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

Abstract

Background: Psychostimulants remain first-line treatment options for the management of attention-deficit/hyperactivity disorder (ADHD). A multilayer extended-release bead methylphenidate capsule (provisional name Aptensio XR™, MPH-MLR) with unique release properties is being investigated for the treatment of ADHD.

Objective: The aim of this study was to assess the efficacy (primary) and safety and tolerability (secondary) of MPH-MLR compared with placebo in children and adolescents aged 6-18 years with ADHD.

Methods: This study was a parallel, double-blind, multicenter, placebo-controlled, forced-dose, phase III study in which patients were randomized to placebo or MPH-MLR 10, 15, 20, or 40 mg given once daily. There were four study phases: (1) 4-week screening/baseline; (2) 1-week, double-blind treatment (DBP); (3) 11-week, open-label, dose-optimization period; and (4) 30-day follow-up call. During the open-label dose-optimization period all patients started with MPH-MLR 10 mg, unless the investigator deemed it necessary to begin at a higher dose, and were titrated to an optimized dose (10, 15, 20, 30, 40, 50, 60 mg; all given once daily) based on response and adverse events (AEs). The primary endpoint was the change from baseline to end of DBP in ADHD Rating Scale, 4th Edition (ADHD-RS-IV) total score. Secondary endpoints included changes in ADHD-RS-IV subscales and Clinical Global Impression-Improvement Scale (CGI-I) at the end of the DBP. The primary analysis was an analysis of covariance including terms for treatment, site, and baseline ADHD-RS-IV total score.

Results: A total of 221 patients completed the DBP. The primary endpoint had a statistically significant difference among treatments (p = 0.0046) and sites (p = 0.0018), and baseline covariate made a significant contribution (p < 0.0001). As the MPH-MLR dose increased, the ADHD-RS-IV total score improved; the 20 and 40 mg doses were statistically different (p = 0.0145 and p = 0.0011, respectively) from placebo. Females responded differently than did males (p = 0.0238); there was a significant difference among treatments for males but not for females, partly because only one-third of subjects were female and partly because some females who received placebo had considerable improvement during the DBP. Similarly, the ADHD-RS-IV subscales and CGI-I scores at the end of the DBP also showed more improvement as the dose of MPH-MLR increased. During the open-label phase, ADHD-RS-IV total scores improved (mean change from baseline -22.5) and correlated as the dose of MPH-MLR increased; CGI-I scores also improved. No unexpected AEs were noted.

Conclusions: Dose-related improvements in ADHD-RS-IV scores that exceeded those of placebo were observed in patients treated with MPH-MLR. No new safety signals were noted.

Trial registration: ClinicalTrials.gov NCT01239030.

Fig. 1

Patient disposition

Fig. 2

Mean decrease in ADHD-RS-IV total score (a); hyperactivity subscale score (b); and inattention subscale score (c) from baseline (day 0) to the end of the double-blind phase (day 7; efficacy population; n = 221). ADHD-RS-IV Attention-Deficit/Hyperactivity Disorder Rating Scale, 4th Edition, MPH-MLR methylphenidate multilayer extended-release capsules. *p = 0.0145 vs. placebo; **p = 0.0011 vs. placebo; ^† p = 0.0840 vs. placebo; ^†† p = 0.0061 vs. placebo; ^‡ p = 0.0118 vs. placebo; ^‡‡ p = 0.0026 vs. placebo

Fig. 3

Mean CGI-I scores at end of the double-blind phase (day 7: efficacy population; n = 221). CGI-I Clinical Global Impression-Improvement Scale, MPH-MLR methylphenidate multilayer extended-release capsules, SD standard deviation. *p = 0.0311 vs. placebo; **p = 0.0072 vs. placebo

Fig. 4

Arithmetic mean ADHD-RS-IV total scores (lower numbers indicate improvement) from 1 week following the beginning of open-label dose optimization (visit 4) to the end of the open-label phase (visit 8) (efficacy population; n = 221). ADHD-RS-IV Attention-Deficit/Hyperactivity Disorder Rating Scale, 4th Edition

Fig. 5

Arithmetic mean CGI-I scores from 1 week following the beginning of open-label dose optimization (visit 4) to the end of the open-label phase (visit 8) (efficacy population; n = 221). CGI-I Clinical Global Impression-Improvement Scale

Fig. 6

Mean ADHD-RS-IV total score and mean MPH-MLR dose from 1 week following the beginning of open-label dose optimization (visit 4) to the end of the open-label phase (visit 8) (patients completing open-label phase, n = 200). ADHD-RS-IV Attention-Deficit/Hyperactivity Disorder Rating Scale, 4th Edition, MPH-MLR methylphenidate multilayer extended-release capsules