Translating Attention-Deficit/Hyperactivity Disorder Rating Scale-5 and Weiss Functional Impairment Rating Scale-Parent Effectiveness Scores into Clinical Global Impressions Clinical Significance Levels in Four Randomized Clinical Trials of SPN-812 (Viloxazine Extended-Release) in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder

Abstract

Objectives: Clinical trials in psychiatry frequently report results from lengthy, comprehensive assessments to characterize a subject emotionally, cognitively, and behaviorally before and after treatment. However, the potential treatment implications of these results and how they translate into clinical practice remain unclear. Conversely, the Clinical Global Impressions (CGI) scales are quick, intuitive assessments used to assess the functional impact of a treatment in clinically relevant terms. The objectives of the present analyses are to translate scores from comprehensive assessments of symptom severity and functional impairment into clinically meaningful CGI levels. Methods: These post-hoc analyses use data integrated from four pivotal Phase 3 trials in attention-deficit/hyperactivity disorder (ADHD) in children and adolescents treated with the novel nonstimulant SPN-812 (Viloxazine Extended-Release). In this study, we evaluated the ADHD Rating Scale-5 (ADHD-RS-5) and Weiss Functional Impairment Rating Scale-Parent (WFIRS-P), assessments of symptom severity and functional impairment, respectively, by linking these scales with the CGI scales at baseline and end of study. Results: For participants that improved, a one-level change on the CGI-Improvement (CGI-I) was associated with a 10-15-point change on the ADHD-RS-5, and a 0.2-0.5-point change on the WFIRS-P. On the CGI-I, ratings of much improved and very much improved were associated with a percent score decrease (i.e., improvement) of ∼55% and 80% on the ADHD-RS-5 and ∼40% and 70% on the WFIRS-P, respectively. Differences between children and adolescents were minor and are unlikely to be clinically meaningful. Conclusion: These post-hoc analyses provide clinically meaningful benchmarks for the interpretation of scores on the ADHD-RS-5 and WFIRS-P in terms of CGI evaluations in subjects with ADHD. These results may be useful for physicians seeking to understand a treatment's potential impact on their ADHD patients or for researchers looking to define their study results within a clinically relevant context. Data are from clinical trials NCT03247530, NCT03247543, NCT03247517, and NCT03247556.

Keywords: Clinical Global Impressions Scale; SPN-812; Viloxazine Extended-Release; attention-deficit/hyperactivity disorder; clinical relevance.

Conflict of interest statement

This study was fully sponsored by Supernus Pharmaceuticals, Inc. The study Sponsor was fully involved in all aspects of the work, including data analysis and interpretation, and article drafting and editing.

A.N., A.R.K., T.L., P.Q., J.T.H., G.D.B., W.O., and J.R. are employees of Supernus Pharmaceuticals, Inc. For a list of M.F.'s lifetime disclosures, please see https://mghcme.org/faculty/faculty-detail/maurizio_fava S.V.F. has received income, potential income, travel expenses continuing education support and/or research support from Takeda, OnDosis, Tris, Otsuka, Arbor, Ironshore, Rhodes, Akili Interactive Laboratories, Enzymotec, Supernus, and Genomind. With his institution, he has US patent US20130217707 A1 for the use of sodium/hydrogen exchange inhibitors in the treatment of attention-deficit/hyperactivity disorder (ADHD). He also receives royalties from books published by Guilford Press: Straight Talk about Your Child's Mental Health, Oxford University Press: Schizophrenia: The Facts and Elsevier: ADHD: Non-Pharmacologic Interventions. He is Program Director of www.adhdinadults.com

Figures

FIG. 1.

Treatment effects as assessed by the CGI-I. More subjects treated with SPN-812 achieved clinically meaningful improvements (i.e., CGI-I assessment of much improved or very much improved) than subjects receiving placebo. Fisher's exact test, two-sided. *p < 0.05, **p < 0.01, ****p < 0.0001. CGI, Clinical Global Impressions; CGI-I, CGI-Improvement.

FIG. 2.

Link functions for ADHD-RS scores and CGI-S/CGI-I levels. Children (blue lines) and adolescents (red lines) are from the present analysis in pediatric patients treated with SPN-812 or placebo. Shaded bands represent 95% confidence intervals for link functions by age group, that is, collapsed across study. For clarity, some points were omitted without changing the shape of the line: included on (A) and (B) is every second point; on (C), every sixth point. (A) Baseline ADHD-RS-5 Total scores and CGI-S levels. (B) ADHD-RS-5 Total score absolute change from baseline and CGI-I levels at the end of study. (C) ADHD-RS-5 Total score percent change from baseline and CGI-I levels at the end of study. ADHD-RS-5, Attention-Deficit/Hyperactivity Disorder Rating Scale 5; CGI, Clinical Global Impressions; CGI-I, CGI-Improvement; CGI-S, CGI-Severity.

FIG. 3.

Link functions for ADHD-RS scores and CGI-S/CGI-I Levels compared with a previous trial of lisdexamfetamine. children (blue line) and adolescents (red triangles) are from the present analysis in pediatric patients treated with SPN-812 or placebo (using ADHD-RS-5); Children 6–12 years (black dotted line) are from a previously-published analysis in children treated with lisdexamfetamine or placebo using ADHD-RS-IV (Goodman et al. 2010). Shaded bands represent 95% confidence intervals by age group. For clarity, some points were omitted without changing the shape of the line: included on (A) and (B) is every second point; on (C), every sixth point. (A) Baseline ADHD-RS Total scores and CGI-S levels. (B) ADHD-RS Total score absolute change from baseline and CGI-I levels at the end of study. (C) ADHD-RS Total score percent change from baseline and CGI-I levels at the end of study. ADHD-RS, Attention-Deficit/Hyperactivity Disorder Rating Scale; CGI, Clinical Global Impressions; CGI-I, CGI-Improvement; CGI-S, CGI-Severity.

FIG. 4.

Link functions for WFIRS-P scores and CGI-S/CGI-I Levels. Children (blue line) and adolescents (red triangles) are from the present analysis in pediatric patients treated with SPN-812 or placebo. Shaded bands represent 95% confidence intervals by age group. (A) Baseline WFIRS-P Total Average scores and CGI-S levels. (B) WFIRS-P Total Average scores absolute change from baseline and CGI-I levels at the end of study. (C) WFIRS-P Total Average scores percent change from baseline and CGI-I levels at the end of study. CGI, Clinical Global Impressions; CGI-I, CGI-Improvement; CGI-S, CGI-Severity; WFIRS-P, Weiss Functional Impairment Rating Scale-Parent.