Effect of a Multi-Layer, Extended-Release Methylphenidate Formulation (PRC-063) on Sleep in Adults with ADHD: A Randomized, Double-Blind, Forced-Dose, Placebo-Controlled Trial Followed by a 6-month Open-Label Extension

Abstract

Background: The effects of stimulant treatment on sleep in adults with attention-deficit/hyperactivity disorder (ADHD) are complex and varied, with some individuals experiencing worsening of sleep but others experiencing improvement.

Methods: Data from previously reported trials of the clinical efficacy and safety of the long-acting methylphenidate formulation PRC-063 (Adhansia XR® in the USA; Foquest® in Canada) in adults with ADHD were used to evaluate patient-reported sleep outcomes, as captured using the Pittsburgh Sleep Quality Index (PSQI) and adverse events of insomnia. The trials comprised 4 weeks of randomized, forced-dose PRC-063 treatment at a dose of 0 (placebo), 25, 45, 70, or 100 mg/day followed by an optional 6 months of open-label PRC-063 treatment at an individually optimized dose of 25-100 mg/day.

Results: At the end of double-blind treatment, PRC-063 (all doses combined; N = 297) showed no significant difference versus placebo (N = 78) in least squares mean change in global PSQI score from baseline (- 0.7 vs. - 1.3; P = 0.0972) or in scores for each of the seven subscales of the PSQI. For patients enrolled in the open-label extension (N = 184), mean ± standard deviation global PSQI score improved from 7.8 ± 3.55 at the end of double-blind treatment to 5.8 ± 3.11 at 1 month and 5.4 ± 3.21 at 6 months (P < 0.0001). A greater proportion of patients were good sleepers (global PSQI score ≤ 5) at the end of the open-label extension (57.3%) than at baseline (20.9%) or at the end of double-blind treatment (26.0%). In a logistic regression analysis, baseline global PSQI score (odds ratio 1.491; P < 0.0001), but not randomized study treatment (P = 0.1428), was a significant predictor of poor sleep (global PSQI score > 5) at the end of double-blind treatment. Adverse event rates for insomnia (15.8 vs. 3.8%) and initial insomnia (6.1 vs. 1.3%) during double-blind treatment were higher for PRC-063 (all doses combined) than for placebo. Two patients receiving PRC-063 in the double-blind study and one patient in the open-label study were withdrawn because of insomnia adverse events.

Conclusions: Our findings indicate that, on average, PRC-063 had no significant impact on overall sleep quality in adults with ADHD. Although insomnia was observed as an adverse event, when sleep was measured over time as an outcome in its own right for patients receiving dose-optimized PRC-063 open-label, more patients showed improvement in sleep than deterioration. CLINICALTRIALS.

Gov identifer: NCT02139124 and NCT02168127.

Conflict of interest statement

MW has received consulting fees/honoraria from Tris, Purdue, Adlon, Takeda, Huron, Mundipharma, and CBPartners; support for travel to meetings, manuscript preparation, or other purposes from World Federation of ADHD, Eunethydis, Canadian Attention Deficit Disorder Resource Alliance (CADDRA), Children and Adults with Attention Deficit Disorder (CHADD), American Professional Society for ADHD and Related Disorders (APSARD), Israeli Federation of ADHD, Purdue CA, Purdue US, Rhodes Pharmaceutical, Akili, Takeda, Global Medical Education, and Boston Children’s Hospital; payment for lectures from Global Medical Education, Centre for ADHD Awareness Canada (CADDAC), and CADDRA; and royalties from Multi Health Systems and Johns Hopkins University Press. CS has received consulting fees from Eisai, McNeil, NLS Pharma, Nutricia, Pfizer, Adlon/Purdue, Rhodes, Shire, Somaxon, Sunovion, Takeda, and Teva; payment for lectures from Alcobra, Arbor, Janssen, Janssen-Ortho, McNeil, Novartis, Shire, Reed/MGH Academy (multiple companies), and GME CME (multiple companies); research funding from Abbot, Cephalon, Hilda and Preston Davis Foundation, Eli Lilly, Magceutics/Neurocentria, Johnson & Johnson/McNeil, Lundbeck, Merck, Nordic Naturals, Shire, and Takeda; and royalties from Berkeley/Penguin (for FAST MINDS. How to Thrive if You Have ADHD (or Think You Might)) and Humana/Springer (for ADHD in Adults: A Practical Guide to Evaluation and Management). AK has received consulting fees/honoraria and payment for lectures from Elysium and Purdue. EH is a full-time employee of Imbrium Therapeutics, a subsidiary of Purdue Pharma L.P., the sponsor of this study. MC is a full-time employee of Purdue Pharma L.P., the sponsor of this study. GD is an employee of Purdue Pharma (Canada).

Figures

Fig. 1

Global Pittsburgh Sleep Quality Index (PSQI) score during a the double-blind (DB) study and b the open-label (OL) extension study. PBO placebo, PRC PRC-063, PSQI Pittsburgh Sleep Quality Index, SD standard deviation

Fig. 2

Shift in sleep status during a the double-blind study and b the open-label extension study. Data show the shift in sleep status from baseline to end of study, where baseline for the open-label extension study is defined as the end of the double-blind study. Sleep status is based on global PSQI score, with a score of >5 indicating poor sleep and a score ≤5 good sleep. Data for sleep status at baseline and/or end of study were missing for 19 patients treated with PRC-063 in the double-blind study, six patients treated with placebo in the double-blind study, and 60 patients in the open-label extension study. Further information is provided in ESM 2. PSQI Pittsburgh Sleep Quality Index