Hy Dad Presentation Final

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8 months for patient inclusion (about 8 patients/week)◦ January through August

1 month to complete follow-up 1 month to close database 1 month to write the Clinical Study Report Expected completion of the study is about 1 year

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Four arm Randomized◦ 1 of 3 groups of GXR (2, 3, or 4 mg/day) or placebo, in

1:1:1:1 ratio Placebo-controlled Trial Multi-center - 48 Centers in US◦Expected enrollment 270 patients

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Assess the efficacy and safety of an extended-release formulation of Guanfacine (GXR) compared with placebo for the treatment of children and adolescents with attention-deficit/hyperactivity disorder (ADHD)

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Primary Outcome measurement will include:◦Attention-Deficit/Hyperactivity Disorder Rating Scale IV total

score

Secondary Outcome measurements will include:◦Clinical Global Impression of Severity (CGI-S)◦Clinical Global Impression of Improvement (CGI-I)◦Parent's Global Assessment (PGA)◦Conners’ Parent Rating Scale-Revised: Short Form (CPRS-R)◦Conners' Teacher Rating Scale-Revised: Short Form (CTRS-R)

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Central Action:◦Stimulation of α2 adrenoceptors in the brainstem reduces

sympathetic tone, causing a centrally mediated vasodilatation and reduction in heart rate

Vascular smooth muscle:◦ α2 adrenoceptors located on vascular smooth muscle open

Ca2+ channels and cause vasoconstriction

Prejunctional action:◦Stimulation of a2 adrenoceptors located prejunctionally on

peripheral neurons reduces norepinephrine release

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Treatment Rationale

Guanfacine is a centrally acting antihypertensive with α2-adrenoceptor agonist properties

Goal of antihypertensive therapy is to reduce blood pressure

Binds to postsynaptic α2 adrenoceptors in the prefrontal cortex which have been implicated in attention and organizational functions.

Guanfacine is a drug of benefit in the treatment of attention deficit hyperactivity disorder (ADHD)

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Dose Schedule

GXR doses escalated in 1 mg increments/week to a total of 4 tablets

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Placebo

Randomization

GXR 1 mg/day

GXR 1 mg/day

GXR 2 mg/day

GXR 3 mg/day

Placebo

GXR 4 mg/dayGXR 1 mg/day

IP Packaging◦GXR and placebo will be identical tablets to be taken orally

prepackaged in weekly individual study kits◦Each kit will contain 4 tablets- a combination of placebo

and study drug, placebo only, or study drug only

Patients will be assigned the next available drug kit in ascending order of the drug kit number

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Drug storage◦Secured Drug to be stored ambient (20-30ºc)◦Drug accountability records maintained on all received and

dispensed study drug◦All kits (used and unused) maintained until end of study ◦Tear off portion of labels to be affixed to CRF◦CRA to inventory and return all kits

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No dose modifications will be made

All patients will be titrated off study:◦End of treatment- 8 weeks◦Extension study- titrate to 2 mg/day open-label

Patients who come off study will be titrated down at a rate of 1 mg/day

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1) Patients aged 6-17 years inclusive and met DSM criteria for a primary diagnosis of ADHD combined subtype, predominantly inattentive subtype, or predominantly hyperactive-impulsive subtype

2) Patients required to function intellectually at age appropriate levels

3) ECG results within the reference range4) Blood pressure measurements within 95th

percentile for appropriate age, gender and height

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1) Current, uncontrolled, co-morbid psychiatric diagnosis (except oppositional defiant disorder) w/significant symptoms such as any severe co-morbid Axis II disorder or severe Axis 1 disorder, contraindicated GXR treatment or confound efficacy or safety assessments

2) Patients who weighed <55 lb or were morbidly overweight or obese,

3) Pregnant or lactating4) Hypertensive5) QTc interval of >440 milliseconds6) History of seizure during the past 2 years

