A Phase II Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy, Safety, and Tolerability of Arbaclofen Administered for the Treatment of Social Function in Children and Adolescents With Autism Spectrum Disorders: Study Protocol for AIMS-2-TRIALS-CT1.

Mara Parellada,Jeremy R Parr,Evdokia Anagnostou,Celso Arango,Antonia San José Cáceres,Tony Charman,Melanie Palmer,Emily J H Jones,Eva Loth,Andre Strydom,Declan G M Murphy,Richard Delorme,Paul P Wang

doi:10.3389/fpsyt.2021.701729

Abstract

Background: Autism Spectrum Disorder (ASD or autism) is characterized by difficulties in social communication and interaction, which negatively impact on individuals and their families' quality of life. Currently no pharmacological interventions have been shown to be effective for improving social communication in autism. Previous trials have indicated the potential of arbaclofen for improving social function among autistic children and adolescents with fluent speech. The AIMS2TRIALS-Clinical Trial 1 (AIMS-CT1) will examine whether arbaclofen is superior to placebo in improving social function and other secondary outcomes over 16 weeks, along with safety and tolerability profiles.Methods: AIMS-CT1 is an international, multi-site, double-blind, parallel group Phase II randomized clinical trial. It will include 130 males and females aged 5:0–17:11 years, with a diagnosis of ASD and fluent speech. Eligible participants will be randomized on a ratio of 1:1 for a 16-week treatment period. Medication will be titrated over 5 weeks. The primary outcome is the effect on social function from weeks 0 to 16 measured on the Socialization domain of the Vineland Adaptive Behavior Scales, 3rd editionTM. Secondary outcome measures include the CGI–S (Clinical Global Impression–Severity), CGI–I (Clinical Global Impression–Improvement), other areas of adaptive function, social communication and other autism symptoms, co-occurring behavior problems and health-related quality of life. Genetic and electrophysiological markers will be examined as potential stratifiers for treatment response. Exploratory novel digital technologies will also be used to measure change, examining simultaneously the validity of digital biomarkers in natural environments. The safety and tolerability of the drug will also be examined. Our protocol is very closely aligned with a parallel Canadian trial of 90 participants (ARBA Study, US NCT number: NCT03887676) to allow for secondary combined analyses. Outcomes will be compared using both an Intent-to-reat and Per Protocol approach.Discussion: The outcomes of this trial, combined with the parallel Canadian trial, will contribute to the evidence base for medications used to help social difficulties among young autistic individuals; demonstrate the capabilities of the AIMS-2-TRIALS network of academic centers to deliver clinical trials; and support future drug development.Clinical Trial Registration: EudraCT number: 2018-000942-21 and ClinicalTrials.gov registry number: NCT03682978. Currently under protocol v.7.2, dated 20.11.2020.

Highlights

Autism Spectrum Disorder (ASD or autism) is characterized by difficulties in social communication and interaction, which negatively impact on individuals and their families’ quality of life
The study of differential neuropathological pathways that lead to distinct phenotypes and the possibility of finding biomarkers that may index differential pathways or disease trajectories within ASD is one of the most prominent topics in the study of the etiology of ASD and one included in the main objectives of the AIMS2 TRIALS network
The primary objective of AIMS-CT1 is to examine the effect of arbaclofen vs. placebo on social function and behavior, as assessed through the Socialization Domain of the Vineland Adaptive Behavior Scales, 3rd edition [VABS−3; [26]]

Summary

Introduction

Autism Spectrum Disorder (ASD or autism) is characterized by difficulties in social communication and interaction, which negatively impact on individuals and their families’ quality of life. Clinical presentation is highly heterogeneous, depending mainly on age, language, global cognitive levels and Abbreviations: ABC-C, Aberrant Behavior Checklist-Community version; ADHD, Attention-Deficit/Hyperactivity Disorder; ADOS−2, Autism Diagnostic Observation Schedule, 2nd Edition; AE, Adverse Event; AIM, Autism Impact Measure; ANCOVA, Analysis of Covariance; ASD, Autism Spectrum Disorder; BOSCC, Brief Observation of Social Communication Change; CBCL, Child Behavior Checklist; CGI–I, Clinical Global Impression – Improvement; CGI– S, Clinical Global Impression – Severity; C-SSRS, Columbia-Suicide Severity Rating Scale; CONSORT, Consolidated Standards of Reporting Trials; DMC, Data Monitoring Committee; DSM-5, Diagnostic and Statistical Manual of Mental Disorders, 5th Edition; ECG, Electrocardiogram; EEG, Electroencephalogram; E-I, Excitatory/Inhibitory; ESS-CHAD, Epworth Sleepiness Scale for Children and Adolescents; FXS, Fragile X Syndrome; GABA, Gamma-Aminobutyric Acid; GABAB, GABA type B; IRB/IEC, Institutional Review Board/Independent Ethics Committee; ITT, Intent-to-Treat; IWRS, Interactive Web Response System; PedsQL, Pediatric Quality of Life Inventory; POND, Province of Ontario Neurodevelopmental Disorders Network; PP, Per Protocol; PRN, Pro Re Nata; SAE, Serious Adverse Event; SAP, Statistical Analysis Plan; SCQ, Social Communication Questionnaire; SMURF, Safety Monitoring Uniform Report Form; SRS−2, Social Responsiveness Scale, 2nd edition; SUSAR, Suspected, Unexpected Serious Adverse Reactions; UMCU, University Medical Center Utrecht; VABS−2, Vineland Adaptive Behavior Scales, 2nd Edition; VABS−3, Vineland Adaptive Behavior Scales, 3rd Edition. Among the most evidence-supported mechanisms is an excitatory-inhibitory unbalance that affects in, as yet unknown way, the proper coordination of the GABA and glutamate action at the appropriate developmental stages [7]

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