Open-Label Extension Study of Kuvan for Autism

• Sponsor: The Children's Health Council (Other)
• Overall Status: Completed
• CT.gov ID: NCT00943579
• Collaborator: BioMarin Pharmaceutical (Industry)
• Enrollment: 41
• Location: 1
• Arm: 1
• Duration (Months): 31
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

This is an open-label extension study available only to subjects who completed an earlier double-blind, placebo-controlled study of sapropterin in children with autism.

Condition or Disease	Intervention/Treatment	Phase
Autistic Disorder	Drug: Kuvan®	Phase 2/Phase 3

Detailed Description

This is an open-label extension study available only to subjects who completed an earlier double-blind, placebo-controlled study of sapropterin in children with autism. During this protocol, all subjects will be receiving brand-name Kuvan 20 mg/kg/day for 16 weeks; subject who complete the first 16 weeks will have the option of continuing on Kuvan at the same dose for up to 90 days after the last subject has completed the first 16 weeks of this protocol. The purpose of the study primarily is to gather additional information on safety and efficacy in this population.

Study Design

• Study Type: Interventional
• Actual Enrollment: 41 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Kuvan® (Sapropterin) as a Treatment for Autistic Disorder: An Open Label Extension Protocol
• Study Start Date: Aug 1, 2009
• Actual Primary Completion Date: Dec 1, 2011
• Actual Study Completion Date: Mar 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Kuvan® Kuvan® (sapropterin) will be administered to all subjects at 20 mg/kg/day for 16 weeks.	Drug: Kuvan®; Brand-name Kuvan® (sapropterin) will be administered to all subjects at a dose of 20 mg/kg/day for 16 weeks.; Other Names: sapropterin tetrahydrobiopterin

Outcome Measures

Primary Outcome Measures

1. Clinical Global Impressions Scale [16 weeks]

   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 (1) very much improved, (2) much improved, (3) minimally improved (4) no change, (5) minimally worse, (6) much worse and (7) very much worse. Chi-square analyses were used to assess change in CHI-I scores (by group, post-test)Mixed-effects regression models 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. The mixed-effects models accounted for each participant's outcome data at each time point. The mixed-effects regression model is robust to data dependency that occurs with the repeated assessments of individuals over time & can handle missing data. 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. Vineland Adaptive Behavior Scale, 2nd Edition [Weeks baseline (week 16 from CHC-0901), 8 and 16. Primary outcome assessment looked at change between baseline (week 16 from CHC-0901 and week 16 of CHC-0902).]

   The Vineland-2 is semi-structured interview designed to communication, 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. The scales generate raw or sum, V-, and age-equivalent scores; raw scores were selected for use in this study. Higher subscale scores indicate more skills. Raw scores can range from 0 to 766 for the overall adaptive behavior composite. Subscales are combined to form the overall Adaptive Behavior Composite, which is essentially a weighted average of the various subscales combined.

2. Children's Yale Brown Obsessive Compulsive Scale [Weeks 8 & 16]

   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.

3. Parental Global Assessment [Weeks 8 & 16]

   this is a measure of parents impression of improvement.

4. Preschool Language Scale, 4th Edition (PLS-4) [Weeks baseline (week 16 from CHC-0901), 8 and 16. Primary outcome assessment looked at change between baseline (week 16 from CHC-0901 and week 16 of CHC-0902).]

   Measures expressive & receptive language and total scores in ages 0 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 raw scores indicate better language skills. 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. The mixed-effects models accounted for each participant's outcome data at each time point. We used random intercept & trend modeling that accounts for each individual's initial level of symptom severity/functioning & rate of change/time

5. Connor's Preschool ADHD Questionnaire [Weeks 8 & 16]

   This is a measure of behavioral symptomatology in children 2-6 years of age. The ADHD scale is one subdomain.

6. Aberrant Behavior Checklist (ABC) [Weeks baseline (week 16 from CHC-0901), 8 and 16. Primary outcome assessment looked at change between baseline (week 16 from CHC-0901 and week 16 of CHC-0902).]

