Post-Hoc Analyses of the Effects of Baseline Sleep Quality on SHP465 Mixed Amphetamine Salts Extended-Release Treatment Response in Adults with Attention-Deficit/Hyperactivity Disorder

Abstract

Objective: Sleep problems are common in adults with attention-deficit/hyperactivity disorder (ADHD). The presence of sleep problems at the time of presentation for ADHD treatment could impact the level of improvement in ADHD symptoms or executive function occurring with ADHD pharmacotherapy. Therefore, we examined the influence of baseline sleep quality on the effects of SHP465 mixed amphetamine salts (MAS) extended-release.

Methods: Adults (18-55 years) with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision-defined ADHD and baseline ADHD Rating Scale IV (ADHD-RS-IV) total scores ≥ 24 were randomized to once-daily SHP465 MAS (12.5-75 mg) or placebo in a 7-week, double-blind, dose-optimization study. Post-hoc analyses evaluated SHP465 MAS treatment effects on ADHD symptoms, using the ADHD-RS-IV, and executive function, using the Brown Attention-Deficit Disorder Scale (BADDS), based on baseline sleep quality as defined by Pittsburgh Sleep Quality Index (PSQI) scores [sleep quality impaired (PSQI total score > 5; PSQI component scores 2 or 3) versus not impaired (PSQI total score ≤ 5; PSQI component scores 0 or 1)]. Analyses were conducted in the intent-to-treat population.

Results: Of 280 enrolled participants, 272 were randomized (placebo, n = 135; SHP465 MAS, n = 137). The intent-to-treat population consisted of 268 participants (placebo, n = 132; SHP465 MAS, n = 136), and 170 participants (placebo, n = 76; SHP465 MAS, n = 94) completed the study. Treatment differences nominally favored SHP465 MAS over placebo in both sleep impairment groups regarding ADHD-RS-IV total score changes (all nominal p < 0.05), except for those with impairment defined by sleep efficiency (p = 0.2696), and regarding BADDS total score changes (all nominal p < 0.05), except for those with impairment defined by sleep duration (p = 0.1332) and sleep efficiency (p = 0.8226). There were no statistically significant differences in SHP465 MAS treatment effects between sleep impairment groups.

Conclusions: Improvements in ADHD symptoms and executive function occurred with dose-optimized SHP465 MAS, regardless of baseline impairment in some aspects of sleep in adults with ADHD, with no significant differences observed as a function of sleep impairment.

Clinical trials registration: ClinicalTrials.gov identifier-NCT00150579.

Conflict of interest statement

C. B. H. Surman reports disclosures for speaking/education for Arbor, McNeil, Janssen, Janssen-Ortho, Novartis, Shire, Reed/Massachusetts General Hospital Academy, Global Medical Education, and the North American Center for Continuing Medical Education (the latter three funded by multiple companies); research support for the Massachusetts General Hospital Adult ADHD Program (National Institutes of Health, Abbott, Cephalon, Hilda and Preston Davis Foundation, Eli Lilly, Magceutics, J & J/McNeil, Merck, Magceutics/Neurocentria, Nordic Naturals, Nestle/Pamlab, Pfizer, Organon, Shire, and Takeda); consulting for McNeil, NLS Pharma, Nutricia/Dannone, Purdue, Rhodes, Shire, Somaxon, Sunovion, Supernus, Takeda, Teva, and Vaya; and book royalties for Fast Minds—How to Thrive If You Have ADHD [or Think You Might]; ADHD in Adults—A Practical Guide to Evaluation and Management. B. Robertson and J. Chen are employees of Shire, a member of the Takeda group of companies, and hold Takeda stock. S. Cortese reports not receiving any honorarium for this work; he has received honoraria from the Association of Child and Adolescent Mental Health (ACAMH), a United Kingdom charity, for speaking about ADHD.

