Efficacy & Safety of KAPVAY™ Extended-Release in Children & Adolescents With Attention Deficit Hyperactivity Disorder

Study Overview
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Brief Summary
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The purpose of this study is to determine the long-term efficacy and safety of KAPVAY™ (clonidine hydrochloride) extended-release in children and adolescents with Attention Deficit Hyperactivity Disorder (ADHD)

Official Title
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A 40-Week, Phase 4, Double-Blind, Placebo-Controlled, Multicenter, Randomized-Withdrawal Study to Evaluate the Long-Term Efficacy and Safety of KAPVAY™ (Clonidine Hydrochloride) Extended-Release in Children and Adolescents With ADHD

Conditions
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Attention Deficit Hyperactivity Disorder

Intervention / Treatment
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* Drug: clonidine hydrochloride
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, aged 6 to 17 years inclusive Subject as well as parent/guardian is able to sign the informed assent or consent form Subject meets Diagnostic and Statistical Manual of Mental Disorders 4th edition, Text Revision (DSM-IV-TR) criteria for a primary diagnosis of Attention Deficit Hyperactivity Disorder (ADHD), combined subtype, hyperactive/impulsive subtype, or inattentive sub-type based on a detailed psychiatric evaluation using the Shorter version of the Kiddie-Schedule for Affective Disorders and Schizophrenia-Present and Lifetime (MINI-Kid) or DSM-IV TR based checklist for ADHD Subject has a minimum of Attention Deficit Hyperactivity Disorder-Rating Scale-4th edition (clinician version) total score of 28 at baseline (Visit 2) Subject has a minimum of Clinical Global Impressions-Severity of Illness Scale of 4 at baseline (Visit 2) Subject is able to swallow intact tablets based upon interview and screening procedures Subject is functioning at an age-appropriate level intellectually with an estimated intelligence quotient of at least 70 based on interview and history Subject and parent/guardian understand, are willing, to fully comply with the study requirements, procedures, and restrictions defined in this protocol Subject has a supine and standing blood pressure measurement within the 95th percentile for age, gender, and height If a female has experienced menarche, she must have a negative serum beta human chorionic gonadotropin pregnancy test at screening (Visit 1), negative urine pregnancy test at baseline (Visit 2), agree to be abstinent from sexual activity that could result in pregnancy, or use acceptable contraceptives throughout the period of the study drug exposure and for 30 days after the last dose of the study drug Exclusion Criteria: Subject has a current comorbid psychiatric condition (except oppositional defiant disorder) that is controlled (requiring a prohibited medication or behavioral modification program) or uncontrolled. Subject has any condition or illness including clinically significant abnormal screening (Visit 1) laboratory values that, in the opinion of the investigator, represents an inappropriate risk to the subject and/or could confound the interpretation of the study Subject has a known history or presence of structural cardiac abnormalities, serious heart rhythm abnormalities, syncope, cardiac conduction problems (eg, clinically significant heart block), exercise-related cardiac events including syncope and presyncope, or clinically significant bradycardia Subject is pregnant or nursing (lactating) or deemed by the investigator and staff to be at a significant risk of becoming pregnant. Subject has orthostatic hypotension or a known history of controlled or uncontrolled hypertension Subject has clinically significant electrocardiogram (ECG) findings as judged by the investigator with consideration of the central ECG laboratory's interpretation. Current use of any prohibited medication or other medications including herbal supplements that affect blood pressure, or heart rate, or that have central nervous system effects, or affect cognitive performance such as sedating antihistamines and decongestant sympathomimetics (inhaled bronchodilators are permitted); or a history of chronic use of sedating medications (ie, antihistamines) in violation of the protocol specified washout criteria at baseline (Visit 2) Subject has used an investigational product within 30 days prior to baseline (Visit 2) Subject is significantly overweight based on body mass Index (BMI) for age-and gender-specific charts compiled by Center for Disease Control and Prevention. Significantly overweight is defined as a BMI of ≥95th percentile Subject is significantly underweight based on BMI for age-and gender-specific charts compiled by Center for Disease Control and Prevention. Subject has a known or suspected allergy, hypersensitivity, or clinically significant intolerance to clonidine hydrochloride Clinically important abnormality on drug and alcohol screening (excluding the subject's current ADHD stimulant if applicable) at screening (Visit 1) Subject has a history of alcohol, other substance abuse, or dependence as defined by DSM-IV-TR (with the exception of nicotine) within the last 6 months. Subject is currently considered a suicidal risk in the opinion of the investigator, has previously made a suicide attempt, has a prior history of, or is currently demonstrating active suicidal ideation based on the Columbia Suicide Severity Rating Scale (C-SSRS). Subject has a history of failure to respond to an adequate trial of an alpha 2-agonist with stimulant or non-stimulant drug alone or in combination for the treatment of ADHD. Subject has a history of a seizure disorder (other than a single childhood febrile seizure occurring before the age of 3 years) or the presence of a serious tic disorder (including Tourette syndrome) Subjects who have been treated with an immediate release clonidine and/ KAPVAY™ or guanfacine (INTUNIV™) within the past 30 days

