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

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

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01439126

Enrollment

135

Registered

2011-09-22

Start date

2011-08-31

Completion date

2012-10-31

Last updated

2014-10-27

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Attention Deficit Hyperactivity Disorder

Keywords

Attention Deficit Hyperactivity Disorder

Brief summary

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)

Interventions

DRUGclonidine hydrochloride

KAPVAY™ (clonidine hydrochloride) 0.1 mg, 0.2 mg, 0.3 mg, or 0.4 mg from Weeks 11-36

DRUGPlacebo

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

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

6 Years to 17 Years

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
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	From randomization to end of the randomized-withdrawal period (26 weeks)	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.

Secondary

Measure	Time frame	Description
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)	From randomization to end of the randomized-withdrawal period (26 weeks)	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.
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)	From randomization to end of the randomized-withdrawal period (26 weeks)	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.
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)	From randomization to end of the randomized-withdrawal period (26 weeks)	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.
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 From randomization to treatment failure (up to 26 weeks)	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
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)	Visit 20 (Week 40)	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: 1. Wish to be Dead 2. Non-Specific Active Suicidal Thoughts 3. Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 4. Active Suicidal Ideation with Some Intent to Act, without Specific Plan 5. Active Suicidal Ideation with Specific Plan and Intent
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)	From randomization to end of the randomized-withdrawal period (26 weeks)	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.

Participant flow

Recruitment details

The study was conducted at 34 sites in the US. First patient was enrolled on September 8, 2011 and last patient completed on October 29, 2012

Pre-assignment details

The study population included male or female subjects 6 to 17 years of age, who met the Diagnostic and Statistical Manual of Mental Disorders 4th Edition Text Revision (DSM-IV-TR) criteria for Attention Deficit Hyperactivity Disorder (ADHD).

Participants by arm

Arm	Count
Subjects on KAPVAY (Clonidine Hydrochloride) Subjects in the KAPVAY arm received their optimal dose of KAPVAY (as determined after a 4-week, open-label, dose optimization period) for the duration of the 26-week randomized-withdrawal period	68
Subjects on Placebo Subjects randomized to the placebo arm were tapered off their optimal dose of KAPVAY (as determined after a 4-week, open-label, dose optimization period) at weekly intervals in decrements of 0.1 mg/day until reaching the dose of 0 mg/day, and then received only placebo for the rest of the study	67
Total	135

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	2	0
Overall Study	Lost to Follow-up	6	3
Overall Study	Other-Miscellaneous	12	12
Overall Study	Other-Use of prohibited treatment	0	2
Overall Study	Protocol Violation	6	4
Overall Study	Withdrawal by Subject	5	21

Baseline characteristics

Characteristic	Subjects on KAPVAY (Clonidine Hydrochloride)	Subjects on Placebo	Total
Age, Continuous	10.7 Years STANDARD_DEVIATION 2.77	10.9 Years STANDARD_DEVIATION 2.98	10.8 Years STANDARD_DEVIATION 2.88
BMI	18.29 kg/m^2 STANDARD_DEVIATION 2.921	18.79 kg/m^2 STANDARD_DEVIATION 3.485	18.54 kg/m^2 STANDARD_DEVIATION 3.203
Ethnicity (NIH/OMB) Hispanic or Latino	12 Participants	20 Participants	32 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	56 Participants	47 Participants	103 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Height	145.64 cm STANDARD_DEVIATION 17.737	145.45 cm STANDARD_DEVIATION 17.928	145.55 cm STANDARD_DEVIATION 17.833
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) Black or African American	23 Participants	14 Participants	37 Participants
Race (NIH/OMB) More than one race	7 Participants	3 Participants	10 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	37 Participants	50 Participants	87 Participants
Sex: Female, Male Female	25 Participants	16 Participants	41 Participants
Sex: Female, Male Male	43 Participants	51 Participants	94 Participants
Weight	40.49 kg STANDARD_DEVIATION 15.721	41.61 kg STANDARD_DEVIATION 16.978	41.05 kg STANDARD_DEVIATION 16.35

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	15 / 68	7 / 67
serious Total, serious adverse events	0 / 68	2 / 67

Outcome results

Primary

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.

Time frame: From randomization to end of the randomized-withdrawal period (26 weeks)

Population: Double-Blind Full Analysis Set. This set included all randomized subjects who took at least 1 dose of study medication during the double blind (randomized-withdrawal) phase

Arm	Measure	Value (NUMBER)
Subjects on KAPVAY (Clonidine Hydrochloride)	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	31 % of Participants
Subjects on Placebo	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	42 % of Participants

Secondary

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.

Time frame: From randomization to end of the randomized-withdrawal period (26 weeks)