Sapropterin as a Treatment for Autistic Disorder

This study has been completed.
Sponsor:
Collaborator:
BioMarin Pharmaceutical
Information provided by (Responsible Party):
Glen R. Elliott, The Children's Health Council
ClinicalTrials.gov Identifier:
NCT00850070
First received: February 20, 2009
Last updated: January 27, 2014
Last verified: January 2014
  Purpose

This study is intended to provide a definitive test of the hypothesis that elevating sapropterin (tetrahydrobiopterin, a cofactor for several key brain enzymes)concentrations in the CNS will result in measurable improvements in core symptoms of autism in young individuals, under age 6 years. The study will entail a double-blind, placebo-controlled 16-week intervention.


Condition Intervention Phase
Autistic Disorder
Drug: sapropterin
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Sapropterin as a Treatment for Autistic Disorder: A Phase II Randomized, Double-Blind, Placebo-Controlled Trial

Resource links provided by NLM:


Further study details as provided by The Children's Health Council:

Primary Outcome Measures:
  • Clinical Global Impression -- Improvement (CGI-I) Scale [ Time Frame: Weekly for 4 weeks, then monthly, with 16-week end point. Primary outcome assessment used two time points, baseline and 16 weeks. ] [ Designated as safety issue: No ]
    The CGI-I assessed the number of participants showing much or very much improvement on the CGI-I scale. This is a summary judgment made by a trained clinician based on observed and reported behaviors of the child compared to baseline. It is a 7-point scale from very much worse (1) to very much improved (7). Chi-square analyses were used to assess change in CHI-I scores (by group, post-test). Mixed-effects regression models via SPSS MIXED determined the main effects attributed to differences by group (BH4 and placebo), time (treated as categorical at levels baseline, 8 weeks, and 16 weeks) and the group-by-time interaction. We used random intercept and trend modeling that accounts for each individual's initial level of symptom severity/functioning and rate of change/time

  • Clinical Global Impression -- Severity (CGI-S) Scale [ Time Frame: Baseline, 8 weeks, and 16 weeks. Primary outcome assessment used 2 time points, baseline and 16 weeks. ] [ Designated as safety issue: No ]
    The CGI-S assessed the number of participants with improved severity illness on the CGI-S scale. This is a summary judgment made by a trained clinician of symptom severity. It is a 7-point scale that rates the severity of the patient's illness at time of assessment with 1 - normal, not at all, to 7 - extremely ill. Mixed-effects regression models via SPSS MIXED determined the main effects attributed to differences by group (BH4 and placebo), time (treated as categorical at levels baseline, 8 weeks, and 16 weeks) and the group-by-time interaction. We used random intercept and trend modeling that accounts for each individual's initial level of symptom severity/functioning and rate of change/time


Secondary Outcome Measures:
  • Preschool Language Scale-Fourth Edition (PLS-4). Assesses Expressive and Receptive Language Skills in Ages Birth Through 6 Years, 11 Months. [ Time Frame: Primary outcome assessment examined the difference in scores between baseline and week 16. ] [ Designated as safety issue: No ]
    Measures expressive & receptive language and total scores in ages birth to 6 years 11 months. The scales generate raw, standard, and age-equivalent scores; raw scores for the total scale were selected for use in this study. Total is average of subscales. Minimum raw score = 0, maximum = 130. Higher scores indicate better language abilities. Mixed-effects regression models via SPSS MIXED determined the main effects attributed to differences by group (BH4 and placebo), time (treated as categorical at levels baseline, 8 weeks, and 16 weeks) and the group-by-time interaction. For the outcome effect, the difference between baseline and 16 weeks was determined as an indicator for change.

  • Vineland Adaptive Behavior Scale-II. [ Time Frame: Primary outcome assessment used two time points, baseline and 16 weeks. ] [ Designated as safety issue: No ]
    the Vineland-2 is a semi-structured interview designed to assess communicatino, daily living, socialization and motor skills. The Vineland-2 is comprised of a total Adaptive Composite scale; we chose to use 10 subscales that specifically address functional domains relevant for a young ASD sample - Receptive Communication, Expressive Communication, Personal Daily Living Skills, Domestic Daily Living Skills, Community Daily Living Skills, Interpersonal Relations, Play Skills, Coping Skills, Gross Motor Skills, Fine Motor Skills. Scales generate raw or sum, V-, and age-equivalent scores; raw scores were selected for use in the study. Raw score ranges from 0 to 108 depending on the scale. Total raw scale range is from 0 to 766. Subscale scores are averaged to create the total adaptive behavior composite. Higher subscale scores indicate more skills. Difference between baseline and week 16 was used as an indicator of change.

