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Sapropterin as a Treatment for Autistic Disorder

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ClinicalTrials.gov Identifier: NCT00850070
Recruitment Status : Completed
First Posted : February 24, 2009
Results First Posted : February 28, 2014
Last Update Posted : May 1, 2018
Sponsor:
Collaborator:
BioMarin Pharmaceutical
Information provided by (Responsible Party):
Glen R. Elliott, The Children's Health Council

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Autistic Disorder
Interventions Drug: sapropterin
Drug: Placebo
Enrollment 46
Recruitment Details Recruitment spanned from 4/09 to 6/11. A variety of methods were used to advertise the study, but most successful recruitment was word-of-mouth from study participants.
Pre-assignment Details Few participants were excluded. Most common exclusions were failure to meet inclusion criteria, mostly absence of an autism diagnosis or cognitive functioning below the required minimum.
Arm/Group Title Sapropterin Placebo
Hide Arm/Group Description tetrahydrobiopterin (BH4); dosage was 20mg/kg/day administered once per day orally in tablet form. Pills could be crushed and mixed with a variety of food substances (e.g., liquids or solids). sugar pill; matched identical tablet, dosage was 20mg/kg/day administered once per day orally in tablet form. Pills could be crushed and mixed with a variety of food substances (e.g., liquids or solids).
Period Title: Overall Study
Started 23 23
Completed 20 22
Not Completed 3 1
Reason Not Completed
Lack of Efficacy             1             1
Adverse Event             2             0
Arm/Group Title Sapropterin Placebo Total
Hide Arm/Group Description tetrahydrobiopterin (BH4) sugar pill Total of all reporting groups
Overall Number of Baseline Participants 23 23 46
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 23 participants 23 participants 46 participants
<=18 years
23
 100.0%
23
 100.0%
46
 100.0%
Between 18 and 65 years
0
   0.0%
0
   0.0%
0
   0.0%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 23 participants 23 participants 46 participants
5  (1) 5  (1) 5  (1)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 23 participants 23 participants 46 participants
Female
3
  13.0%
5
  21.7%
8
  17.4%
Male
20
  87.0%
18
  78.3%
38
  82.6%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 23 participants 23 participants 46 participants
23 23 46
1.Primary Outcome
Title Clinical Global Impression -- Improvement (CGI-I) Scale
Hide 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.
Hide Outcome Measure Data
Hide Analysis Population Description
This was an Intent-to-Treat Analysis with Last Observation Carried Forward.Analyses looked at percentage of children who improved (showing much or very much improved ratings) at 16-week time frame.
Arm/Group Title Sapropterin Placebo
Hide Arm/Group Description:
sapropterin 20 mg/kg/day
sugar pill
Overall Number of Participants Analyzed 23 23
Measure Type: Number
Unit of Measure: participants
5 3
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sapropterin, Placebo
Comments Chi-square analyses were used to assess CGI-I scores. There were no transformations.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.35
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 2
Estimation Comments Estimated value comparison was active treatment minus placebo.
2.Primary Outcome
Title Clinical Global Impression -- Severity (CGI-S) Scale
Hide 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.
Hide Outcome Measure Data
Hide Analysis Population Description
This was an Intent-to-Treat Analysis with Last Observation Carried Forward.Analyses looked at number of children who improved (from markedly, severely or extremely ill to markedly, mildly or no illness) at 16-week time frame.
Arm/Group Title Sapropterin Placebo
Hide Arm/Group Description:
sapropterin 20 mg/kg/day
sugar pill
Overall Number of Participants Analyzed 23 23
Measure Type: Number
Unit of Measure: participants
3 1
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sapropterin, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.06
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 2
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Preschool Language Scale-Fourth Edition (PLS-4). Assesses Expressive and Receptive Language Skills in Ages Birth Through 6 Years, 11 Months.
Hide 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.
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat analysis; all subjects included. Difference in scores between baseline and 16 weeks was used as treatment outcome.
Arm/Group Title Sapropterin Placebo
Hide Arm/Group Description:
tetrahydrobiopterin (BH4)
sugar pill
Overall Number of Participants Analyzed 23 23
Mean (Standard Deviation)
Unit of Measure: units on a scale
84  (29) 60  (25)
4.Secondary Outcome
Title Vineland Adaptive Behavior Scale-II.
Hide 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.
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat analysis; all subjects included. Includes mean at 16-week outcome.
Arm/Group Title Sapropterin Placebo
Hide Arm/Group Description:
tetrahydrobiopterin (BH4)
sugar pill
Overall Number of Participants Analyzed 23 23
Mean (Standard Deviation)
Unit of Measure: units on a scale
344.76  (50.0) 294.9  (70.1)
5.Secondary Outcome
Title Children's Yale Brown Obsessive Compulsive Scale (C-YBOCS)
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
The data was not analyzed secondary to lack of significant findings in the primary outcome measure. Also, limited data collected secondary to the age range of the children we saw.The data cannot now be provided as the research team has since disbanded and it is not possible to reanalyze the data at this time.
Arm/Group Title Sapropterin, 100 mg Capsules Placebo, Matching Active Drug
Hide Arm/Group 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.

sapropterin: Patients will receive sapropterin 20 mg per kilogram per day 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.

Placebo: Patients will receive a placebo identical in form and dosage to the active drug daily for 16 weeks.

