

2. TMC207 700 mg Day 1; 500 mg Day 2; 400 mg Days 3-14 + pyrazinamide (dosed by weight)

Days 1-14;

3. TMC207 700 mg Day 1; 500 mg Day 2; 400 mg Days 3-14 +PA-824 200 mg Days 1-14;


5. PA-824 200 mg + pyrazinamide (dosed by weight) + moxifloxacin 400 mg Days 1-14;

6. Rifafour e-275 which is the standard, first-line TB treatment group (isoniazid, rifampicin,

pyrazinamide and ethambutol per South African National TB Control Programme

requirements) Days 1-14.

5.2. Methods of Assigning Participants to Treatment Groups

Eligible participants who have given written, informed consent will be enrolled onto the trial during

Visit 1 (Days -9 to -4) and will be identified by a study generated participant identification code for

anonymity (subject number). Participants who meet all of the inclusion criteria and none of the

exclusion criteria will be randomized and assigned a treatment number.

The Investigational Medicinal Product will be centrally randomized by persons not directly involved

with the trial. Two separate randomisations will occur:

Randomization (1):

TMC207 and PA-824 (excluding the TMC207 plus PA-824) containing treatment arms plus 8 Rifafour

e275 participants;

Randomization (2):

TMC207 plus PA-824 containing treatment arm plus 2 of the Rifafour 2e75 participants.

The randomization (2) participants will be enrolled after full enrollment for the other 5 treatment

arms is complete. Participants, study investigators and staff, site pharmacists/dispensers, including

laboratory staff, sponsor staff and applicable CROs will be partially blinded. All will know whether


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the participant is on a TMC207, PA-824 or Rifafour e-275 containing treatment arm. However,

the following blinding will occur:


PA-824 plus pyrazinamide treatment arm blinded against PA-824 plus pyrazinamide plus

moxifloxacin treatment arm;

TMC207 plus PA-824 and Rifafour e-275 treatment arms will be open-label.

A treatment pack will be available for each participant which will be identified by a treatment

number.

In order to ensure there is no bias, the study medication will be retained by the site

pharmacist/registered dispenser. The site pharmacist/registered dispenser will not have any

interaction with the participants or participant care responsibilities. On randomization, the site will

request the site pharmacist/registered dispenser to assign an IMP treatment pack to the

participant. The site pharmacist/registered dispenser will assign to the participant the next

available treatment pack, in a sequential basis starting from the lowest unused treatment number.

This process will be fully documented. Randomization by the pharmacist/registered dispenser may

occur once all the screening results are available and the investigator has determined that the

participant is eligible for the trial. Randomization must occur prior to the Visit 4 (Day -1) ECGs.


exception to this is those participants who are discontinued due to QT prolongation on Day 1, who

will be replaced. For these participants the site staff will inform the Randomization Monitor that

the participant was withdrawn due to QT prolongation on Day 1 and the treatment number of that

participant. The randomization monitor who will determine and inform the applicable site

pharmacist/registered dispenser of the next available sequential treatment number for the next

patient to be randomized. Replacement participant will be assigned to the treatment group of the

participant who was withdrawn but may be assigned to any site. The randomization monitor will

be responsible for working with the site pharmacists/registered dispensers to ensure that the

above process is managed so that the required number of participants per treatment arm are

randomized onto the study.

5.3. IMP Administration

5.3.1. TMC207 and PA-824 Treatment Groups


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The TMC207 containing treatment arms will be administered in the morning (within 30 minutes

after breakfast) with 240 ml water.

The PA-824 containing treatment arms will be administered under fasting conditions in the morning

(at least 4 hours before breakfast) with 240 ml water. The minimum duration of the fast is to be

eight hours prior to dosing and 4 hours post-dosing.

The TMC207 plus PA-824 containing treatment arm will be administered as follows:

The PA-824 and TMC207 open-label tablets will be administered at different times, per their

dosing requirements, that is:

o The PA-824 open-label tablets will be administered under fasting conditions in the

morning (at least 4 hours before breakfast) with 240 ml water. The minimum

duration of the fast is to be eight hours prior to dosing and 4 hours post-dosing.

o The TMC207 open-label tablets will be administered in the morning (within 30

minutes after breakfast) with 240 ml water.

5.3.2. First-line standard TB treatment per SA national guidelines (Rifafour e-275 tablets)

Treatment Group

The Rifafour e-275 will be administered with a full glass of water 1 hour before, or 2 hours after a

meal (as per the package insert (Appendix 2)).

5.3.3. Participant Compliance

The IMP will be administered by the investigator/designated site personnel. The date, time and

number of tablets administered will be recorded in the participant’s CRF and in the source

documents. All IMP will be administered with water. Participants will be checked for IMP

compliance by the Investigators or trial personnel via the hand-and-mouth procedure. Both the

hand and mouth of the participant will be checked to ensure that the participant has swallowed the

IMP.

5.4. Blinding and Procedures for Breaking the Blind

Individual treatment code break envelopes for the blinded treatment arms will be supplied to:

the sponsor’s medical monitor;

the site;


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the monitoring CRO.

The treatment code must not be broken except in the case of a medical emergency, where

treatment of the participant is influenced by the knowledge of what dose and type of IMP the

participant is receiving. Prior to breaking the code, if practical, the Investigator is to discuss the

breaking of the blind with the sponsor’s medical monitor. The Investigator must document on the

code break envelope and in the participant’s source documentation that the blind was broken, plus

the reason for breaking it. The time and date of breaking the blind must be completed. The

sponsor must be informed that the blind has been broken within 24 hours of the event. The

sponsor reserves the right to break the blind in order to fulfill any regulatory requirements

regarding reporting of SAEs.

In the absence of any medical emergencies requiring a code break, the randomization code will

only be broken once all clinical data, as well as all outcome parameters have been captured and no

more data queries are pending. The statistical analysis plan will also have been finalized. The only

exception to this rule is that the blind may be broken prior to:

The availability of results of specific microbiological tests of isolated M. tuberculosis cultures

from sputum (MIC against PA-824, TMC207 and moxifloxacin, first-line drug-susceptibility

testing, strain speciation by PCR). Un-blinding will occur before these results are known and

therefore before definitive database closure. The rationale for this exception lies in the long

time needed for completion of these microbiological assessments (they will take at least 6

weeks and can be further delayed by technical difficulties with the subsequent repetition of

tests), and these tests are objective parameters not influenced by blinding/un-blinding.

Visit 20 (Day 28), by the biostatistician responsible for the EBA efficacy analyses only. All other

sponsor, CRO, laboratory, statistical and site personnel will remain blinded. The efficacy

biostatistician may perform the efficacy analyses and inform the sponsor of the high level EBA

efficacy results by treatment arm only, in order for this information to be utilised in the decision

making for future clinical trial design. No un-blinded individual subject results will be supplied

by the biostatistician until formal database closure has occurred. The EBA biostatistician has no

role in the remaining analyses.

5.5. IMP Packaging and Labeling


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The TMC207 tablets are white to off-white oval tablets. The complete formulations of TMC207 are

provided in the TMC207 Investigator’s Brochure (7). The PA-824 tablets are white to off-white oval

tablets. The complete formulations of PA-824 are provided in the Investigator’s Brochure(13) . The

pyrazinamide and matching placebo tablets are white, round, scored tablets. The moxifloxacin and

matching placebo are oblong, dull red film-coated tablets. The complete formulation of

moxifloxacin is provided in the Investigator’s Brochure (34).The complete formulations of

pyrazinamide and Rifafour e275® is provided in the applicable package inserts (Appendices 6 and

2).

The TMC207 and PA-824 containing treatment arms will be blister packed in individual treatment

packs identified by a unique treatment number.

Participants will receive the following trial medication, depending on which group they are

randomized to (see Table 4 below).

Table 4 : Investigational Medicinal Product Details

Group Active Placebo

TMC207 alone Day 1: 7 TMC207 100 mg tablets Day 2: 5 TMC207 100 mg tablets Day 3-14: 4 TMC207 100 mg tablets

Days 1-14: 4 pyrazinamide placebo tablets

TMC207 plus pyrazinamide Day 1: 7 TMC207 100 mg tablets Day 2: 5 TMC207 100 mg tablets Day 3-14: 4 TMC207 100 mg tablets + Days 1-14: 4 active pyrazinamide 500 mg tablets

TMC207 plus PA-824 Day 1: 7 TMC207 100 mg tablets Day 2: 5 TMC207 100 mg tablets Day 3-14: 4 TMC207 100 mg tablets + Days 1-14: 1 PA-824 200 mg tablet

PA-824 plus pyrazinamide Days 1-14: 1 PA-824 200 mg tablet + 4 active pyrazinamide 500 mg tablets

Days 1-14: 1 moxifloxacin 400 mg placebo tablet


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Group Active Placebo

PA-824 plus pyrazinamide and moxifloxacin

Days 1-14: 1 PA-824 200 mg tablet + 4 active pyrazinamide 500 mg tablets + 1 active moxifloxacin 400 mg tablet

Rifafour e-275 treatment group.

Days 1-14:

Dosing per weight:

30-37 kg 2 tablets

38-54 kg 3 tablets 55-70 kg 4 tablets 71 kg and over 5 tablets

All PA-824 and TMC207 (excluding the TMC207 plus PA-824) containing treatment arms blister

packs will contain 4 pyrazinamide or matching placebo tablets. From these 4 tablets the participant

will be administered the required number of tablets dependent on their weight (see Table 5).

Table 5: Pyrazinamide dosing per weight

Participants weight Daily Dose No. of tablets per day

55 kg 1000 mg 2

>55kg – 75 kg 1500 mg 3

> 75 kg 2000 mg 4

Rifafour e-275 will be commercially purchased, labeled as per the randomization code and

provided un-blinded to the participating sites.

5.5.1. PA-824 and TMC207 Containing Treatment Arms

The IMP Arms will be packaged in an individual treatment pack. The outer packaging of each

treatment pack will be labeled with, at a minimum, the following information:

Name of Sponsor.

Name of medication.

Dosage, quantity and method of administration.

Reference/Lot Number.

Treatment Number.

Directions for use.

The statement “For Clinical Trial Use Only”.

Space for completion of Name of Investigator.


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Storage conditions.

The statement “Keep out of reach of children”.

Expiry Date.

The inner packaging of each treatment pack will be labeled with, at a minimum, the following

information:

Name of Sponsor.

Name of medication.

Dosage, quantity and method of administration.

Reference Number.

Treatment Number.

Directions for use.

The statement “For Clinical Trial Use Only”.

5.5.2. Standard, first line TB treatment

Labels will be provided to be added to the commercial pack to denote the treatment code and that

it is for use in this clinical trial. These labels will conform to the requirements as described in

Section 5.5.1.

5.6. Storage

All study medication will be kept securely stored by the site pharmacist/registered dispenser in a

secured area with limited access to designated site personnel only.

Blinded treatment arms will be stored in the supplied containers between 15 to 25 degrees Celsius.

Rifafour e-275 will be stored at <25 degrees Celsius, in the tightly closed container that it is

supplied in, protected from light.

5.7. Dispensing and Accountability

The site pharmacist/registered dispenser will be responsible for dispensing the IMP. Accurate

accountability records will be kept by the site to assure that the IMP will not be dispensed to any

person who is not a participant under the terms and conditions set forth in this protocol i.e.

delivery to site, inventory at site, use by participant, destruction etc. The Investigator/designee will

immediately inform the sponsor of any quality issues arising with respect to the trial medication.

The sponsor will take whatever action is required should such a situation arise.


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The Investigator undertakes to use the trial medication only as indicated in this protocol.

5.8. Returns and Destruction

Upon completion or termination of the trial, all unused and/or partially used IMPs must be

returned to sponsor (or designated contractor). If no supplies remain, this fact will be indicated in

the drug accountability section of the final report.

6. TRIAL VARIABLES

6.1. Demographic and Background Variables

The following demographic and background variables will be collected:

Written informed consent.

Demographic data: Date of birth, race, gender.

Clinically significant medical and treatment history (including ophthalmological history and for

females menstrual history including any history of irregular or missed periods).

Inclusion and exclusion criteria.

Chest X-ray for confirmation of radiological picture compatible with TB.

Urine drug screen.

Urine test for isoniazid.

Serum pregnancy test (women of child-bearing potential only, whether they are sexually active

or not).

Serum endocrinology (males only): testosterone, luteinizing hormone (LH), follicle-stimulating

hormone (FSH).

Serology: HIV and CD4 count.

Spot sputum:

o rapid test for isoniazid and rifampicin resistance;

o confirmation of MTB prior to randomization;

o Adequate bacterial load;

o Estimate of adequate sputum production.

Concomitant Medications.

Height (meters (m)).