   This is a 58-item informant-based, factor-analyzed scale comprised of a total scale and 5 subscales that generate raw scores. Scores based on a likert scale ranging from 0-3 where 0 is not a problem to 3 where the problem is severe. Subscales include: Irritability, Social Withdrawal, Stereotypic Behaviors, Hyperactivity and Inappropriate Speech. Total maximum score is 174. Higher subscale scores indicate more symptoms. Scores are totaled to compute subscale scores. 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. The mixed-effects models accounted for each participant's outcome data at each time point. We used random intercept and trend modeling that accounts for each individual's initial level of symptom severity/functioning and rate of change/time

7. Adverse Events Reporting [Cummulative throughout study]

   This is not a standardized measure but instead a set of questions, both closed and open ended, asked of families about their child's response to the medication. Used for determining whether treatment needed to be discontinued.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• All subjects must have completed earlier trial, CHC 0901 (NCT00850070)

• Parents must be willing and able to sign informed consent

Exclusion Criteria:

• Child failed to complete CHC 0901 (NCT00850070)

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, PhD, MD, 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: NCT00943579
• Other Study ID Numbers: CHC-0902
• First Posted: Jul 22, 2009
• Last Update Posted: May 2, 2018
• Last Verified: Apr 1, 2018

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

Study Results

Participant Flow

Recruitment Details	Recruitment spanned from 08/09 - 10/11. Only individuals who completed 0901 (NCT00850070) were eligible to participate in this study thus recruitment was restricted to those already enrolled in that trial. When participants were at their 12-week visit for 0901 (NCT00850070) they were asked if they wanted to continue in the open label extension.
Pre-assignment Detail	All participants who consented went straight from the randomized control trial in 0901 (NCT00850070) to entering this trial. No washout period was needed. No participants were excluded who had completed the previous trial.

Arm/Group Title	Kuvan Following Placebo	Kuvan Following Active Treatment
Arm/Group Description	Kuvan® (sapropterin) will be administered to all subjects at 20 mg/kg/day for 16 weeks. Participants in this arm received Kuvan following the randomized control trial in which they were on placebo.	Kuvan® (sapropterin) will be administered to all subjects at 20 mg/kg/day for 16 weeks. Participants in this arm received Kuvan following the randomized control trial in which they were on active medication.
Period Title: Overall Study
STARTED	21	20
COMPLETED	15	15
NOT COMPLETED	6	5

Baseline Characteristics

Arm/Group Title	Kuvan Following Placebo	Kuvan Following Active Treatment	Total
Arm/Group Description	Kuvan® (sapropterin) will be administered to all subjects at 20 mg/kg/day for 16 weeks. Participants in this arm received Kuvan following the randomized control trial in which they were on placebo.	Kuvan® (sapropterin) will be administered to all subjects at 20 mg/kg/day for 16 weeks. Participants in this arm received Kuvan following the randomized control trial in which they were on active medication.	Total of all reporting groups
Overall Participants	21	20	41
Age (Count of Participants)
<=18 years	21 100%	20 100%	41 100%
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	5 23.8%	5 25%	10 24.4%
Male	16 76.2%	15 75%	31 75.6%
Region of Enrollment (participants) [Number]
United States	21 100%	20 100%	41 100%

Outcome Measures

1. Primary Outcome

Title	Clinical Global Impressions Scale
Description	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 (1) very much improved, (2) much improved, (3) minimally improved (4) no change, (5) minimally worse, (6) much worse and (7) very much worse. Chi-square analyses were used to assess change in CHI-I scores (by group, post-test)Mixed-effects regression models 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. The mixed-effects models accounted for each participant's outcome data at each time point. The mixed-effects regression model is robust to data dependency that occurs with the repeated assessments of individuals over time & can handle missing data. 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	16 weeks

Outcome Measure Data

Analysis Population Description

The number of participants analyzed included those who completed the open label extension of this study.

Arm/Group Title	Kuvan Following Placebo	Kuvan Following Active Treatment
Arm/Group Description	Kuvan® (sapropterin) will be administered to all subjects at 20 mg/kg/day for 16 weeks. Participants in this arm received Kuvan following the randomized control trial in which they were on placebo.	Kuvan® (sapropterin) will be administered to all subjects at 20 mg/kg/day for 16 weeks. Participants in this arm received Kuvan following the randomized control trial in which they were on active medication.
Measure Participants	15	15
Number [# participants much - very much improved]	3 14.3%	3 15%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Kuvan Following Placebo, Kuvan Following Active Treatment
	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	>.05
	Comments
	Method	Chi-squared
	Comments

