Sapropterin as a Treatment for Autistic Disorder

• Sponsor: The Children's Health Council (Other)
• Overall Status: Completed
• CT.gov ID: NCT00850070
• Collaborator: BioMarin Pharmaceutical (Industry)
• Enrollment: 46
• Location: 1
• Arms: 2
• Duration (Months): 31
• Patients Per Site Per Month: 1.5

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Autistic Disorder	Drug: sapropterin; Drug: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 46 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Sapropterin as a Treatment for Autistic Disorder: A Phase II Randomized, Double-Blind, Placebo-Controlled Trial
• Study Start Date: Mar 1, 2009
• Actual Primary Completion Date: Aug 1, 2011
• Actual Study Completion Date: Oct 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
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 Names: sugar pill

Outcome Measures

Primary Outcome Measures

1. Clinical Global Impression -- Improvement (CGI-I) Scale [Weekly for 4 weeks, then monthly, with 16-week end point. Primary outcome assessment used two time points, baseline and 16 weeks.]

   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

2. Clinical Global Impression -- Severity (CGI-S) Scale [Baseline, 8 weeks, and 16 weeks. Primary outcome assessment used 2 time points, baseline and 16 weeks.]

   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

1. Preschool Language Scale-Fourth Edition (PLS-4). Assesses Expressive and Receptive Language Skills in Ages Birth Through 6 Years, 11 Months. [Primary outcome assessment examined the difference in scores between baseline and week 16.]

   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.

2. Vineland Adaptive Behavior Scale-II. [Primary outcome assessment used two time points, baseline and 16 weeks.]

   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.

3. Children's Yale Brown Obsessive Compulsive Scale (C-YBOCS) [Baseline, 8 weeks, and 16 weeks]

   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.

4. Connor's Preschool ADHD Questionnaire [Baseline, 8 weeks, and 16 weeks]

   Conners Early Childhood, addresses child behavior for ages 2 years to 6 years with a variety of scales, including an ADHD subdomain.

5. Adverse Events Scale [Every 1-2 weeks for 16 weeks]

   This was not a standardized scale but a set of questions that was asked of each family - some standard and others open ended.

6. Aberrant Behavior Checklist (ABC) - Inappropriate Speech [Primary outcome assessment used two time points, baseline and 16 weeks.]

   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.

7. Social Responsiveness Scale (SRS) [Primary outcome assessment used two time points, baseline and 16 weeks.]

   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.

8. Parent Global Assessment (PGA) Scale [Baseline, 8 weeks, and 16 weeks]

   This is a measure where parents rate their impression of their child's improvement, in a global manner.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 3 Years to 6 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Glen R. Elliott, Chief Psychiatrist and Medical Director, The Children's Health Council
• ClinicalTrials.gov Identifier: NCT00850070
• Other Study ID Numbers: CHC-0901
• First Posted: Feb 24, 2009
• Last Update Posted: May 1, 2018
• Last Verified: Apr 1, 2018

• Keywords provided by Glen R. Elliott, Chief Psychiatrist and Medical Director, The Children's Health Council: autism
• Additional relevant MeSH terms: Autistic Disorder

Study Results

Participant Flow

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 Detail	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
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

Baseline Characteristics

Arm/Group Title	Sapropterin	Placebo	Total
Arm/Group Description	tetrahydrobiopterin (BH4)	sugar pill	Total of all reporting groups
Overall Participants	23	23	46
Age (Count of Participants)
<=18 years	23 100%	23 100%	46 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	5 (1)	5 (1)	5 (1)
Sex: Female, Male (Count of Participants)
Female	3 13%	5 21.7%	8 17.4%
Male	20 87%	18 78.3%	38 82.6%
Region of Enrollment (participants) [Number]
United States	23 100%	23 100%	46 100%

Outcome Measures

1. Primary Outcome

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.

Outcome Measure Data

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
Arm/Group Description	sapropterin 20 mg/kg/day	sugar pill
Measure Participants	23	23
Number [participants]	5 21.7%	3 13%

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
Statistical Test of Hypothesis	p-Value	<.35
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimated value comparison was active treatment minus placebo.

2. Primary Outcome

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.

Outcome Measure Data

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
Arm/Group Description	sapropterin 20 mg/kg/day	sugar pill
Measure Participants	23	23
Number [participants]	3 13%	1 4.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sapropterin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.06
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

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.
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.

Outcome Measure Data

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
Arm/Group Description	tetrahydrobiopterin (BH4)	sugar pill
Measure Participants	23	23
Mean (Standard Deviation) [units on a scale]	84 (29)	60 (25)

4. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

Intent-to-treat analysis; all subjects included. Includes mean at 16-week outcome.

Arm/Group Title	Sapropterin	Placebo
Arm/Group Description	tetrahydrobiopterin (BH4)	sugar pill
Measure Participants	23	23
Mean (Standard Deviation) [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)
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

Outcome Measure Data

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
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.
Measure Participants	0	0

6. Secondary Outcome

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

Outcome Measure Data

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
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).
Measure Participants	0	0

7. Secondary Outcome

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

Outcome Measure Data

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
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).
Measure Participants	0	0

8. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

Intent to treat analysis

Arm/Group Title	Sapropterin	Placebo
Arm/Group Description	sapropterin 20 mg/kg/day	sugar pill
Measure Participants	23	23
Mean (Standard Deviation) [units on a scale]	2.6 (1.9)	3.9 (3.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sapropterin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.05
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.9
	Estimation Comments

9. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

Intent-to-treat analysis; all subjects included. Includes mean at 16-week outcome.

Arm/Group Title	Sapropterin	Placebo
Arm/Group Description	tetrahydrobiopterin (BH4)	sugar pill
Measure Participants	23	23
Mean (Standard Deviation) [units on a scale]	76.7 (10.9)	83.2 (10.4)

10. Secondary Outcome

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

Outcome Measure Data

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
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).
Measure Participants	0	0

Adverse Events

Time Frame	Adverse events were monitored for the length of the study, i.e., 16 weeks.
Arm/Group Title	Sapropterin		Placebo
Arm/Group Description	sapropterin 20 mg/kg/day		sugar pill
All Cause Mortality
	Sapropterin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Sapropterin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/23 (8.7%)		1/23 (4.3%)
Nervous system disorders
seizure disorder	0/23 (0%)		1/23 (4.3%)
Skin and subcutaneous tissue disorders
transient viral rash	2/23 (8.7%)		0/23 (0%)
Other (Not Including Serious) Adverse Events
	Sapropterin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/23 (43.5%)		14/23 (60.9%)
Gastrointestinal disorders
Change in Bowel Habits	0/23 (0%)		4/23 (17.4%)
Nervous system disorders
difficulty sleeping	2/23 (8.7%)		4/23 (17.4%)
repetitive behaviors	1/23 (4.3%)		2/23 (8.7%)
hyperactivity	2/23 (8.7%)		1/23 (4.3%)
Psychiatric disorders
irritablity	5/23 (21.7%)		4/23 (17.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.