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Method of Birth Control: Male and Female participants.

Restrictions: restricted food and beverages, restricted activity, prohibited mediation.

Post Trial Treatment TB Programme Attendance: attendance at the local TB clinic, inclusion

onto the National TB Programme.

Hospitalization.

6.2. Efficacy Variables

The following efficacy variables will be assessed for evaluation of the efficacy endpoints:

The change in number of sputum CFU of M. tuberculosis on solid media (logCFU) over time.

The change in TTP in liquid media (the MGIT system) over time.

6.3. Pharmacokinetic Variables

The following pharmacokinetic variables will be assessed for the evaluation of the pharmacokinetics

of PA-824, TMC207, TMC207 metabolite M2, pyrazinamide and moxifloxacin (except in the Rifafour

e275® treatment arms):

Maximum observed plasma concentration (Cmax).

Time at which Cmax is observed (Tmax).

Minimum observed plasma concentration 24 hours following the last dose (Cmin).

Area under the plasma concentration time (t) curve from zero to 24 hours AUC(0-24)

No PK sampling will be performed on the Rifafour e275® treatment arm.

6.4. Safety Variables

The following safety variables will be assessed for evaluation of the safety endpoints:

Laboratory Parameters:

o Hematology: hemoglobin, hematocrit, red blood cell count, white blood cell count with

differential, platelet count.

o Coagulation: activated partial thromboplastin time (APTT), prothrombin time (PT),

international normalized ratio (INR) for PT.

o Clinical Chemistry: Albumin, urea, creatinine, direct, indirect and total bilirubin, uric acid,

cholesterol (total), triglycerides, total protein, total amylase, lipase, alkaline phosphatase

(ALP), creatine phosphokinase (CPK), AST, ALT, gamma-glutamyl transferase (GGT), lactate


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dehydrogenase (LDH), phosphate, sodium, potassium, calcium (corrected for albumin),

chloride, random/fasting glucose, bicarbonate/CO2.

o Urinalysis; pH, specific gravity, protein, glucose, micro-albumin, ketones, bilirubin,

creatinine, nitrite, sodium, urobilinogen, blood, leukocytes, microscopy.

12-lead ECG: Normal, Abnormal, Heart rate, PR interval, QT, QTc (QTcB and QTcF), QRS.

Physical Examination. Height is measured at screening only.

Ophthalmological Exam [to include visual acuity, fundoscopy and slit lamp examination.

Vital signs: supine systolic and diastolic blood pressure (SBP and DBP), heart rate, axillary body

temperature, weight, calculated body mass index (BMI).

Adverse Events.

Concomitant medication.

6.5. Mycobacterial Characterization

The following characteristics of the participants’ MTB strains will be assessed:

MIC of PA-824, TMC207 and moxifloxacin.

Drug susceptibility testing of the M. tuberculosis isolates with MGIT system for sensitivity to

isoniazid, rifampicin, ethambutol and pyrazinamide.

Speciation of the infecting organism by PCR.

Due to the complexities involved with the above mycobacteriological testing, which can result in

repeated testing being required in order to produce a result, the above tests will be performed

once. If a result is not available from this test it will be repeated once. Should this repeated test

also not produce a result the sample will be reported as “no result available”.

7. TRIAL PROCEDURES

7.1. Sputum Sampling

7.1.1. Spot Sputum

Purpose 1:

Determining participant eligibility: Direct microscopy for acid-fast bacilli. This serves as

confirmation of MTB infection prior to randomization and ensures adequate bacterial load (at

least 1+ on the IUATLD/WHO scale (Appendix 3).

Purpose 2:


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Determining participant eligibility: Rapid test for isoniazid and rifampicin resistance.

Sample Collection Methodology:

The spot sputum sample collection methodology and requirements will be described in a

separate document, The Laboratory Manual, which will be provided to the site prior to trial

start.

Spot sputum samples are to be collected in the appropriate clean, 40 ml sterile containers

supplied. The screw caps must be fitted tightly to avoid leakage. The spot specimens should

have a volume of 3-5 ml. In defining a good sputum specimen, satisfactory quality implies the

presence of mucoid or mucopurulent particles. This is of greater significance than quantity.

The samples will be sent via courier to the designated trial mycobacteriology laboratory for

handling and assessment.

Testing performed by:

Trial appointed mycobacteriology laboratory.

7.1.2. Overnight Sputum

Purpose 1:

Calculating efficacy variables: The change of sputum colony forming units of M tuberculosis

(logCFU) over time and the change of time to culture positivity (TTP) in the MGIT system over

time.

Note: Should the spot sputum results for direct microscopy for acid-fast bacilli as described in

section 5.1.1 purpose 1 be negative or insufficient, but the results from the day -2 overnight

sample be positive as required and described in Section 5.1.1 the participant may be

randomized based on these results.

Purpose 2:

Determining mycobacteriologic characteristics of the participants’ MTB strains:

o MIC of PA-824, TMC207 and moxifloxacin.

o Drug susceptibility testing of the M. tuberculosis isolates with MGIT system for sensitivity to

isoniazid, rifampicin, ethambutol and pyrazinamide.

o Speciation of the infecting organism by PCR.



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The overnight sputum sample collection methodology and requirements will be described in a

separate document, The Laboratory Manual, which will be provided to the site prior to trial

start.

Overnight sputum sampling will start on Visit 2 (Day -3) and will be collected from the afternoon

and for 16 hours overnight. The 16-hour sputum sampling for each of these sampling days must

be finished prior to the administration of each day’s IMP. Each participant’s overnight sputum

samples will be collected (pooled) in an appropriate clean, 120-180 ml container. The screw

caps must fit tightly to avoid leakage. Each overnight pooled specimen should consist of

approximately 20-30 ml with a minimum of 10 ml being required. In defining a good sputum

specimen, satisfactory quality implies the presence of mucoid or mucopurulent particles. This is

of greater significance than quantity. Pooled specimens must remain at the participant’s

bedside until the 16-hour collection is completed. The samples will be sent via courier to the

designated trial mycobacteriology laboratory for handling and assessment.


Trial appointed mycobacteriology laboratory.

7.2. Clinical Laboratory Tests

7.2.1. Safety Laboratory Tests

Test Details:

Hematology: hemoglobin, hematocrit, red blood cell count, white blood cell count with

differential, platelet count.

Coagulation: APTT, PT, INR for PT.

Clinical Chemistry: Albumin, urea, direct, indirect and total bilirubin, uric acid, cholesterol

(total), triglycerides, total protein, total amylase, lipase, alkaline phosphatase (ALP), creatinine,

creatine phosphokinase (CPK), AST, ALT, gamma-glutamyl transferase (GGT), lactate

dehydrogenase (LDH), phosphate, sodium, potassium, calcium (corrected for albumin), chloride,

random/fasting glucose, bicarbonate/CO2. If total amylase results are Grade 2 or higher, further

testing of pancreatic amylase and trypsin-like immunoreactivity should be considered after

consultation with the Sponsor Medical Monitor. Note: It is preferable for a fasting glucose to

be obtained at screening. However if the participant arrives at the screening visit not in a


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fasting condition, a random glucose may be done. If the resulting glucose is significantly

elevated (>11.1 mmol/L) the following procedures must be followed during screening:

o The investigator is to question the participant about possible clinical symptoms and look for

possible clinical signs of diabetes.

o The urinalysis glucose results are also to be taken into consideration.

If based on these results, it is the opinion of the investigator that the participant may have a

significant endocrine abnormality the participant should not be enrolled (screening failure).

Urinalysis: pH, specific gravity, protein, glucose, microalbumin, ketones, bilirubin, creatinine,

nitrite, sodium, urobilinogen, blood, leukocytes, microscopy.

Purpose:

Safety Monitoring


The laboratory sample collection methodology and requirement will be described in a separate

document, The Laboratory Manual, which will be provided to the site prior to trial start.


Trial appointed safety laboratory.Other laboratory Tests

Test Details:

Pregnancy: Serum βHCG. Women of child-bearing potential only whether sexually active or not.

HIV and CD4 count. Prior to HIV testing and on receipt of the results, participants will be

counseled on HIV by trained counselors. Approval for this to be performed will be obtained

from participants in the written informed consent process.

Urine Drug Screen: cannabinoids, cocaine, amphetamines, opiates, benzodiazepines,

barbiturates.

Urine test for isoniazid.

Serum Endocrinology: testosterone, luteinizing hormone (LH), follicle-stimulating hormone

(FSH). These will be performed on male participants only. The serum endocrinology sampling (in

males, only) may be repeated in the morning (ideally 8 am) if the original results show an

isolated abnormal value (i.e., only 1 of the 3 hormones is abnormal). Only the item which was

abnormal in the original testing needs to be repeated.

Purpose:



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Determining participant eligibility.



document, The Laboratory Manual, which will be provided to the site prior to trial start.


Trial appointed safety laboratory or mycobacteriology laboratory.

7.3. Plasma Pharmacokinetics (PK)

Purpose:

Determining pharmacokinetic variables.


4 ml blood sample will be collected in a vacutainer tube containing:

Lithium Heparin for TMC207 (excluding TMC207 plus PA-824) Containing Treatment Arms;

K2 EDTA for PA-824 (excluding TMC207 plus PA-824) Containing Treatment Arms;

The TMC207 plus PA-824 Containing Treatment Arm will be collected in vacutainers containing:

o Lithium Heparin for TMC207 identified time points (Flow Chart Section 1.3);

o K2 EDTA for PA-824 identified time points (Flow Chart Section 1.3).The sample will be

centrifuged, plasma separated, and stored in a freezer set at -80°C. The overall duration of

sample processing, from collection to freezing, should be less than 2 hours. The following

processing, storage, and shipping procedures should be followed:

1. After obtaining the 4 ml blood sample, mix collection tube thoroughly by slowly inverting the

collection tube several times.

2. Within 60 minutes of collection, process collection tubes in a centrifuge set at approximately

3000 RPM for 10 minutes at room temperature.

3. Transfer a 1.0 ml aliquot of plasma using standard laboratory technique into each of two

appropriately-labeled tubes (or the remaining plasma if 1.0 ml is not available). These aliquots

will be designated for the PK testing.

4. Tube labels will be provided by the designated laboratory. Labels should be secured to each

storage tube so they do not come off during storage at -80°C or shipping on dry ice. Labels will

contain the following information: Protocol number; site number, participant number; and time

point of sample collection (e.g., 5 hours post-dose).

5. Samples will be stored in an upright position at -80°C until shipped.


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6. Plasma samples for PK determinations will be couriered in batches to the designated laboratory

in two separate shipments packed in dry ice sufficient to last for 3 days. The first set of aliquots

from all participants will be sent to the designated laboratory first. Once the lab confirms the

first shipment has arrived in good condition, the second set of aliquots will be sent. Shipments

should be made by overnight courier.


Sponsor-appointed pharmacokinetics laboratories.

7.4. Electrocardiography (ECG)

Purpose:

Safety monitoring (please refer to PK-ECG flow charts in section 1.3) for immediate on-site

safety assessment and central evaluation at prospectively defined time points.

For the designated on-site safety assessment ECGs (section 1.3.), the site staff will immediately

check the ECG readings performed by the provided ECG machine for QT prolongation safety

margins, defined for this purpose as a QTc interval of 470msec or an increase of 40msec from

baseline (for PA-824 (excluding TMC207 plus PA-824) containing treatment arms, the comparison

will be to the time-matched pre-treatment ECG). If these safety margins are not met, the site staff

will immediately notify the designated appropriately trained physician who will manually read the

ECG tracing in question to determine if the QTc prolongation criteria for patient withdrawal (see

section 9.7) have been met.

In addition, prior to dosing on each treatment day, clinical assessment of the previous day’s safety

ECGs are to be performed for safety monitoring (section 9.7) by the designated appropriately

trained physician. When ECGs are obtained in triplicate, the first recorded ECG should be used for

the on-site QT safety evaluation. The investigator’s interpretation of each safety ECG will be

recorded in the CRF. For PA-824 containing treatment arms, the post-treatment ECG evaluations

will be compared to the time-matched pre-treatment ECGs. All clinically significant changes must

be accompanied by further specification in the CRF.

If the initial physician-conducted review of the post-treatment ECGs suggests that the corrected QT

interval (corrected QTcB and QTcF) has increased by more than 60 msec, additional ECGs will be

collected at 15 minute intervals until the corrected QT interval has returned to baseline or the

increase has been satisfactorily explained. However, because this assessment is based on an initial

(on-site) impression prior to centralized measurement by the centralized ECG laboratory, an


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increase in corrected QT interval of more than 60 msec need not be reported as an AE unless it is

accompanied by signs or symptoms of myocardial ischemia or developing cardiac arrhythmia or

that the overall value is above 500 msec.

