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This multi-center parallel study is designed to study the efficacy and safety of fixed doses of methylphenidate extended release (ER) capsules of four dose levels compared with a placebo group in pediatric patients with Attention Deficit Hyperactivity Disorder (ADHD) who are between 6 and 18 years old.
This is a parallel, randomized, double-blind, multi-center, placebo-controlled, forced dose, phase 3 study to evaluate the safety and efficacy of Biphentin® methylphenidate hydrochloride (HCl) extended release (ER) capsules in the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in pediatric and adolescent patients aged 6 up to 18 years.
The primary objective was to assess the efficacy of Biphentin compared to placebo, in the clinic setting, as measured by the clinician-administered parent version of the ADHD-RS-IV.
Subjects who met study entry criteria were enrolled in the Double-blind Phase and were randomized to either a fixed dose of Biphentin (!0, 15, 20, or 40 mg/day) or placebo capsule taken daily in the morning for 1 week. Subjects then continued into an Open-label Phase that included dose optimization with doses starting at 10 mg and allowed up to 60 mg. The open-label period following the one double-blind fixed dose week provides additional opportunity for subjects to receive treatment with Biphentin. Extra unscheduled dose optimization visits are allowed as needed for additional dose titration visits during the open-label period.
The safety and tolerability, and efficacy assessments will be conducted throughout the study.
Biphentin® is designed to be a single daily dose alternative to separate doses of immediate release methylphenidate by providing a biphasic plasma profile. It achieves a first Cmax more similar to immediate release methylphenidate.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 10 mg | Active Comparator | Biphentin Methylphenidate Hydrochloride Extended Release Capsules 10 mg |
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| 15 mg | Active Comparator | Biphentin Methylphenidate Hydrochloride Extended Release Capsules 15 mg |
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| 20 mg | Active Comparator | Biphentin Methylphenidate Hydrochloride Extended Release Capsules 20 mg |
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| 40 mg | Active Comparator | Biphentin Methylphenidate Hydrochloride Extended Release Capsules 40 mg |
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| Placebo | Placebo Comparator | Placebo capsules |
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| Methylphenidate HCl ER Capsules (10, 15, 20, 40, 50 or 60 mg) | Experimental |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Methylphenidate Hydrochloride Extended Release Capsules | Drug | Biphentin Methylphenidate ER Once-A-Day Capsules |
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| Measure | Description | Time Frame |
|---|---|---|
| Change in ADHD-RS-IV Total Score From Baseline (Visit 2) to the End of the Double-Blind Phase (Visit 3) | Change in ADHD-RS-IV Total Score from Baseline (Visit 2) to end of Double Blind Phase (Visit 3); [Calculations of baseline values (Visit 2) minus end of Double Blind values (Visit 3), higher differences means better outcomes]. Attention Deficit Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV): The home version of the ADHD-RS-IV comprising symptoms of ADHD was used. This 18-item scale incorporates each of the ADHD symptoms regardless of assigned subtype. Trained clinicians administered questionnaire to parents. Scoring was based on symptom severity on a 4-point scale: 0=never or rarely, 1=sometimes, 2=often, and 3=very often. The Total Score is the sum of the scores for all 18 items, and could range from 0 (no impairment) to 54 (maximal impairment). | From baseline (visit 2) to end of of Double-Blind phase (visit 3) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Wei-wei Chang, Ph.D. | NuTec Incorporated | Study Director |
| Laurence Greenhill, M.D. | New York State Psychiatric Institute / Columbia University | Principal Investigator |
| Sharon B. Wigal, Ph.D. | University of California, Irvine / Child Development Center | Principal Investigator |
| Robert J. Kupper, Ph.D. | Rhodes Phamaceuticals, L.P. | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Clinical Study Centers, LLC | Little Rock | Arkansas | 72205 | United States | ||
