A randomized trial of edivoxetine in pediatric patients with attention-deficit/hyperactivity disorder.
OBJECTIVE
The purpose of this study was to assess the efficacy and safety of edivoxetine (LY2216684), a selective norepinephrine reuptake inhibitor, in pediatric patients with attention-deficit/hyperactivity disorder (ADHD).


METHODS
A fixed-dose, randomized, double-blind, 8 week study was conducted in patients 6-17 years of age, who were randomized by two strata: 1) Patients with prior stimulant use randomized to placebo, edivoxetine 0.1 mg/kg/day, 0.2 mg/kg/day, or 0.3 mg/kg/day arms in a 1:1:1:1 ratio; 2) Stimulant-naïve patients randomized to placebo, edivoxetine 0.1mg/kg/day, 0.2 mg/kg/day, 0.3 mg/kg/day, or osmotic-release oral system methylphenidate (OROS MPH) (18-54 mg/day based on body weight) arms in a 1:1:1:1:1 ratio. The primary efficacy measure was baseline-to-week 8 change of ADHD Rating Scale (ADHD-RS) total score for edivoxetine 0.2 mg/kg/day and 0.3 mg/kg/day.


RESULTS
A total of 340 patients were randomized to placebo (n=78); edivoxetine 0.1 mg/kg/day (n=76), 0.2 mg/kg/day (n=75), or 0.3 mg/kg/day (n=75); or OROS MPH (n=36). In the stimulant-naïve stratum, the positive control, OROS MPH, was significantly superior to placebo in mean ADHD-RS total score change at end-point (-19.46, p=0.015). The edivoxetine 0.2 mg/kg/day and 0.3 mg/kg/day arms had statistically significantly greater improvement than the placebo arm in mean ADHD-RS total score change at end-point (placebo -10.35; edivoxetine 0.2 mg/kg/day -16.09, p<0.010; edivoxetine 0.3 mg/kg/day -16.39, p<0.010) and Clinical Global Impressions-Improvement score (placebo 3.05; edivoxetine 0.1 mg/kg/day 3.01, p=0.860; edivoxetine 0.2 mg/kg/day 2.54, p=0.013; edivoxetine 0.3 mg/kg/day 2.53, p=0.013). In the overall efficacy-analyses data set (n=270), the effect size estimates for edivoxetine doses 0.1 mg/kg/day, 0.2 mg/kg/day and 0.3 mg/kg/day at the week 8 time point were 0.17, 0.51, and 0.54, respectively (for the stimulant-naïve stratum, the effect size estimate for OROS MPH was 0.69). Compared with placebo, edivoxetine treatment was associated with statistically significant increases in blood pressure and pulse (p<0.050), and a smaller increase or slight decrease in weight.


CONCLUSIONS
Edivoxetine at doses of 0.2 mg/kg/day and 0.3 mg/kg/day demonstrated efficacy in ADHD treatment, despite the presence of a sizeable placebo response. No unexpected adverse events were identified. Clinical Trial Registry identifier: NCT00922636.
1 Eli Lilly and Company , Indianapolis, Indiana.
Daniel Y
DY
Lin
Christopher J
CJ
Kratochvil
Wen
W
Xu
Ling
L
Jin
Deborah N
DN
D'Souza
William
W
Kielbasa
Albert J
AJ
Allen
D000293:Adolescent; D018759:Adrenergic Uptake Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy*; D000697:Central Nervous System Stimulants / Q000627:therapeutic use; D002648:Child; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008774:Methylphenidate / Q000627:therapeutic use*; D009025:Morpholines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D010626:Phenylethyl Alcohol / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011569:Psychiatric Status Rating Scales; D012720:Severity of Illness Index; D016896:Treatment Outcome
D018759:Adrenergic Uptake Inhibitors; D000697:Central Nervous System Stimulants; D009025:Morpholines; C568831:alpha-((5-fluoro-2-methoxyphenyl)methyl)-alpha-(tetrahydro-2H-pyran-4-yl)-2-morpholinemethanol; D008774:Methylphenidate; D010626:Phenylethyl Alcohol