Efficacy, safety, and tolerability of arbaclofen in Autistic children and adolescents, the AIMS-2-TRIALS-CT1: a randomized, double-blind, placebo-controlled phase II trial

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Background: Previous trials have indicated the potential of arbaclofen for improving social difficulties among autistic children and adolescents with fluent speech. AIMS-2-TRIALS-Clinical Trial 1 (AIMS-2-CT1) examined whether arbaclofen is superior to placebo in improving social function and other secondary outcomes, along with safety and tolerability profiles. Methods: AIMS-2-CT1 is a multi-site, placebo-controlled double-blind, parallel group Phase II randomized clinical trial. Recruitment was conducted in 7 sites in Spain, United Kingdom and France between September 2019 and September 2022. Eligible participants were randomized 1:1, stratified by age and site, for a 16-week treatment period. Age of participants ranged from 5 to 17 years of age. Primary outcome: Socialization domain of the Vineland Adaptive Behavior Scales change. Secondary outcome measures: CGI-S (Clinical Global Impression-Severity), CGI-I (Clinical Global Impression-Improvement), Social Responsiveness Scale (SRS-2), Autism Impact Measure (AIM), behavioral measurements (CBCL, ABC-C) and Quality of Life (PedsQL). Safety and tolerability were assessed via several instruments. Clinical trial registration: EudraCT number: 2018-000942-21 and ClinicalTrials.gov registry number: NCT03682978. Last protocol v.9.1, dated June 18th, 2022. Findings: 122 participants (out of 123 randomized) comprised the Intention-to-treat sample (59/63 arbaclofen/placebo); 85%/95% of participants on arbaclofen/placebo completed the study.Improvements in the primary endpoint and pre-specified key secondary outcomes did not achieve statistical significance [effect size 1.30 (95% CI: -2.6, 5.1)]. Results on all secondary endpoints favored arbaclofen, with significant improvements on many secondary outcomes including the SRS, the AIM Total scores, some subscales of the ABC, and QoL measures. One Serious Adverse Event (psychotic symptoms) was reported on placebo. Sleep-related problems were more frequent on arbaclofen (N = 34, 57.6% in participants on arbaclofen and N = 22, 34.9% in participants on placebo). Interpretation: Although we found no significant effect on the primary outcome, improvements were apparent on several secondary measures of autistic related behaviors as well as quality of life. Arbaclofen shows promise in addressing some autistic difficulties and in improving quality of life, but larger scale trials are needed to further advance our understanding of its potential and to inform future drug development in autism. Funding: Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 777394.

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