Efficacy and Safety of HLD200, Delayed-Release and Extended-Release Methylphenidate, in Children with Attention-Deficit/Hyperactivity Disorder.

Steven R Pliszka,Andrea Marraffino,Samantha Bostrom,Andrew J Cutler,Timothy E Wilens,Norberto J Desousa,Frank A López,Jeffrey H Newcorn,Bev Incledon,Floyd R Sallee,Valerie K Arnold

doi:10.1089/cap.2017.0084

Abstract

Objective: Evening-dosed HLD200 is a delayed-release and extended-release methylphenidate (DR/ER-MPH) formulation consisting of uniform, dual-layered microbeads with an inner drug-loaded core. DR/ER-MPH is designed to delay the initial release of drug by 8–10 hours, and thereafter, provide a controlled, extended drug release to target onset of effect upon awakening that lasts into the evening. This phase 3 study evaluated the safety and efficacy of DR/ER-MPH on symptoms and temporal at-home functional impairment in children with attention-deficit/hyperactivity disorder (ADHD).Methods: This 3-week, randomized, double-blind, multicenter, placebo-controlled, parallel-group, forced-dose titration trial evaluated DR/ER-MPH (40–80 mg/day) in children aged 6–12 years with ADHD. Primary efficacy endpoint was the ADHD rating scale–IV (ADHD-RS-IV), and the key secondary endpoints were the Before-School Functioning Questionnaire (BSFQ), and Parent Rating of Evening and Morning Behavior-Revised, morning (PREMB-R AM) and evening (PREMB-R PM). Safety measures included spontaneously reported treatment-emergent adverse events (TEAEs) and two TEAEs of special interest, appetite suppression and insomnia (with direct questioning on sleep disturbance).Results: One hundred sixty-one participants were included in the intent-to-treat population (DR/ER-MPH, n = 81; placebo, n = 80). After 3 weeks, DR/ER-MPH achieved significant improvements versus placebo in ADHD symptoms (least-squares [LS] mean ADHD-RS-IV: 24.1 vs. 31.2; p = 0.002), and at-home early morning (LS mean BSFQ: 18.7 vs. 28.4; p < 0.001; LS mean PREMB-R AM: 2.1 vs. 3.6; p < 0.001) and late afternoon/evening (LS mean PREMB-R PM: 9.4 vs. 12.2; p = 0.002) functional impairment. Commonly reported TEAEs (≥10%) were insomnia and decreased appetite.Conclusions: DR/ER-MPH was generally well tolerated and demonstrated significant improvements versus placebo in ADHD symptoms and at-home functional impairments in the early morning, late afternoon, and evening in children with ADHD.

Highlights

Attention-deficit/hyperactivity disorder (ADHD), the most common childhood-onset neurodevelopmental disorder, is a chronic condition characterized by developmentally inappropriate symptoms and impaired functioning from the time of awakening until bedtime (Harpin 2005; Wolraich et al 2011; Sasser et al 2017)
A recent survey of 201 primary caregivers of youth with attention-deficit/hyperactivity disorder (ADHD) revealed that, despite routine morning administration of stimulant medication, *75.6% of caregivers regarded the early morning as a time associated with moderate-to-severe ADHD-related functional impairment in their children (Sallee 2015). These findings were corroborated by a subsequent survey of 350 primary caregivers of youth with and without ADHD, which found that early morning functional (EMF) impairment in stimulant-treated youth with ADHD significantly diminished the emotional well-being of caregivers and exerted a pervasive functional burden on the entire family unit (Faraone et al 2017). These findings suggest that inadequately controlled early morning ADHD symptoms and EMF impairment remain significant burdens on stimulant-treated youth with ADHD and their families
The DR/ER-MPH group had a small increase in mean diastolic blood pressure from baseline to week 3, whereas the placebo group had little change. The results of this trial demonstrated that 3 weeks of treatment with evening-dosed DR/ER-MPH is more effective than placebo in improving ADHD symptoms and at-home functional impairments from early morning to evening in children with ADHD

Summary

Introduction

Attention-deficit/hyperactivity disorder (ADHD), the most common childhood-onset neurodevelopmental disorder, is a chronic condition characterized by developmentally inappropriate symptoms and impaired functioning from the time of awakening until bedtime (Harpin 2005; Wolraich et al 2011; Sasser et al 2017). No formulation provides all-day coverage of symptoms, and, because of constraints in the various technologies used to deliver MPH, there is often a delay in the initial onset of action of up to 2 hours (Childress 2016). This leaves the patient vulnerable to inadequate symptom control and impaired functioning during the early morning routine (Childress and Tran 2016; Sallee 2015)

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