4.23 PIVOTAL PHASE 3 TRIAL EVALUATING THE EFFICACY AND SAFETY OF HLD200, A NOVEL DELAYED-RELEASE AND EXTENDED-RELEASE FORMULATION OF METHYLPHENIDATE, IN CHILDREN WITH ATTENTION-DEFICIT/HYPERACTIVITY DISORDER

Objectives: Evening-dosed HLD200 delays the initial release of methylphenidate (MPH) by approximately 8-10 hours, targeting the onset of clinically meaningful treatment effect upon awakening and lasting to the evening. The objective was to determine whether HLD200 improves control of ADHD symptoms and at-home early morning and evening functioning versus placebo (PLA) in children with ADHD. Safety and tolerability were also assessed. Methods: This was a pivotal, randomized, double-blind, multicenter, PLA-controlled, parallel-group, phase 3 trial of HLD200 in children (age 6-12 years) with ADHD (Clinical Trial: NCT02520388). Subjects had current or prior response on MPH. After a screening period of ≤ 2 weeks with a 3- to 7-day washout, subjects were randomized (1:1) to HLD200 or PLA once daily each evening for 3 weeks. After 1 week, the initial 40-mg dose of HLD200 was titrated in 20-mg weekly increments to 60 and 80 mg, as tolerated, with a one-step, down-titration as permitted. The primary efficacy measure was the ADHD Rating Scale (ADHD-RS-IV) Total Score following 3 weeks of treatment. The key secondary efficacy measures 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) subscales after 3 weeks of treatment. Safety measures included treatment-emergent adverse events (TEAEs), with a focus on sleep and appetite. Results: Of 163 children enrolled across 22 sites, 161 were included in the intent-to-treat population. After 3 weeks of treatment, children on HLD200 achieved a significant improvement versus those on PLA in ADHD symptoms [least-squares (LS) mean ADHD-RS-IV: 24.1 vs. 31.2; P = 0.002], at-home early morning functioning (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 at-home evening functioning (LS mean PREMB-R PM: 9.4 vs. 12.2; P = 0.002). There were no serious TEAEs, and all reported TEAEs were consistent with the known effects of MPH. All sleep-related TEAEs were transient and mild or moderate in severity. Conclusions: After daily evening administration, HLD200 was well tolerated and demonstrated significant improvements in ADHD symptoms and both at-home early morning and evening functioning versus PLA in children with ADHD.