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7) Tic disorder8) Family history of Tourette’s disorder9) A positive urine drug screen10) Abnormal thyroid function not properly treated11) Cardiac condition or family history of cardiac

condition12) Patients who had taken an investigational drug

within 28 days13) Taking meds that effect that effect BP or heart rate

or CNS effects or affect performance

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Written informed consent must be fully executed by (obtained from) each patients parent or legal guardian (prior to study specific, non-standard-of-care activities)

Written assent must be obtained from each patient involved in the study

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Schedule ScreeningPeriod

WashoutPeriod

Visit 1 (Week 1)

Visit 2 (Week 2)

Visit 3 (Week 3)

Visit 4 (Week 4)

Visit 5 (Week 5)

Visit 6 (Week 6)

Visit 7 (Week 7)

Visit 8 (Week 8)

Visit 9 (Week 9)

ADHD-RS-IV √ √ √ √ √ √CGI-S √ √CGI-I √ √ √ √ √PGA √ √ √CPRS-R √ √ √CTRS-R √ √ √Vital Signs √ √ √ √ √ √ √ √ √ √ √Lab Tests √ √Physical Exam √ √12-lead ECG* √ √ * √ √ √AE’s √ √ √ √ √ √ √ √ √ √ √Con Meds √ √ √ √ √ √ √ √ √ √ √

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Screening Visit◦Screening period must be done within 14 days to determine

eligibility Measure severity of patients condition on the Clinical Global

Impression of Severity (CGI-S) Using Parent’s Global Assessment (PGA)

Parent or guardian should note children's behavior during previous week Concomitant medication assessment Laboratory tests and physical examination, including weight and

height Adverse events, Vital signs, 12-lead ECG Clinical laboratory tests (hematology; chemistry, including cortisol

levels and HGH; and urinalysis)

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Washout Period Patient’s current ADHD medication should be discontinued for ~1

week, or at a minimum, 5 times the established half-life of meds Administer ADHD-RS-IV Measure severity of patients condition on the Clinical Global

Impression of Severity (CGI-S) AE’s assessed and vital sign measurements, including BP and pulse

rate Minimum 3 ECGs to determine baseline (mean)

Last day of washout period Administer Conners’ Parent Rating Scale-Revised: Short Form (CPRS-R) Administer Conners’ Teacher Rating Scale-Revised: Short Form CTRS-R

Concomitant medication assessment

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Treatment Period◦Visit 1 & 2 (Week 1 & 2)

Administer ADHD-RS-IV Administer Clinical Global Impression of Improvement (CGI-I)

Clinicians to assess change in patients clinical status relative to the baseline

AE’s should be assessed and vital sign measurements, including BP and pulse rate

Concomitant medication assessment

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Treatment Period◦Visit 3 (Week 3)

Administer ADHD-RS-IV Administer Clinical Global Impression of Improvement (CGI-I) AE’s should be assessed and vital sign measurements, including

BP and pulse rate Administer 12-lead ECG

Concomitant medication assessment

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Treatment Period◦Visit 4 & 5 (Week 4 & 5)

Administer ADHD-RS-IV Administer Clinical Global Impression of Improvement (CGI-I) Administer PGA

Parents or guardian to assess changes in relation to baseline ratings AE’s should be assessed and vital sign measurements, including

BP and pulse rate Administer CPRS-R and CTRA-R

Parents should complete the CPRS-R at 6am, 6pm and 8pm Teachers should complete the CTRS-R at 10am and 2pm

Concomitant medication assessment

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Treatment Period◦Visit 6 (Week 6)

AE’s should be assessed and vital sign measurements, including BP and pulse rate

Concomitant medication assessment

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Treatment Period◦Visit 7 (Week 7)

AE’s should be assessed and vital sign measurements, including BP and pulse rate Administer 12-lead ECG

Concomitant medication assessment Offer patients the option to enroll in an open-label extension study

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Treatment Period◦Visit 8 (Week 8)

AE’s should be assessed and vital sign measurements, including BP and pulse rate

Concomitant medication assessment

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Treatment Period◦Visit 9 (Week 9)