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Subjects on KAPVAY™ (clonidine hydrochloride)<br>Subjects in the KAPVAY™ arm receive their optimal dose of KAPVAY™ for the 26-week randomized-withdrawal period (Period 3) | Drug: clonidine hydrochloride<br>* KAPVAY™ (clonidine hydrochloride) 0.1 mg, 0.2 mg, 0.3 mg, or 0.4 mg from Weeks 11-36<br>* Other names: KAPVAY™;|
| Placebo Comparator: Subjects on Placebo<br>Subjects in placebo arm tapered off optimal dose of KAPVAY™ (ie, Period 2 Maintenance Dose) at weekly intervals in decrements of 0.1 mg/day until reaching dose of 0 mg/day; subjects then receive only placebo for the rest of the study | Drug: Placebo<br>* KAPVAY™ (clonidine hydrochloride) 0.1 mg, 0.2 mg, or 0.3 mg at Week 11; KAPVAY™ 0.1 mg, KAPVAY™ 0.2 mg, or placebo at Week 12; KAPVAY™ 0.1 mg or placebo at Week 13; placebo from Weeks 14-36<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Long-term Maintenance of Efficacy of KAPVAY in Children and Adolescents With Attention Deficit Hyperactivity Disorder (ADHD) as Measured by the Percentage of Treatment Failures in the KAPVAY vs. Placebo Groups | Treatment failure a ≥30 percentage increase (worsening)(ADHD-RS-IV, clinician version) total score and a ≥2 point increase (worsening) in Clinical Global Impressions-Severity of Illness Scale (CGI-S) at any two consecutive visits during the randomized-withdrawal period. The ADHD-RS-IV of 2 subscales: inattention - 9 items and hyperactivity-impulsivity - 9 items. Each gives a score ranging from 0 (none, never or rarely) to 3 (severe, very often), for a total score ranging from 0 to 54 (higher score worse). The CGI-S is a 7-point scale,1 (Normal, not at all ill) to 7 (extremely ill patients).The CGI-Severity (CGI-S) asks the clinician one question: Considering your total clinical experience with this particular population, how mentally ill is the patient at this time? which is rated on the following seven-point scale: 1=normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among the most extremely ill patients. | From randomization to end of the randomized-withdrawal period (26 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To Evaluate the Long-term Efficacy of KAPVAY in Children and Adolescents With Attention Deficit Hyperactivity Disorder (ADHD) as Measured by the Time to Treatment Failure From the Start of Randomized-withdrawal Period | Time to treatment failure was calculated as follows: Treatment failure (not premature termination) = visit date where the failure criteria was met - visit 9 date + 1; Treatment failure (premature termination) = termination date - visit 9 date + 1 | Time From randomization to treatment failure (up to 26 weeks) | 
| Long-term Efficacy of KAPVAY in Children and Adolescents With ADHD as Measured by the Change From Randomization to the End of the Randomized-withdrawal Period on the ADHD-Rating Scale-4th Edition (ADHD-RS-IV) | The ADHD-RS-IV (clinician version), has been widely used as a measure of efficacy in clinical trials of treatments in children and adolescents with ADHD. It is derived from the 18 inattentive and hyperactive/impulsive diagnostic criteria for ADHD from the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR). The clinician version of the ADHD-RS-IV has a large base of normative data and has demonstrated reliability and discriminant validity in children and adolescents. The ADHD-RS-IV of 2 subscales: inattention - 9 items and hyperactivity-impulsivity - 9 items. Each gives a score ranging from 0 (none, never or rarely) to 3 (severe, very often), for a total score ranging from 0 to 54 (higher score worse and a lower score more favourable). Two subscales are summed. | From randomization to end of the randomized-withdrawal period (26 weeks) | 
