Mixed Amphetamine Salts Extended-Release in the Treatment of Adult ADHD:A Randomized, Controlled Trial

Abstract

Introduction: Attention-deficit/hyperactivity disorder (ADHD) is a serious neurobehavioral disorder of childhood onset that often persists into adolescence and adulthood. Functional impairments, underachievement, and difficult interpersonal relationships illustrate the need for effective treatment of ADHD through adulthood.Method: This prospective, multisite, randomized, double-blind, placebo-controlled, parallel-group, dose-escalation study was conducted to assess the efficacy, safety, and duration of action of mixed amphetamine salts extended-release (MAS XR) in adults with ADHD, combined type. Adults ≥ 18 years of age were given placebo or MAS XR 20, 40, or 60 mg/day for 4 weeks. The main outcome measures were the ADHD Rating Scale and Conners' Adult ADHD Rating Scale Short Version Self-Report (CAARS-S-S).Results: Two hundred fifty-five subjects were randomly assigned to treatment with MAS XR or placebo. MAS XR treatment was associated with statistically and clinically significant ADHD symptom reduction at endpoint; mean ADHD Rating Scale scores were 18.5 for the 20-mg group (P=.001), 18.4 for the 40-mg group (P<.001), and 18.5 for the 60-mg group (P<.001). Adults with severe symptoms (ADHD Rating Scale score ≥32 at baseline) had significantly greater symptom reduction with the highest MAS XR dose (60 mg/day), however, this dose-response relationship was determined by post-hoc analysis. The mean MAS XR effect size was 0.8. Statistically significant (P<.05) improvements in CAARS-S-S ADHD index scores occurred at 4- and 12-hours postdose for all MAS XR groups, indicating a 12-hour duration of effect. Symptoms improved within the first treatment week. Most adverse events reported were mild or moderate in intensity, arid the most commonly reported adverse events were consistent with the known profile of stimulant medications. Vital signs and electrocardiograms showed no clinically significant cardiovascular changes.Conclusion: These results suggest that MAS XR is safe and effective in adults with ADHD and controlled ADHD symptoms for up to 12 hours.

Triple-Bead Mixed Amphetamine Salts (SHP465) in Adults With ADHD: Results of a Phase 3, Double-Blind, Randomized, Forced-Dose Trial

“…This finding is consistent with a previous publication in which a dose response for efficacy was not observed for MAS XR (20, 40, and 60 mg) in adults with ADHD in a 4-week, double-blind, fixed-dose study (Weisler et al, 2006). However, a post hoc analysis of participants with baseline ADHD-RS-IV total scores ≥32 from the same MAS XR study demonstrated that treatment differences in ADHD-RS-IV total score reductions with 60 mg MAS XR were significantly greater than with 20 mg MAS XR (p = .001) and approached significance compared with 40 mg MAS XR (p = .10) (Weisler et al, 2006). Possible contributing factors to the lack of a dose response in this study may be related to the use of forced-dose design, which may not allow for the optimum balance between efficacy and tolerability to be obtained in individual participants, and to the steps used in the titration schedule.…”

“…Symptom reductions with triplebead MAS were observed as early as Week 1 and continued through 6 weeks of treatment. However, as has previously been observed for MAS XR (Weisler et al, 2006), the key secondary analysis indicated there were no statistically significant differences in the change from baseline ADHD-RS-IV total score at EOS between triple-bead MAS doses. Score reductions on the ADHD-RS-IV subscales followed the same pattern observed for total score, with nominally greater improvement versus placebo observed for all triplebead MAS doses.…”

“…As measured by the CGI-I, triple-bead MAS also produced nominally greater improvement in global symptom severity than placebo. The ES for treatment differences in ADHD-RS-IV total score reductions from baseline averaged across triple-bead MAS doses in this study was 0.91, which compared favorably to the ES of 0.80 for MAS XR when averaged across doses of 20, 40, and 60 mg (Weisler et al, 2006). These efficacy findings are consistent with those of a previously published dose-optimization study in which 7 weeks of triple-bead MAS (12.5-75 mg) produced significantly greater reductions in ADHD-RS-IV total score than placebo (Spencer et al, 2008).…”

“…Sample size was estimated based on an unpublished effect size (ES) analysis of MAS XR data from a previously published study (Weisler et al, 2006), where an ES of 0.424 (based on a mean difference of 5.3 and standard deviation of 12.5) was observed between 60 mg MAS XR and 20 mg MAS XR in individuals with baseline ADHD-RS-IV total scores ≥32. Based on this unpublished analysis, the ES for the treatment differences between 75 mg triple-bead MAS and placebo and between 75 mg triple-bead MAS and 25 mg triple-bead MAS was assumed to be 0.424 for the sample size estimate.…”

Management of attention-deficit hyperactivity disorder in adults: focus on methylphenidate hydrochloride

“…Response rates of greater than 75% have been demonstrated with higher doses of both methylphenidate and mixed amphetamine salts. [37][38][39][40] Lisdexamphetamine (Vyvanse ® ; Shire Pharmaceuticals), the once daily prodrug stimulant, was approved by the United States Food and Drug Administration (FDA) for treatment of adult ADHD in 2007. In a study of 420 adults with moderate to severe ADHD by DSM-IV criteria, lisdexamphetamine was superior to placebo in all 3 doses, and patients tolerated it well with minimal side effects.…”