Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Feb;30(1):2-14.
doi: 10.1089/cap.2019.0070. Epub 2019 Aug 29.

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

Affiliations
Free PMC article

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

Ann C Childress et al. J Child Adolesc Psychopharmacol. .
Free PMC article

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.

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

Conflict of interest statement

Dr. A.C.C. has received research support from Aevi Genomic Medicine, Inc., Akili Interactive Labs, Alcobra Pharma, Arbor Pharmaceuticals, Eli Lilly, Forest Laboratories, Ironshore Pharmaceuticals & Development, Inc., KemPharm, Inc., Lundbeck, Neos Therapeutics, Neurovance, Inc., Noven Pharmaceuticals, Inc., Otsuka America Pharmaceutical, Inc., Pearson, Pfizer, Purdue Pharma, Rhodes Pharmaceuticals, Shire, Sunovion Pharmaceuticals, Inc., Supernus Pharmaceuticals, Inc., Tris Pharma, Inc. She has consulted and/or served on advisory boards for Akili Interactive Labs, Arbor Pharmaceuticals, Cingulate Therapeutics, Ironshore Pharmaceuticals & Development, Inc., Neos Therapeutics, Neurovance, Inc., NLS Pharma, Noven, Pfizer, Purdue Pharma, Rhodes Pharmaceuticals, Shire, Sunovion Pharmaceuticals, Inc., Supernus Pharmaceuticals, Inc., and Tris Pharma, Inc.; participated in speakers bureaus for Arbor Pharmaceuticals, Ironshore Pharmaceuticals Inc., Neos Therapeutics, Pfizer, Shire, Tris Pharma, Inc.; and has received writing support from Arbor Pharmaceuticals, Ironshore Pharmaceuticals & Development, Inc., Neos Therapeutics, Pfizer, Purdue Pharma, Rhodes Pharmaceuticals, Shire, Sunovion Pharmaceuticals, Inc., and Tris Pharma, Inc. Dr. A.J.C. has received research support from Aevi Genomic Medicine, Inc., Akili Interactive Labs, Allergan, Arbor Pharmaceuticals, Ironshore Pharmaceuticals & Development, Inc., KemPharm, Inc., Lundbeck, Neos Therapeutics, Noven Pharmaceuticals, Inc., Otsuka America Pharmaceutical, Inc., Purdue Pharma, Rhodes Pharmaceuticals, Shire, Sunovion Pharmaceuticals, Inc., Supernus Pharmaceuticals, Inc., Takeda, and Tris Pharma, Inc. He has consulted and/or served on advisory boards for Aevi Genomic Medicine, Inc., Akili Interactive Labs, Allergan, Arbor Pharmaceuticals, Cingulate Therapeutics, Ironshore Pharmaceuticals & Development, Inc., KemPharm, Inc., Lundbeck, Neos Therapeutics, NLS Pharma, Noven Pharmaceuticals, Inc., Otsuka America Pharmaceutical, Inc., Purdue Pharma, Rhodes Pharmaceuticals, Shire, Sunovion Pharmaceuticals, Inc., Supernus Pharmaceuticals, Inc., Takeda, and Tris Pharma, Inc.; participated in speakers bureaus for Allergan, Arbor Pharmaceuticals, Ironshore Pharmaceuticals Inc., Neos Therapeutics, Otsuka America Pharmaceutical, Inc., Shire, Sunovion Pharmaceuticals, Inc., Takeda, and Tris Pharma, Inc.; and is a board member of the Neuroscience Education Institute. Dr. A.M. has received research support from Acadia Pharmaceuticals, Akili Interactive Labs, Allergan, Arbor Pharmaceuticals, Avanir, Boehringer Ingelheim Pharmaceuticals, Inc., Eisai, Inc., Ironshore Pharmaceuticals & Development, Inc., KemPharm, Inc., Neos Therapeutics, Novartis Pharmaceuticals Corporation, Otsuka America Pharmaceutical, Inc., Purdue Pharma, Roche, Sage Therapeutics, Shire, Sunovion Pharmaceuticals, Inc., Supernus Pharmaceuticals, Inc., Takeda, Tonix Pharmaceuticals, and Tris Pharma, Inc., She has consulted for Ironshore Pharmaceuticals & Development, Inc., KemPharm, Inc., and Supernus Pharmaceuticals, Inc; participated in speakers bureaus for Ironshore Pharmaceuticals Inc. Dr. M.A.M. has received research support from Ironshore Pharmaceuticals & Development, Inc., Purdue Pharma, and Rhodes Pharmaceuticals. Dr. J.M.T. has received research support from Eli Lilly, Inc., Ironshore Pharmaceuticals & Development, Inc., Pfizer, Inc., Shionogi Pharmaceuticals, Shire US, and Tris Pharma, Inc., and has consulted for Celltech US, Shionogi Pharmaceuticals and Shire US. Dr. M.B. has served on advisory boards for Neos Therapeutics, Shire, and Tris Pharma, Inc., and has participated in speakers bureaus for Neos Therapeutics, Lundbeck, Otsuka, Sunovion Pharmaceuticals, Inc., Takeda, and Tris Pharma, Inc. Mr. N.J.D. and Dr. B.I. are consultants/employees of Ironshore Pharmaceuticals & Development, Inc. Dr. F.R.S. is an employee of Ironshore Pharmaceuticals Inc., and serves on the advisory board/board of directors of P2D Bioscience. Dr. S.B.W. has received research support from Akili Interactive Labs, Ironshore Pharmaceuticals & Development, Inc., Neurovance, Inc., NLS Pharma, NuTec, Pfizer, Purdue Pharma, Rho, Rhodes Pharmaceuticals, Shire, Sunovion Pharmaceuticals,1 Inc., and Tris Pharma, Inc. She has consulted for Arbor Pharmaceuticals, Atentiv, Ironshore Pharmaceuticals & Development, Inc., Neos Therapeutics, Neurovance, Inc., NLS Pharma, NuTec, Pfizer, Purdue Pharma, Rho, Rhodes Pharmaceuticals, Shire, Sunovion Pharmaceuticals, Inc., Takeda, and Tris Pharma, Inc., and served on speaker/advisory boards for Cingulate Therapeutics, Ironshore Pharmaceuticals Inc./Ironshore Pharmaceuticals & Development, Inc., NLS Pharma, NuTec, Otsuka, Pfizer, Purdue Pharma, Rho, Rhodes Pharmaceuticals, Shire, Sunovion Pharmaceuticals, Inc., Supernus Pharmaceuticals, Inc., TouchPoint Solutions, and Tris Pharma, Inc.