Methodology:

ECGs will be recorded for 10 seconds. Timing and registration technique for ECGs will be

standardized for all participants. Participants should be lying down (recumbent) for at least 5

minutes prior to each 12-lead ECG evaluation. ECGs will be performed as single (TMC207

(including TMC207 plus PA-824) and Rifafour e275® containing treatment arms) or in single or

triplicate (PA-824 (excluding TMC207 plus PA-824) containing treatment arms). Please refer to

Section 1.3 PK and ECG Chart. The inter-ECG interval being 30 to 180 seconds for triplicate

ECGs. For each participant, the ECGs should to every extent possible be collected at

approximately the same time of day and in the same fed/fast state (e.g. 4 hours after lunch).

7.5. Ophthalmology Examinations

Purpose:

Safety monitoring and participant eligibility.

Methodology:

The same ophthalmologist should perform the Visit 1 (Day -9 to -4) and Visit 22 (Day

104±14days) ophthalmology examination for a given participant, if at all possible. A limited

number of ophthalmologists will be involved in the study to reduce observer variability. The

exception to this is the fundoscopy which is performed by the Investigator at Visit 19 (Day 15)

and Visit 21 (Day 42) or at early withdrawal.

An ophthalmologic medical history will be obtained from the participant.

One or all of the following examinations will be performed per the timelines in section 1.3 at

the designated visit:

o Visual acuity test and slit lamp examination after dilatation.

o Fundoscopy (to be performed by the Ophthalmologist at Screening and by the

Investigator at subsequent visits).

The slit lamp examination results will be documented using the AREDS2 Clinical Lens Opacity

Classification and Grading System(35-37). With this system the lens will be evaluated and graded

by comparison to a series of standard photographs for each possible type of lens opacity, the


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location and degree of lens opacity being determined. The possible type of lens opacity and its

grading will be documented. The possible lens opacity types are nuclear (9 possible grades),

cortical (9 possible grades) and posterior subcapsular (PSC) (9 possible grades). The

ophthalmologists will be trained on the AREDS2 clinical lens classification and grading system

prior to performing the study ophthalmologic examinations.

AREDS2 Lens Opacity Classification and Grading System Methodology:

The AREDS2 Clinical Lens Opacity Classification and Grading System methodology and

requirements will be described in a separate document which will be provided to the study

ophthalmologists prior to trial start.

7.6. Physical Examinations and Vital Signs

Purpose:

Safety monitoring.

Methodology:

The investigator will conduct a complete physical examination and any clinically significant

findings will be recorded. Complete physical exam includes a history of menstrual cycle (e.g.

possible irregularities, missed cycles) at the screening visit.

Systolic and diastolic blood pressure (mmHg) to be measured supine (after 5 minutes of rest)

using an appropriately sized cuff, and using the same type of sphygmomanometer, if possible by

the same observer, at each relevant visit.

Heart rate (bpm).

Axillary body temperature (ºC).

Weight (kg) (in light clothing and with no shoes).

Height (m) only at Visit 1 (Day -9 to -4)

To be performed within 2 hours before dosing on Days 1 through 14 and within 2 hours before the

time dosing would have occurred on Day 15. For the TMC207 plus PA-824 treatment arm these are

to be performed within 2 hours before the PA-824 dose.

7.7. Chest X-ray

Purpose:


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Determining participant eligibility: Chest x-ray for confirmation of radiological picture

compatible with TB.

Methodology:

A chest x-ray picture will be obtained from the clinic appointed radiology department. The

investigator is responsible for its review and analysis.

7.8. Retention Sample Collection

Purpose:

Additional plasma, serum, urine and sputum collections will be made on certain days when

samples are collected for other protocol-specified activities. These collections will be stored for

possible future analysis (e.g., for TMC207 or PA-824 metabolism). These samples will not be

used for genetic testing. The collection of these samples will be described in the informed

consent document.

7.8.1. Plasma and Serum

Methodology:


document, The Laboratory Manual, which will be provided to the site prior to study start. The

plasma and serum samples will be collected, handled and couriered to the designated archive

laboratory.

The designated archive laboratory will be determined prior to study start and all contact and

shipping details provided to the sites.

7.8.2. Sputum

Methodology:

If sufficient overnight sputum is available, the microbiology laboratory will collect up to three

1-ml aliquots from the overnight sputum samples collected by the investigational site. The

investigational site will not be required to process these retention samples in any way. The

microbiology laboratory will sample, freeze and ship the aliquots to the designated archive

laboratory.


shipping details provided to the laboratory.

7.8.3. Urine


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Methodology:

The urine sample collection methodology and requirement will be described in a separate

document, The Laboratory Manual, which will be provided to the site prior to study start.


shipping details provided to the sites.

8. ADVERSE EVENTS

The Investigators are responsible for eliciting adverse events by observing the participant and

recording all adverse events observed by him/her or reported by the participant during the trial.

8.1. Definitions

8.1.1. Adverse Event (AE)

Any untoward medical occurrence in a patient or clinical investigation subject administered a

pharmaceutical product and which does not necessarily have a causal relationship with this

treatment. An adverse event can therefore be any unfavorable and unintended sign (including an

abnormal laboratory finding), symptom, or disease temporally associated with the use of a

medicinal product, whether or not related to the medicinal product.

8.1.2. Serious Adverse Event (SAE)

Any untoward medical occurrence that at any dose:

results in death;

is life threatening (any 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);

requires inpatient hospitalization or prolongation of existing hospitalization;

results in persistent or significant disability/incapacity;

is a congenital anomaly/birth defect; or

is a medically important event.

Note:

Medical and scientific judgment should be exercised in deciding which is a medically important

event that may not be immediately life-threatening or result in death or hospitalization, but may

jeopardize the participant or may require medical or surgical intervention to prevent one of the

outcomes listed above. Examples of such events are intensive treatment in an emergency room or


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at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in

hospitalization, or the development of drug dependency or drug abuse. A “suspected transmission

of infectious agent by a medicinal product” is also considered a serious adverse event under the

SAE criterion “Other medically important condition”.

8.1.3. Unlisted (Unexpected) Adverse Event

An adverse reaction, the nature or severity of which is not consistent with the applicable product

information (e.g., Investigator’s Brochure for an unapproved investigational product or package

insert/summary of product characteristics for an approved product).

8.1.4. Life Threatening

Any 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.

8.1.5. Associated With the Use of the Drug

An adverse event is considered associated with the use of the drug if the attribution is possible,

probable or very likely.

8.2. Attribution Definitions

The following definitions for rating relatedness will be used:

Not Related: An adverse event, which is not related to the use of the drug.

Doubtful: An adverse event for which an alternative explanation is more likely, e.g.,

concomitant drug(s) or concomitant disease(s), and/or the relationship in time suggests that a

causal relationship is unlikely.

Possible: An adverse event, which might be due to the use of the drug. An alternative

explanation, e.g., concomitant drug(s) or concomitant disease(s), is inconclusive. The

relationship in time is reasonable; therefore the causal relationship cannot be excluded.

Probable: An adverse event, which might be due to the use of the drug. The relationship in time

is suggestive, e.g., confirmed by dechallenge. An alternative explanation is less likely, e.g.,

concomitant drug(s) or concomitant disease(s).

Very Likely: An adverse event, which is listed as a possible adverse reaction and cannot be

reasonably explained by an alternative explanation, e.g., concomitant drug(s) or concomitant

disease(s).

The definitions for rating severity will be based on the DMID Adult Toxicity Table (Appendix 4).


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8.3. Reporting

8.3.1. Adverse Event Reporting

Adverse events will be collected by the Investigator from the time a participant signs the Informed

Consent Form through to:

for TMC207 (excluding TMC207 plus PA-824) containing treatment arms:

all AEs and SAEs - the end of Visit 21 (Day 42);

for PA-824 (excluding TMC207 plus PA-824) containing treatment arms:


only ophthalmologic related adverse events and all serious adverse events - from Visit 20

(Day 28) through to the end of Visit 22 (Day 104);

for TMC207 plus PA-824 and Rifafour e275® treatment arms:


only ophthalmologic related adverse events and all serious adverse events - from Visit 21

(Day 42) through to the end of Visit 22 (Day 104).

Any AE (serious or non-serious) observed by the Investigator or reported by the participant will be

recorded on the Adverse Event Case Report Form. Diagnosis of the AE, if possible, should be

recorded by the Investigator. In the case where an overall diagnosis cannot be made, each specific

sign and/or symptom should be recorded as individual AEs.

The Investigator will review each AE and assess its relationship to drug treatment based on all

available information at the time of the completion of the case report form. Each sign or symptom

reported will be graded on a 4-point severity scale using the definitions according to the DMID

Adult Toxicity Table November 2007 (Appendix 4). Additionally, the date and time of onset,

relationship to IMP, duration, action taken, and outcome (recovered with sequelae, recovered

without sequelae, persisting, fatal, or unknown (lost to follow-up)) of each event will be noted.

8.3.2. Serious Adverse Event Reporting

Any AE that occurs which is serious must be reported by the Investigator to the study monitor and

copied to the Sponsor Medical Monitor within 24 hours of the site first being aware of the SAE,

whether or not the serious event is deemed drug-related.


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In addition, the Investigator will provide a detailed, signed, written, and complete SAE report form

that addresses the Investigator’s estimates of the relationship to the study drug and seriousness of

the AE in question to the study monitor within 24 hours of becoming aware of the SAE.

The study monitor will confirm receipt of the SAE Form with the Investigator and review the initial

information on the SAE for diagnosis, consistency and completeness of data.

For submission of updated or additional information on a previously reported SAE, the Investigator

will provide the study monitor with a newly completed Serious Adverse Event Form, designated as

a follow-up report. This will be submitted to the study monitor within 24 hours of the Investigator

receiving the information.

The study monitor will query for additional information from the Investigator, if necessary, to

complete the profile of the SAE reported.

The Investigator/designee will inform Regulatory Authorities and/or IEC/IRB of all SAEs in

accordance with local requirements and ICH guidelines for GCP.

The sponsor/designee will forward Safety Notification letters to Investigator for submission to the

IEC/IRB.

8.3.3. Follow-up of Adverse Events

During and following a participant’s participation in a clinical trial, the Investigator must ensure that

adequate medical care is provided to the participant for all AEs, including significant laboratory

values related to the trial. The Investigator should inform the participant when medical care is

needed for any AEs he/she becomes aware of.

All AEs must be followed until satisfactory clinical resolution or stabilization or until the end of the

follow-up period, and until all queries on these AEs have been resolved. Certain long-term AEs

cannot be followed until resolution within the setting of this protocol; in these cases follow-up will

be the responsibility of the treating physician. However, this has to be agreed upon with the

sponsor.

8.3.4. Follow-up of Post Trial Adverse Events

Any new SAEs reported by the participant to the Investigator that occur after the last scheduled

contact, and are determined by the Investigator to be possible, probable or very likely related to


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the use of the IMP, will be reported to the sponsor, IEC/IRB and regulatory authorities on an

expedited basis as required in accordance with local requirements and ICH guidelines for GCP.

8.3.5. Clinical Laboratory Adverse Events

Changes in the results of the Clinical Laboratory assessment results which the investigator feels are

clinically significant will be reported as adverse events. It is the investigators’ responsibility to

review the results of all laboratory tests as they become available. This review must be

documented by the investigators’ dated signature on the laboratory report. For each abnormal

laboratory test result, the investigator needs to ascertain and document if this is a clinically

significant change from baseline for that individual participant. This determination, however, does

not necessarily need to be made the first time an abnormal value is observed. The investigator may

repeat the laboratory test or request additional tests to verify the results of the original laboratory

tests. If this laboratory value is determined by the investigator to be a clinically significant change

from baseline for that participant, it is considered to be an adverse event.

8.3.6. Pregnancy

During the trial and for 1 week (PA-824 (excluding TMC207 plus PA-824) and Rifafour e275®

containing treatment arms) or 6 months (TMC207(including TMC207 plus PA-824) containing

treatment arms) after last dose of IMP, all women of childbearing potential will be instructed to

contact the Investigator immediately if they suspect they might be pregnant (for example, missed

or late menses). If pregnancy is suspected while the participant is receiving IMP, the IMP will be

withheld immediately until the result of the pregnancy test is known. If pregnancy is confirmed,

the IMP will be permanently discontinued in an appropriate manner and the participant withdrawn

from the trial.

The Investigator will immediately notify the sponsor of any pregnancy associated with IMP

exposure. The pregnancy will be recorded on the Pregnancy form and forwarded to the sponsor.

