Efficacy and Safety of SHP465 Mixed Amphetamine Salts in the Treatment of Attention-Deficit/Hyperactivity Disorder in Adults: Results of a Randomized, Double-Blind, Placebo-Controlled, Forced-Dose Clinical Study

Abstract

Objective: The objective of this randomized, double-blind, placebo-controlled study was to evaluate the efficacy and safety of SHP465 mixed amphetamine salts (MAS) in adults with attention-deficit/hyperactivity disorder (ADHD).

Methods: Eligible adults [aged 18-55 years; meeting the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ADHD criteria; baseline ADHD Rating Scale with Adult Prompts (ADHD-RS-AP) total scores ≥28] were randomized 1:1:1 to placebo or forced-dose SHP465 MAS (12.5 or 37.5 mg/day) for 4 weeks. The ADHD-RS-AP total score change from baseline to week 4 (primary endpoint) and Clinical Global Impressions-Improvement score at week 4 (key secondary endpoint) were assessed using linear mixed-effects models for repeated measures. Other efficacy endpoints were changes from baseline to week 4 on the ADHD-RS-AP hyperactivity/impulsivity and inattentiveness subscales and the percentage of participants categorized as improved on the dichotomized Clinical Global Impressions-Improvement. Safety and tolerability assessments were treatment-emergent adverse events, vital sign and weight changes, Columbia-Suicide Severity Rating Scale responses, and electrocardiogram results.

Results: Of 369 screened participants, 275 were randomized (placebo, n = 91; 12.5 mg/day of SHP465 MAS, n = 92; 37.5 mg/day of SHP465 MAS, n = 92) and 236 completed the study (placebo, n = 80; 12.5 mg/day of SHP465 MAS, n = 80; 37.5 mg/day of SHP465 MAS, n = 76). Least-squares mean (95% confidence interval) treatment differences at week 4 significantly favored SHP465 MAS over placebo for the ADHD-RS-AP total score change from baseline [12.5 mg/day: -8.1 (-11.7, -4.4), effect size = 0.67; 37.5 mg/day: -13.4 (-17.1, -9.7), effect size = 1.11; both p < 0.001] and Clinical Global Impressions-Improvement score [12.5 mg/day: -0.8 (-1.1, -0.4), effect size = 0.68; 37.5 mg/day: -1.2 (-1.6, -0.9), effect size = 1.11; both p < 0.001]. Treatment differences for the change from baseline at week 4 favored 12.5 and 37.5 mg/day of SHP465 MAS, respectively, over placebo on the ADHD-RS-AP hyperactivity/impulsivity (both nominal p < 0.001; effect size = 0.56 and 0.91) and inattentiveness (both nominal p < 0.001; effect size = 0.70 and 1.19) subscales. At the final on-treatment assessment, the percentage of participants categorized as improved on Clinical Global Impressions-Improvement was higher with both SHP465 MAS doses than with placebo (both nominal p < 0.001). Treatment-emergent adverse events reported (>5%) with SHP465 MAS were decreased appetite, dry mouth, insomnia, headache, anxiety, initial insomnia, irritability, and bruxism. Severe treatment-emergent adverse events and treatment-emergent adverse events leading to discontinuation, respectively, were reported by 8 and 12 participants (placebo, n = 2 and 0; 12.5 mg/day SHP465 MAS, n = 1 and 7; 37.5 mg/day SHP465 MAS, n = 5 and 5). At the final on-treatment assessment, mean ± standard deviation increases from baseline were observed with 12.5 and 37.5 mg/day of SHP465 MAS for pulse (3.3 ± 10.52 and 7.1 ± 11.48 bpm) and blood pressure (systolic 0.2 ± 7.24 and 1.7 ± 9.99 mmHg; diastolic 1.0 ± 7.46 and 2.8 ± 7.90 mmHg) and decreases were observed for weight (-0.97 ± 1.523 and -1.65 ± 2.333 kg), body mass index (-0.33 ± 0.519 and -0.56 ± 0.777 kg/m2), and Fridericia corrected QT interval (-3.0 ± 10.72 and -1.6 ± 13.70 ms). No participant in any treatment group had a positive response for on-study Columbia-Suicide Severity Rating Scale assessments.