| University of California, Irvine/Child Development Center |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 25877989 | Derived | Wigal SB, Nordbrock E, Adjei AL, Childress A, Kupper RJ, Greenhill L. Efficacy of Methylphenidate Hydrochloride Extended-Release Capsules (Aptensio XR) in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: A Phase III, Randomized, Double-Blind Study. CNS Drugs. 2015 Apr;29(4):331-40. doi: 10.1007/s40263-015-0241-3. |
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This study planned to randomize approximately 225 subjects to the Double-Blind phase of the study with the goal of approximately 200 subjects completing the double-blind parallel treatment
23 December 2010 (First subject screened) 09 November 2011 (Last subject visit in Open-Label Phase)
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| ID | Title | Description |
|---|---|---|
| FG000 | 10 mg (Double-Blind) Then Methylphenidate HCl ER Capsules 10, 15, 20, 40, 50 or 60 mg (Open Label) | Subjects randomized to 10 mg Methylphenidate HCl ER Capsules for 1 week of Double-Blind phase, then entered an 11-week Open Label phase where subject doses were optimized to either Methylphenidate HCl ER Capsules 10, 15, 20, 40, 50 or 60 mg via titration Methylphenidate Hydrochloride Extended Release Capsules 10 mg then Methylphenidate Hydrochloride Extended Release Capsules 10, 15, 20, 40, 50 or 60 mg Once-A-Day Capsules |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Double Blind |
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Biphentin Methylphenidate Hydrochloride Extended Release Capsules (10, 15, 20, 40, 50 or 60 mg) - Open Label Phase |
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| Placebo | Drug | Placebo capsules |
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| Irvine |
| California |
| 92612 |
| United States |
| Synergy Research | National City | California | 91950 | United States |
| Florida Clinical Research Center, LLC | Bradenton | Florida | 34201 | United States |
| Behavioral Clinical Research, Inc. | Lauderhill | Florida | 33319 | United States |
| Martin Kane, DO | Maitland | Florida | 32751 | United States |
| Segal Institute for clinical Research, North Miami Outpatient Clinic | North Miami | Florida | 33161 | United States |
| South Shore Psychiatric Services, PC | Marshfield | Massachusetts | 02050 | United States |
| Precise Research Center | Madison | Mississippi | 39110 | United States |
| Center for Psychiatry and Behavioural Medicine Inc | Las Vegas | Nevada | 89128 | United States |
| New York State Psychiatric Institute/Columbia University | New York | New York | 10032 | United States |
| Department of Psychiatry, Duke University Medical Center | Durham | North Carolina | 27705 | United States |
| CTMG | New Bern | North Carolina | 28562 | United States |
| University of Cincinnati College of Medicine/PPSI | Cincinnati | Ohio | 45219 | United States |
| University Hospital Case Medical Center | Cleveland | Ohio | 44106 | United States |
| Wharton Research Center, Inc. | Wharton | Texas | 77488 | United States |
| FG001 | 15 mg (Double-Blind) Then Methylphenidate HCl ER Capsules 10, 15, 20, 40, 50 or 60 mg (Open Label) | Subjects randomized to 15 mg Methylphenidate HCl ER Capsules for 1 week of Double-Blind phase, then entered an 11-week Open Label phase where subject doses were optimized to either Methylphenidate HCl ER Capsules 10, 15, 20, 40, 50 or 60 mg via titration Methylphenidate Hydrochloride Extended Release Capsules 15 mg then Methylphenidate Hydrochloride Extended Release Capsules 10, 15, 20, 40, 50 or 60 mg Once-A-Day Capsules |
| FG002 | 20 mg (Double-Blind) Then Methylphenidate HCl ER Capsules 10, 15, 20, 40, 50 or 60 mg (Open Label) | Subjects randomized to 20 mg Methylphenidate HCl ER Capsules for 1 week of Double-Blind phase, then entered an 11-week Open Label phase where subject doses were optimized to either Methylphenidate HCl ER Capsules 10, 15, 20, 40, 50 or 60 mg via titration Methylphenidate Hydrochloride Extended Release Capsules 20 mg then Methylphenidate Hydrochloride Extended Release Capsules 10, 15, 20, 40, 50 or 60 mg Once-A-Day Capsules |
