Efficacy and safety of extended-release guanfacine hydrochloride in children and adolescents with attention-deficit/hyperactivity disorder: A randomized, controlled, Phase III trial

Abstract

Guanfacine extended-release (GXR), a selective α2A-adrenergic agonist, is a non-stimulant treatment for attention-deficit/hyperactivity disorder (ADHD). This study assessed the efficacy (symptoms and function) and safety of dose-optimized GXR compared with placebo in children and adolescents with ADHD. An atomoxetine (ATX) arm was included to provide reference data against placebo. Patients (6-17 years) were randomized at baseline to dose-optimized GXR (0.05-0.12mg/kg/day - 6-12 years: 1-4mg/day; 13-17 years: 1-7mg/day), ATX (10-100mg/day) or placebo for 4 or 7 weeks. The primary efficacy measure was change from baseline in ADHD Rating Scale version IV (ADHD-RS-IV). Key secondary measures were Clinical Global Impression-Improvement (CGI-I) and the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P; learning and school, and family domains). Safety assessments included treatment-emergent adverse events (TEAEs), electrocardiograms and vital signs. A total of 272 (80.5%) patients from Europe, the USA and Canada completed the study. Significant differences were observed in least squares mean change from baseline in ADHD-RS-IV total score (placebo-adjusted differences) (GXR: [-8.9, p<0.001]; ATX: [-3.8, p<0.05]), the difference from placebo in the percentage of patients showing improvement (1 ['very much improved'] or 2 ['much improved']) for CGI-I (GXR: [23.7, p<0.001]; ATX: [12.1, p<0.05]), WFIRS-P learning and school domain (GXR: [-0.22, p<0.01]; ATX: [-0.16, p<0.05]) and WFIRS-P family domain (GXR: [-0.21, p<0.01]; ATX: [-0.09, p=0.242]). Most common TEAEs for GXR were somnolence, headache and fatigue; 70.1% of GXR subjects reported mild-to-moderate TEAEs. GXR was effective and well tolerated in children and adolescents with ADHD.

Long-term safety and efficacy of guanfacine extended release in children and adolescents with ADHD

“…BL baseline, FA final assessment, FU follow-up participants receiving GXR. Of these, 7.8 and 1.9% of participants, respectively, withdrew because of adverse events [17,19]. In line with the previous short-and long-term studies, the most frequently reported TEAEs were somnolence, headache, and fatigue [15-18, 20, 21].…”

“…Both antecedent studies enrolled children (aged 6-12 years) and adolescents (aged 13-17 years) with an Attention-Deficit/ Hyperactivity Disorder Rating Scale IV (ADHD-RS-IV) total score of at least 32 and a Clinical Global Impressions-Severity of Illness (CGI-S) score of at least 4 at baseline [17,19]. Participants in SPD503-316 were randomized to receive GXR, atomoxetine or placebo, and participants in SPD505-315 were randomized to receive either GXR or placebo.…”

“…SPD503-301 and SPD503-304 were 5-6 week, forced-dose, phase 3 studies of GXR doses of up to 4 mg/day in children and adolescents [15,16]. SPD503-312 (adolescents) and SPD503-316 (children and adolescents) were 10-13-week, flexible-dose, phase 3 studies of GXR doses of up to 7 mg/day [17,18]. The need for ongoing GXR treatment was demonstrated in SPD503-315, a 39-week doubleblind, randomized, placebo-controlled withdrawal study of participants who had responded to an initial 13-week openlabel GXR treatment phase.…”

Profile of guanfacine extended release and its potential in the treatment of attention-deficit hyperactivity disorder

“…41 It is recommended that patients commence treatment with a dose of 1 mg per day, thereafter adjusting in weekly increments of no more than 1 mg, depending on clinical response and tolerability. 24,25,49,50 However, weightadjusted doses are preferable, by using a dosing regime on a milligram-per-kilogram basis, considering the results from randomized controlled trials (RCTs), starting at doses in the range of 0.05-0.08 mg/kg/day, up to 0.12 mg/kg/day. 33,49,51,52 Indeed, as reported in an open-label dose-escalation pharmacokinetic evaluation, 40 with equal doses of GXR, observed guanfacine plasma concentrations were higher in children than in adolescents and adults, presumably due to the lower body weight of children.…”

“…More recently, Hervas et al 49 assessed the efficacy and safety of once-daily dose-optimized GXR (0.05-0.12 mg/kg/ day: 6-12 years, 1-4 mg/day; 13-17 years, 1-7 mg/day) compared with placebo and ATX (10-100 mg/day) in the treatment of children and adolescents with ADHD. GXR and ATX were significantly more effective than placebo in improving core symptoms, as assessed by changes from baseline in ADHD-RS-IV total score (GXR -23.9, versus ATX -18.8, versus placebo -15.0); in addition, there was a significantly greater reduction in ADHD-RS-IV total score in GXR compared with ATX (-5.1, ES 0.440; P=0.001).…”