Effects of guanfacine extended release on oppositional symptoms in children aged 6-12 years with attention-deficit hyperactivity disorder and oppositional symptoms: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate the efficacy and safety of guanfacine extended release (XR, Intuniv; Shire Development Inc., Wayne, PA, USA) in the treatment of oppositional symptoms in children aged 6-12 years with a diagnosis of attention-deficit hyperactivity disorder (ADHD) and the presence of oppositional symptoms. SUBJECTS AND METHODS: In this randomized, double-blind, placebo-controlled, multicentre, flexible-dose, dose-optimization study, children aged 6-12 years were randomized to receive guanfacine XR (1-4 mg/day) or placebo for 9 weeks. Screening and washout periods were followed by a 5-week dose-optimization period, a 3-week dose-maintenance period and a 1-week tapering period. The primary efficacy measure was change from baseline to endpoint in the oppositional subscale of the Conners' Parent Rating Scale-Revised: Long Form (CPRS-R:L) score. Change in ADHD Rating Scale IV (ADHD-RS-IV) total score was a secondary efficacy measure. Safety assessments included adverse events (AEs), vital signs, ECG readings and laboratory studies.
RESULTS: A total of 217 children were enrolled: 138 were randomized to receive guanfacine XR and 79 to receive placebo. Least-squares mean reductions from baseline to endpoint in CPRS-R:L oppositional subscale scores were 10.9 in the guanfacine XR group compared with 6.8 in the placebo group (p < 0.001; effect size = 0.59). A significantly greater reduction in ADHD-RS-IV total score from baseline to endpoint was also seen in the guanfacine-treated group compared with the placebo group (23.8 vs 11.5, respectively; p < 0.001; effect size = 0.92). A post hoc correlation analysis between percentage reduction from baseline to endpoint in CPRS-R:L oppositional subscale and ADHD-RS-IV total scores indicated that the decreases in oppositional symptoms and ADHD symptoms were highly correlated (r = 0.74). The most commonly reported, treatment-emergent AEs (TEAEs) in the guanfacine XR group were somnolence (50.7%), headache (22.1%), sedation (13.2%), upper abdominal pain (11.8%) and fatigue (11.0%) and most were mild or moderate in severity. TEAEs of sedation, somnolence or hypersomnia were experienced by 62.5% of subjects in the guanfacine XR group. These events were most common during the dose-titration period but most (63.5%) resolved prior to the taper period. TEAEs of fatigue, lethargy and asthenia were reported in 11.0%, 3.7% and 0.0% of subjects in the guanfacine XR group, respectively. Most subjects receiving guanfacine XR demonstrated modest changes in blood pressure, pulse rate and ECG readings that were not considered clinically significant.
CONCLUSIONS: In this population of children aged 6-12 years with ADHD and the presence of oppositional symptoms, significant reductions in CPRS-R:L oppositional subscale and ADHD-RS-IV total scores were observed with guanfacine XR treatment compared with placebo. Treatment with guanfacine XR at optimized doses was associated with mostly mild or moderate TEAEs. The findings of this study support the efficacy of guanfacine XR in the treatment of children with ADHD and the presence of oppositional symptoms. CLINICAL TRIAL REGISTRATION NUMBER: NCT00367835.

RCT Entities:   Population Interventions Outcomes