ADHD, Attention Deficit Hyperactivity Disorder
Conditions
Keywords
inattention, impulsivity, hyperactivity, ADHD
Brief summary
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.
Detailed description
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.
Interventions
DRUGMethylphenidate Hydrochloride Extended Release Capsules
Biphentin Methylphenidate ER Once-A-Day Capsules
DRUGPlacebo
Placebo capsules
Sponsors
Rhodes Pharmaceuticals, L.P.
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 18 Years
Healthy volunteers
No
Inclusion criteria
* Males and females ages 6 up to 18 * ADHD diagnosis with ADHD Rating Scale - 4th Edition scores ≥ 90th percentile * In need of treatment for ADHD and able to have 2-day washout from previous medication * Females of child-bearing potential not pregnant and practice birth control * Subject and parent/guardian willing to comply with protocol * Signed consent and assent
Exclusion criteria
* Estimated Full Scale intellectual level below 80 using Wechsler Abbreviated Scale of Intelligence (WASI) * Current primary psychiatric diagnosis of other listed disorders * Chronic medical illnesses: seizure, hypertension, thyroid disease, cardiac, family history of sudden death, glaucoma * Use of psychotropic central nervous system (CNS) meds having effect exceeding 14 days from screening * Planned use of prohibited drugs * Is pregnant or breast-feeding * Significant ECG or laboratory abnormalities * Experimental drug or medical device within 30 days prior to screening * Hypersensitivity to methylphenidate * Inability or unwillingness to comply with protocol * Well controlled on current ADHD treatment * Inability to take oral capsules
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in ADHD-RS-IV Total Score From Baseline (Visit 2) to the End of the Double-Blind Phase (Visit 3) | From baseline (visit 2) to end of of 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). |
Countries
United States
Participant flow
Recruitment details
23 December 2010 (First subject screened) 09 November 2011 (Last subject visit in Open-Label Phase)
Pre-assignment details
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
Participants by arm
| Arm | Count |
|---|---|
| 10 mg Biphentin Methylphenidate Hydrochloride Extended Release Capsules 10 mg
Methylphenidate Hydrochloride Extended Release Capsules: Biphentin Methylphenidate ER Once-A-Day Capsules | 49 |
| 15 mg Biphentin Methylphenidate Hydrochloride Extended Release Capsules 15 mg
Methylphenidate Hydrochloride Extended Release Capsules: Biphentin Methylphenidate ER Once-A-Day Capsules | 44 |
| 20 mg Biphentin Methylphenidate Hydrochloride Extended Release Capsules 20 mg
Methylphenidate Hydrochloride Extended Release Capsules: Biphentin Methylphenidate ER Once-A-Day Capsules | 45 |
| 40 mg Biphentin Methylphenidate Hydrochloride Extended Release Capsules 40 mg
Methylphenidate Hydrochloride Extended Release Capsules: Biphentin Methylphenidate ER Once-A-Day Capsules | 45 |
| Placebo Placebo capsules
Placebo: Placebo Capsules | 47 |
| Total | 230 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Dose Optimization (Open Label) | Adverse Event | 2 | 0 | 2 | 0 | 5 |
| Dose Optimization (Open Label) | Lost to Follow-up | 1 | 1 | 0 | 0 | 1 |
| Dose Optimization (Open Label) | Physician Decision | 0 | 0 | 0 | 1 | 0 |
| Dose Optimization (Open Label) | Withdrawal by Subject | 4 | 1 | 0 | 2 | 1 |
| Double Blind | Adverse Event | 0 | 1 | 0 | 2 | 0 |
| Double Blind | Lost to Follow-up | 1 | 1 | 0 | 0 | 0 |
| Double Blind | Physician Decision | 0 | 1 | 0 | 0 | 0 |
| Double Blind | Withdrawal by Subject | 0 | 1 | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | 10 mg | 15 mg | 20 mg | 40 mg | Placebo | Total |
|---|---|---|---|---|---|---|
| ADHD-RS-IV | 37.6 units on a scale STANDARD_DEVIATION 8.32 | 38.0 units on a scale STANDARD_DEVIATION 8.64 | 36.2 units on a scale STANDARD_DEVIATION 8.46 | 35.6 units on a scale STANDARD_DEVIATION 9.16 | 33.4 units on a scale STANDARD_DEVIATION 11.01 | 36.1 units on a scale STANDARD_DEVIATION 9.25 |
| Age, Categorical <=18 years | 49 Participants | 44 Participants | 45 Participants | 45 Participants | 47 Participants | 230 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 10.5 years STANDARD_DEVIATION 2.89 | 10.2 years STANDARD_DEVIATION 3.08 | 11.1 years STANDARD_DEVIATION 3.51 | 11.2 years STANDARD_DEVIATION 2.49 | 10.9 years STANDARD_DEVIATION 3.05 | 10.8 years STANDARD_DEVIATION 3.02 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 8 Participants | 7 Participants | 4 Participants | 3 Participants | 26 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 45 Participants | 36 Participants | 38 Participants | 41 Participants | 44 Participants | 204 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 13 Participants | 11 Participants | 9 Participants | 11 Participants | 9 Participants | 53 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 3 Participants | 3 Participants | 1 Participants | 3 Participants | 12 Participants |
| Race (NIH/OMB) White | 34 Participants | 26 Participants | 33 Participants | 32 Participants | 33 Participants | 158 Participants |
| Region of Enrollment United States | 49 participants | 44 participants | 45 participants | 45 participants | 47 participants | 230 participants |
| Sex: Female, Male Female | 19 Participants | 14 Participants | 14 Participants | 12 Participants | 17 Participants | 76 Participants |
| Sex: Female, Male Male | 30 Participants | 30 Participants | 31 Participants | 33 Participants | 30 Participants | 154 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 49 | 0 / 44 | 0 / 45 | 0 / 45 | 0 / 47 | 0 / 221 |
| other Total, other adverse events | 11 / 49 | 10 / 44 | 12 / 45 | 11 / 45 | 2 / 47 | 116 / 221 |
| serious Total, serious adverse events | 0 / 49 | 1 / 44 | 0 / 45 | 0 / 45 | 0 / 47 | 1 / 221 |
Outcome results
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).
Time frame: From baseline (visit 2) to end of of Double-Blind phase (visit 3)
Population: Efficacy Population (N = 221) comprises subjects who completed ADHD-RS-IV assessments on Day 0 and Day 7.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 10 mg | Change in ADHD-RS-IV Total Score From Baseline (Visit 2) to the End of the Double-Blind Phase (Visit 3) | 9.3 units on a scale | Standard Deviation 8.86 |
| 15 mg | Change in ADHD-RS-IV Total Score From Baseline (Visit 2) to the End of the Double-Blind Phase (Visit 3) | 11.2 units on a scale | Standard Deviation 12.06 |
| 20 mg | Change in ADHD-RS-IV Total Score From Baseline (Visit 2) to the End of the Double-Blind Phase (Visit 3) | 12.3 units on a scale | Standard Deviation 9.84 |
| 40 mg | Change in ADHD-RS-IV Total Score From Baseline (Visit 2) to the End of the Double-Blind Phase (Visit 3) | 13.2 units on a scale | Standard Deviation 10.29 |
| Placebo | Change in ADHD-RS-IV Total Score From Baseline (Visit 2) to the End of the Double-Blind Phase (Visit 3) | 5.1 units on a scale | Standard Deviation 10.29 |
p-value: 0.0046ANCOVA