Protocol-required procedures for trial discontinuation and follow-up will be performed unless

contraindicated by the pregnancy. In addition, the Investigator will report to the sponsor follow-up

information regarding the outcome of the pregnancy, including perinatal and neonatal outcome.

Infants will be followed for 6 months. SAE reporting will also occur if the pregnancy outcome is a

congenital anomaly.


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Should the female partner of a male participant become pregnant during the study or in the 12

weeks after the completion of IMP and the Investigator becomes aware that this situation has

occurred, the Investigator will immediately notify the sponsor of any pregnancy associated with

IMP exposure. Consent will be requested from the female partner for collection of information on

her pregnancy history and for information on the current pregnancy and birth. If consent is

obtained, the pregnancy will be recorded on the Pregnancy forms and forwarded to the sponsor

and the Investigator will report to the sponsor information regarding the course of the pregnancy

including perinatal and neonatal outcome. Infants will be followed for 6 months. SAE reporting will

also occur if the pregnancy outcome is a congenital anomaly.

8.3.7. Disease Under Study

Symptoms of the disease under study (TB) experienced by the participant whilst on the study will

be assessed by the Investigator. If the symptom has worsened whilst the participant is in the study,

and the Investigator assesses it as clinically significant, it will be recorded as an adverse event. If

there is no change and the Investigator assesses the symptom as due to the participant’s TB and

not clinically significant, it will not be recorded as an AE and this will be noted in the participant’s

source documentation. If the Investigator is unsure as to whether the symptom is clinically

significant or not, it is to be classified as significant and reported as an AE.

All TB related symptoms that meet SAE criteria will be recorded and reported as a SAE.

9. MONITORING AND SAFETY FOR SPECIFIC TOXICITIES

AEs still ongoing at the end of treatment in the trial will be followed until satisfactory clinical

resolution or stabilization or until the end of the follow-up period, and until all queries on these AEs

have been resolved. The exception to this is all grade 3 and grade 4 laboratory abnormalities and

laboratory abnormalities resulting in an increase of 2 grades from baseline will be followed until

return to baseline or within one grade from baseline.

Note: For grade 3 or 4 laboratory toxicities, participants should have a confirmatory measurement

within 48 hours where possible. This management scheme is for confirmed lab abnormalities and

not for isolated events

Monitoring for specific toxicities is based upon target organs defined in preclinical toxicity studies

(see Investigator’s Brochures).

9.1. ALT and AST


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Management will be at the discretion of the Investigator, according to generally accepted medical

practice standards.

Grade 1 (> 1.0 to < 2.0 x ULN), Grade 2 (≥ 2.0 to < 3.0 x ULN) AST or ALT elevation:

Patients may continue IMP. Patients should be followed until resolution (return to baseline) or

stabilization of AST/ALT elevation.

Grade 3 (≥ 3.0 to ≤ 8.0 x ULN) or Grade 4 (> 8.0 x ULN ) AST or ALT elevation:

Patients will permanently discontinue IMP and be withdrawn from the trial. It is recommended

that the investigator contacts the sponsor to discuss the case of AST or ALT elevation. Patients

should be followed until resolution (return to baseline) or stabilization of AST/ALT elevation.

9.2. Amylase elevation

Grade 1 (> 1.0 to ≤ 1.5 x ULN) or Grade 2 (> 1.5 to ≤ 2.0 x ULN):

Participants may continue IMP and should be carefully evaluated and followed closely.

Grade 3 (> 2.0 to ≤ 5.0 x ULN) or Grade 4 (> 5.1 x ULN):

Further testing of pancreatic amylase and trypsin-like immunoreactivity should be considered after

consultation with the Sponsor Medical Monitor.

9.3. Pancreatic amylase and/or lipase elevation

Management will be at the discretion of the Investigator, according to generally accepted medical

practice standards.

Grade 1 (> 1.0 to ≤ 1.5 x ULN) or Grade 2 (> 1.5 to ≤ 2.0 x ULN):


Grade 3 (> 2.0 to ≤ 5.0 x ULN) or Grade 4 (> 5.0 x ULN):

For asymptomatic grade 3 pancreatic amylase elevations with no history or concomitant disease of

pancreatitis, participants may continue IMP but should be carefully evaluated and followed closely.

For confirmed grade 4 elevations of pancreatic amylase and confirmed grade 3 or 4 elevations of

lipase, participants will permanently discontinue IMP and be withdrawn from the trial.

9.4. Trypsin-like immunoreactivity ≥ 1.5 times ULN


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Participants should be followed closely. If there is clinical evidence of pancreatitis and elevation of

lipase and amylase of grade 3 or higher, participants will permanently discontinue IMP and be

withdrawn from the trial.

9.5. Musculo-skeletal System and Cardiac Muscle

Myalgia

Grade 1 (mild with no limitation of activity):


Grade 2 (muscle tenderness at site other than injection site or with moderate impairment of

activity) or Grade 3 (severe muscle tenderness with marked impairment of activity) or Grade

4 (frank myonecrosis):

Participants will permanently discontinue IMP and be withdrawn from the trial. CPK should be

fractionated for CPK-MB subunit.

Participants having grade 3 (3.1 to 6 x ULN) or grade 4 (> 6 x ULN) elevation in CPK-MB subunit will

permanently discontinue IMP and be withdrawn from the trial when grade 3 or 4 CPK –MB

elevation is accompanied by ECG and clinical evidence of ischemic heart disease.

9.6. LDH and LDH-isoenzymes

For participants with LDH elevation >2.5 x ULN, LDH isoenzymes will be assessed.

9.7. Cardiac Rhythm Disturbances

Grade 1 (asymptomatic) or Grade 2 (asymptomatic, transient rhythm abnormality not

requiring any treatment) cardiac rhythm disturbances:


Grade 3 (recurrent, persistent, symptomatic arrhythmia requiring treatment) or Grade 4

(unstable dysrhythmia requiring treatment) cardiac rhythm disturbances:

Participants will permanently discontinue IMP and be withdrawn from the trial.

QTc prolongation

A participant should be withdrawn if they have a QTcB and QTcF interval greater than 500 msec; or

an increase from baseline values greater than 60 msec, present on repeated ECGs and exceeding


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the values 430 msec (for males) and 450 msec (for females) and accompanied with clinically

relevant T-wave morphology changes. For PA-824 containing treatment arms (excluding the

TMC207 plus PA-824 arm), the post-treatment ECG evaluations will be compared to the time-

matched pre-treatment ECGs.

If the initial review of the post-treatment ECGs suggests that the corrected QT interval (corrected

QTcB and QTcF) has increased by more than 60 msec, additional ECGs will be collected at 15 minute

intervals until the corrected QT interval has returned to baseline or the increase has been

satisfactorily explained. However, because this assessment is based on an initial (on-site)

impression prior to centralized measurement by the centralized ECG laboratory, an increase in

corrected QT interval of more than 60 msec need not be reported as an AE unless it is accompanied

by signs or symptoms of myocardial ischemia or developing cardiac arrhythmia or that the overall

value is above 500 msec.

9.8. Gastrointestinal System

Participants with Grade 4 elevation of gastrointestinal parameters will not be withdrawn from the

trial, however should be monitored closely.

9.9. Other toxicities

Grade 1 or 2

Participants who develop grade 1 or 2 AE or laboratory toxicity may continue intake of IMP.

Grade 3 or 4

Participants who develop grade 3 or 4 AE or laboratory toxicity (see Appendix 4 for specifics) will be

carefully evaluated by the Investigator. Participants may continue intake of IMP or be withdrawn

from the trial if, in the opinion of the Investigator, the AE or laboratory toxicity poses a significant

risk for the subject in case of continued participation in the trial. Participants should be followed as

appropriate until resolution of the AE or toxicity.

10. STATISTICAL ANALYSIS

There are no interim analyses planned for this study. All randomized participants will be included in

the analyses. Additional details of the analyses specified in this section will be provided in the

statistical analysis plan (SAP) and/or the clinical study report.

10.1. Sample Size


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This is a Phase II trial to investigate the EBA and safety, tolerability and PK of TMC207 alone,

TMC207 plus pyrazinamide, TMC207 plus PA-824, PA-824 plus pyrazinamide and PA-824 plus

pyrazinamide and moxifloxacin. The planned sample size of 15 participants per treatment group is

in keeping with other Phase II trials of this type and accounts for the possibility of up to 3 drop-outs

per arm, which based on previous studies of this type conducted at these sites, represents a

conservative estimate of the expected drop-out rate. Previous EBA studies indicate that the

between participant standard deviation of logCFU can be approximately 0.2. Therefore, assuming

similar variability in the new trial the expected standard errors of group mean EBA and

corresponding width of 95% confidence intervals are in Table 6.

Table 6: Expected Standard Errors of Group mean log CFU and confidence intervals

Group Size Standard Error Width of 95%CI

15 0.052 0.101

10 0.063 0.124

10.2. Primary Efficacy Analysis

The primary efficacy analysis will be the rate of change in CFU over the period Day tx-ty, with tx

being Day 0 and ty being Day 14, which may be described with linear, bi-linear or non-linear

regression of logCFU over time.

The values of EBA(tx - ty) will be calculated using the following formula:

EBA(tx -ty)=[mean logCFU(Day tx)- logCFU(Day ty)]/ (ty- tx)

It is important to note that the regression may be non-linear, i.e. to accommodate the possibility of

varying rate of change. One form of non-linear regression to be considered is bi-linear in which the

trend in logCFU is linear with a certain slope over the period Day tx to Day , and then linear with a

different slope over Day to Day ty; note that is a parameter to be estimated. Some other form

of non-linear regression may be fitted. Whatever its form, bi-linear or otherwise, the essential

measure of efficacy is the rate of change described over the period Day x-y. Fitting of all regression

relations will be by the method of least squares. Regressions will be fitted to the data of individual

participants and then appropriately averaged to estimate population trends and to compare the

treatment groups. This is, in effect, a non-linear random effects model approach.

10.3. Secondary Efficacy Analysis


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The secondary efficacy endpoints are:

The EBA (EBA0-2, EBA2-14 and EBA7-14) as determined by the rate of change of logCFU in

sputum over the period Day 0 to Day 2, Day 2 to Day 14 and Day 7 to Day 14, in participants,

which may be described with linear, bi-linear or non-linear regression of logCFU on time.

The time to sputum culture positivity (TTP) (TTP0-2, TTP0-14, TTP2-14, and TTP7-14) in the

Mycobacterium Growth Indicator Tube (Bactec MGIT960) system as determined by the rate

of change in TTP in sputum over the periods Day 0 to Day 2, Day 0 to Day 14, Day 2 to Day

14 and Day 7 to Day 14 in participants, which may be described with linear, bi-linear or non-

linear regression of TTP on time.

These EBAs will be based on the fitted regressions as described above, and their summary statistics,

for example means and confidence limits, will be obtained.

Time to positivity (TTP) in the MGIT system will be recorded for the same time points as the logCFU.

Serial TTP measurements are a relatively new and not fully validated method for the assessment of

the change of the viable bacterial load on sputum over time. Because of its technical simplicity it is

anticipated that TTP might replace logCFU in future trials so that collecting such data for this trial is

essential. In analogy to the primary outcome parameter described above, linear or some other

form of non-linear regression will be fitted by the method of least squares.

In addition, post hoc analyses of the EBA and TTP data over time periods other than those stated

above (0-2, 0-14, 2-14 and 7-14) may be performed.

10.4. Pharmacokinetic Analysis

The following PK parameters will be estimated for TMC207, TMC207 metabolite M2, PA-824,

pyrazinamide and moxifloxacin from participants’ individual plasma concentrations (except in the

Rifafour e275® treatment arm) by applying a noncompartmental approach using PK software such

as WinNonlin Professional. Concentration values reported as below the limit of quantitation will be

set to zero. Each parameter will be calculated separately using plasma concentrations of TMC207,

TMC207 metabolite M2, PA-824, pyrazinamide or moxifloxacin. PK parameters will be estimated for

TMC-207 treatment arms on Day 14 only and for PA-824 on Days 1, 8 and 14.

Cmax: Maximum observed plasma drug concentration.

Tmax: Time at which Cmax is observed (obtained without interpolation).

Cmin: Minimum observed plasma drug concentration 24 hours following the last dose.


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AUC(0-24):Area under the drug concentration-time curve calculated using linear trapezoidal

summation from time zero to time 24 hours.

Descriptive statistics including mean, standard deviation, coefficient of variation, median, minimum

and maximum, geometric mean and geometric mean CV% will be computed for each PK parameter

by group. Grouping will be by gender.

In addition, mean and median concentration-versus-time graphs will be provided (with error bars as

appropriate).

