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

J Child Adolesc Psychopharmacol. 2020 Feb;30(1):2-14. doi: 10.1089/cap.2019.0070. Epub 2019 Aug 29.


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.

Trial registration: ClinicalTrials.gov NCT02493777.

Keywords: DR/ER-MPH; attention-deficit/hyperactivity disorder; duration; functional impairment; methylphenidate; safety.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Attention Deficit Disorder with Hyperactivity / drug therapy*
  • Central Nervous System Stimulants / adverse effects
  • Central Nervous System Stimulants / therapeutic use
  • Child
  • Delayed-Action Preparations / adverse effects
  • Delayed-Action Preparations / therapeutic use
  • Double-Blind Method
  • Female
  • Humans
  • Male
  • Psychiatric Status Rating Scales / statistics & numerical data


  • Central Nervous System Stimulants
  • Delayed-Action Preparations

Associated data

  • ClinicalTrials.gov/NCT02493777