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The purpose of this study is to determine the long-term efficacy and safety of KAPVAYâ„¢ (clonidine hydrochloride) extended-release in children and adolescents with Attention Deficit Hyperactivity Disorder (ADHD)
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Subjects on KAPVAYâ„¢ (clonidine hydrochloride) | Active Comparator | Subjects in the KAPVAYâ„¢ arm receive their optimal dose of KAPVAYâ„¢ for the 26-week randomized-withdrawal period (Period 3) |
|
| Subjects on Placebo | Placebo Comparator | Subjects in placebo arm tapered off optimal dose of KAPVAYâ„¢ (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 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| clonidine hydrochloride | Drug | KAPVAYâ„¢ (clonidine hydrochloride) 0.1 mg, 0.2 mg, 0.3 mg, or 0.4 mg from Weeks 11-36 |
|
| 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) |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Shionogi Clinical Trials Administrator Clinical Support Help Line | Shionogi | Study Director |
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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).
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
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. All subjects were given study medication at the baseline visit (Visit 2, open label) and instructed to take 1 x 0.1 mg tablet each evening (Day 1) at bedtime until the next visit. Subjects who required an increase in total dose to 0.2 mg/day took 1 x 0.1 mg tablet (0.1 mg) in the morning and at bedtime until the next visit. Those who required a further increase in dose to 0.3 mg/day took 1 x 0.1 mg tablet in the morning and 2 x 0.1 mg tablets at bedtime until the next visit. Patient increasing dose to 0.4 mg/day were instructed to take 2 x 0.1 mg tablets in the morning and at bedtime until the next visit. Of 68 Subjects randomized to KAPVAY: 24 (35.3%) oral dose of 0.4 mg/day 25 (36.8%) oral dose of 0.3 mg/day 14 (20.6%) oral dose of 0.2 mg/day 5 (7.4%) oral dose of 0.1 mg/day |
| FG001 | 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 Of 67 Subjects randomized to Placebo: 26 (38.8%) oral dose of 0.4 mg/day 24 (35.8%) oral dose of 0.3 mg/day 15 (22.4%) oral dose of 0.2 mg/day 2 (3.0%) oral dose of 0.1 mg/day |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 |
| BG001 | Subjects on Placebo |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | 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 | Posted | Number | % of Participants | From randomization to end of the randomized-withdrawal period (26 weeks) |
Throughout the study
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Suicidal ideation | Psychiatric disorders | MedDRA 14.0 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Somnolence | Nervous system disorders | MedDRA 14.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| John AR McCleery, CPA, CA, Managing Director and CFO | Concordia Pharmaceuticals Inc. | 1-246-256-1861 | jmccleery@concordiarx.com |
| ID | Term |
|---|---|
| D001289 | Attention Deficit Disorder with Hyperactivity |
| ID | Term |
|---|---|
| D019958 | Attention Deficit and Disruptive Behavior Disorders |
| D065886 | Neurodevelopmental Disorders |
| D001523 | Mental Disorders |
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| ID | Term |
|---|---|
| D003000 | Clonidine |
| ID | Term |
|---|---|
| D048288 | Imidazolines |
| D007093 | Imidazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
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| Placebo | Drug | KAPVAYâ„¢ (clonidine hydrochloride) 0.1 mg, 0.2 mg, or 0.3 mg at Week 11; KAPVAYâ„¢ 0.1 mg, KAPVAYâ„¢ 0.2 mg, or placebo at Week 12; KAPVAYâ„¢ 0.1 mg or placebo at Week 13; placebo from Weeks 14-36 |
|
| 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:
| Visit 20 (Week 40) |
| Protocol Violation |
|
| Lost to Follow-up |
|
| Other-Use of prohibited treatment |
|
| Other-Miscellaneous |
|
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 |
| BG002 | Total | Total of all reporting groups |
| Years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Weight | Mean | Standard Deviation | kg |
|
| Height | Mean | Standard Deviation | cm |
|
| BMI | Mean | Standard Deviation | kg/m^2 |
|
|
|
|
| Secondary | 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 | Double-Blind Full Analysis Set | Posted | Median | 95% Confidence Interval | days | Time From randomization to treatment failure (up to 26 weeks) |
|
|
|
| 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. | Double-Blind Full Analysis Set | Posted | Mean | Standard Deviation | scores on a scale | From randomization to end of the randomized-withdrawal period (26 weeks) |
|
|
|
| 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 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. | Double-Blind Full Analysis Set | Posted | Mean | Standard Deviation | scores on a scale | From randomization to end of the randomized-withdrawal period (26 weeks) |
|
|
|
| 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 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. | Double-Blind Full Analysis Set | Posted | Mean | Standard Deviation | units on a scale | From randomization to end of the randomized-withdrawal period (26 weeks) |
|
|
|
| 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 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. | Double-Blind Full Analysis Set | Posted | Mean | Standard Deviation | units on a scale | From randomization to end of the randomized-withdrawal period (26 weeks) |
|
|
|
| Secondary | 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 | Double-Blind Full Analysis Set | Posted | Number | Participants | From study start to study end (40 weeks) |
|
|
|
| Secondary | 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:
| Double-Blind Full Analysis Set | Posted | Number | participants | Visit 20 (Week 40) |
|
|
|
| 0 |
| 68 |
| 15 |
| 68 |
| EG001 | 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 | 2 | 67 | 7 | 67 |
| Sickle cell anemia with crisis | Blood and lymphatic system disorders | MedDRA 14.0 | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA 14.0 | Systematic Assessment |
|
| Sedation | Nervous system disorders | MedDRA 14.0 | Systematic Assessment |
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| Dizziness postural | Nervous system disorders | MedDRA 14.0 | Systematic Assessment |
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| Abdominal pain upper | Gastrointestinal disorders | MedDRA 14.0 | Systematic Assessment |
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| Fatigue | General disorders | MedDRA 14.0 | Systematic Assessment |
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| Electrocardiogram QT | Investigations | MedDRA 14.0 | Systematic Assessment |
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| Weight increased | Investigations | MedDRA 14.0 | Systematic Assessment |
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| Affect lability | Psychiatric disorders | MedDRA 14.0 | Systematic Assessment |
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The sponsor can embargo results from a PI's center until the combined results from the completed study have been published in full or the sponsor confirms there will be no multicenter study publication. Results communications must be provided to the sponsor for review at least 60 days before submission for publication. By written request, the sponsor can extend the embargo up to an additional 60 days. The sponsor cannot require changes to scientific content and cannot further extend the embargo.
| D006571 |
| Heterocyclic Compounds |
| Any SAE |
|
| Treatment Emergent AE leading to discontinuation |
|
| Any Treatment-Related AE |
|
| Vital Signs Abnormalities |
|