Efficacy and Safety of Lisdexamfetamine Dimesylate and Atomoxetine in the Treatment of Attention-Deficit/Hyperactivity Disorder: a Head-to-Head, Randomized, Double-Blind, Phase IIIb Study

Abstract

ObjectivesThe aim of this study was to compare the efficacy and safety of the prodrug psychostimulant lisdexamfetamine dimesylate (LDX) and the non-stimulant noradrenergic compound atomoxetine (ATX) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) who had previously responded inadequately to methylphenidate (MPH).MethodsThis 9-week, head-to-head, randomized, double-blind, active-controlled study (SPD489-317; ClinicalTrials.gov NCT01106430) enrolled patients (aged 6–17 years) with at least moderately symptomatic ADHD and an inadequate response to previous MPH therapy. Patients were randomized (1:1) to an optimized daily dose of LDX (30, 50 or 70 mg) or ATX (patients <70 kg, 0.5–1.2 mg/kg with total daily dose not to exceed 1.4 mg/kg; patients ≥70 kg, 40, 80 or 100 mg). The primary efficacy outcome was time (days) to first clinical response. Clinical response was defined as a Clinical Global Impressions-Improvement (CGI-I) score of 1 (very much improved) or 2 (much improved). Secondary efficacy outcomes included the proportion of responders at each study visit and the change from baseline in ADHD Rating Scale (ADHD-RS-IV) and CGI-Severity scores. Tolerability and safety were assessed by monitoring treatment-emergent adverse events (TEAEs), height and weight, vital signs and electrocardiogram parameters. Endpoint was defined as the last post-baseline, on-treatment visit with a valid assessment.ResultsOf 267 patients randomized (LDX, n = 133; ATX, n = 134), 200 (74.9 %) completed the study. The median time to first clinical response [95 % confidence interval (CI)] was significantly shorter for patients receiving LDX [12.0 days (8.0–16.0)] than for those receiving ATX [21.0 days (15.0–23.0)] (p = 0.001). By week 9, 81.7 % (95 % CI 75.0–88.5) of patients receiving LDX had responded to treatment compared with 63.6 % (95 % CI 55.4–71.8) of those receiving ATX (p = 0.001). Also by week 9, the difference between LDX and ATX in least-squares mean change from baseline (95 % CI) was significant in favour of LDX for the ADHD-RS-IV total score [−6.5 (−9.3 to −3.6); p < 0.001; effect size 0.56], inattentiveness subscale score [−3.4 (−4.9 to −1.8); p < 0.001; effect size 0.53] and the hyperactivity/impulsivity subscale score [−3.2 (−4.6 to −1.7); p < 0.001; effect size 0.53]. TEAEs were reported by 71.9 and 70.9 % of patients receiving LDX and ATX, respectively. At endpoint, both treatments were associated with mean (standard deviation) increases in systolic blood pressure [LDX, +0.7 mmHg (9.08); ATX, +0.6 mmHg (7.96)], diastolic blood pressure [LDX, +0.1 mmHg (8.33); ATX, +1.3 mmHg (8.24)] and pulse rate [LDX, +3.6 bpm (10.49); ATX, +3.7 bpm (10.75)], and decreases in weight [LDX, −1.30 kg (1.806); ATX, −0.15 kg (1.434)].ConclusionsLDX was associated with a faster and more robust treatment response than ATX in children and adolescents with at least moderately symptomatic ADHD who had previously responded inadequately to MPH. Both treatments displayed safety profiles consistent with findings from p...

Animal model of methylphenidate's long-term memory-enhancing effects

“…Most clinical efficacy studies only report inattention/hyperactivity-impulsivity measures (ADHD IV) (Dittmann et al 2013) and clinical global impression (CGI) (Setyawan et al 2013). These studies do not assess efficacy in improving LTM.…”

The Safety of Atomoxetine for the Treatment of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: A Comprehensive Review of Over a Decade of Research

“…Reductions in body weight have also been detected in children and adolescents treated with lisdexamfetamine [74] and methylphenidate [21,75,86] in some comparative studies using atomoxetine. In a 9-week randomized, double-blind study, reductions in body weight were greater with lisdexamfetamine (mean [SD] -1.30 kg [1.81]) than with atomoxetine (-0.15 kg [1.43]), and a greater proportion of patients had a C7 % reduction in weight from baseline with lisdexamfetamine (26.8 %; N = 34/127) than with atomoxetine (4.5 %; N = 6/132) [74].…”

“…Weight In short-term controlled and open-label studies (B18 weeks), reductions in weight have been reported in children and adolescents during treatment with atomoxetine [18,53,55,62,65,67,74,79,82,89]. However, reductions in body weight are not universally reported: the authors of some short-term studies (B14 weeks) report either no change or a small increase in mean weight [55,69,75,80,81] and/or describe weight changes as not ''clinically significant'', not ''clinically meaningful'', or ''small'' [55,67,79,80,86].…”

“…We found seven studies that reported the proportions of patients who experienced particular percentage reductions in weight [18,21,69,74,78,82,87]. For example, in a short-term (6-week) RCT with a patient population aged 6-16 years, ''clinically important weight loss'' (C7 % from baseline) was observed in 9.7 % of 72 atomoxetine-treated patients versus 6.1 % of 33 placebo-treated patients [82].…”

Lisdexamfetamine dimesylate in the treatment of attention-deficit/hyperactivity disorder: pharmacokinetics, efficacy and safety in children and adolescents

“…This study was conducted in 267 children and adolescents, comparing LDX (in doses of 30, 50 or 70 mg) and atomoxetine (0.5 to 1.2 mg/kg) over 9 weeks 37 . LDX was associated with a significantly more rapid and robust treatment response than atomoxetine.…”