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

Abstract

BackgroundIn 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.ObjectiveData 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).MethodsIn 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.ResultsThe 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.ConclusionsGXR 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 identifierNCT00997984.

Systematic review of quality of life and functional outcomes in randomized placebo-controlled studies of medications for attention-deficit/hyperactivity disorder

“…1 ). In support of this conceptualization, severity of or improvement in ADHD symptoms correlated moderately to strongly (but not perfectly) with severity of or improvement in functional impairment and HRQoL deficits, both in the included studies for which this was reported [ 42 , 62 , 66 , 86 ] and elsewhere in the literature [ 18 , 19 , 21 , 32 , 47 , 81 , 92 , 95 ]. Furthermore, effect sizes (when available) of active medications versus placebo were smaller for functional or HRQoL outcomes than for symptom-based outcomes in nearly all of the included studies (Tables 4 , 5 ).…”

“…Five of the nine studies that assessed functional impairment in children and adolescents used the parent-rated WFIRS-P. Four of these five studies (three short-term studies and one randomized withdrawal study) reported significant placebo-adjusted effects of treatment on WFIRS-P total score (Table 4 ) [ 14 , 15 , 51 , 86 ]. Scores in the Family domain and the Learning and School domain were most consistently improved relative to placebo in these studies.…”

“…Effect sizes were greater for ADHD symptom outcomes than for HRQoL or functional outcomes in all but two studies of children and adolescents; the exceptions were a 2-week study of TD-MPH (effect sizes 0.90 for ADHD-RS-IV and 1.08 for investigator-rated BSFQ) and an 8-week study of ATX (effect sizes 0.33, 0.62 and 0.60 for ADHD-RS-IV total score and 0.47, 0.66 and 0.87 for CHQ-PF50 Psychosocial summary score [low, medium and high dose, respectively]) [ 66 , 99 ]. Effect sizes were 0.5 or above for both ADHD symptoms and at least one aspect of HRQoL or functioning in five out of 13 non-stimulant treatment groups (ATX or GXR) [ 42 , 66 , 86 , 91 , 94 ] and five out of six stimulant treatment groups (LDX, OROS-MPH or TD-MPH) [ 14 , 15 , 99 ]. Effect sizes of active medications versus placebo were 0.5 or above for ADHD symptoms but below 0.5 for HRQoL or functioning in five out of 13 non-stimulant treatment groups (ATX or GXR) [ 17 , 37 , 51 , 68 , 101 ] and one out of six stimulant treatment groups (MPH) [ 1 ].…”

“…Escobar et al [ 42 ] reported that CHIP-CE:PRF Risk Avoidance domain T-scores correlated moderately with ADHD-RS-IV total scores at baseline (Pearson’s R, −0.46; p < 0.05), with weak but significant correlations in the other four domains of the CHIP-CE:PRF and in the Risk Avoidance and Comfort domains of the self-rated CHIP-CE:SRF/AE. In an 8-week GXR study, mean changes from baseline in WFIRS-P total score were significantly greater in patients who responded symptomatically (defined as a CGI-Improvement score of 1 or 2 with ≥30% reduction in ADHD-RS-IV total score) than in those who did not ( p < 0.001) [ 86 ]. Finally, improvement in ADHD-RS-IV total score was significantly correlated with improvement in CHQ-PF-50 scores in a post hoc analysis [ 62 ] of an 8-week study of ATX [ 66 ].…”

Relationship Between Symptomatic and Functional Improvement and Remission in a Treatment Response to Stimulant Trial

“…The objective of this study is to determine the extent to which children and adolescents who meet the conventional definitions for symptom improvement and remission also meet empirical criteria for functional improvement and remission. Previous clinical trials have demonstrated that the WFIRS-P is sensitive to change in functional impairment (Banaschewski et al 2013 , 2014 ; Stein et al 2015 ; Wilens et al 2015 ; Nagy et al 2016 ) and sensitive to change as measured against change in ADHD symptoms (Gajria et al 2015 ).…”