Figures

Fig. 1

Study design summary and timing of study assessments. ADHD-RS-IV ADHD Rating Scale version IV, BADDS Brown Attention-Deficit Disorder Scale, ET early termination, MAS mixed amphetamine salts, PSQI Pittsburgh Sleep Quality Index, V visit. aDuring the dose maintenance phase, participants were maintained on the optimized dose established during the dose-optimization phases. bMidweek visits were required if participants were titrated to 75 mg SHP465 MAS at visit 3 and if participants were downtitrated to 62.5 mg MAS SHP465 at visit 4

Fig. 2

Change from baseline to endpoint in ADHD-RS-IV total score (a) and from baseline to week 7/ET in BADDS total score (b) by baseline sleep qualitya, ITT population. ADHD-RS-IV Attention-Deficit/Hyperactivity Disorder Rating Scale, version IV, BADDS Brown Attention-Deficit Disorder Scale, ET early termination, ITT intent-to-treat, MAS mixed amphetamine salts, PSQI Pittsburgh Sleep Quality Index, SD standard deviation. aSleep quality not impaired (baseline PSQI global score ≤ 5; baseline PSQI component score of 0 or 1), sleep quality impaired (baseline PSQI global score > 5; baseline PSQI component score of 2 or 3)

Fig. 3

Treatment differences (SHP465 MAS − placebo) in ADHD-RS-IV total score change (a), hyperactivity/impulsivity subscale score change (b), and inattentiveness subscale score change (c) by baseline sleep qualitya, ITT populationb. ADHD-RS-IV Attention-Deficit/Hyperactivity Disorder Rating Scale, version IV, CI confidence interval, ITT intent-to-treat, MAS mixed amphetamine salts, PSQI Pittsburgh Sleep Quality Index. aSleep quality not impaired (baseline PSQI global score ≤5; baseline PSQI component score of 0 or 1), sleep quality impaired (baseline PSQI global score >5; baseline PSQI component score of 2 or 3). bBased on the following sample sizes: sleep quality not impaired [global score (placebo, 61; SHP465 MAS, 58), sleep efficiency (placebo, 111; SHP465 MAS, 123), sleep duration (placebo, 114; SHP465 MAS, 116), sleep latency (placebo, 78; SHP465 MAS, 70), sleep disturbance (placebo, 88; SHP465 MAS, 89), days dysfunctional due to sleepiness (placebo, 86; SHP465 MAS, 82)]; sleep quality impaired [global score (placebo, 69; SHP465 MAS, 77), sleep efficiency (placebo, 20; SHP465 MAS, 12), sleep duration (placebo, 17; SHP465 MAS, 20), sleep latency (placebo, 53; SHP465 MAS, 66), sleep disturbance (placebo, 43; SHP465 MAS, 47), days dysfunctional due to sleepiness (placebo, 44; SHP465 MAS, 54)]. *Nominal p < 0.05; **nominal p ≤ 0.01; ***nominal p ≤ 0.001 (SHP465 MAS versus placebo)

Fig. 4

Treatment differences (SHP465 MAS − placebo) in BADDS total (a) and cluster [organizing and activating to work (b), sustaining attention and concentration (c), sustaining energy and effort (d), managing affective interference (e), using working memory and accessing recall (f)] score changes by baseline sleep qualitya, ITT populationb. BADDS Brown Attention-Deficit Disorder Scale, CI confidence interval, ITT intent-to-treat, MAS mixed amphetamine salts, PSQI Pittsburgh Sleep Quality Index. aSleep quality not impaired (baseline PSQI global score ≤ 5; baseline PSQI component score of 0 or 1), sleep quality impaired (baseline PSQI global score > 5; baseline PSQI component score of 2 or 3). bBased on the following sample sizes: sleep quality not impaired [global score (placebo, 58; SHP465 MAS, 58), sleep efficiency (placebo, 107; SHP465 MAS, 118), sleep duration (placebo, 109; SHP465 MAS, 111), sleep latency (placebo, 75; SHP465 MAS, 68), sleep disturbance (placebo, 84; SHP465 MAS, 85), days dysfunctional due to sleepiness (placebo, 83; SHP465 MAS, 79)]; sleep quality impaired [global score (placebo, 65; SHP465 MAS, 70), sleep efficiency (placebo, 17; SHP465 MAS, 10), sleep duration (placebo, 15; SHP465 MAS, 18), sleep latency (placebo, 49; SHP465 MAS, 61), sleep disturbance (placebo, 40; SHP465 MAS, 44), days dysfunctional due to sleepiness (placebo, 40; SHP465 MAS, 50)]. *Nominal p < 0.05; **nominal p ≤ 0.01; ***nominal p ≤ 0.001 (SHP465 MAS versus placebo)