AE’s should be assessed and vital sign measurements, including BP and pulse rate

Concomitant medication assessment Laboratory tests and physical examination, including weight and

height Vital signs, 12-lead ECG Clinical laboratory tests (hematology; chemistry, including cortisol levels

and HGH; and urinalysis) Discontinue dosing for non-extension study patients

Extension study patients will undergo end-of-study assessments Patients should return to the clinic 2 to 4 days later for assessments

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Visit 10◦ 30 days after the last dose of the study drug, patients must

return to the clinic for a final visit (visit 10)

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Any new untoward medical occurrence or worsening of a pre-existing medical condition in a patient administered a medicinal product and that does not necessarily have a causal relationship with the treatment◦ For this study, the timeline for reporting an AE begins a the time of the

first does of study drug, and continues until 30 days after the last dose of study drug. Any event prior to the first dose should be recorded as part of the baseline medical history.

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The investigator or designee should elicit AE information through open ended questioning of the patient, physical examination, and review of the laboratory results.

All AEs, whether serious or not, must be described in the source documents and the adverse event page of the case report form.

All new events, as well as those that worsen in intensity or frequency relative to baseline, which occur after administration of study drug through the period of protocol-specified follow-up must be captured.

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Information to be reported in the description of each AE includes:◦ A medical diagnosis of the event (if a medical diagnosis can not be

determined, a description of each sign or symptom characterizing the event should be recorded)

◦ The dates of onset and resolution of the event◦ Action taken in relation to the event (e.g. any change in study drug

dosing, treatments/medications required, hospitalization required, discontinuation from the study as a result of the AE, etc.)

◦ Outcome of the event (e.g. patient recovered (with or without sequelae), death, etc.)

◦ Whether the event is serious or not

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Each AE will be graded according to the following criteria:

◦Mild - corresponds to an event not resulting in disability or incapacity but which requires intervention

◦Moderate - corresponds to an event not resulting in disability or incapacity, but which requires intervention

◦Severe - corresponds to an event resulting in temporary disability or incapacity and which requires intervention

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The investigator must attempt to determine if an adverse event is in some way related to the use of the study drug. Use the following definitions:

Definite/Certain: there is a reasonable causal relationship between the IP and the AE: the event responds to withdrawal of the IP (de-challenge) and recurs with re-challenge when clinically feasible.

Probable: there is a reasonable causal relationship between the IP and the AE; the event responds to de-challenge and re-challenge is not required/

Possible: there is a reasonable causal relationship between the IP and the AE; de-challenging information is lacking or unclear

Not Likely: there is a temporal (timely) relationship to the IP administration, but there is not a reasonable causal relationship between the IP and the AE

Unrelated: there is not a temporal relationship to the IP administration, or there is a reasonable relationship between another drug, concurrent disease, or circumstance and AE

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In the case of emergencies only, when it is essential for the clinical management or safety of the subject, the Investigator may unblind the subject’s study treatment assignment by applying for disclosure of the treatment allocation of an individual patient by the study pharmacist.

In cases of unblinding the Investigator is required to notify the Sponsor immediately that unblinding has occurred, but the Investigator should not reveal the treatment assignment to the Sponsor, unless asked to do so

The Investigator must also document the date and reason for unblinding the study treatment on the subject’s source documentation and applicable CRF.

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An SAE is any AE meeting any of the following criteria:◦Results in death◦ Is life threatening◦Requires or prolongs hospitalization◦Results in persistent or significant disability/incapacity◦Pregnancy or results in congenital anomaly or birth defect◦Results in the development of drug dependency or drug abuse◦ Is an important medical event

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Sponsor must be notified within 24 hours of becoming aware of the event!

Complete SAE form and fax to (888) 555-1212

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REMEMBER TO NOTIFY WITHIN 24 HOURS!

Medical Monitor - Anne Cunniffe-Marcy◦ 415-555-7272

Project Manager - Leigh Shinn◦ 415-555-7273

CRA - Michael Hovis◦ 415-555-7274

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