| FG003 | 40 mg (Double Blind) Then Methylphenidate HCl ER Capsules 10, 15, 20, 40, 50 or 60 mg (Open Label) | Subjects randomized to 40 mg Methylphenidate HCl ER Capsules for 1 week of Double-Blind phase, then entered an 11-week Open Label phase where subject doses were optimized to either Methylphenidate HCl ER Capsules 10, 15, 20, 40, 50 or 60 mg via titration Methylphenidate Hydrochloride Extended Release Capsules 40 mg then Methylphenidate Hydrochloride Extended Release Capsules 10, 15, 20, 40, 50 or 60 mg Once-A-Day Capsules |
| FG004 | Placebo (Double Blind) Then Methylphenidate HCl ER Capsules 10, 15, 20, 40, 50 or 60 mg (Open Label) | Subjects randomized Placebo Capsules for 1 week of Double-Blind phase, then entered an 11-week Open Label phase where subject doses were optimized to either Methylphenidate HCl ER Capsules 10, 15, 20, 40, 50 or 60 mg via titration Placebo Capsules then Methylphenidate Hydrochloride Extended Release Capsules 10, 15, 20, 40, 50 or 60 mg Once-A-Day Capsules |
| COMPLETED |
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| NOT COMPLETED |
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| Dose Optimization (Open Label) |
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| ID | Title | Description |
|---|---|---|
| BG000 | 10 mg | Biphentin Methylphenidate Hydrochloride Extended Release Capsules 10 mg Methylphenidate Hydrochloride Extended Release Capsules: Biphentin Methylphenidate ER Once-A-Day Capsules |
| BG001 | 15 mg | Biphentin Methylphenidate Hydrochloride Extended Release Capsules 15 mg Methylphenidate Hydrochloride Extended Release Capsules: Biphentin Methylphenidate ER Once-A-Day Capsules |
| BG002 | 20 mg | Biphentin Methylphenidate Hydrochloride Extended Release Capsules 20 mg Methylphenidate Hydrochloride Extended Release Capsules: Biphentin Methylphenidate ER Once-A-Day Capsules |
| BG003 | 40 mg | Biphentin Methylphenidate Hydrochloride Extended Release Capsules 40 mg Methylphenidate Hydrochloride Extended Release Capsules: Biphentin Methylphenidate ER Once-A-Day Capsules |
| BG004 | Placebo | Placebo capsules Placebo: Placebo Capsules |
| BG005 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
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| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| ADHD-RS-IV | Attention Deficit Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV): The home version of the ADHD-RS-IV comprising symptoms of ADHD was used. This 18-item scale incorporates each of the ADHD symptoms regardless of assigned subtype. Trained clinicians administered questionnaire to parents. Scoring was based on symptom severity on a 4-point scale: 0=never or rarely, 1=sometimes, 2=often, and 3=very often. The Total Score is the sum of the scores for all 18 items, and could range from 0 (no impairment) to 54 (maximal impairment). Lower scores are better outcomes. | Baseline analysis is based on efficacy population (N = 221). | Mean | Standard Deviation | units on a scale |
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| 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 | Change in ADHD-RS-IV Total Score From Baseline (Visit 2) to the End of the Double-Blind Phase (Visit 3) | Change in ADHD-RS-IV Total Score from Baseline (Visit 2) to end of Double Blind Phase (Visit 3); [Calculations of baseline values (Visit 2) minus end of Double Blind values (Visit 3), higher differences means better outcomes]. Attention Deficit Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV): The home version of the ADHD-RS-IV comprising symptoms of ADHD was used. This 18-item scale incorporates each of the ADHD symptoms regardless of assigned subtype. Trained clinicians administered questionnaire to parents. Scoring was based on symptom severity on a 4-point scale: 0=never or rarely, 1=sometimes, 2=often, and 3=very often. The Total Score is the sum of the scores for all 18 items, and could range from 0 (no impairment) to 54 (maximal impairment). | Efficacy Population (N = 221) comprises subjects who completed ADHD-RS-IV assessments on Day 0 and Day 7. | Posted | Mean | Standard Deviation | units on a scale | From baseline (visit 2) to end of of Double-Blind phase (visit 3) |
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Treatment-Related Adverse event data during the 12 week study by phase of study. Double Blind phase (one week duration) followed by Open Label phase (11 week duration).
