The role of placebo response in the efficacy outcome assessment in viloxazine extended‐release pivotal trials in paediatric subjects with attention‐deficit/hyperactivity disorder

• Published in: British journal of clinical pharmacology Vol. 88; no. 11; pp. 4828 - 4838
• Main Authors: Nasser, Azmi, Gomeni, Roberto, Wang, Zhao, Hull, Joseph T., Busse, Gregory D., Melyan, Zare, Fava, Maurizio, O'Neal, Welton, Rubin, Jonathan
• Format: Journal Article
• Language: English
• Published: England 01.11.2022
• Subjects: ADHD, ADHD‐RS‐5, attention‐deficit/hyperactivity disorder, band‐pass analysis, placebo response, treatment effect, viloxazine extended‐release; Attention Deficit Disorder with Hyperactivity - drug therapy; Central Nervous System Stimulants; Child; Clinical Trials, Phase III as Topic; Delayed-Action Preparations - therapeutic use; Dose-Response Relationship, Drug; Humans; Outcome Assessment, Health Care; Placebo Effect; Treatment Outcome; Viloxazine - therapeutic use; ADHD, ADHD-RS-5, attention-deficit/hyperactivity disorder, band-pass analysis, placebo response, treatment effect, viloxazine extended-release
• ISSN: 0306-5251; 1365-2125; 1365-2125
• DOI: 10.1111/bcp.15412

Aims: Four Phase 3 studies evaluated efficacy and safety of viloxazine extended‐release in the treatment of attention‐deficit/hyperactivity disorder (ADHD). The primary efficacy objective—change from baseline in ADHD Rating Scale‐5 (ADHD‐RS‐5) Total score at end of study (EOS)—was not met in one of the studies (812P304). A band‐pass analysis was performed to evaluate the impact of placebo response on the results. Methods: The distribution of placebo response at EOS of each trial was evaluated. The 2.5th and 97.5th percentiles of the distribution of ADHD‐RS‐5 Total score were used as boundaries for the band‐pass analysis. An independent mixed model for repeated measures analysis was conducted for each trial using all eligible data (active and placebo) from the total and band‐pass filtered populations. Results: The 2.5th and 97.5th percentiles at EOS were 3.5 and 53.5, respectively. Application of the band‐pass filter (filtering out all subjects [active, n = 305 (32.1%) and placebo, n = 134 (33.5%)] of clinical sites with placebo scores <3.5 or >53.5) revealed statistically significant improvement at the primary endpoint (600‐mg/d viloxazine ER vs. placebo) in Study 812P304 (mean [confidence interval] = 4.9537 [0.5405–9.3669]), previously masked by a high placebo response (mean [confidence interval] = 3.5756 [−0.3332–7.4844]). The outcome of the analysis indicated that the impact of the band‐pass adjustment is greater when placebo response is higher. Conclusion: This analysis indicated that a higher placebo response in Study 812P304 confounded the assessment of treatment effect. Application of the band‐pass methodology confirmed the positive results of the 3 prior studies and the signal detection confounder in the fourth study.