Back to resultsSapropterin as a Treatment for Autistic Disorder
Primary Purpose
Autistic Disorder
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
sapropterin
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Autistic Disorder focused on measuring autism
Eligibility 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
Sites / Locations
- The Children's Health Council
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
sapropterin, 100 mg capsules
Placebo, matching active drug
Arm Description
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.
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.
Outcomes
Primary Outcome Measures
Clinical Global Impression -- Improvement (CGI-I) Scale
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
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.
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.
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)
The C-YBOCS is a scale is designed to rate the severity of obsessive and compulsive symptoms in children and adolescents, ages 6 to 17 years. It can be administered by a clinican or trained interviewer in a semi-structured fashion. In general, the ratings depend on the child's and parent's report; however, the final rating is based on the clinical judgement of the interviewer. Rate the characteristics of each item over the prior week up until, and including, the time of the interview. Scores should reflect the average of each item for the entire week, unless otherwise specified.
Connor's Preschool ADHD Questionnaire
Conners Early Childhood, addresses child behavior for ages 2 years to 6 years with a variety of scales, including an ADHD subdomain.
Adverse Events Scale
This was not a standardized scale but a set of questions that was asked of each family - some standard and others open ended.
Aberrant Behavior Checklist (ABC) - Inappropriate Speech
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)
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
This is a measure where parents rate their impression of their child's improvement, in a global manner.
Full Information
NCT ID
NCT00850070
First Posted
February 20, 2009
Last Updated
April 27, 2018
Sponsor
The Children's Health Council
Collaborators
BioMarin Pharmaceutical
1. Study Identification
Unique Protocol Identification Number
NCT00850070
Brief Title
Sapropterin as a Treatment for Autistic Disorder
Official Title
Sapropterin as a Treatment for Autistic Disorder: A Phase II Randomized, Double-Blind, Placebo-Controlled Trial
Study Type
Interventional
2. Study Status
Record Verification Date
April 2018
Overall Recruitment Status
Completed
Study Start Date
March 2009 (undefined)
Primary Completion Date
August 2011 (Actual)
Study Completion Date
October 2011 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
The Children's Health Council
Collaborators
BioMarin Pharmaceutical
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Autistic Disorder
Keywords
autism
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
46 (Actual)
8. Arms, Groups, and Interventions
Arm Title
sapropterin, 100 mg capsules
Arm Type
Experimental
Arm Description
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.
Arm Title
Placebo, matching active drug
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
sapropterin
Other Intervention Name(s)
Kuvan, tetrahydrobiopterin
Intervention Description
Patients will receive sapropterin 20 mg per kilogram per day for 16 weeks
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
sugar pill
Intervention Description
Patients will receive a placebo identical in form and dosage to the active drug daily for 16 weeks.
Primary Outcome Measure Information:
Title
Clinical Global Impression -- Improvement (CGI-I) Scale
Description
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
Time Frame
Weekly for 4 weeks, then monthly, with 16-week end point. Primary outcome assessment used two time points, baseline and 16 weeks.
Title
Clinical Global Impression -- Severity (CGI-S) Scale
Description
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
Time Frame
Baseline, 8 weeks, and 16 weeks. Primary outcome assessment used 2 time points, baseline and 16 weeks.
Secondary Outcome Measure Information:
Title
Preschool Language Scale-Fourth Edition (PLS-4). Assesses Expressive and Receptive Language Skills in Ages Birth Through 6 Years, 11 Months.
Description
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.
Time Frame
Primary outcome assessment examined the difference in scores between baseline and week 16.
Title
Vineland Adaptive Behavior Scale-II.
Description
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.
Time Frame
Primary outcome assessment used two time points, baseline and 16 weeks.
Title
Children's Yale Brown Obsessive Compulsive Scale (C-YBOCS)
Description
The C-YBOCS is a scale is designed to rate the severity of obsessive and compulsive symptoms in children and adolescents, ages 6 to 17 years. It can be administered by a clinican or trained interviewer in a semi-structured fashion. In general, the ratings depend on the child's and parent's report; however, the final rating is based on the clinical judgement of the interviewer. Rate the characteristics of each item over the prior week up until, and including, the time of the interview. Scores should reflect the average of each item for the entire week, unless otherwise specified.
Time Frame
Baseline, 8 weeks, and 16 weeks
Title
Connor's Preschool ADHD Questionnaire
Description
Conners Early Childhood, addresses child behavior for ages 2 years to 6 years with a variety of scales, including an ADHD subdomain.
Time Frame
Baseline, 8 weeks, and 16 weeks
Title
Adverse Events Scale
Description
This was not a standardized scale but a set of questions that was asked of each family - some standard and others open ended.
Time Frame
Every 1-2 weeks for 16 weeks
Title
Aberrant Behavior Checklist (ABC) - Inappropriate Speech
Description
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.
Time Frame
Primary outcome assessment used two time points, baseline and 16 weeks.
Title
Social Responsiveness Scale (SRS)
Description
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.
Time Frame
Primary outcome assessment used two time points, baseline and 16 weeks.
Title
Parent Global Assessment (PGA) Scale
Description
This is a measure where parents rate their impression of their child's improvement, in a global manner.
Time Frame
Baseline, 8 weeks, and 16 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
3 Years
Maximum Age & Unit of Time
6 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Glen R Elliott, Ph.D., M.D.
Organizational Affiliation
The Children's Health Council
Official's Role
Principal Investigator
Facility Information:
Facility Name
The Children's Health Council
City
Palo Alto
State/Province
California
ZIP/Postal Code
94304
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
23782126
Citation
Klaiman C, Huffman L, Masaki L, Elliott GR. Tetrahydrobiopterin as a treatment for autism spectrum disorders: a double-blind, placebo-controlled trial. J Child Adolesc Psychopharmacol. 2013 Jun;23(5):320-8. doi: 10.1089/cap.2012.0127.
Results Reference
result
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Sapropterin as a Treatment for Autistic Disorder
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