| Long-term Efficacy of KAPVAY in Children and Adolescents With ADHD as Measured by the Change From Randomization to the End of the Randomized-withdrawal Period on the Clinical Global Impressions-Severity of Illness Scale (CGI-S) | The CGI-S is a clinician rated instrument designed to assess the subject's current illness state. The CGI-Severity (CGI-S) asks the clinician one question: Considering your total clinical experience with this particular population, how mentally ill is the patient at this time? which is rated on the following seven-point scale: 1=normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among the most extremely ill patients. This rating is based upon observed and reported symptoms, behavior, and function in the past seven days. | From randomization to end of the randomized-withdrawal period (26 weeks) | 
| Long-term Efficacy of KAPVAY in Children and Adolescents With ADHD as Measured by the Change From Randomization to the End of the Randomized-withdrawal Period on the Weiss Functional Impairment Rating Scale-Parent (WFIRS-P) | The WFIRS-P is designed to assess the impact of child's behavior or emotional problems on 7 domains related to function: Family (10 items), School Learning (4 items), School Behavior (6 items), Life Skills (10 items), Child's Self-concept (3 items), Social Activities (7 items), and Risky Activities (10 items). Each item was scored on a scale ranging from 0 (never or not at all) to 3 (very often or very much). Each scale score was calculated as the average for that scale. The total score is the average of all non-missing items. Higher scores are associated with greater impact of disease on functioning. | From randomization to end of the randomized-withdrawal period (26 weeks) | 
| Long-term Efficacy of KAPVAY in Children and Adolescents With ADHD as Measured by the Change From Randomization to the End of the Randomized-withdrawal Period on the Epworth Sleepiness Scale for Children (ESS-C) | Change in the ESS-C scale from randomization to end of randomized-withdrawal period. The ESS-C is a simple eight-tem Likert scale designed to assess daytime sleepiness in children aged 2-18 years. The scale takes less than two minutes to be completed by patient or by parent rating. Sleepiness is a common symptom in both medicated and unmedicated children with ADHD given the predominance of impaired sleep quality. The total score achieved when the chance of dozing in each situation is added up serves as the outcome measure. The ESS-C comprises 8 items describing various daytime activities. Item scores ranging from 0 (would never doze or sleep) to 3 (high chance of dozing or sleeping). A total score is derived as the sum of the items, with higher total scores indicative of a greater level of sleepiness (worse outcome). Total scores range from 0 to 24. | From randomization to end of the randomized-withdrawal period (26 weeks) | 
| Long-term Safety of KAPVAY in Children and Adolescents With ADHD Based on the Assessment of Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Leading to Study Drug Discontinuation, Clinically Significant Changes or Abnormalities in Vital Signs |  | From study start to study end (40 weeks) | 
| Long-term Safety of KAPVAY in Children and Adolescents With ADHD Based on the Assessment of Changes in the Columbia Suicide Severity Rating Scale (C-SSRS) | The outcome reported is the number of subjects that responded Yes to the question Do you have a wish to be dead at Visit 20. C-SSRS is a clinician-rated instrument designed to provide consistent and systematic assessment of both suicidal ideation and behavior within a study, as well as across studies. The scale is a feasible, low burden series of questions that appropriately assess and track all suicidal events, including ideation. Suicidal ideation is assessed according to yes/no responses to 5 questions of increasing severity (from a wish to die to an active thought of killing oneself with plan and intent) as follows: Wish to be Dead Non-Specific Active Suicidal Thoughts Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act Active Suicidal Ideation with Some Intent to Act, without Specific Plan Active Suicidal Ideation with Specific Plan and Intent | Visit 20 (Week 40) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Attention Deficit Hyperactivity Disorder