2. Secondary Outcome

Title	Vineland Adaptive Behavior Scale, 2nd Edition
Description	The Vineland-2 is semi-structured interview designed to communication, 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. The scales generate raw or sum, V-, and age-equivalent scores; raw scores were selected for use in this study. Higher subscale scores indicate more skills. Raw scores can range from 0 to 766 for the overall adaptive behavior composite. Subscales are combined to form the overall Adaptive Behavior Composite, which is essentially a weighted average of the various subscales combined.
Time Frame	Weeks baseline (week 16 from CHC-0901), 8 and 16. Primary outcome assessment looked at change between baseline (week 16 from CHC-0901 and week 16 of CHC-0902).

Outcome Measure Data

Analysis Population Description

All participants who completed the open label extension were analyzed.

Arm/Group Title	Kuvan Following Placebo	Kuvan Following Active Treatment
Arm/Group Description
Measure Participants	15	15
Mean (Standard Error) [units on a scale]	275 (10.77)	321 (10.78)

3. Secondary Outcome

Title	Children's Yale Brown Obsessive Compulsive Scale
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	Weeks 8 & 16

Outcome Measure Data

Analysis Population Description

The data was not analyzed secondary to lack of significant findings in primary outcome measures and limited data collected on this measure. 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	Kuvan®
Arm/Group Description	Kuvan® (sapropterin) will be administered to all subjects at 20 mg/kg/day for 16 weeks. Kuvan®: Brand-name Kuvan® (sapropterin) will be administered to all subjects at a dose of 20 mg/kg/day for 16 weeks.
Measure Participants	0

4. Secondary Outcome

Title	Parental Global Assessment
Description	this is a measure of parents impression of improvement.
Time Frame	Weeks 8 & 16

Outcome Measure Data

Analysis Population Description

the data were not analyzed secondary to lack of findings in primary outcome measure as well as the nature of an open label study. 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	Kuvan Following Placebo	Kuvan Following Active Treatment
Arm/Group Description	Kuvan® (sapropterin) will be administered to all subjects at 20 mg/kg/day for 16 weeks. Participants in this arm received Kuvan following the randomized control trial in which they were on placebo.	Kuvan® (sapropterin) will be administered to all subjects at 20 mg/kg/day for 16 weeks. Participants in this arm received Kuvan following the randomized control trial in which they were on active medication.
Measure Participants	0	0

5. Secondary Outcome

Title	Preschool Language Scale, 4th Edition (PLS-4)
Description	Measures expressive & receptive language and total scores in ages 0 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 raw scores indicate better language skills. 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. The mixed-effects models accounted for each participant's outcome data at each time point. We used random intercept & trend modeling that accounts for each individual's initial level of symptom severity/functioning & rate of change/time
Time Frame	Weeks baseline (week 16 from CHC-0901), 8 and 16. Primary outcome assessment looked at change between baseline (week 16 from CHC-0901 and week 16 of CHC-0902).

Outcome Measure Data

Analysis Population Description

All participants completed the open label extension were analyzed in the study.

Arm/Group Title	Kuvan Following Placebo	Kuvan Following Active Treatment
Arm/Group Description	Kuvan® (sapropterin) will be administered to all subjects at 20 mg/kg/day for 16 weeks. Participants in this arm received Kuvan following the randomized control trial in which they were on placebo.	Kuvan® (sapropterin) will be administered to all subjects at 20 mg/kg/day for 16 weeks. Participants in this arm received Kuvan following the randomized control trial in which they were on active medication.
Measure Participants	15	15
Mean (Standard Error) [units on a scale]	57.24 (5.48)	77.83 (5.27)

6. Secondary Outcome

Title	Connor's Preschool ADHD Questionnaire
Description	This is a measure of behavioral symptomatology in children 2-6 years of age. The ADHD scale is one subdomain.
Time Frame	Weeks 8 & 16

Outcome Measure Data

Analysis Population Description

Data was not analyzed secondary to lack of significant findings in primary outcome measure and reduced number of completed questionnaires. 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	Kuvan Following Placebo	Kuvan Following Active Treatment
Arm/Group Description	Kuvan® (sapropterin) will be administered to all subjects at 20 mg/kg/day for 16 weeks. Participants in this arm received Kuvan following the randomized control trial in which they were on placebo.	Kuvan® (sapropterin) will be administered to all subjects at 20 mg/kg/day for 16 weeks. Participants in this arm received Kuvan following the randomized control trial in which they were on active medication.
Measure Participants	0	0