Treatment-Related AEs for Safety Population. Since subjects received multiple dose levels during the open label phase and a subject may have experienced an adverse event which started on one dose level and was ongoing at subsequent dose level(s), the adverse events are presented for all dose levels combined.
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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 | Double Blind Phase - Biphentin 10 mg | Double Blind Phase (Week 1) - Biphentin 10 mg: Methylphenidate Hydrochloride Extended Release Capsules 10 mg. Once-A-Day Capsules | 0 | 49 | 0 | 49 | 11 | 49 |
| EG001 | Double Blind Phase - Biphentin 15 mg | Double Blind Phase (Week 1) - Biphentin 15 mg: Methylphenidate Hydrochloride Extended Release Capsules 15 mg. Once-A-Day Capsules | 0 | 44 | 1 | 44 | 10 | 44 |
| EG002 | Double Blind Phase - Biphentin 20 mg | Double Blind Phase (Week 1) - Biphentin 20 mg: Methylphenidate Hydrochloride Extended Release Capsules 20 mg. Once-A-Day Capsules | 0 | 45 | 0 | 45 | 12 | 45 |
| EG003 | Double Blind Phase - Biphentin 40 mg | Double Blind Phase (Week 1) - Biphentin 40 mg: Methylphenidate Hydrochloride Extended Release Capsules 40 mg. Once-A-Day Capsules | 0 | 45 | 0 | 45 | 11 | 45 |
| EG004 | Double Blind Phase - Placebo | Double Blind Phase (Week 1) - Placebo capsules Once daily | 0 | 47 | 0 | 47 | 2 | 47 |
| EG005 | Open Label Phase - Biphentin (10, 15, 20, 30, 40, 50 or 60 mg) | Open Label Phase (Week 2-Week 12) - Biphentin Methylphenidate Hydrochloride Extended Release Capsules (10, 15, 20, 30, 40, 50, or 60 mg as directed by Clinician). Once daily | 0 | 221 | 1 | 221 | 116 | 221 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Adjustment disorder with mixed disturbance or emotion and conduct | Psychiatric disorders | MedDRA (Unspecified) | Non-systematic Assessment | Not related to study drug |
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| Migraine | Nervous system disorders | MedDRA (Unspecified) | Non-systematic Assessment | Not related to study drug - INJURY INDUCED MIGRAINE HEADACHE |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| headache | Nervous system disorders | MedDRA (Unspecified) | Non-systematic Assessment |
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| Insomnia | Nervous system disorders | MedDRA (Unspecified) | Non-systematic Assessment |
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| abdominal pain upper | Gastrointestinal disorders | MedDRA (Unspecified) | Non-systematic Assessment |
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| decreased appetite | Metabolism and nutrition disorders | MedDRA (Unspecified) | Non-systematic Assessment |
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| fatigue | General disorders | MedDRA (Unspecified) | Non-systematic Assessment |
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| irritability | Psychiatric disorders | MedDRA (Unspecified) | Non-systematic Assessment |
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| Affect Liability | Psychiatric disorders | MedDRA (Unspecified) | Non-systematic Assessment |
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PI is restricted from using, disclosing, presenting, or publishing trial information without the prior written consent from the Sponsor
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Akwete Adjei, PhD | Rhodes Pharmaceuticals | 401-202-9408 | Akwete.Adjei@pharma.com |
| ID | Term |
|---|---|
| D001289 | Attention Deficit Disorder with Hyperactivity |
| D007175 | Impulsive Behavior |
| D013035 | Spasm |
| ID | Term |
|---|---|
| D019958 | Attention Deficit and Disruptive Behavior Disorders |
| D065886 | Neurodevelopmental Disorders |
| D001523 | Mental Disorders |
| D001519 | Behavior |
| D020879 | Neuromuscular Manifestations |
| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| Withdrawal by Subject |
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| Lost to Follow-up |
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| Physician Decision |
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