A Randomized, Double-Blind, Placebo-Controlled Study of HLD200, a Delayed-Release and Extended-Release Methylphenidate, in Children with Attention-Deficit/Hyperactivity Disorder: An Evaluation of Safety and Efficacy Throughout the Day and Across Settings

Abstract

Objectives: HLD200, a once-daily, evening-dosed, delayed-release and extended-release methylphenidate (DR/ER-MPH), was designed to provide therapeutic effect beginning upon awakening and lasting into the evening. This pivotal, randomized, double-blind, multicenter, placebo-controlled, phase 3 trial assessed improvements in functional impairment across the day using multiple validated measures tailored for different settings and time of day in children (6-12 years) with attention-deficit/ hyperactivity disorder (ADHD). Methods: Following a 6-week, open-label titration of DR/ER-MPH to an optimal dose (20, 40, 60, 80, or 100 mg/day) and dosing time (8:00 PM-1.5 hours), participants were randomized to treatment-optimized DR/ER-MPH or placebo for 1 week. The primary endpoint was the model-adjusted average of postdose Swanson, Kotkin, Agler, M-Flynn, and Pelham Scale combined scores (SKAMP CS) over a 12-hour laboratory classroom day (8:00 AM to 8:00 PM). The key secondary endpoint was the Parent Rating of Evening and Morning Behavior-Revised, Morning (PREMB-R AM) subscale. Secondary/exploratory measures included the PREMB-R Evening (PREMB-R PM) subscale and Permanent Product Measure of Performance (Attempted [PERMP-A] and Correct [PERMP-C]). Safety endpoints included treatment-emergent adverse events (TEAEs). Results: After the treatment-optimization phase, the mean optimized dose was 66.2 mg and the most common prescribed dosing time was 8:00 PM. Double-blind DR/ER-MPH treatment significantly improved functional impairment versus placebo in the early morning (PREMB-R AM: p < 0.001), averaged over the classroom day (SKAMP CS: p < 0.001), and in the late afternoon/evening (PREMB-R PM: p = 0.003) in the intent-to-treat population (N = 117). Average PERMP-A (p = 0.006) and PERMP-C (p = 0.009) also indicated improved classroom performance with DR/ER-MPH versus placebo. In the double-blind phase, TEAEs did not differ between DR/ER-MPH and placebo groups and no serious TEAEs or TEAEs leading to discontinuation were reported. Conclusion: DR/ER-MPH was well tolerated and demonstrated significant improvements versus placebo in functional impairment throughout the day across different settings in children with ADHD.

A Post Hoc Comparison of Prior ADHD Medication Dose and Optimized Delayed-release and Extended-release Methylphenidate Dose in a Pivotal Phase III Trial

“…These post hoc analyses were performed on data from a Phase III, multicenter, randomized, double-blind, placebo-controlled, forced-withdrawal, parallelgroup, laboratory classroom study of DR/ER-MPH in children (aged 6e12 years) with ADHD. 15 Key inclusion criteria included but were not limited to: diagnosis of ADHD based on the Diagnostic and Statistical Manual of Mental Disorders (5th edition); a baseline ADHD Rating Scale-IV (ADHD-RS-IV) score in at least the 90th percentile normalized for sex and age in at least one of the following categories: inattentive, hyperactive-impulsive, or total score, and a total score 26 at baseline; Clinical Global Impression of Severity (CGI-S) score 4 and Conners' Global IndexeParent (CGI-P) score >10 at baseline; and prior response to MPH therapy or treatment with the same dose of MPH and clinical response with acceptable tolerability for 2 weeks before screening. Key exclusion criteria included but were not limited to: history of or current medical condition or laboratory result that could interfere with study participation, participant safety, or satisfactory completion of the study; any cardiac problems that may place the participant at increased vulnerability to the sympathomimetic effects of a stimulant drug; history of psychosis, bipolar disorder, anorexia nervosa, bulimia, or suicide attempt; and current depression, anxiety, conduct disorder, substance use disorder, or other psychiatric condition that may jeopardize participant safety or interfere with the satisfactory completion of the study.…”

“…The study was conducted in 3 phases: a screening/ washout phase lasting up to 4 weeks with washout of ADHD treatment for 5 days; a 6-week, open-label, DR/ER-MPH treatment-optimization phase; and a 1week, randomized, double-blind, placebo-controlled, parallel-group phase ending with a laboratory classroom test day ( Figure 1). 15 At the baseline visit, all participants initiated DR/ER-MPH treatment at either 20 mg or 40 mg once daily at 8:00 PM (±30 min), with the starting dose dependent on their previous treatment history and at the discretion of the investigator. Over the first 4 weeks of the open-label treatment-optimization phase, weekly dose titrations were permitted in 20-or 40-mg increments or decrements until an optimized dose was achieved or a maximum daily dose of 100 mg/d or 3.7 mg/kg per day was reached.…”

“…This outcome shows that the doses achieved at the end of the treatment-optimization phase resulted in substantial improvements in ADHDrelated symptoms and functional impairment, well beyond the 33% improvement from baseline prespecified as meaningful control. 15 Mean (SD) ADHD-RS-IV scores improved from 42.5 (6.60) at…”

“…Demographic and baseline characteristics of the enrolled study population have been described in detail elsewhere. 15 Briefly, 68% of participants were male, the mean age was 9.4 years, and 79.2% of participants were White. The majority of participants (86.4%) had combined-type ADHD, the mean baseline ADHD-RS-IV total score was 42.7, and the baseline CGI-S score was 5 (ie, markedly ill) in 42% of participants.…”

“…14 The efficacy and tolerability of DR/ER-MPH have been shown in two pivotal Phase III trials of children with ADHD. 15,16 Treatment guidelines are increasingly recommending that the goal of treatment should be all-day control of ADHD-related symptoms and functional impairment, and that physicians should change ADHD medications if responses to current medications are not optimal (eg, a lack of all-day coverage). 17,18 Transitioning between stimulants is complex, and each particular medication provides unique drug exposure in each individual patient.…”