10.5. Pharmacokinetic and Pharmacodynamic Statistical Analysis

For the TMC207 and PA-824 containing treatment arms, the following PK-PD correlations will be

calculated and presented for TMC207, PA-824, pyrazinamide and moxifloxacin:

EBAs versus the following PK variables (Day 14 only) separately and by gender:

Cmax;

AUC(0-24) ;

Time over MIC (for PA-824, TMC207 and moxifloxacin).

For each of the above the following will be presented:

A plot of all the individual values for each PK-PD comparison on an X vs. Y graph, with r

(Pearson’s correlation coefficient) noted.

Tables including a simple r.

10.6. Safety and Tolerability Analyses

All adverse events will be coded using the Medical Dictionary for Regulatory Activities

(MedDRA) and will be presented by Preferred Term within each MedDRA System Organ Class

(SOC).

The incidence of the following events will be summarized by treatment group for further

medical analysis:

o Treatment-emergent adverse events (TEAEs) by severity.

o Potentially IMP-related TEAEs.

o TEAEs with a fatal outcome.

o Serious TEAEs.


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o Discontinuations due to TEAEs.

Other safety variables: Laboratory Parameters, Physical Examination, Ophthalmological Exam,

Vital signs (see Appendix 5), Concomitant medication. Descriptive summary statistics will be

presented.

Cardiovascular Safety (see Appendix 5). ECGs will be centrally read. QT intervals will be

adjusted using Fridericia’s correction and Bazett’s correction. QT/QTc values and changes from

pre-dose (average of Screening and Day 1 values) at each time point will be summarized using

descriptive statistics by group and time of collection. For TMC207 and PA-824 containing

treatment arms, the potential correlations between the plasma concentration of IMP and the

change from baseline of QT interval corrected by Fridericia’s method (QTcF) and change from

baseline of QT interval corrected by Bazett’s method (QTcB) with respect to time for the

different treatment groups will be explored. These will be presented as descriptive analyses,

and no inferential tests will be carried out.

o Post-baseline QT/QTc intervals will be classified into the following categories:

o QT/QTc < 450 msec

o 450 msec < QT/QTc < 480 msec

o 480 msec < QT/QTc < 500 msec

o QT/QTc > 500 msec

o QTc changes from baseline will be classified into the following categories:

o increase < 30 msec,

o > 30 msec and < 60 msec, and

o increase > 60 msec.

Frequency counts will be used to summarize the number of participants at each time point

according to the above categories.

o ECG results will be classified as normal or abnormal and summarized using frequency counts

by dose group and time of collection.

10.7. Mycobacteriology Characterization


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Descriptive summary statistics of the mycobacterial characteristics of the participants’ MTB strains

assessed will be presented.

11. RECORDS MANAGEMENT

11.1. Data Collection

All CRF pages will be completed for each participant who receives any amount of IMP. For

screening failure participants a screening failure CRF will be completed. For participants who are

prematurely withdrawn, the visits up to withdrawal plus the withdrawal and follow-up visits need

to be completed.

11.2. Source Documents

Source data are defined as all information in original records and certified copies of original records

of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction

and evaluation of the trial. Source documents will include, but are not limited to, progress notes,

electronic data, screening logs, and recorded data from automated instruments.

All source documents pertaining to this trial will be maintained by the Investigators. The

Investigator has to permit trial-related monitoring, audits, Independent Ethics

Committee/Institutional Review Board (IEC/IRB) review and regulatory inspections providing

authorized persons direct access to source data/documents.

11.3. File Management at the Trial Center

It is the responsibility of the Investigators to ensure that the trial center files are maintained in

accordance with the Guidelines for Good Practice in the Conduct of Clinical Trials in Human Patients

in South Africa 2006 (SA GCP), International Conference on Harmonization Good Clinical Practice

(ICH GCP) and the ethical principles that have their origin in the Declaration of Helsinki.

11.4. Records Retention at the Trial Center

The Principal Investigator is obliged to retain records and data from the trial for safety reasons and

for audit and inspection subsequent to trial completion. The essential documents should be

retained for not less than 5 years after the last approval of a marketing application and until there

are no pending or contemplated marketing applications or at least 5 years have elapsed since the

formal discontinuation of clinical development of the IMP.


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The sponsor will make financial provisions for the Investigator to deposit the documents at an

external site for safekeeping for as long as required by regulations and the sponsor.

12. QUALITY CONTROL AND QUALITY ASSURANCE

12.1. Site Procedures

The Investigator undertakes to perform the clinical trial in accordance with this protocol, SA GCP,

ICH GCP and the ethical principles that have their origin in the Declaration of Helsinki.

The Investigator undertakes to complete the CRFs according to the Sponsor’s requirements, in a

timely, accurate and legible manner. Print-outs of laboratory reports and ECG tracings will be

attached to the applicable page of the CRF. CRF entries will be verifiable to source documentation

other than the CRF.

Site Standard Operating Procedures will be adhered to for all clinical and bioanalytical activities

relevant to the quality of the study. Participant compliance will be monitored throughout the study

via procedures such as a Screening questionnaire to review inclusion and exclusion criteria, urine

drug and alcohol screens at Screening, mouth check following dosing, and confinement for conduct

of all procedures with clinical research staff on site at all times.

The Investigator will sign and date any analysis results (e.g. laboratory, ECG, etc.) to verify that the

results have been reviewed.

The Investigator may appoint other sub-investigators to assist with the study. However the

Investigator maintains responsibility for the study and will supervise the sub-investigators. Written

IEC/IRB approval will be obtained prior to involvement in the study.

The Investigator will ensure that all site personnel are adequately trained in SA GCP, ICH GCP, the

protocol, IB and all study procedures and requirements.

12.2. Monitoring

The Principal Investigator is responsible for the validity of all data collected at the clinical site and

must accept the various monitoring procedures employed by the Sponsor. The purpose of

monitoring is to verify that the rights and well being of human patients are protected; that trial

data are accurate, complete and verifiable with source data; and that the trial is conducted in

compliance with the protocol, SA GCP, ICH GCP and the ethical principles that have their origin in

the Declaration of Helsinki and the applicable regulatory requirements.


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Monitors assigned by the Sponsor will conduct regular site visits for the purpose of monitoring

various aspects of the study. Visits will take place usually within a predetermined interval, but this

may vary during the course of the study. The Investigator and site staff will allow the study monitor

and authorized representatives of the Sponsor to (1) inspect all CRFs, written informed consent

documents and corresponding source documents (e.g. original medical records), participant records

and laboratory raw data, and (2) access clinical supplies, dispensing and storage areas. The

Investigator and site staff should also (1) agree to assist with monitoring activities if requested and

(2) provide adequate time and space for monitoring visits.

The monitor will query any missing, confusing, spurious, or otherwise ambiguous data with the

Investigator. All queries should be resolved in a timely manner. A monitoring log will be

maintained recording each visit, the reason for the visit, the monitor’s signature and Investigator or

designee’s confirmation signature.

12.3. Auditing

For the purpose of compliance with SA GCP, ICH GCP and regulatory agency guidelines, it may be

necessary for Sponsor-authorized Quality Assurance personnel and/or authorized personnel from

an external regulatory agency to conduct an audit or inspection of the investigational site. The

purpose of an audit is to assess the quality of data with regard to accuracy, adequacy and

consistency, and to assure that studies are in accordance with the guidelines. Having the highest

quality data from studies is an essential aspect of drug development.

The Investigator and site staff will be given sufficient notice to prepare for such visits, which will

usually last between one and two days and may be conducted at any stage during the study. The

audit will involve the review of all study-related documentation required by GCP to be maintained

by each site; drug storage, dispensing and return; all study-related supplies; and source documents

against the CRFs to assure the adequacy and accuracy of the information which has been recorded,

including the verification of any AEs which have occurred.

In the event of the site being notified of a Regulatory Inspection, the Sponsor will help with

preparation. It is essential that the Sponsor be notified of the inspection as soon as possible.

13. ETHICS AND RESPONSIBILITY

13.1. Basic Principles


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This research will be carried out in accordance with South African GCP guidelines Second Edition

2006, the principles enunciated in the Declaration of Helsinki (revised version of Seoul, October

2008; and the ICH harmonized tripartite guideline regarding Good Clinical Practice (E6 Consolidated

Guidance, 10 June 1996).

13.2. Independent Ethics Committee/Institutional Review Board (IEC/IRB) Review

The protocol and required study related documents will be reviewed by the sites respective

IEC/IRB. The study will not start until the IEC/IRB has approved the protocol, written informed

consent, any written information to be provided to the participant or any modification thereof, plus

any other study related documents required for review. The IEC/IRB shall be constituted and shall

operate in accordance with SA GCP guidelines Second Edition 2006, principles enunciated in the

Declaration of Helsinki (revised version of Seoul, October 2008); and the ICH GCP (E6 Consolidated

Guidance, 10 June 1996). The Investigator will maintain an accurate and complete record of all

submissions made to the IRB/IEC. The records should be filed in the Investigator’s Study File, and

copies will be sent to the Sponsor.

13.3. Regulatory Authorities

The Regulatory Authorities will receive the protocol, amendments, reports on SAEs, and the

Integrated Clinical Trial Report according to national regulations. Written approval will be obtained

from the Regulatory Authorities prior to commencement of the trial.

13.4. Informed Consent

Written informed consent will be obtained from all participants (or legally acceptable

representative) before any trial-related procedures (including any screening or pre-treatment

procedures) are performed. Investigators may discuss the availability of the trial and the

opportunity for entry with a potential participant without first obtaining consent. However,

informed consent must be obtained and documented prior to initiation of any procedures that are

performed solely for the purpose of determining eligibility for research, including withdrawal from

current medication(s). When this is done in anticipation of, or in preparation for, the research, it is

considered to be part of the research.

The Investigators have both ethical and legal responsibility to ensure that each participant being

considered for inclusion in this trial is given a full explanation of the protocol. This shall be

documented on a written informed consent form that shall be approved by the same IEC/IRB


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responsible for approval of this protocol. Each informed consent form shall include the elements

required by the SA GCP and ICH GCP guidelines and must adhere to the ethical principles that have

their origin in the Declaration of Helsinki.

Once the appropriate essential information has been provided to the participant and fully explained

by the Investigators (or qualified designees) and it is felt that the participant understands the

implications of participating, the IEC/IRB approved written informed consent form will be signed

and dated by both the participant and the person obtaining consent (Investigators or designees),

and by any other parties required by the IEC/IRB.

In accordance with the SA GCP guidelines, the original signed informed consent form will be kept

with the trial records and a copy of signed informed consent form will be provided to the

participant. Another copy of the signed informed consent form and a source document identifying

the trial and recording the dates of participation will be placed in the participant’s medical record.

All of the above mentioned activities will be completed prior to the participant’s participation in the

trial.

The monitor will inspect the original completed consent form(s) for all participants.

13.5. Confidentiality

All site staff, the Sponsor, and any sponsor representatives will preserve the confidentiality of all

participants taking part in the study, in accordance with ICH GCP, applicable South African national

and local regulations and, to the extent applicable, the U.S. Health Insurance Portability and

Accountability Act of 1996 (“HIPAA”). Subject to the requirement for source data verification by

the study personnel by reference to the participant’s notes, confidentiality of all participant

identities will be maintained. Only participant study number and initials will be used on the CRF

and in all study correspondence, as permitted. No material bearing a participant’s name will be

kept on file by the Sponsor. The written informed consent will contain a clause granting permission

for review of the participants’ source data.

13.6. Publication Policy

The definition of publication for this purpose is any public presentation of the data emerging from

this study.


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All unpublished information given to the Investigator by the Sponsor shall not be published or

disclosed to a third party, other than to the responsible IEC/IRB, within the understanding of the

confidentiality of their nature, without the prior written consent of the Sponsor.

Results of this research will be submitted for publication as soon as feasible upon completion of the

study in the form of a joint publication(s) between Sponsor and Investigator(s), including site

clinical and laboratory investigators, as appropriate.

13.7. Protocol Amendment Policy

Any change to the protocol will be effected by means of a protocol amendment. Any changes

which affect participant safety or welfare will be submitted to the IEC/IRB and Regulatory

Authorities prior to implementation. The Investigator, IEC/IRB, and Sponsor must agree on all

amendments. No amendment will be implemented until approved by the relevant Authorities and

signed by all required parties. Exceptions to this are when the Investigator considers that the

participant’s safety is compromised.

Protocol amendments detailing minor administrative changes should be submitted by the

Investigator to the IEC/IRB and Regulatory Authorities for notification purposes as appropriate.

13.8. Financial Aspects, Insurance and Indemnity

The study sponsor is the Global Alliance for TB Drug Development (TB Alliance). The TB Alliance is a

not for profit, product development partnership accelerating the discovery and development of

new TB drugs that will shorten treatment, be effective against susceptible and resistant strains, be

compatible with antiretroviral therapies for those HIV-TB participants currently on such therapies,

and improve treatment of latent infection.

