Abstract
BackgroundAutism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by impairments in social interaction and communication. Oxytocin (OXT), as a neuropeptide, plays a role in emotional and social behaviors. Lactobacillus reuteri (L. reuteri) supplementation led to an OXT-dependent behavioral improvement in ASD mouse models. Despite some promising results from animal studies, little is known about the efficacy of supplementation with L. reuteri, alone or with exogenous OXT therapy, on social-behavioral functions in ASD patients. This paper presents a protocol for a pilot randomized controlled trial to evaluate the feasibility of conducting a full trial comparing oral supplementation of L. reuteri probiotics and intranasal OXT spray to placebo on the effect of social and behavioral functions in ASD patients. The study will also capture preliminary estimates of the efficacy of the proposed interventions in ASD patients.MethodsThis pilot trial is a two-staged, randomized, double-blind, placebo-controlled, parallel-group study. Throughout the study (0–24 weeks), 60 patients with ASD will be randomly assigned to receive either oral L. reuteri probiotics or placebo. In the second study stage (13–24 weeks), all participants will receive intranasal OXT spray. As primary outcomes, serum OXT levels will be assayed and social behaviors will be assessed via the Autism Behavior Checklist and the Social Responsiveness Scale which are validated questionnaires, an objective emotional facial matching test, and a new video-based eye-tracking test. Secondary outcomes include the GI-severity-index and Bristol Stool Chart to assess GI function and gut microbiome/short-chain fatty acids. All the outcomes will be assessed at baseline and weeks 12 and 24.DiscussionThis pilot study will provide important information on the feasibility of recruitment, blinding and concealment, treatment administration, tolerability and adherence, specimen collection, outcome assessment, potential adverse effects, and the preliminary efficacy on both primary and secondary outcomes. If successful, this pilot study will inform a larger randomized controlled trial fully powered to examine the efficacies of oral L. reuteri probiotics and/or intranasal OXT spray on social-behavioral improvement in ASD patients.Trial registrationClinicalTrials.gov, NCT03337035. Registered 8 November 2017.
Highlights
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by impairments in social interaction and communication
In the first stage of this pilot trial, we will randomly assign 60 patients, with a 1:1 ratio, to either L. reuteri treatment or placebo in order to assess the effects of 12-week administration of L. reuteri alone on the behavioral measurements of ASD, and whether treatment response depends on the degree of baseline OXT level and/or endogenous OXT signaling induction by L. reuteri probiotics
This study is the first pilot and feasibility study that explores the implementation of a psychotropic L. reuteri probiotics strain alone and in combination with exogenous OXT administration as a treatment for ASD symptoms
Summary
Study design This protocol describes a pilot trial to test the study feasibility and intervention tolerability and is available online at ClinicalTrials.gov (NCT03337035). Analyses based on the intent-to-treat principle are designed to examine the treatment effect of L. reuteri probiotics vs placebo at the end of the first stage of trial on primary outcomes, which are behavioral scores (i.e., ABC and SRS-2), behavioral testing results (i.e., eye-tracking and emotional face matching tests), and serum OXT changes. Compliance to intervention will be assessed by determining the number of capsules and sprays returned at each follow-up visit at week 12 and week 24 from the treatment packs dispensed The adherence of this trial will be assessed by (1) changes of serum OXT levels, (2) changes in microbial relative abundances and diversity, and (3) changes in fecal short-chain fatty acid metabolites. Feasibility target Feasibility targets will be set to greater than or equal to 30 enrollments per 6 months, greater than or equal to 70% adherence rate, and greater than or equal to 70% data collection completion rate
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