  • Children's Yale Brown Obsessive Compulsive Scale (C-YBOCS) [ Time Frame: Baseline, 8 weeks, and 16 weeks ] [ Designated as safety issue: No ]
  • Connor's Preschool ADHD Questionnaire [ Time Frame: Baseline, 8 weeks, and 16 weeks ] [ Designated as safety issue: No ]
  • Adverse Events Scale [ Time Frame: Every 1-2 weeks for 16 weeks ] [ Designated as safety issue: Yes ]
  • Aberrant Behavior Checklist (ABC) - Inappropriate Speech [ Time Frame: Primary outcome assessment used two time points, baseline and 16 weeks. ] [ Designated as safety issue: No ]
    Subscale assessing echolalia & other odd speech. Higher subscale scores indicate more symptoms. 4 items comprise the subscale, with range of scores from 0-4. Total score range on this subscale is 0 to 16. Scores are averaged to compute overall score. Difference in scores between baseline and week 16 were used as indicator of change.

  • Social Responsiveness Scale (SRS) [ Time Frame: Primary outcome assessment used two time points, baseline and 16 weeks. ] [ Designated as safety issue: No ]
    The SRS is a 65-item scale used to measure the severity of symptoms in ASD as they occur in natural social settings. The SRS is comprised of 1 Total scale and 5 subscales that generate raw scores that can be converted to standard T-scores (with mean of 50 and standard deviation of 10) for gender and rater type; standard scores were selected for use in this study. A total T-score of 76 or higher is considered severe and strongly associated with a clinical diagnosis of autistic disorder. A t-score of 60-75 is in the mild to moderate range and considered typical for children with mild or 'high-functioning' ASD, while a T-score of 59 or less suggests an absence of ASD symptoms. A total raw score of >75 were associated with a sensitivity value of .85 and a specificity value of .75 for ASD. Difference in scores between baseline and week 16 were used as an indicator of change.

  • Parent Global Assessment (PGA) Scale [ Time Frame: Baseline, 8 weeks, and 16 weeks ] [ Designated as safety issue: No ]

Enrollment: 46
Study Start Date: March 2009
Study Completion Date: October 2011
Primary Completion Date: August 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: sapropterin, 100 mg capsules
Sapropterin was supplied as a 100 mg tablet and dosage was based on 20 mg/kg/d, rounding to the nearest 100 mg. Most subjects crushed the tablets and administered it in liquid or a food to mask the taste. Subjects took the same dose daily for 16 weeks.
Drug: sapropterin
Patients will receive sapropterin 20 mg per kilogram per day for 16 weeks
Other Names:
  • Kuvan
  • tetrahydrobiopterin
Placebo Comparator: Placebo, matching active drug
The placebo was supplied as a 100 mg tablet, and dosage was based on 20 mg/kg/d, rounding to the nearest 100 mg. Most subjects crushed the tablets and administered it in liquid or a food to mask the taste. Subjects took the same dose daily for 16 weeks.
Drug: Placebo
Patients will receive a placebo identical in form and dosage to the active drug daily for 16 weeks.
Other Name: sugar pill

Detailed Description:

Over the past 20 years, several studies have suggested that sapropterin (tetrahydrobiopterin) might ameliorate core symptoms of autism at least in young (under age 6) subjects. However, those studies had somewhat questionable methodologies, a major one being that the doses of sapropterin used were roughly one tenth that thought to be needed to provide physiologically meaningful increases of sapropterin in the central nervous system (CNS). This study will look at the impact of a sustained exposure to this higher dose in well-diagnosed young children with autism.

  Eligibility

Ages Eligible for Study:   3 Years to 6 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Parents sign informed consent
  • Child meets criteria for autistic disorder (based on score on the Autism Diagnostic Interview—Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS), given by a certified administrator, research reliable)
  • Child has a Developmental Quotient (DQ) ≥ 50 (Vineland Adaptive Scales, Interview Edition)
  • Parents agree to delay initiation of other treatments during double-blind trial

Exclusion Criteria:

  • Child has had seizures in past 6 months or a change in seizure medications in past 4 weeks.
  • Child has > 18 points on subscale of (Autism Behavior Checklist) ABC-I
  • Child is taking any psychoactive medication other than supplements, anticonvulsants, or soporifics (melatonin, diphenhydramine)
  • Child has had any change in standing medications in the past 4 weeks.
  • Child has known genetic disorders
  • Child has known severe neurological disorders, including cerebral palsy
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00850070

Locations
United States, California
The Children's Health Council
Palo Alto, California, United States, 94304
Sponsors and Collaborators
The Children's Health Council
BioMarin Pharmaceutical
Investigators
Principal Investigator: Glen R Elliott, Ph.D., M.D. The Children's Health Council
  More Information

Publications:
Responsible Party: Glen R. Elliott, Chief Psychiatrist and Medical Director, The Children's Health Council
ClinicalTrials.gov Identifier: NCT00850070     History of Changes
Other Study ID Numbers: CHC-0901
Study First Received: February 20, 2009
Results First Received: August 31, 2012
Last Updated: January 27, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by The Children's Health Council:
autism

Additional relevant MeSH terms:
Autistic Disorder
Disease
Child Development Disorders, Pervasive
Mental Disorders
Mental Disorders Diagnosed in Childhood
Pathologic Processes
Verapamil
Anti-Arrhythmia Agents
Calcium Channel Blockers
Cardiovascular Agents
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses
Vasodilator Agents

ClinicalTrials.gov processed this record on October 20, 2014