Dose Finding Study of Pioglitazone in Children With Autism Spectrum Disorders (ASD) (PIO)

A Pilot Dose Finding Study of Pioglitazone in Children With ASD

The investigators propose a pilot, single blind, placebo run-in, dose finding study of pioglitazone in children with autism with the ultimate goal of identifying appropriate dosing and outcome measures for a larger follow-up randomized placebo controlled clinical trial. The specific aims of this study are: 1) To examine the safety of pioglitazone in children with autism spectrum disorders (ASD) ages 5-12 years; 2) To identify appropriate outcome measures to be used in a follow-up multisite randomized control trial of pioglitazone in children with ASD; 3) To determine the maximum tolerated dose to be used in the follow-up multisite randomized controlled trial; 4) To examine the effect of pioglitazone on markers of inflammation (cytokine levels) and oxidative stress (superoxide dismutase, malonyl aldehydes); 5) To explore the relationship between different doses and response to treatment.

Study Overview

• Status: Completed
• Conditions: Autism Spectrum Disorders
• Intervention / Treatment: Drug: Pioglitazone; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M4G 1R8
      • Holland Bloorview Kids Rehabilitation Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 12 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female outpatients 5-12 years of age inclusive (see Note below).
2. Meet Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV) criteria. DSM-IV criteria for Autistic Disorder or Asperger's Disorder (autism spectrum disorder) will be confirmed by a clinician with expertise with individuals with ASD. Best estimate Diagnosis will be reached using DSM-IV criteria, the Autism Diagnostic Observation Schedule (ADOS-G) and the Autism Diagnostic Interview-Revised (ADI-R).
3. Have a Clinical Global Impression-Severity (CGI-S) score ≥ 4 (moderately ill) at Baseline.
4. If already receiving stable non-pharmacologic educational, behavioural, and/or dietary interventions, have continuous participation during the preceding 3 months prior to Screening and will not electively initiate new or modify ongoing interventions for the duration of the study.
5. Have normal physical examination and laboratory test results at Screening. If abnormal, the finding(s) must be deemed clinically insignificant by the Investigator.

Exclusion Criteria:

1. Patients born prior to 35 weeks gestational age.
2. Families without sufficient command of the English Language.
3. Patients with any primary psychiatric diagnosis other than autism at Screening.
4. Patients with a current neurological disease, including, but not limited to, movement disorder, tuberous sclerosis, fragile X, and any other known genetic syndromes.
5. Pregnant female patients, female patients who are sexually active, female patients using the birth control pill for whatever reason.
6. Patients with a medical condition that might interfere with the conduct of the study, confound interpretation of the study results, or endanger their own well-being. Patients with evidence or history of malignancy or any significant hematological, endocrine, cardiovascular (including any rhythm disorder), respiratory, renal, hepatic, or gastrointestinal disease. Patients with stable epilepsy (no seizures for 6 months) and on stable doses of antiepileptic medications (no changes in 3 months) will be allowed in the study.
7. Patients taking psychoactive medication(s).
8. Patients taking insulin.
9. Patients unable to tolerate venipuncture procedures for blood sampling.
10. Patients with parent(s)/caregiver(s) who smoke.
11. Patients who have had previous bladder infection(s).
12. Patients with a family history of bladder cancer.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; There will be a 2 week period of placebo run-in.
Experimental: Pioglitazone; A modified dose finding method will be used to determine safety and dose response among three dose levels (0.25mg/kg QD, 0.5mg/kg QD, and 0.75mg/kg QD). There will be 14 weeks of active treatment.	Drug: Pioglitazone; A modified dose finding method will be used to determine safety and dose response among three dose levels (0.25mg/kg QD, 0.5mg/kg QD, and 0.75mg/kg QD). The dose has been based on the per weight maximum adult dose. Specifically, the FDA has approved 45mg as the maximum adult dose. For a 60kg adult, this is 0.75mg/kg. There will be 14 weeks of active treatment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety of pioglitazone in children with ASD ages 5-12 years	This will be measured by the Clinical Global Impressions - Improvement Scale - Global (CGI-I-Global)	16 Weeks
Safety of pioglitazone in children with ASD ages 5-12 years	This will be measured by the Safety Monitoring Uniform Report Form (SMURF)	16 Weeks
Efficacy of outcome measure to be used in a follow-up multisite randomized control trial of pioglitazone in children with ASD	This will be measured by the Aberrant Behavior Checklist (ABC)	16 Weeks
Efficacy of outcome measure to be used in a follow-up multisite randomized control trial of pioglitazone in children with ASD	This will be measured the Social Responsiveness Scale (SRS)	16 Weeks
Efficacy of outcome measure to be used in a follow-up multisite randomized control trial of pioglitazone in children with ASD	This will be measured by the the Child Yale-Brown Obsessive-Compulsive Scale (CY-BOCS)	16 Weeks
Efficacy of outcome measure to be used in a follow-up multisite randomized control trial of pioglitazone in children with ASD	This will be measured by the Repetitive Behavior Scale - Revised (RBS-R)	16 Weeks
Efficacy of outcome measure to be used in a follow-up multisite randomized control trial of pioglitazone in children with ASD	This will be measured by the Behavioral Assessment System for Children (BASC-2)	16 Weeks
Efficacy of outcome measure to be used in a follow-up multisite randomized control trial of pioglitazone in children with ASD	This will be measured by the Child and Adolescent Symptom Inventory (CASI) - Anxiety Subscale	16 Weeks
Maximum tolerated dose to be used in the follow-up multisite randomized controlled trial	Maximum Tolerated Dose (MTD)	16 Weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy of pioglitazone on markers of inflammation (cytokine levels) and oxidative stress (superoxide dismutase, malonyl aldehydes)	Cytokine level and oxidative stress marker measurement	16 Weeks
Relationship between different doses and response to treatment	Pioglitazone dose and treatment response	16 Weeks

Collaborators and Investigators

• Sponsor: Evdokia Anagnostou
• Collaborators: Holland Bloorview Kids Rehabilitation Hospital
• Investigators: Principal Investigator: Evdokia Anagnostou, M.D., Holland Bloorview Kids Rehabilitation Hospital

Publications and helpful links

General Publications

• Capano L, Dupuis A, Brian J, Mankad D, Genore L, Hastie Adams R, Smile S, Lui T, Odrobina D, Foster JA, Anagnostou E. A pilot dose finding study of pioglitazone in autistic children. Mol Autism. 2018 Nov 26;9:59. doi: 10.1186/s13229-018-0241-5. eCollection 2018.

Study record dates

Study Major Dates

• Study Start: April 1, 2013
• Primary Completion (Actual): September 1, 2015
• Study Completion (Actual): September 1, 2015

Study Registration Dates

• First Submitted: September 16, 2010
• First Submitted That Met QC Criteria: September 17, 2010
• First Posted (Estimate): September 20, 2010

Study Record Updates

• Last Update Posted (Actual): March 20, 2017
• Last Update Submitted That Met QC Criteria: March 17, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: ASD
• Additional Relevant MeSH Terms: Mental Disorders; Neurodevelopmental Disorders; Child Development Disorders, Pervasive; Autism Spectrum Disorder; Hypoglycemic Agents; Physiological Effects of Drugs; Pioglitazone
• Other Study ID Numbers: 10-002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No