Overall Number of Participants Analyzed 0 0
No data displayed because Outcome Measure has zero total analyzed.
6.Secondary Outcome
Title Connor's Preschool ADHD Questionnaire
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
Data was not analyzed secondary to lack of significant findings in primary outcome measures and limited data collected on this instrument. The data cannot now be provided as the research team has since disbanded and it is not possible to reanalyze the data at this time.
Arm/Group Title Sapropterin Placebo
Hide Arm/Group Description:
tetrahydrobiopterin (BH4); dosage was 20mg/kg/day administered once per day orally in tablet form. Pills could be crushed and mixed with a variety of food substances (e.g., liquids or solids).
sugar pill; matched identical tablet, dosage was 20mg/kg/day administered once per day orally in tablet form. Pills could be crushed and mixed with a variety of food substances (e.g., liquids or solids).
Overall Number of Participants Analyzed 0 0
No data displayed because Outcome Measure has zero total analyzed.
7.Secondary Outcome
Title Adverse Events Scale
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
We did not specifically analyze this data but instead use it as a guide to determine if a drug should be discontinued for a particular child.
Arm/Group Title Sapropterin Placebo
Hide Arm/Group Description:
tetrahydrobiopterin (BH4); dosage was 20mg/kg/day administered once per day orally in tablet form. Pills could be crushed and mixed with a variety of food substances (e.g., liquids or solids).
sugar pill; matched identical tablet, dosage was 20mg/kg/day administered once per day orally in tablet form. Pills could be crushed and mixed with a variety of food substances (e.g., liquids or solids).
Overall Number of Participants Analyzed 0 0
No data displayed because Outcome Measure has zero total analyzed.
8.Secondary Outcome
Title Aberrant Behavior Checklist (ABC) - Inappropriate Speech
Hide 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.
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to treat analysis
Arm/Group Title Sapropterin Placebo
Hide Arm/Group Description:
sapropterin 20 mg/kg/day
sugar pill
Overall Number of Participants Analyzed 23 23
Mean (Standard Deviation)
Unit of Measure: units on a scale
2.6  (1.9) 3.9  (3.6)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sapropterin, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.05
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -2
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.9
Estimation Comments [Not Specified]
9.Secondary Outcome
Title Social Responsiveness Scale (SRS)
Hide 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.
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat analysis; all subjects included. Includes mean at 16-week outcome.
Arm/Group Title Sapropterin Placebo
Hide Arm/Group Description:
tetrahydrobiopterin (BH4)
sugar pill
Overall Number of Participants Analyzed 23 23
Mean (Standard Deviation)
Unit of Measure: units on a scale
76.7  (10.9) 83.2  (10.4)
10.Secondary Outcome
Title Parent Global Assessment (PGA) Scale
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
Data was not analyzed secondary to lack of significant findings in primary outcome measures and limited data collected on this instrument. The data cannot now be provided as the research team has since disbanded and it is not possible to reanalyze the data at this time.
Arm/Group Title Sapropterin Placebo
Hide Arm/Group Description:
tetrahydrobiopterin (BH4); dosage was 20mg/kg/day administered once per day orally in tablet form. Pills could be crushed and mixed with a variety of food substances (e.g., liquids or solids).
sugar pill; matched identical tablet, dosage was 20mg/kg/day administered once per day orally in tablet form. Pills could be crushed and mixed with a variety of food substances (e.g., liquids or solids).
Overall Number of Participants Analyzed 0 0
No data displayed because Outcome Measure has zero total analyzed.
Time Frame Adverse events were monitored for the length of the study, i.e., 16 weeks.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Sapropterin Placebo
Hide Arm/Group Description sapropterin 20 mg/kg/day sugar pill
All-Cause Mortality
Sapropterin Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Sapropterin Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   2/23 (8.70%)   1/23 (4.35%) 
Nervous system disorders     
seizure disorder  [1]  0/23 (0.00%)  1/23 (4.35%) 
Skin and subcutaneous tissue disorders     
transient viral rash  [2]  2/23 (8.70%)  0/23 (0.00%) 
Indicates events were collected by systematic assessment
[1]
New-onset seizures
[2]
Viral or autoimmune rashes
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Sapropterin Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   10/23 (43.48%)   14/23 (60.87%) 
Gastrointestinal disorders     
Change in Bowel Habits  [1]  0/23 (0.00%)  4/23 (17.39%) 
Nervous system disorders     
difficulty sleeping  [2]  2/23 (8.70%)  4/23 (17.39%) 
repetitive behaviors  [3]  1/23 (4.35%)  2/23 (8.70%) 
hyperactivity  [4]  2/23 (8.70%)  1/23 (4.35%) 
Psychiatric disorders     
irritablity  [5]  5/23 (21.74%)  4/23 (17.39%) 
Indicates events were collected by systematic assessment
[1]
Changes in stool consistency or bowel movement frequency
[2]
Persistent changes in sleep, including onset insomnia, frequent wakening during the night, lightening of sleep
[3]
Sustained changes in or appearance of stereotypies or other odd, repetitive behaviors
[4]
Persistent increase in overall activity level in a variety of settings.
[5]
Increased irritablility in a variety of settings
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Name/Title: Glen R. Elliott, Ph.D., M.D.
Organization: The Children's Health Council
Phone: 650.688.3649
Responsible Party: Glen R. Elliott, The Children's Health Council
ClinicalTrials.gov Identifier: NCT00850070     History of Changes
Other Study ID Numbers: CHC-0901
First Submitted: February 20, 2009
First Posted: February 24, 2009
Results First Submitted: August 31, 2012
Results First Posted: February 28, 2014
Last Update Posted: May 1, 2018