Dataset Information

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 Two patients receiving PRC-063 in the double-blind study and one patient in the open-label study were withdrawn because of insomnia adverse events.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.

SUBMITTER: Weiss MD

PROVIDER: S-EPMC8219576 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Objective: To determine the safety and efficacy of PRC-063, a once-daily, multilayer, extended-release (ER) formulation of methylphenidate (MPH) hydrochloride, in the treatment of attention-deficit/hyperactivity disorder (ADHD) in children in a randomized, double-blind, parallel group, dose-optimized, placebo-controlled phase 3 study. Methods: Boys and girls aged 6-12 years diagnosed with ADHD were enrolled. During a 6-week, open-label, dose-optimization phase, subjects began treatment at 25 mg/day of PRC-063 and were titrated until an optimal dose (maximum 85 mg/day) was reached. During the double-blind period, subjects were randomized to receive treatment with their optimal dose of PRC-063 or placebo for 1 week. Efficacy was assessed in a laboratory classroom setting on the final day of the double-blind treatment using the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Rating Scale and Permanent Product Measure of Performance (PERMP). Safety was assessed measuring adverse events (AEs), vital signs, and electrocardiograms. Results: The study was completed by 147 subjects. In the primary efficacy analysis, significant improvements were demonstrated with PRC-063 versus placebo (p < 0.0001) when SKAMP-Combined scores were averaged over the 13-hour full-day laboratory classroom (least squares mean difference = -8.6, 95% confidence interval = -10.6 to -6.6). Mean average PERMP-Total scores were also significantly improved with PRC-063 versus placebo at all time points postdose (p < 0.01). The onset of treatment effect was present by 1-hour postdose (the first time point measured) and duration of efficacy was up to and including 13 hours postdose. AEs reported in ≥5% of subjects during the dosing optimization period were decreased appetite, abdominal pain upper, affect lability, weight decreased, headache, irritability, and insomnia. Conclusions: PRC-063 was effective in improving attention and reducing symptoms of ADHD versus placebo and had a rapid onset and extended duration of effect. AEs were consistent to those reported with other ER MPH treatments. Clinical Trial Registry: NCT03172481.

Project description:BackgroundThe prescription use of the stimulants methylphenidate and amphetamine for the treatment of attention deficit-hyperactivity disorder (ADHD) has been increasing. In 2007, the Food and Drug Administration mandated changes to drug labels for stimulants on the basis of findings of new-onset psychosis. Whether the risk of psychosis in adolescents and young adults with ADHD differs among various stimulants has not been extensively studied.MethodsWe used data from two commercial insurance claims databases to assess patients 13 to 25 years of age who had received a diagnosis of ADHD and who started taking methylphenidate or amphetamine between January 1, 2004, and September 30, 2015. The outcome was a new diagnosis of psychosis for which an antipsychotic medication was prescribed during the first 60 days after the date of the onset of psychosis. To estimate hazard ratios for psychosis, we used propensity scores to match patients who received methylphenidate with patients who received amphetamine in each database, compared the incidence of psychosis between the two stimulant groups, and then pooled the results across the two databases.ResultsWe assessed 337,919 adolescents and young adults who received a prescription for a stimulant for ADHD. The study population consisted of 221,846 patients with 143,286 person-years of follow up; 110,923 patients taking methylphenidate were matched with 110,923 patients taking amphetamines. There were 343 episodes of psychosis (with an episode defined as a new diagnosis code for psychosis and a prescription for an antipsychotic medication) in the matched populations (2.4 per 1000 person-years): 106 episodes (0.10%) in the methylphenidate group and 237 episodes (0.21%) in the amphetamine group (hazard ratio with amphetamine use, 1.65; 95% confidence interval, 1.31 to 2.09).ConclusionsAmong adolescents and young adults with ADHD who were receiving prescription stimulants, new-onset psychosis occurred in approximately 1 in 660 patients. Amphetamine use was associated with a greater risk of psychosis than methylphenidate. (Funded by the National Institute of Mental Health and others.).