The TB Alliance works with public and private partners worldwide. It is committed to ensuring that

approved new regimens are affordable, adopted and available to those who need them.

The TB Alliance operates with funding mainly from the Bill & Melinda Gates Foundation, the

Netherlands Ministry of Foreign Affairs (DGIS), the United Kingdom Department for International

Development (DFID), and the United States Agency for International Development (USAID).

The participants will not receive any incentives for their involvement in the study. The sponsor has

made provision to reimburse the participants for out-of-pocket expenses such as travelling to and

from the study site and other miscellaneous costs as a result of their study participation.


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The sponsor certifies that it has liability insurance coverage for itself and will provide an associated

certificate upon request. The insurance does not relieve the Investigators of the obligation to

maintain their own liability insurance as required by applicable law. The sponsor does not assume

any obligation for the medical treatment of other injuries and illnesses.


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14. REFERENCES

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patients with pulmonary tuberculosis. Am Rev Respir Dis 1980; 121 (6): 939-49.

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pulmonary tuberculosis. Antimicrob Agents Chemother 2001; 47 (7): 1972-6.

4. Donald PR, Sirgel FA, Venter A, et al. Early bactericidal activity of antituberculosis agents.

Expert Rev Anti-infect Ther 2003; 1 (1): 141-55.

5. Johnson JL, Hadad DJ, Boom WH, et al. Early and extended early bactericidal activity of

levofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis. Int J Tuberc Lung Dis

2006; 10 (6): 1-8.

6. Rustomjee R, Diacon AH, Allen J, et al. Early bactericidal activity and pharmacokinetics of the

diarylquinoline TMC207 in treatment of pulmonary tuberculosis. Antimicrob Agents

Chemother 2008 Aug; 52(8): 2831-5. Epub 2008 May 27.

7. TMC207 Investigator’s Brochure, Tibotec Pharmaceuticals Ltd., Edition 5 June 2008, Addendum

May 2009.

8. Koul A, Dendouga N, Vergauwen K, et al. Diarylquinolines target subunit c of mycobacterial

ATP synthase. Nat Chem Biol 2007; 3: 323-4.

9. Andries K, Verhasselt P, Guillemont J, et al. A diarylquinoline drug active on the ATP synthase

of Mycobacterium turberculosis. Science 2005; 307: 223-7.

10. Huitric E, Verhasselt P, Andries K, Hoffner SE. In vitro antimycobacterial spectrum of a

diarylquinoline ATP synthase inhibitor. Antimicrob Agents Chemother 2007; 51: 4202-4.

11. Koul A, Vranckx L, Dendouga N, et al. Diarylquinolines are bactericidal for dormant

mycobacteria as a result of disturbed homeostasis. J Biol Chem 2008; 283: 25273-80.

12. Ibrahim M, Andries K, Lounis N, et al. Synergistic activity of R207910 combined with

pyrazinamide against murine tuberculosis. Antimicrob Agents Chemother 2007; 51: 1011-15.

13. Investigator’s Brochure, Global Alliance for TB Drug Development, PA-824, 11 June 2009.

14. Stover, C. K., P. Warrener, D. R. VanDevanter, et al. 2000. A small-molecule nitroimidazopyran

drug candidate for the treatment of tuberculosis. Nature 405:962–966.

15. Anne J. Lenaerts, Veronica Gruppo, Karen S. Marietta, Christine M. Johnson, Diane K. Driscoll,

Nicholas M. Tompkins, Jerry D. Rose, Robert C. Reynolds, and Ian M. Orme. Preclinical Testing

of the Nitroimidazopyran PA-824 for Activity against Mycobacterium tuberculosis in a Series of

In Vitro and In Vivo Models. Antimicrob Agents Chemother. 2005 June; 49(6): 2294–2301.

16. Sandeep Tyagi, E. Nuermberger, T. Yoshimatsu, K. Williams, I. Rosenthal, N. Lounis, W. Bishai,

and J. Grosset. Bactericidal Activity of the Nitroimidazopyran PA-824 in a Murine Model of

Tuberculosis. Antimicrob Agents Chemother. 2005 June; 49(6): 2289–2293.

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17. Baohong PI, Lounis N, Maslo C, Truffot-Pernot C, Bonnafous P, Grosset J. In vitro and in vivo

activities of moxifloxacin and clinafloxacin against Mycobacterium tuberculosis.

Antimicrob.Agents Chemother. 1998; 42(8):2066-9.

18. Miyazaki E, Miyazaki M, Chen JM, Chaisson RE, Bishai WR. Moxifloxacin (BAY12-8039), a new 8-

methoxyquinolone, is active in a mouse model of tuberculosis. Antimicrob. Agents Chemother.

1999; 43(1):85-9.

19. Nuermberger EL, Yoshimatsu T, Tyagi S, O'Brien RJ, Vernon AN, Chaisson RE et al. Moxifloxacin-

containing regimen greatly reduces time to culture conversion in murine tuberculosis.

Am.J.Respir.Crit.Care Med. 2003; 169:421-6.

20. O'Brien RJ. Scientific blueprint for tuberculosis drug development. Tuberculosis 2001;

81(S1):19-45.

21. Gosling RD, Uiso LO, Sam NE, Bongard E, Kanduma EG, Nyindo M et al. The bactericidal activity

of moxifloxacin in patients with pulmonary tuberculosis. Am J Respir Crit Care Med 2003; 168

(11):1342-5.

22. Pletz MWR, De Roux A, Roth A et al. Early Bactericidal Activity of Moxifloxacin in Treatment of

Pulmonary Tuberculosis: a Prospective, Randomized Study. Antimicrob. Agents Chemother

2004; 48 (3); 780-2.

23. Burman W, Goldberg S, Johnson JL, et al. Moxifloxacin versus ethambutol in the first 2 months

of treatment for pulmonary tuberculosis. Am J Respir Crit Care Med 2006; 174: 331-38.

24. Rustomjee R, Lienhardt C, Kanyok T et al. Gatifloxacin for TB (OFLOTUB) study team. A phase II

study of the sterilizing activities of ofloxacin, gatifloxacin and moxifloxacin in pulmonary

tuberculosis. Int J Tuberc Lung Dis 2008; 12:128-38.

25. Conde MB, Efron A, Loredo C et al. Moxifloxacin versus ethambutol in the initial treatment of

tuberculosis: a double-blind, randomized, controlled phase II trial. Lancet 2009; 373: 1183-89.

26. Dorman SE, Johnson JL, Goldberg S, et al. Substitution of Moxifloxacin for Isoniazid during

Intensive Phase Treatment of Pulmonary Tuberculosis. Am J Respir Crit Care Med 2009; 180:

273-80.

27. Zhang Y and Mitchison D. The curious characteristics of pyrazinamide: a review. Int J Tuberc

Lung Dis; 7 (1): 6-21.

28. Rokeya Tasneen, Sandeep Tyagi, Kathy Williams, Jacques Grosset, and Eric Nuermberger

Enhanced Bactericidal Activity of Rifampin and/or Pyrazinamide When Combined with PA-824

in a Murine Model of Tuberculosis. Antimicrob Agents Chemother 2008 Oct; 52(10): 3664–8

29. Nuermberger E, Tyagi S, Tasneen R, Williams K and Almeida D, Rosenthal I and Grosset J.

Powerful Bactericidal and Sterilizing Activity of a Regimen Containing PA-824, Moxifloxacin and

Pyrazinamide in a Murine Model of Tuberculosis. Antimicrob.Agents Chemother.

2008;52:1522-4


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30. WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI Ethical Principles for Medical

Research Involving Human Subjects Adopted by the 18th WMA General Assembly, Helsinki,

Finland, June 1964, and amended by the:

29th WMA General Assembly, Tokyo, Japan, October 1975

35th WMA General Assembly, Venice, Italy, October 1983

41st WMA General Assembly, Hong Kong, September 1989

48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996

52nd WMA General Assembly, Edinburgh, Scotland, October 2000

53rd WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 added)

55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added)

59th WMA General Assembly, Seoul, October 2008.

31. INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR

REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE. ICH HARMONISED TRIPARTITE

GUIDELINE. GUIDELINE FOR GOOD CLINICAL PRACTICE, E6(R1). www.ich.org. 2002

32. Chaves AA, Keller WJ, O’Sullivan S, Williams MA, Fitzgerald LE, McPherson HE, et al.

Cardiovascular monkey telemetry: sensitivity to detect QT interval prolongation. J Pharmacol

Toxicol Methods. 2006 Sep-Oct;54(2):150-8

33. Diacon A, Pym A, Grobusch M, et al. The Diarylquinoline TMC207 for Multidrug-Resistant

Tuberculosis. 2009; 360 (23): 2397-405.

34. Moxifloxacin Investigator’s Brochure, Bayer Schering Pharma., V11,01 Feb 09.

35. The age-related eye disease study (AREDS) system for classifying cataracts from photographs:

AREDS report no. 4. American Journal of Ophthalmology, Volume 131, Issue 2, February 2001,

Pages 167-175. The Age-Related Eye Disease Study Research Group.

36. A Randomized, Placebo-Controlled, Clinical Trial of High-Dose Supplementation With Vitamins

C and E and Beta Carotene for Age-Related Cataract and Vision Loss: AREDS Report No. 9. Arch

Ophthalmol. 2001 October ; 119(10): 1439–1452. Age-Related Eye Disease Study Research

Group.

37. A Randomized, Double-Masked, Placebo-Controlled Clinical Trial of Multivitamin

Supplementation for Age-Related Lens Opacities Clinical Trial of Nutritional Supplements and

Age-Related Cataract Report No. 3. Ophthalmology 2008;115:599 – 607 © 2008 by the

American Academy of Ophthalmology. Clinical Trial of Nutritional Supplements and Age-

Related Cataract Study Group.

38. Mdluli, K and Nuermberger, E. Pre-Clinical Drug Combination Studies to Identify Novel

Regimens for TB. In: Recent Advances in TB Drug Development symposium, 40th Union World

Conference, International Union Against TB and Lung Disease, Cancun, Mexico, 2009.

http://www.ich.org/

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APPENDIX 1: PROTOCOL SIGNATURE PAGES

Not Applicable.

This document does not require formal approval as it is a working document containing a combination of:

Protocol 27 April 2010

Protocol Administrative Change Number 01; 09 September 2010

Protocol Amendment Number 01; 06 December 2010

which comprise the formal approved documents.


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APPENDIX 2: RIFAFOUR E-275 PACKAGE INSERT

RIFAFOUR®e-275 TABLETS SCHEDULING STATUS: S4 PROPRIETARY NAME (and dosage form):

RIFAFOUR®e-275 TABLETS COMPOSITION: Each tablet contains: Rifampicin 150 mg Isoniazid 75 mg Pyrazinamide 400 mg Ethambutol 275 mg Contains sodium ascorbate as anti-oxidant. PHARMACOLOGICAL CLASSIFICATION: A 20.2.3 Tuberculostatic combinations PHARMACOLOGICAL ACTION: Rifafour e-275 tablets is a combination of four first line agents used in the treatment of tuberculosis. Rifampicin is a semi-synthetic, broad-spectrum bactericidal antibiotic. Isoniazid is a synthetic, antitubercular agent which is bacteriostatic against semi-dormant bacilli and bactericidal against actively dividing mycobacteria. Pyrazinamide may be bactericidal or bacteriostatic, depending on its concentration and the susceptibility of the organism. Ethambutol is a synthetic, bacteriostatic antitubercular agent. All agents are readily absorbed following oral administration, with wide distribution to most tissues and fluids including cerebrospinal fluid. INDICATIONS: Initial phase treatment of pulmonary and extrapulmonary tuberculosis in new adult patients and re-treatment of adult cases. CONTRA-INDICATIONS: Rifafour e-275 tablets are contra-indicated in: • patients with hypersensitivity to rifamycins, isoniazid, pyrazinamide, ethambutol or other chemically related

medication.

• the presence of jaundice or active hepatic disease.

• patients with optic neuritis. Safety in pregnancy has not been established. All agents of Rifafour e-275 tablets are excre

ted in breast milk. Safety during lactation has not beer established.

