Effects of SHP465 mixed amphetamine salts in adults with ADHD in a simulated adult workplace environment

Abstract

Objectives: Evaluate the efficacy, duration of effect, and safety of 25 mg SHP465 mixed amphetamine salts (MAS) extended-release versus placebo in adults with attention-deficit/hyperactivity disorder (ADHD). Methods: Adults (18-55 years) with ADHD and with ADHD Rating Scale-IV (ADHD-RS-IV) scores ≥24 were randomized to treatment in a double-blind, 2-period, 2-treatment crossover study utilizing the Adult Workplace Environment (AWE), as described by Wigal and Wigal (J Atten Disord 2006;10:92-111). On day 7 of each 7-day treatment period, efficacy was assessed during a 16.5-hour postdose period. The primary endpoint, Permanent Product Measure of Performance (PERMP) total score, was analyzed in the intent-to-treat population using a mixed linear model of analysis of variance. Secondary endpoints, for which the study was not powered, included PERMP problems attempted and answered correctly, ADHD clinician ratings based on counselor observations and inputs during the Time Segment Rating System (Co-ADHD-RS TSRS), and the ADHD self-rating scale (ADHD-SRS). Safety and tolerability assessments included treatment-emergent adverse events (TEAEs) and vital signs. Results: The least squares mean (95% CI) treatment difference (SHP465 MAS-placebo) for PERMP total score significantly favored SHP465 MAS over placebo when averaged across all postdose assessments (19.29 [10.95, 27.63]; P < 0.0001), with significant treatment differences favoring SHP465 MAS over placebo observed at 4-16 hours postdose (all P < 0.01). TEAEs observed with SHP465 MAS (≥5% of participants) included insomnia, decreased appetite, dry mouth, headache, and anorexia. Mean pulse and blood pressure increases with SHP465 MAS exceeded those of placebo. Conclusions: SHP465 MAS (25 mg) was superior to placebo on PERMP total score, with treatment differences observed from 4 to 16 hours postdose; nominal treatment differences on the ADHD-SRS, but not the Co-ADHD-RS TSRS, were also observed. The safety and tolerability profile of SHP465 MAS was similar to previous reports for SHP465 MAS and other long-acting

A randomized, double-blind, 3-way crossover, analog classroom study of SHP465 mixed amphetamine salts extended-release in adolescents with ADHD

“…The observed effects of SHP465 MAS on secondary efficacy endpoints generally complemented the primary endpoint, with nominal superiority of SHP465 MAS over placebo observed for PERMP problems attempted and answered correctly and for ADHD-SRS, SKAMP, CPRS-R, and ADHD-RS-IV scores. The findings for SHP465 MAS from this study are partially consistent with those of similarly designed studies in adults that used the AWE model [16,17], with 25 mg SHP465 MAS and 50/75 mg SHP465 MAS producing significantly greater PERMP total score improvements than placebo when averaged over a 16-hour postdose period. Although onset of efficacy was observed at 2 hours postdose with 50/75 mg SHP465 MAS in adults with ADHD [17], the onset of efficacy was observed at 4 hours postdose with 25 mg SHP465 MAS in adults with ADHD [16].…”

“…The findings for SHP465 MAS from this study are partially consistent with those of similarly designed studies in adults that used the AWE model [16,17], with 25 mg SHP465 MAS and 50/75 mg SHP465 MAS producing significantly greater PERMP total score improvements than placebo when averaged over a 16-hour postdose period. Although onset of efficacy was observed at 2 hours postdose with 50/75 mg SHP465 MAS in adults with ADHD [17], the onset of efficacy was observed at 4 hours postdose with 25 mg SHP465 MAS in adults with ADHD [16]. The reason for the later onset of efficacy in adults treated with 25 mg SHP465 MAS is unknown at this time.…”

“…The short-term safety and tolerability of SHP465 MAS in adolescents with ADHD in the current study are consistent with data from short-term phase 3 efficacy studies of SHP465 MAS in adults with ADHD [9][10][11] and children/adolescents with ADHD [12], with phase 2 AWE studies of SHP465 MAS in adults with ADHD [16,17], and with other duration-of-efficacy studies for long-acting stimulants in pediatric populations (aged 6--12 years) with ADHD [4][5][6]21,22]. In this study, the most frequently reported TEAEs with SHP465 MAS (insomnia, anorexia, headache, and decreased appetite) were the same as those reported in similarly designed AWE studies of SHP465 MAS [16,17]. The overall frequency of insomnia as a TEAE in the present study (25 mg SHP465 MAS, 20.9%; 50 mg SHP465 MAS, 56.1%) generally fell within a range observed for other long-acting psychostimulants in pediatric populations from laboratory classroom studies that used a dose-optimization phase (lisdexamfetamine, 27.1% [6]; multilayer release methylphenidate, 30.8% [22]) and with another study that did not include a dose-optimization phase (MAS XR, 12.5-32% [5]).…”

“…In both studies, which utilized the Adult Workplace Environment (AWE) model [18], SHP465 MAS produced significantly greater improvement than placebo in PERMP total score averaged across all postdose time assessments from 2 to 16 hours. Significantly greater PERMP total scores versus placebo were observed for 25 mg SHP465 MAS from 4 to 16 hours postdose [16] and for 50/ 75 mg SHP465 MAS from 2 to 16 hours postdose [16,17]. The most frequently reported treatment-emergent adverse events (TEAEs) with SHP465 MAS in these studies were insomnia, anorexia, decreased appetite, dry mouth, and headache [16,17].…”

“…Two different SHP465 MAS studies [16,17], which used crossover designs similar to this study, were conducted in adults with ADHD [16,17]. In both studies, which utilized the Adult Workplace Environment (AWE) model [18], SHP465 MAS produced significantly greater improvement than placebo in PERMP total score averaged across all postdose time assessments from 2 to 16 hours.…”