Does Guanfacine Extended Release Impact Functional Impairment in Children with Attention-Deficit/Hyperactivity Disorder? Results from a Randomized Controlled Trial

Abstract

Background: In clinical trials of medications to treat attention-deficit/hyperactivity disorder (ADHD) in children, effects on functional impairment have been less well-studied than changes in ADHD symptoms.

Objective: Data regarding functional impairment were analyzed from a multicenter, double-blind, placebo-controlled study of guanfacine extended release (GXR) in children with ADHD, using the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P). The correspondence of changes in WFIRS-P scores with symptomatic and global response to GXR treatment was also examined, with treatment response defined by scores on both the ADHD Rating Scale IV (ADHD-RS-IV) and the Clinical Global Impressions-Improvement Scale (CGI-I).

Methods: In this 8-week, double-blind, placebo-controlled, dose optimization study at 47 sites across the USA and Canada, children aged 6-12 years with a diagnosis of ADHD [Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria, and an ADHD-RS-IV score ≥28 and CGI-Severity of Illness Scale score ≥4 at baseline], were randomized 1:1:1 into three groups: GXR AM [GXR (1-4 mg/day) in the morning, placebo in the evening], GXR PM [placebo in the morning, GXR (1-4 mg/day) in the evening], or twice-daily placebo. Parents rated their children on the WFIRS-P at screening, baseline, the end of dose optimization, and at the final on-treatment assessment.

Results: The efficacy population was composed of 333 subjects (GXR AM: n = 107; GXR PM: n = 114; placebo: n = 112). At the final on-treatment assessment, there were significant improvements from baseline in the placebo-adjusted difference in least-squares (LS) mean (95 % confidence interval) WFIRS-P Total scores for both GXR treatment groups combined [GXR all-active: -0.16 (-0.25, -0.07), effect size (ES) = 0.448, P <0.001] and separately [GXR AM: -0.15 (-0.26, -0.05), ES = 0.417, P = 0.004; GXR PM: -0.18 (-0.28, -0.07), ES = 0.478, P = 0.001]. Significant improvements in WFIRS-P domain scores for Family, Learning and School (including Academic Performance and Behavior in School), Social, and Risky Behavior were found for both GXR cohorts compared with placebo. However, the Life Skills and Self-Concept domain scores of the WFIRS-P did not improve with GXR treatment. Post hoc stratification by responder status revealed that significant (P <0.001) improvements in WFIRS-P Total and all domain scores were associated with symptomatic treatment response in the GXR all-active group.

Conclusions: GXR treatment in children with ADHD was associated with reductions in WFIRS-P functional impairment scores compared with placebo, regardless of time of GXR administration. Changes in WFIRS-P scores were congruent with clinical response, as determined by both ADHD symptom reduction and CGI-I scores. CLINICALTRIALS.

Gov identifier: NCT00997984.

Figures

Fig. 1

LS mean change from baseline in WFIRS-P scores at Visit 10 (last observation carried forward) for a GXR am [GXR (1–4 mg/day) in the morning, placebo in the evening], b GXR pm [placebo in the morning, GXR (1–4 mg/day) in the evening], and c GXR all-active; full analysis set. LS mean and P values were based on type III sum of squares from an analysis of covariance model for the change from baseline, including treatment group as a fixed effect and baseline value as a covariate. A negative difference in LS mean (GXR-placebo) indicates a positive effect of the active treatment over placebo. LS least-squares, WFIRS-P Weiss Functional Impairment Rating Scale–Parent Report, GXR guanfacine extended release. *P <0.05

Fig. 2

Mean change from baseline in WFIRS-P scores at Visit 10 (last observation carried forward) by treatment response to GXR treatment; full analysis set (GXR all-active group). Responders are defined as subjects with ADHD-RS-IV Total score reduction from baseline ≥30 % and a CGI-I score of 1 or 2. WFIRS-P Weiss Functional Impairment Rating Scale–Parent Report, GXR guanfacine extended release, ADHD-RS-IV Attention-Deficit/Hyperactivity Disorder, CGI-I Clinical Global Impressions–Improvement Scale. ***P <0.001