Rifafour e-275 should not be used in children under 13 years of age. WARNINGS: Liver function should be checked before and during treatment and special care should be exercised in alcoholic patients, the elderly or those with pre-existing liver disease. Caution should be observed with the use of Rifafour e-275 tablets in the following patients: • Impaired kidney function: dosage adjustment may be required according to the serum concentration of ethambutol

• Patients with visual defects: should visual disturbances occur during treatment these must be reported immediately and the medicine discontinued pending visual evaluation

• Patients at risk of neuropathy or pyridoxine deficiency, including those who are diabetic, alcoholic, malnourished, uraemic or pregnant: pyridoxine supplementation (in a 10 mg to 50 mg daily dose) is usually required in these instances

• Patients with a history of gout

• Patients with porphyria

• Patients with epilepsy, as convulsions may be precipitated

• Patients with a history of psychosis

• Patients with diabetes: pyrazinamide may cause interference with urine ketone determinations

• Rifampicin may decrease the effect of oral contraceptives and patients are advised to change to non-hormonal methods of birth control


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• Treatment with Rifafour e-275 tablets may produce reddish colouration of urine, tears and saliva. Contact lenses may be irreversibly stained.

DOSAGE AND DIRECTIONS FOR USE: Take Rifafour e-275 tablets with a full glass of water 1 hour before, or 2 hours after a meal. However, if gastrointestinal irritation occurs, the tablets may be taken with food. If aluminium-containing antacids are taken, administer one hour after the tablet dose. The recommended treatment dosages, based on the patient's body weight, given daily for the 2 month initial-phase treatment in adults and children over 13 years of age are as follows:

30-37 kg 2 tablets

38-54 kg 3 tablets

55 - 70 kg 4 tablets

71 kg and over 5 tablets

SIDE-EFFECTS AND SPECIAL PRECAUTIONS: Side-effects associated with rifampicin: Some patients may experience a cutaneous syndrome which presents 2 to 3 hours after a daily or intermittent dose i.e. facial flushing, itching, rash, eye irritation. A 12 hour "flu" syndrome, usually occurring after 3 to 6 months of intermittent treatment and usually with doses of 20 mg/kg or more, may present as fever, chills, bone pain and malaise. Gastrointestinal effects include nausea, vomiting, anorexia, diarrhoea and epigastric distress, which may be alleviated by administration with food. There have been reports of pseudomembranous colitis. Hepatitis and the prodromal symptoms of hepatitis may occur (nausea, vomiting, unusual tiredness/fatigue). Rifampicin can cause thrombocytopenia and purpura usually with intermittent regimens. Other haematological adverse effects include eosinophilia, leucopenia and haemolytic anaemia. Nervous system effects include headache, drowsiness, dizziness, ataxia, numbness, visual disturbances and muscular weakness. Alterations in kidney function and renal failure have occurred. Rifampicin may cause orange-red discoloration of urine and other body fluids. Menstrual disturbances have been reported. Side-effects associated with isoniazid: Elevated liver enzymes associated with clinical signs of hepatitis such as nausea, vomiting or fatigue may indicate hepatic damage. The incidence of liver damage is highest in patients over 35 years of age, those who are slow acetylators and those who consume alcohol on a daily basis. Gastrointestinal effects (nausea, vomiting, pellagra) and hypersensitivity reactions (skin eruptions including erythema multiforme, fever, lymphadenopathy, vasculitis) may occur. Haematological effects have been reported (sideroblastic anaemia, agranulocytosis, haemolytic anaemia, thrombocytopenia, neutropenia, eosinophiliaand less frequently, aplastic anaemia). Neurological effects include psychotic reactions and convulsions. Other effects: hyperglycaemia, metabolic acidosis, lupus-like syndrome, rheumatoid syndrome, urinary retention and gynaecomastia. Optic neuritis has also been reported. Peripheral neuropathy has also been associated with isoniazid administration. Pyridoxine supplementation prevents the development of peripheral neuritis, as well as most other nervous system dysfunctions. Side-effects associated with pyrazinamide: The most serious side-effect is hepatotoxicity and its frequency appears to be dose-related. Hyperuricaemia commonly occurs, occasionally accompanied by arthralgia and may lead to attacks of gout. Photosensitivity and skin rash have been reported less frequently. Other side-effects that have been reported are anorexia, nausea and vomiting, malaise, fever, sideroblastic anaemia and dysuria. Side-effects associated with ethambutol: Retrobulbar neuritis with a reduction in visual acuity, constriction of visual field, central or peripheral scotoma, and green-red colour blindness may occur, affecting one or both eyes. The degree of visual impairment appears to depend on the dose and duration of therapy. Retinal haemorrhage has occurred less frequently. Renal clearance of urate may be reduced and acute gout has been precipitated. Hypersensitivity reactions include skin rash, pruritis, leucopenia, fever and joint pains. Gastrointestinal disturbances include metallic taste, nausea, vomiting, anorexia and abdominal


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pain. Other adverse effects: Confusion, disorientation, hallucinations, headache, dizziness, malaise, jaundice or transient liver dysfunction, peripheral neuritis. SPECIAL PRECAUTIONS: In the following cases, treatment with Rifafour e-275 tablets should be stopped immediately and the patient evaluated: jaundice, rash and fever, elevated liver enzymes associated with the clinical signs of hepatitis, visual impairment. If liver damage is confirmed, the medicine should not be recommenced. Treatment should be discontinued permanently should thrombocytopenia, purpura, shock or renal failure occur. Periodic eye examinations during treatment is suggested. INTERACTIONS: Rifampicin: Concurrent use of alcohol, acetaminophen, isoniazid and other hepatotoxic medication may increase the incidence of rifampicin-induced hepatotoxicity. The effectiveness of oestrogen-containing oral preparations is reduced. Rifampicin accelerates the metabolism of certain medicines by inducing microsomal enzymes. Medicines that are affected include: atorvaquone, azathioprine, chloramphenicol, cimetidine, clofibrate, corticosteroids, coumarin anticoagulants, cyclosporin, dapsone, diazepam and other benzodiazepines, doxycycline, azole antifungals (ketoconazole, itraconazole, fluconazole), haloperidol, hexobarbitone, methadone, oral hypoglycaemic agents, phenytoin, quinine, sulphasalazine, thyroxine, theophylline, zidovudine, beta-blockers, digitoxin, digoxin, antiarrhythmic agents (e.g. disopyramide, verapamil) and calcium channel blockers. Isoniazid: Chronic use of isoniazid may decrease the plasma clearance and prolong the duration of action of alfentanil, coumarin anticoagulants, benzodiazepines, carbamazepine, phenytoin, ethosuximide, chlorzoxazone, and theophylline. Appropriate adjustment of the anticonvulsant dose may be required. Concurrent use of paracetamol, alcohol, rifampicin and other hepatotoxic medication, may increase the potential for isoniazid-induced hepatotoxicity. Aluminium-containing antacids may delay absorption and decrease serum concentrations of isoniazid. Ingestion of certain types of cheese e.g. Swiss or Cheshire, or fish e.g. tuna, may result in itching of the skin, rapid or pounding heart, chills or headache. Glucocorticoid corticosteroids may increase hepatic metabolism and/or excretion of isoniazid. Concurrent use of cycloserine, disulfiram and other neurotoxic medicines may increase the potential for CNS toxicity. Isoniazid may increase the formation of potentially nephrotoxic inorganic fluoride metabolites when used concurrently with enflurane. Interactions with ketoconazole and miconazole have been reported. False positive reactions with copper sulphate urine glucose tests may occur. Pyrazinamide: Pyrazinamide may decrease the efficacy of gout therapy (e.g. allopurinol, colchicine, probenecid or sulphinpyrazone) and dosage adjustments of this medication may be necessary. Ethambutol: Concurrent administration of neurotoxic medication with ethambutol may potentiate neurotoxic effects such as optic and peripheral neuritis. KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT: For symptoms of overdosage, refer to "Side-Effects". Treatment of overdosage consists of gastric lavage, symptomatic and supportive therapy. IDENTIFICATION: Purple, round, film coated tablets. PRESENTATION: Securitainers of 40, 60, 80, 100 and 500 tablets. STORAGE INSTRUCTIONS: Store in a cool place, below 25°C in well-closed containers, protected from light. KEEP OUT OF REACH OF CHILDREN. REGISTRATION NUMBER: 34/20.2.3/0187 NAME AND BUSINESS ADDRESS OF THE APPLICANT: Aventis Pharma (Pty) Ltd 2 Bond Street, Midrand, 1685 DATE OF PUBLICATION OF THIS PACKAGE INSERT: 11 February 2002 Aventis Pharma (Pty) Ltd 2 Bond Street Midrand 1685


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APPENDIX 3: THE IUATLD SCALE

The IUATLD scale proposes five groups for reporting the results of reading smears for acid fast bacilli. They should be recorded as follows:

FINDING RECORDING

No acid-fast bacilli found in at least 100 fields

negative

1 to 9 acid-fast bacilli per 100 fields exact figure/100/scanty positive

10 to 99 acid-fast bacilli per 100 fields +

1 to 10 acid-fast bacilli per field in at least 50 fields

++

More than 10 acid-fast bacilli per field in at least 20 fields

+++

Reference: The Public Health Service National Tuberculosis Reference Laboratory and the National Laboratory Network. Minimum Requirements, Role and Operation in a Low-Income Country. International Union Against Tuberculosis and Lung Disease 1998


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APPENDIX 4: DIVISION OF MICROBIOLOGY AND INFECTIOUS DISEASES (DMID) ADULT TOXICITY TABLE ABBREVIATIONS: Abbreviations utilized in the Table:

ULN = Upper Limit of Normal LLN = Lower Limit of Normal Rx = Therapy Req = Required Mod = Moderate IV = Intravenous ADL = Activities of Daily Living Dec = Decreased

ESTIMATING SEVERITY GRADE For abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to estimate grade of severity: GRADE 1 Mild Transient or mild discomfort (< 48 hours); no medical

intervention/therapy required GRADE 2 Moderate Mild to moderate limitation in activity - some

assistance may be needed; no or minimal medical intervention/therapy required

GRADE 3 Severe Marked limitation in activity, some assistance usually required; medical intervention/therapy required, hospitalizations possible

GRADE 4 Potentially Life-threatening Extreme limitation in activity, significant assistance required; significant medical intervention/therapy required, hospitalization or hospice care probable

SERIOUS OR LIFE-THREATENING AEs ANY clinical event deemed by the clinician to be serious or life-threatening should be considered a grade 4 event. Clinical events considered to be serious or life-threatening include, but are not limited to: seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular coagulation, diffuse petechiae, paralysis, acute psychosis, severe depression. COMMENTS REGARDING THE USE OF THESE TABLES • Standardized and commonly used toxicity tables (Division of AIDS, NCI’s Common Toxicity

Criteria (CTC), and World Health Organization (WHO)) have been adapted for use by the Division of Microbiology and Infectious Diseases (DMID) and modified to better meet the needs of patients in DMID trials.

• For parameters not included in the following Toxicity Tables, sites should refer to the “Guide

For Estimating Severity Grade” located above. • Criteria are generally grouped by body system.

• Some protocols may have additional protocol specific grading criteria, which will supercede the use of these tables for specified criteria.


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HEMATOLOGY

Grade 1

Grade 2

Grade 3

Grade 4

Hemoglobin

9.5 - 10.5 gm/dL

8.0 - 9.4gm/dL

6.5 - 7.9 gm/dL

< 6.5 gm/dL

Absolute Neutrophil Count

1000-1500/mm

3

750-999/mm

3

500-749/mm

3

<500/mm

3

Platelets

75,000-99,999/mm

3

50,000-74,999/mm

3

20,000-49,999/mm

3

<20,000/mm

3

WBCs 11,000-13,000/ mm3 13,000-

15,000 /mm3

15,000- 30,000/mm

3

>30,000 or <1,000 /mm

3

% Polymorphonuclear Leucocytes + Band Cells

> 80% 90 – 95% >95% ----------

Abnormal

Fibrinogen

Low:

100-200 mg/dL

High:

400-600 mg/dL

Low:

<100 mg/dL

High:

>600 mg/dL

Low:

< 50 mg/dL

----------

Fibrinogen associated with gross bleeding or with disseminated coagulation

Fibrin Split Product

20-40 mcg/ml

41-50 mcg/ml

51-60 mcg/ml

> 60 mcg/ml

Prothrombin Time (PT)

1.01 - 1.25 x ULN

1.26-1.5 x ULN

1.51 -3.0 x ULN

>3 x ULN

Activated Partial Thromboplastin (APPT)

1.01 -1.66 x ULN

1.67 - 2.33 x ULN

2.34 - 3 x ULN

> 3 x ULN

Methemoglobin

5.0 - 9.9 %

10.0 - 14.9 %

15.0 - 19.9%

> 20.0 %


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CHEMISTRIES

Grade 1

Grade 2

Grade 3

Grade 4

Hyponatremia

130-135 mEq/L

123-129 mEq/L

116-122 mEq/L

< 116 mEq/L or abnormal sodium with mental status changes or seizures

Hypernatremia

146-150 mEq/L

151-157 mEq/L

158-165 mEq/L

> 165 mEq/L or abnormal sodium with mental status changes or seizures

Hypokalemia

3.0 - 3.4 mEq/L

2.5 - 2.9 mEq/L

2.0 - 2.4 mEq/L or intensive replacement therapy or hospitalization required

< 2.0 mEq/L or abnormal potassium with paresis, ileus or life-threatening arrhythmia