7. Secondary Outcome

Title	Aberrant Behavior Checklist (ABC)
Description	This is a 58-item informant-based, factor-analyzed scale comprised of a total scale and 5 subscales that generate raw scores. Scores based on a likert scale ranging from 0-3 where 0 is not a problem to 3 where the problem is severe. Subscales include: Irritability, Social Withdrawal, Stereotypic Behaviors, Hyperactivity and Inappropriate Speech. Total maximum score is 174. Higher subscale scores indicate more symptoms. Scores are totaled to compute subscale scores. 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. The mixed-effects models accounted for each participant's outcome data at each time point. 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	Weeks baseline (week 16 from CHC-0901), 8 and 16. Primary outcome assessment looked at change between baseline (week 16 from CHC-0901 and week 16 of CHC-0902).

Outcome Measure Data

Analysis Population Description

all participants who completed the open label extension were analyzed.

Arm/Group Title	Kuvan Following Placebo	Kuvan Following Active Treatment
Arm/Group Description	Kuvan® (sapropterin) will be administered to all subjects at 20 mg/kg/day for 16 weeks. Participants in this arm received Kuvan following the randomized control trial in which they were on placebo.	Kuvan® (sapropterin) will be administered to all subjects at 20 mg/kg/day for 16 weeks. Participants in this arm received Kuvan following the randomized control trial in which they were on active medication.
Measure Participants	15	15
Mean (Standard Error) [units on a scale]	16.84 (1.68)	9.70 (1.73)

8. Secondary Outcome

Title	Adverse Events Reporting
Description	This is not a standardized measure but instead a set of questions, both closed and open ended, asked of families about their child's response to the medication. Used for determining whether treatment needed to be discontinued.
Time Frame	Cummulative throughout study

Outcome Measure Data

Analysis Population Description

Data were not specifically analyzed but used instead to determine whether treatment needed to be discontinued. 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	Kuvan Following Placebo	Kuvan Following Active Treatment
Arm/Group Description	Kuvan® (sapropterin) will be administered to all subjects at 20 mg/kg/day for 16 weeks. Participants in this arm received Kuvan following the randomized control trial in which they were on placebo.	Kuvan® (sapropterin) will be administered to all subjects at 20 mg/kg/day for 16 weeks. Participants in this arm received Kuvan following the randomized control trial in which they were on active medication.
Measure Participants	0	0

Adverse Events

Time Frame	Adverse events were monitored for the length of the study, i.e., 16 weeks.
Adverse Event Reporting Description	All participants were asked at each visit regarding adverse events. Specific examples were asked, such as difficulties with sleep, irritability and bowel movements then it was left open ended for parents to describe if other adverse events were noted.
Arm/Group Title	Kuvan Following Placebo		Kuvan Following Active Treatment
Arm/Group Description	Kuvan® (sapropterin) will be administered to all subjects at 20 mg/kg/day for 16 weeks. Participants in this arm received Kuvan following the randomized control trial in which they were on placebo.		Kuvan® (sapropterin) will be administered to all subjects at 20 mg/kg/day for 16 weeks. Participants in this arm received Kuvan following the randomized control trial in which they were on active medication.
All Cause Mortality
	Kuvan Following Placebo		Kuvan Following Active Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Kuvan Following Placebo		Kuvan Following Active Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/21 (0%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	Kuvan Following Placebo		Kuvan Following Active Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/21 (66.7%)		13/20 (65%)
Gastrointestinal disorders
Changes in bowel movements	5/21 (23.8%)		5/20 (25%)
Nervous system disorders
Difficulty Sleeping	6/21 (28.6%)		5/20 (25%)
Hyperactivity	3/21 (14.3%)		0/20 (0%)
Repetitive Behaviors	3/21 (14.3%)		5/20 (25%)
Psychiatric disorders
Irritability	3/21 (14.3%)		4/20 (20%)
Anxiety	2/21 (9.5%)		0/20 (0%)
Skin and subcutaneous tissue disorders
Rash	1/21 (4.8%)		0/20 (0%)

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.