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

Objectives: The 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).

Methods: This 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.

Results: Of 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)].

Conclusions: LDX 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 previous clinical trials.

Figures

Fig. 1

Study design. Visit window ±2 days throughout the evaluation period. Visit window +2 days for safety follow-up visit. ATX atomoxetine, ET early termination, LDX lisdexamfetamine dimesylate, V visit

Fig. 2

Patient disposition. aThe safety population included all patients who were randomized and received at least one dose of study drug. bThe FAS included all patients who were randomized and received at least one dose of study drug. One patient was randomized to ATX but, owing to a drug dispensing error, received LDX. Based on the intent-to-treat principle, this patient was included in the ATX treatment group in the FAS. cStudy completers were patients who completed visits 0–10 (visit 10 being a clinic visit or telephone call). dOther reasons for discontinuation among patients administered LDX were difficulty swallowing capsule (n = 1); early termination requested by the sponsor because of previous marijuana use (n = 1); and early termination requested by the sponsor because patient was unable to meet the study visit schedule (n = 1). eOther reasons for discontinuation among patients administered ATX were refusal to take medication (n = 1); patient relocation due to a family emergency (n = 1); and non-compliance (n = 1). ATX atomoxetine, FAS full analysis set, LDX lisdexamfetamine dimesylate

Fig. 3

Proportion of patients with a clinical response to LDX or ATX treatment (defined as a CGI-I score of 1 or 2) at each weekly study visit using LOCF. Values are shown as the proportion of responders ±95 % confidence intervals based on LOCF. ***p < 0.001, **p < 0.01 based on a Cochran–Mantel–Haenszel test stratified by country comparing LDX treatment with ATX. ATX atomoxetine, CGI-I Clinical Global Impressions-Improvement, LDX lisdexamfetamine dimesylate, LOCF last-observation-carried-forward

Fig. 4

Mean ADHD-RS-IV total scores (using LOCF) in patients treated with LDX or ATX. Mean ADHD-RS-IV total scores are shown ±95 % confidence intervals based on LOCF. ***p < 0.001 for LDX treatment compared with ATX based on an ANCOVA model of the least-squares mean change from baseline including treatment group (effect of interest), country (blocking factor) and the corresponding baseline total score (covariate). ADHD attention-deficit/hyperactivity disorder, ADHD-RS-IV ADHD Rating Scale IV, ANCOVA analysis of covariance, ATX atomoxetine, LDX lisdexamfetamine dimesylate, LOCF last-observation-carried-forward