Hyperkalemia

5.6 - 6.0 mEq/L

6.1 - 6.5 mEq/L

6.6 - 7.0 mEq/l

> 7.0 mEq/L or abnormal potassium with life-threatening arrhythmia

Hypoglycemia

55-64 mg/dL

40-54 mg/dL

30-39 mg/dL

<30 mg/dL or abnormal glucose with mental status changes or coma

Hyperglycemia (nonfasting and no prior diabetes)

116 - 160 mg/dL

161- 250 mg/dL

251 - 500 mg/dL

> 500 mg/dL or abnormal glucose with ketoacidosis or seizures

Hypocalcemia (corrected for albumin)

8.4 - 7.8 mg/dL

7.7 - 7.0 mg/dL

6.9 - 6.1 mg/dL

< 6.1 mg/dL or abnormal calcium with life threatening arrhythmia or tetany


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CHEMISTRIES (continued)

Grade 1

Grade 2

Grade 3

Grade 4

Hypercalcemia (correct for albumin)

10.6 - 11.5 mg/dL

11.6 - 12.5 mg/dL

12.6 - 13.5 mg/dL

> 13.5 mg/dL or abnormal calcium with life threatening arrhythmia

Hypomagnesemia

1.4 - 1.2 mEq/L

1.1 - 0.9 mEq/L

0.8 - 0.6 mEq/L

< 0.6 mEq/L or abnormal magnesium with life-threatening arrhythmia

Hypophosphatemia

2.0 - 2.4 mg/dL

1.5 -1.9 mg/dL or replacement Rx required

1.0 -1.4 mg/dL intensive therapy or hospitalization required

< 1.0 mg/dL or abnormal phosphate with life-threatening arrhythmia

Hyperbilirubinemia (when accompanied by any increase in other liver function test)

1.1 - <1.25 x ULN

1.25 - <1.5 x ULN

1.5 – 1.75 x ULN

> 1.75 x ULN

Hyperbilirubinemia (when other liver function are in the normal range)

1.1 - <1.5 x ULN

1.5 - <2.0 x ULN

2.0 – 3.0 x ULN

> 3.0 x ULN

BUN

1.25 - 2.5 x ULN

2.6 - 5 x ULN

5.1 - 10 x ULN

> 10 x ULN

Hyperuricemia (uric acid) 7.5 – 10.0 mg/dL 10.1 – 12.0 mg/dL 12.1 – 15.0 mg/dL >15.0 mg/dL

Creatinine

1.1 - 1.5 x ULN

1.6 - 3.0 x ULN

3.1 - 6 x ULN

> 6 x ULN or dialysis required


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ENZYMES

Grade 1

Grade 2

Grade 3

Grade 4

AST (SGOT)

1.1 - <2.0 x ULN

2.0 – <3.0 x ULN

3.0 – 8.0 x ULN

> 8 x ULN

ALT (SGPT)

1.1 - <2.0 x ULN

2.0 – <3.0 x ULN

3.0 – 8.0 x ULN

> 8 x ULN

GGT

1.1 - <2.0 x ULN

2.0 – <3.0 x ULN

3.0 – 8.0 x ULN

> 8 x ULN

Alkaline Phosphatase

1.1 - <2.0 x ULN

2.0 – <3.0 x ULN

3.0 – 8.0 x ULN

> 8 x ULN

Amylase

1.1 - 1.5 x ULN

1.6 - 2.0 x ULN

2.1 - 5.0 x ULN

> 5.1 x ULN

Lipase 1.1 - 1.5 x ULN

1.6 - 2.0 x ULN

2.1 - 5.0 x ULN

> 5.1 x ULN

URINALYSIS

Grade 1

Grade 2

Grade 3

Grade 4

Proteinuria 1+

or

200 mg - 1 gm loss/day

2-3+ or 1- 2 gm loss/day

4+ or 2-3.5 gm loss/day

nephrotic syndrome

or

> 3.5 gm loss/day

Hematuria microscopic only

<10 rbc/hpf

gross, no clots

>10 rbc/hpf

gross, with or without clots, OR red blood cell casts

obstructive or required transfusion


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CARDIOVASCULAR

Grade 1

Grade 2

Grade 3

Grade 4

Cardiac Rhythm

asymptomatic, transient signs, no Rx required

recurrent/persistent; symptomatic Rx required

unstable dysrythmia; hospitalization and treatment required

Hypertension

transient increase

> 20 mm/Hg; no treatment

recurrent, chronic increase

> 20mm/Hg.

/treatment required

acute treatment required; outpatient treatment or hospitalization possible

end organ damage or hospitalization required

Hypotension

transient orthostatic hypotension with heart rate increased by <20 beat/min or decreased by <10 mm Hg systolic BP, No treatment required

symptoms due to orthostatic hypotension or BP decreased by <20 mm Hg systolic; correctable with oral fluid treatment

requires IV fluids; no hospitalization required

mean arterial pressure

<60mm/ Hg or end organ damage or shock; requires hospitalization and vasopressor treatment

Pericarditis

minimal effusion

mild/moderate asymptomatic effusion, no treatment

symptomatic effusion; pain; EKG changes

tamponade; pericardiocentesis or surgery required

Hemorrhage, Blood Loss

microscopic/occult

mild, no transfusion

gross blood loss; 1-2 units transfused

massive blood loss; > 3 units transfused


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RESPIRATORY

Grade 1

Grade 2

Grade 3

Grade 4

Cough

transient- no treatment

persistent cough; treatment responsive

Paroxysmal cough; uncontrolled with treatment

--------------------

Bronchospasm, Acute

transient; no treatment; 70% - 80% FEV1

of peak flow

requires treatment; normalizes with bronchodilator; FEV1 50% - 70% (of peak flow)

no normalization with bronchodilator; FEV1 25% - 50% of peak flow; or retractions present

cyanosis: FEV1 < 25% of peak flow or intubation necessary

Dyspnea

dyspnea on exertion dyspnea with normal activity

dyspnea at rest dyspnea requiring Oxygen therapy


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GASTROINTESTINAL

Grade 1

Grade 2

Grade 3

Grade 4

Nausea

mild or transient; maintains reasonable intake

moderate discomfort; intake decreased significantly; some activity limited

no significant intake; requires IV fluids

hospitalization required;

Vomiting

1 episode in 24 hours

2-5 episodes in 24 hours

>6 episodes in 24 hours or needing IV fluids

physiologic consequences requiring hospitalization or requiring parenteral nutrition

Constipation

requiring stool softener or dietary modification

requiring laxatives obstipation requiring manual evacuation or enema

obstruction or toxic megacolon

Diarrhea

mild or transient; 3-4 loose stools/day or mild diarrhea last < 1 week

moderate or persistent; 5-7 loose stools/day or diarrhea lasting >1 week

>7 loose stools/day or bloody diarrhea; or orthostatic hypotension or electrolyte imbalance or >2L IV fluids required

hypotensive shock or physiologic consequences requiring hospitalization

Oral Discomfort/Dysphagia

mild discomfort; no difficulty swallowing

some limits on eating/drinking

eating/talking very limited; unable to swallow solid foods

unable to drink fluids; requires IV fluids


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NEUROLOGICAL

Grade 1

Grade 2

Grade 3

Grade 4

Neuro-Cerebellar

slight incoordination dysdiadochokinesis

intention tremor, dysmetria, slurred speech; nystagmus

locomotor ataxia

incapacitated

Psychiatric

mild anxiety or depression

moderate anxiety or depression; therapy required; change in normal routine

severe mood changes requiring therapy; or suicidal ideation; or aggressive ideation

acute psychosis requiring hospitalization; or suicidal gesture/attempt or hallucinations

Muscle Strength

subjective weakness no objective symptoms/ signs

mild objective signs/symptoms no decrease in function

objective weakness function limited

paralysis

Paresthesia (burning, tingling, etc.)

mild discomfort; no treatment required

moderate discomfort; non-narcotic analgesia required

severe discomfort; or narcotic analgesia required with symptomatic improvement

incapacitating; or not responsive to narcotic analgesia

Neuro-sensory mild impairment in sensation (decreased sensation, e.g., vibratory, pinprick, hot/cold in great toes) in focal area or symmetrical distribution; or change in taste, smell, vision and/or hearing

moderate impairment (mod decreased sensation, e.g., vibratory, pinprick, hot/cold to ankles) and/or joint position or mild impairment that is not symmetrical

severe impairment (decreased or loss of sensation to knees or wrists) or loss of sensation of at least mod degree in multiple different body areas (i.e., upper and lower extremities)

sensory loss involves limbs and trunk; paralysis; or seizures


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MUSCULOSKELETAL

Grade 1

Grade 2

Grade 3

Grade 4

Arthralgia (joint pain)

mild pain not interfering with function

moderate pain, analgesics and/or pain interfering with function but not with activities of daily living

severe pain; pain and/or analgesics interfering with activities of daily living

disabling pain

Arthritis mild pain with inflammation, erythema or joint swelling – but not interfering with function

moderate pain with inflammation, erythema or joint swelling – interfering with function, but not with activities of daily living

severe pain with inflammation, erythema or joint swelling –and interfering with activities of daily living

permanent and/or disabling joint distruction

Myalgia myalgia with no limitation of activity

muscle tenderness (at other than injection site) or with moderate impairment of activity

severe muscle tenderness with marked impairment of activity

frank myonecrosis

SKIN

Grade 1

Grade 2

Grade 3

Grade 4

Mucocutaneous erythema; pruritus diffuse, maculo papular rash, dry desquamation

vesiculation or moist desquamation or ulceration

exfoliative dermatitis, mucous membrane involvement or erythema, multiforme or suspected Stevens-Johnson or necrosis requiring surgery

Induration < 15mm 15-30 mm >30mm

Erythema < 15mm 15-30 mm >30mm

Edema < 15mm 15-30 mm >30mm

Rash at Injection Site < 15mm 15-30 mm >30mm

Pruritus slight itching at injection site

moderate itching at injection extremity

itching over entire body


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SYSTEMIC

Grade 1

Grade 2

Grade 3

Grade 4

Allergic Reaction

pruritus without rash

localized urticaria

generalized urticaria; angioedema

anaphylaxis

Headache mild, no treatment required

transient, moderate; treatment required

severe; responds to initial narcotic therapy

intractable; requires repeated narcotic therapy

Fever: oral

37.7 - 38.5 C or 100.0 - 101.5 F

38.6 - 39.5 C or 101.6 - 102.9 F

39.6 - 40.5 C or 103 - 105 F

> 40 C or > 105 F

Fatigue

normal activity reduced < 48 hours

normal activity decreased 25- 50% > 48 hours

normal activity decreased > 50% can’t work

unable to care for self


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APPENDIX 5: CARDIOVASCULAR SAFETY ECG All important abnormalities from the ECG readings will be reported. The percentage of patients with increases in QTcF and QTcB of <30, 30-60, or > 60 ms from baseline will also be tabulated at each time point. Abnormality Code ECG parameter

HR PR QRS QTcorrected

Abnormalities on actual values

“Abnormally low” ≤ 50 bpm NAP ≤ 50 ms -

“Abnormally high” ≥ 120 bpm ≥ 210 ms ≥ 120 ms -

“+450 ms, 480 ms+ - - - 450 ms < QTc ≤ 480 ms

“+480 ms, 500 ms+ - - - 480 ms < QTc ≤ 500 ms

“More than 500 ms - - - QTc > 500 ms

Abnormalities on changes from baseline

“*30; 60+ ms” - - - [30; 60] ms

“> 60 ms” - - - > 60 ms

Vital Signs The following abnormalities will be defined for vital signs:

Abnormality Code Vital Signs parameter

Pulse DBP SBP

Abnormalities on actual values

“Abnormally low” ≤ 50 bpm ≤ 50 mmHg ≤ 90 mm Hg

“Grade 1 or mild” - > 90 mmHg-<100 mmHg > 140 mmHg-<160 mmHg

“Grade 2 or moderate” - ≥ 100 mmHg-<110 mmHg

≥ 160 mmHg-<180 mmHg

“Grade 3 or severe” - ≥ 110 mmHg ≥ 180 mmHg

“Abnormally high” ≥ 120 bpm - -


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APPENDIX 6: PYRAZINAMIDE PACKAGE INSERT


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APPENDIX 7: MOXIFLOXACIN PACKAGE INSERT


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