A pilot dose finding study of pioglitazone in autistic children

Lucia Capano, Annie Dupuis, Jessica Brian, Deepali Mankad, Lisa Genore, Rianne Hastie Adams, Sharon Smile, Toni Lui, Dina Odrobina, Jane A Foster, Evdokia Anagnostou, Lucia Capano, Annie Dupuis, Jessica Brian, Deepali Mankad, Lisa Genore, Rianne Hastie Adams, Sharon Smile, Toni Lui, Dina Odrobina, Jane A Foster, Evdokia Anagnostou

Abstract

Background: Pioglitazone is a promising compound for treatment of core autism spectrum disorder (ASD) symptoms as it targets multiple relevant pathways, including immune system alterations.

Objective: This pilot study aimed to elucidate the maximum tolerated dose, safety, preliminary evidence of efficacy, and appropriate outcome measures in autistic children ages 5-12 years old.

Methods: We conducted a 16-week prospective cohort, single blind, single arm, 2-week placebo run-in, dose-finding study of pioglitazone. Twenty-five participants completed treatment. A modified dose finding method was used to determine safety and dose response among three dose levels: 0.25 mg/kg, 0.5 mg/kg, and 0.75 mg/kg once daily.

Results: Maximum tolerated dose: there were no serious adverse events (SAEs) and as such the maximum tolerated dose within the range tested was 0.75 mg/Kg once daily.Safety: overall, pioglitazone was well tolerated. Two participants discontinued intervention due to perceived non-efficacy and one due to the inability to tolerate interim blood work. Three participants experienced mild neutropenia.Early evidence of efficacy: statistically significant improvement was observed in social withdrawal, repetitive behaviors, and externalizing behaviors as measured by the Aberrant Behavior Checklist (ABC), Child Yale-Brown Obsessive Compulsive Scale (CY-BOCS), and Repetitive Behavior Scale-Revised (RBS-R). Forty-six percent of those enrolled were deemed to be global responders.

Conclusions and relevance: Pioglitazone is well-tolerated and shows a potential signal in measures of social withdrawal, repetitive, and externalizing behaviors. Randomized controlled trials using the confirmed dose are warranted.

Trial registration: ClinicalTrials.gov, NCT01205282. Registration date: September 20, 2010.

Keywords: Autism spectrum disorder; Clinical trial; Cytokines; Drug therapy; Efficacy; Inflammation; Maximum tolerated dose (MTD); Physiological effects of drugs; Pioglitazone; Safety profile; Treatment.

Conflict of interest statement

The informed consent process was conducted in accordance with the Tri Council Policy Statement, the Declaration of Helsinki, and the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH)–Good Clinical Practice (GCP) guidelines and institutional policy. This study was approved by the Holland Bloorview Research Ethics Board. Ethics committee reference number (research ethics board project number): 10-153.Not applicableDr. Evdokia Anagnostou has received consultation fees from Roche and Takeda; industry funding from SynapDx and Sanofi-Aventis; royalties from APPI and Springer International Publishing; editorial honorarium from Wiley; and other funding from the Canadian Institutes of Health Research, the Ontario Brain Institute, the Department of Defense, the National Institutes of Health (NIH), Brain Canada, Autism Speaks, the National Centers of Excellence, and Physician Services Incorporated. Dr. Jane A. Foster has had work supported by Ontario Brain Institute (OBI) Grant Nos. NSERC (RGPIN-312435-12) and NSERC RTI (EQPEQ407645-2011) as well as an infrastructure grant from the Canada Foundation for Innovation and the Ontario Innovation Trust. The remaining authors have no potential competing interests to disclose.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
CONSORT 2010 flow diagram
Fig. 2
Fig. 2
Change in ABC subscales with treatment
Fig. 3
Fig. 3
Change in anxiety with treatment
Fig. 4
Fig. 4
Change in repetitive behavior with treatment
Fig. 5
Fig. 5
Change in cytokine value with treatment

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