Conclusions: SHP465 MAS was superior to placebo in reducing ADHD symptoms, with a safety profile consistent with other long-acting stimulants. ClinicalTrials.gov Registry Number: NCT02604407.

Conflict of interest statement

Funding

The study was funded by Shire Development LLC (Lexington, MA, USA). Shire Development LLC provided funding to Complete Healthcare Communications, LLC (Chadds Ford, PA, USA) for support in writing and editing this manuscript and provided payment for open-access fees for this publication. The sponsor was involved in the study design, data collection and analysis, and data interpretation. The sponsor was also involved in the writing of the manuscript and in the decision to submit the article for publication, but the final content and decision to submit the manuscript to the CNS Drugs was made by the authors.

Conflict of interest

Richard H. Weisler in the last year has served as a consultant to Alcobra, AltheaDx Inc., Ironshore Pharmaceuticals, Lundbeck, Major League Baseball (certified clinician), National Football League (certified clinician), Neos Therapeutics, Nestlé Health Science-Pamlab Inc., Otsuka America Pharmaceuticals, Rhodes Pharmaceuticals, Shire, Sunovion, Supernus Pharmaceuticals, Takeda, and Validus; has received research support from Alcobra, Allergan, Daiichi Sankyo Pharma Genomind, Janssen, Merck, Neurim, Otsuka America Pharmaceuticals, Roche-Genentech, Shire, and Theravance; and has participated in speakers bureaus for Alcobra, Lundbeck, Neos Therapeutics, Otsuka America Pharmaceuticals, Rhodes Pharmaceuticals, Shire, Sunovion, and Validus. Michael Greenbaum has participated in a speaker’s bureau for Shire, and has received research support from Allergan, Lundbeck, Medgenics, Shire, Supernus, Sunovion, and Takeda. Valerie Arnold has received honoraria from Ironshore, Neos, Rho, and Shire; has served as a consultant for Ironshore; has participated in speaker’s bureaus for Takeda; and holds stock and/or stock options in Supernus. Brian Yan, Ming Yu, Margo Jaffee, and Brigitte Robertson are employees of Shire and hold stock and/or stock options in Shire.

Ethics approval

The study protocol, final approved informed consent document, and all supporting information were submitted to and approved by a central respective institutional review board (Copernicus Group Independent Review Board; Durham, NC, USA) and by the US Food and Drug Administration, as appropriate, before study initiation.

Consent to participate

All participants provided written informed consent before taking part in study procedures. The study was conducted in accordance with the International Conference on Harmonisation and Good Clinical Practice and the principles of the Declaration of Helsinki.

Figures

Fig. 1

Study design. ET early termination, MAS mixed amphetamine salts, PBO placebo, V visit

Fig. 2

Participant disposition. MAS mixed amphetamine salts

Fig. 3

Attention-Deficit/Hyperactivity Disorder Rating Scale with Adult Prompts (ADHD-RS-AP) total score (a) and Clinical Global Impressions-Improvement (CGI-I) score (b) by treatment week. MAS mixed amphetamine salts, SD standard deviation; *p < 0.001 for the least-squares mean treatment difference vs. placebo for the change from baseline in the ADHD-RS-AP total score at week 4 (based on the mixed-effects model for repeated measures, including treatment, visit, and the interaction of treatment with the visit as factors; with the relevant baseline score as a covariate; and with an adjustment for the interaction of the baseline score with the visit); †p < 0.001 for the least-squares mean treatment difference vs. placebo for the CGI-I score at week 4 (based on the mixed-effects model for repeated measures, including treatment, visit, and the interaction of treatment with the visit as factors; with the relevant baseline score as a covariate; and with an adjustment for the interaction of the baseline score with the visit)