Figures

FIG. 1.
FIG. 1.
Study design. DR/ER-MPH, delayed-release and extended-release methylphenidate.
FIG. 2.
FIG. 2.
Participant disposition. aThe ITT population was defined as all randomized participants who received at least one dose of double-blind study drug and had at least one postbaseline evaluation of the primary efficacy assessment. bParticipants who completed the study were those who completed the follow-up phone call 14 ± 3 days following the laboratory classroom day. TEAE, treatment-emergent adverse event; FDA, United States Food and Drug Administration; DR/ER-MPH, delayed-release and extended-release methylphenidate; ITT, intent-to-treat.
FIG. 3.
FIG. 3.
Model-adjusted average of all postdose SKAMP CS (LS Mean ± SE) from 8:00 AM to 8:00 PM at Visit 9. DR/ER-MPH, delayed-release and extended-release methylphenidate; LS, least squares; SE, standard error; SKAMP CS, Swanson, Kotkin, Agler, M-Flynn, and Pelham Scale combined score.
FIG. 4.
FIG. 4.
SKAMP CS from 8:00 AM to 8:00 PM at Visit 9. DR/ER-MPH, delayed-release and extended-release methylphenidate; LS, least squares; SE, standard error; SKAMP CS, Swanson, Kotkin, Agler, M-Flynn, and Pelham Scale combined score.
FIG. 5.
FIG. 5.
PERMP-attempted (A) and PERMP-complete (B) from 8:00 AM to 8:00 PM at Visit 9. DR/ER-MPH, delayed-release and extended-release methylphenidate; LS, least squares; PERMP, Permanent Product Measure of Performance; SE, standard error.
FIG. 6.
FIG. 6.
Early morning (A) and late afternoon/evening (B) functional impairment (LS mean ± SE) assessed at Visit 9. DR/ER-MPH, delayed-release and extended-release methylphenidate; LS, least squares; SE, standard error; 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.

Similar articles

See all similar articles

References

    1. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric Association; 1994
    1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Washington, DC: American Psychiatric Association; 2013
    1. Barkley RA: Psychological assessment of children with ADHD. In: Attention-Deficit Hyperactivity Disorder: A Handbook for Diagnosis and Treatment. Edited by Barkley RA, editor. New York, Guilford Press, 2014, pp. 455–474
    1. Childress A, Mehrotra S, Gobburu J, McLean A, DeSousa NJ, Incledon B.: Single-dose pharmacokinetics of HLD200, a delayed-release and extended-release methylphenidate formulation, in healthy adults and in adolescents and children with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol 28:10–18, 2018 - PMC - PubMed
    1. Childress AC: Methylphenidate HCL for the treatment of ADHD in children and adolescents. Expert Opin Pharmacother 17:1171–1178, 2016 - PubMed

LinkOut - more resources

Feedback