A Pilot Dose Finding Study of Pioglitazone in Children with ASD

Friday, May 12, 2017: 5:00 PM-6:30 PM
Golden Gate Ballroom (Marriott Marquis Hotel)
L. Capano1, J. A. Brian2, D. Mankad1,3, S. Smile1, L. Genore1, R. Hastie Adams1, A. Iaboni1, D. Odrobina1, A. Dupuis4 and E. Anagnostou5, (1)Holland Bloorview Kids Rehabilitation Hospital, Toronto, ON, Canada, (2)Bloorview Research Institute, Toronto, ON, Canada, (3)University of Toronto, Toronto, ON, Canada, (4)The Hospital for Sick Children, Toronto, ON, Canada, (5)HOlland Bloroview Kids Rehab hospita;, University of Toronto, Toronto, ON, Canada

Only two medications have approval for use in autism spectrum disorder (ASD), (risperidone and aripiprazole) and they treat irritability and aggression. However, there are no pharmaceutical treatment options for the core symptoms of autism. Importantly, we have not been able to impact the developmental trajectory of children with ASD, likely because we are not targeting the underlining pathophysiology. Pioglitazone is a promising compound that targets multiple pathways implicated in ASD such as immune dysregulation, oxidative stress, mitochondrial dysfunction, and NMDA inhibition.


The objective of this pilot study of pioglitazone was to elucidate the maximum tolerated dose and safety, provide early data supporting efficacy, and identify appropriate measures sensitive to change in children with ASD ages 5-12 years old. We hypothesized that pioglitazone would be well tolerated at the maximum dose of 0.75mg/kg once daily.


We conducted a 16-week prospective cohort, single blind, 2-week placebo run-in dose-finding clinical trial between June 2013 and September 2015. Interested potential participants (131) were phone screened, 35 consented, 28 participants initiated treatment, and 25 completed treatment. A modified dose finding method was used to determine safety and dose response among three dose levels: 0.25mg/kg, 0.5mg/kg, and 0.75mg/kg once daily. Classical dose-finding escalations were done in groups of five participants, with five participants studied at the first dose level (0.25mg/kg once daily), five participants were studied at the second dose level (0.5mg/kg once daily), and the final 18 participants were studied at the maximum dose level (0.75mg/kg once daily).


Maximum tolerated dose: There were no serious adverse events (SAEs) and as such the maximum tolerated dose within the range tested was determined to be 0.75mg/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 during the study. Adverse events (AEs) were of mild to moderate severity. Three participants experienced mild neutropenia. In one participant this was a pre-existing condition, in another it resolved while staying on medication and in the third it only presented during the final visit and spontaneously recovered. As such, it was deemed to be unrelated to the study intervention.

Early evidence of efficacy: One participant was a responder after 2 weeks of placebo and was removed from the analysis. Regression analyses showed statistically significant improvements within group for social withdrawal and repetitive behaviors, as well as externalizing behaviors as measured by the Aberrant Behavior Checklist (ABC) and Repetitive Behavior Scale –Revised (RBS-R), and after multiple comparisons correction, but not in anxiety or social responsiveness. Forty-six percent of those enrolled were deemed to be global responders. Of particular interest, high pro-inflammatory cytokine levels at baseline as well as changes during the study were correlated with treatment response.


Pioglitazone is well-tolerated and shows a potential signal in measures of social withdrawal, repetitive behaviors, and externalizing behaviors. High levels of pro-inflammatory cytokines at baseline are associated with treatment response. Randomized controlled trials using the confirmed dose are warranted.