Guanfacine extended release for children and adolescents with attention-deficit/hyperactivity disorder: efficacy following prior methylphenidate treatment

Abstract

Guanfacine extended release (GXR) and atomoxetine (ATX) are nonstimulant treatments for attention-deficit/hyperactivity disorder (ADHD). As nonstimulant treatments are often used after stimulants in ADHD, GXR was assessed relative to prior stimulant treatment in a randomized controlled trial (RCT), in which ATX was included as a reference arm, and in the open-label phase of a randomized-withdrawal study (RWS). Participants were 6–17 years old with ADHD Rating Scale version IV (ADHD-RS-IV) scores ≥32 and Clinical Global Impressions – Severity scores ≥4. RCT participants received dose-optimized GXR (1–7 mg/day), ATX (10–100 mg/day), or placebo for 10–13 weeks. RWS participants received dose-optimized GXR (1–7 mg/day) for 13 weeks. Participants’ last stimulant medication prior to enrolment, and reasons for stopping this medication, were collected at baseline. Change from baseline ADHD-RS-IV score and the proportion of responders were assessed by prior stimulant exposure. Of 163 RCT and 296 RWS participants who had previously received stimulant treatment, 142 and 224, respectively, had received methylphenidate (MPH); due to the low number of participants and the heterogeneity of non-MPH treatments, we only report data for prior MPH treatment. The most frequent reasons for stopping MPH were lack of effectiveness or side effects. Placebo-adjusted ADHD-RS-IV changes from baseline were significant in participants receiving GXR (prior MPH, −9.8, P<0.001, effect size [ES] 0.85; stimulant-naïve, −7.6, P<0.001, ES 0.65). In ATX-treated participants, significant placebo-adjusted differences were seen in stimulant-naïve (−5.0, P=0.022, ES 0.43) but not prior MPH-treated (−1.8, P>0.05, ES 0.15) participants. More participants met responder criteria with GXR versus placebo, regardless of prior treatment. GXR response was unaffected by prior stimulant treatment; ATX produced improvement only in stimulant-naïve participants relative to placebo. These findings may be relevant to clinical decision-making regarding sequencing of ADHD treatments.

Functional impairment outcomes in clinical trials of different ADHD medications: post hoc responder analyses and baseline subgroup analyses

“…In the responder analyses, the proportions of stimulant-naïve participants were similar across all treatment groups, suggesting that previous drug status is unlikely to affect the treatment groups differentially. Furthermore, response to LDX and GXR has been shown to be unaffected by prior stimulant treatment [ 18 , 22 ].…”

“…SPD503-316 (ClinicalTrials.gov identifier: NCT01244490) was a 10–13-week, double-blind, efficacy and safety study of GXR in children and adolescents (aged 6–17 years) with ADHD and an ADHD-RS-IV total score of at least 32 and a Clinical Global Impression-Severity (CGI-S) score of at least four, conducted in Europe (45 sites in 11 countries) and North America. Details of the study design, results and previous post hoc analyses have been published [ 11 , 15 , 22 ].…”

Correlations Between Clinical Trial Outcomes Based on Symptoms, Functional Impairments, and Quality of Life in Children and Adolescents With ADHD

“…ATX was included as a reference treatment. Details of the study design, results, and previous post hoc analyses are published (Hervas et al, 2014; Huss et al, 2016).…”

“…The primary efficacy outcome in both studies was the change in ADHD-RS-IV total score from baseline to endpoint (defined as the last on-treatment assessment with valid data, excluding baseline; Coghill et al, 2013;Hervas et al, 2014). Both studies included the WFIRS-P, and the LDX study also included the CHIP-CE:PRF among other secondary efficacy outcome measures (Banaschewski et al, 2013;Coghill et al, 2013;Coghill et al, 2014;Hervas et al, 2014;Huss et al, 2016;Soutullo et al, 2013). In the LDX study, the CHIP-CE:PRF Achievement domain was prespecified as the primary HRQoL outcome (Banaschewski et al, 2013); in the GXR study, the WFIRS-P Learning and School domain and Family domain were prespecified as key secondary efficacy outcomes.…”

Treatment Patterns, Health Care Resource Utilization, and Health Care Cost Associated with Atypical Antipsychotics or Guanfacine Extended Release in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder in Quebec, Canada

“…Clinical trials have established the safety and efficacy of GXR as a monotherapy in patients who are stimulant naive or had prior methylphenidate (MPH) treatment (Huss et al 2016), and as combination therapy with stimulants after a partial response to prior stimulant monotherapy (Wilens et al 2012). In children with ADHD and comorbid oppositional defiant disorder, GXR monotherapy improved ADHD core symptoms and oppositional symptoms (Connor et al 2010).…”