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Clinical Trial
. 2017 Aug;27(6):474-482.
doi: 10.1089/cap.2017.0084. Epub 2017 Jul 21.

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

Steven R Pliszka  1 , Timothy E Wilens  2 , Samantha Bostrom  3 , Valerie K Arnold  4 , Andrea Marraffino  5 , Andrew J Cutler  6 , Frank A López  7 , Norberto J DeSousa  8 , Floyd R Sallee  8 , Bev Incledon  8 , Jeffrey H Newcorn  9
Affiliations
Clinical Trial

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

Steven R Pliszka et al. J Child Adolesc Psychopharmacol. 2017 Aug.

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.

Keywords: attention-deficit/hyperactivity disorder; delayed-release; extended-release; functioning; methylphenidate; symptoms.

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Conflict of interest statement

S.R.P. is a consultant for and has received research support from Ironshore Pharmaceuticals & Development, Inc., and has served as an expert witness for AstraZeneca. T.E.W. received grant support from NIH (NIDA); is a consultant for Alcobra, Ironshore Pharmaceuticals & Development, Inc., NIH (NIDA), Phoenix House and Bay Cove Human Services (Clinical Services), Neurovance/Otsuka, Sunovion, Tris, U.S. National Football League (ERM Associates), and U.S. Minor/Major League Baseball; has published a book, Straight Talk About Psychiatric Medications for Kids (Guilford Press); coedited books, ADHD in Children and Adults (Cambridge Press), Massachusetts General Hospital Comprehensive Clinical Psychiatry (Elsevier), and Massachusetts General Hospital Psychopharmacology and Neurotherapeutics (Elsevier); and is the co-owner of the Before School Functioning Questionnaire and has a licensing agreement with Ironshore Pharmaceuticals & Development, Inc. S.B. has participated in advisory boards for Curemark and Tris Pharma; and has received research support from Arbor Pharmaceuticals, Lundbeck, Neurim Pharmaceuticals, Pearson, Rhodes, Shire, Sunovion, and Supernus. V.K.A. has participated in advisory boards for Ironshore Pharmaceuticals & Development, Inc., Neos, Rho, and Shire; is a consultant for Ironshore Pharmaceuticals & Development, Inc.; and participates in speakers bureau for Lundbeck/Takeda. A.M. is a consultant for Ironshore Pharmaceuticals & Development, Inc. A.J.C. is a consultant and has received research support from Aevi Genomics, Akili Interactive, Alkermes, Allergan, Arbor Pharmaceuticals, Ironshore Pharmaceuticals & Development, Inc., Janssen, Kempharm, Lilly, Lundbeck, Neos Therapeutics, Neurovance, Novartis, Noven, Purdue, Rhodes Pharmaceuticals, Shire, Sunovion, Supernus, and Takeda; and is a speaker for Alkermes, Allergan, Arbor Pharmaceuticals, Janssen, Lilly, Lundbeck, Novartis, Shire, Sunovion, and Takeda. F.A.L. is a consultant or has participated in advisory boards for Ironshore Pharmaceuticals & Development, Inc., Neos, Novartis, Noven, Rhodes, Shionogi, Inc., Shire Canada, Shire Global, Shire U.S., Supernus, and Tris Pharma; and has received research support from Bristol-Myers Squibb, Cephalon, Ironshore Pharmaceuticals & Development, Inc., New River Pharmaceuticals, Novartis, Noven, Shire U.S., Pfizer, and Celltech Medeva. N.J.D. and B.I. are employees of Ironshore Pharmaceuticals & Development, Inc. F.R.S. is an employee of Ironshore Pharmaceuticals & Development, Inc.; and is a member of the Board of Directors for P2D Bioscience. J.H.N. is advisor/consultant for Akili Interactive, Alcobra, Arbor Pharmaceuticals, Cerecor, Enzymotec, Ironshore Pharmaceuticals & Development, Inc., KemPharm, Lundbeck, Medice, Neos, U.S. National Football League, NLS, Pearson, Rhodes, Shire, Sunovion, and Supernus; is a DSMB member of Sunovion; has received research grants from Enzymotec, Lundbeck, and Shire; and has received speaking honoraria (nonpromotional) from Shire and Teva.

Figures

<b>FIG. 1.</b>
FIG. 1.
Study design. aOne down-titration to the previous dose strength was permitted during the 3-week randomized test phase, if necessary, for safety or tolerability. DR/ER-MPH, delayed-release and extended-release methylphenidate.
<b>FIG. 2.</b>
FIG. 2.
Participant disposition. aReasons for discontinuation consisted of the following: noncompliance with study visits (DR/ER-MPH: n = 1); participant off study drug for 5 days before Visit 5 (DR/ER-MPH: n = 1); Visit 5 out of window and parent discontinued dosing except for the night before Visit 5 (DR/ER-MPH: n = 1); error in the distribution of investigational product (DR/ER-MPH: n = 1); lack of efficacy (placebo: n = 2); participant unable to complete Visit 5 within visit window (placebo: n = 1); noncompliance and lost to follow-up (placebo: n = 1). DR/ER-MPH, delayed-release and extended-release methylphenidate; ITT, intent-to-treat.
<b>FIG. 3.</b>
FIG. 3.
ADHD-RS-IV total scores. The primary efficacy endpoint was the ADHD-RS-IV total score at final visit (week 3). aBaseline scores are represented as arithmetic mean scores with error bars denoting SE for comparison purposes. Mean ADHD-RS-IV scores (±SD) at baseline were 43.1 ± 7.3 for DR/ER-MPH and 43.5 ± 6.8 for placebo. ADHD-RS-IV, Attention-Deficit/Hyperactivity Disorder Rating Scale-IV; DR/ER-MPH, delayed-release and extended-release methylphenidate; LS, least-squares; SD, standard deviation; SE, standard error of the mean.
<b>FIG. 4.</b>
FIG. 4.
BSFQ total scores by week. The key secondary endpoint was the total BSFQ score at the final visit (week 3). aBaseline scores are represented as arithmetic mean scores with error bars denoting SE for comparison purposes. Mean BSFQ scores (±SD) at baseline were 44.2 ± 10.28 for DR/ER-MPH and 44.9 ± 10.20 for placebo. BSFQ, Before-School Functioning Questionnaire; DR/ER-MPH, delayed-release and extended-release methylphenidate; LS, least-squares; SD, standard deviation; SE, standard error of the mean.
<b>FIG. 5.</b>
FIG. 5.
PREMB-R AM and PREMB-R PM scores at week 3. DR/ER-MPH, delayed-release and extended-release methylphenidate; LS, least squares; PREMB-R AM, Parent Rating of Evening and Morning Behavior-Revised, morning subscale; PREMB-R PM, Parent Rating of Evening and Morning Behavior-Revised, evening subscale; SD, standard deviation; SE, standard error of the mean.
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