A randomized placebo-controlled double-blind study evaluating the time course of response to methylphenidate hydrochloride extended-release capsules in children with attention-deficit/hyperactivity disorder

Abstract

Objective: The purpose of this study was to assess the time of onset and time course of efficacy over 12.0 hours of extended-release multilayer bead formulation of methylphenidate (MPH-MLR) compared with placebo in children 6-12 years of age with attention-deficit/hyperactivity disorder (ADHD) in a laboratory school setting.

Methods: This randomized double-blind placebo-controlled study included children 6-12 years of age with ADHD. Enrolled children went through four study phases: 1) Screening period (≤4 weeks) and a 2 day medication washout period; 2) open-label period with dose initiation of MPH-MLR 15 mg daily and individual dose optimization treatment period (2-4 weeks); 3) double-blind crossover period in which participants were randomized to sequences (1 week each) of placebo and the optimized MPH-MLR dose given daily; and 4) follow-up safety call. Analog classroom time course evaluations were performed at the end of each double-blind week. The primary efficacy end-point was the mean of the on-treatment/postdose Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP)-Total scores over time points collected 1.0-12.0 hours after dosing. End-points were evaluated using a mixed-effects analysis of covariance.

Results: The evaluable population included 20 participants. The least-squares mean postdose SKAMP-Total score was higher for placebo than for MPH-MLR (2.18 vs. 1.32, respectively; p=0.0001), indicating fewer symptoms with MPH-MLR therapy than with placebo. No difference in SKAMP-Total score between participants who received sequence 1 or sequence 2 was noted. From each of hours 1.0-12.0, least-squares mean SKAMP-Total score was significantly lower for those receiving MPH-MLR than for those receiving placebo (p≤0.0261). Neither serious adverse events nor new or unexpected safety findings were noted during the study.

Conclusions: MPH-MLR showed a significant decrease in SKAMP scores compared with placebo in children with ADHD 6-12 years of age, indicating a decrease in ADHD symptoms. The estimated onset was observed within 1.0 hour, and duration was measured to 12.0 hours postdose.

Trial registration: ClinicalTrials.gov Identifier: NCT01269463.

Figures

FIG. 1.

Study design. *Only in patients weighing >25 kg.

FIG. 2.

Participant disposition. ADHD, attention-deficit/hyperactivity disorder; AE, adverse event.

FIG. 3.

Least-squares (LS) mean† SKAMP-Total scores over time (evaluable population, n=20). MPH-MLR, extended-release multilayer bead methylphenidate; SKAMP, Swanson, Kotkin, Agler, M-Flynn, and Pelham. *p≤0.0261. †Mixed-effects analysis of covariance with fixed terms for treatment, sequence, period, random term for participant within sequence, and covariate term for the predose value.

FIG. 4.

Arithmetic mean ADHD-RS-IV scores (double-blind crossover phase evaluable population, n=20). ADHD-RS-IV, Attention-Deficit/Hyperactivity Disorder Rating Scale–IV; MPH-MLR, extended-release multilayer bead methylphenidate.