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Open-Label Extension Study of Kuvan for Autism

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ClinicalTrials.gov Identifier: NCT00943579
Recruitment Status : Completed
First Posted : July 22, 2009
Results First Posted : July 4, 2013
Last Update Posted : May 2, 2018
Sponsor:
Collaborator:
BioMarin Pharmaceutical
Information provided by (Responsible Party):
Glen R. Elliott, The Children's Health Council

Study Type Interventional
Study Design Allocation: N/A;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Autistic Disorder
Intervention Drug: Kuvan®
Enrollment 41
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 Details 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
Hide 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
Reason Not Completed
Adverse Event             4             3
Lack of Efficacy             2             2
Arm/Group Title Kuvan Following Placebo Kuvan Following Active Treatment Total
Hide 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 Number of Baseline Participants 21 20 41
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 21 participants 20 participants 41 participants
<=18 years
21
 100.0%
20
 100.0%
41
 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 21 participants 20 participants 41 participants
5  (1) 5  (1) 5  (1)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 21 participants 20 participants 41 participants
Female
5
  23.8%
5
  25.0%
10
  24.4%
Male
16
  76.2%
15
  75.0%
31
  75.6%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 21 participants 20 participants 41 participants
21 20 41
1.Primary Outcome
Title Clinical Global Impressions Scale
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 15 15
Measure Type: Number
Unit of Measure: # participants much - very much improved
3 3
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value >.05
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
2.Secondary Outcome
Title Vineland Adaptive Behavior Scale, 2nd Edition
Hide 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).
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who completed the open label extension were analyzed.
Arm/Group Title Kuvan Following Placebo Kuvan Following Active Treatment
Hide Arm/Group Description:
[Not Specified]
[Not Specified]
Overall Number of Participants Analyzed 15 15
Mean (Standard Error)
Unit of Measure: units on a scale
275  (10.77) 321  (10.78)
3.Secondary Outcome
Title Children's Yale Brown Obsessive Compulsive Scale
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 Weeks 8 & 16
Hide Outcome Measure Data
Hide 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®
Hide 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.

Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
4.Secondary Outcome
Title Parental Global Assessment
Hide Description this is a measure of parents impression of improvement.
Time Frame Weeks 8 & 16
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 0 0
No data displayed because Outcome Measure has zero total analyzed.
5.Secondary Outcome
Title Preschool Language Scale, 4th Edition (PLS-4)
Hide 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).
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 15 15
Mean (Standard Error)
Unit of Measure: units on a scale
57.24  (5.48) 77.83  (5.27)
6.Secondary Outcome
Title Connor's Preschool ADHD Questionnaire
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 0 0
No data displayed because Outcome Measure has zero total analyzed.
7.Secondary Outcome
Title Aberrant Behavior Checklist (ABC)
Hide 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).
Hide Outcome Measure Data
Hide Analysis Population Description
all participants who completed the open label extension were analyzed.
Arm/Group Title Kuvan Following Placebo Kuvan Following Active Treatment
Hide 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.
Overall Number of Participants Analyzed 15 15
Mean (Standard Error)
Unit of Measure: units on a scale
16.84  (1.68) 9.70  (1.73)
8.Secondary Outcome
Title Adverse Events Reporting
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
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 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
Hide 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 (%) Affected / at Risk (%)
Total   --/--   --/-- 
Hide Serious Adverse Events
Kuvan Following Placebo Kuvan Following Active Treatment
Affected / at Risk (%) Affected / at Risk (%)
Total   0/21 (0.00%)   0/20 (0.00%) 
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 1%
Kuvan Following Placebo Kuvan Following Active Treatment
Affected / at Risk (%) Affected / at Risk (%)
Total   14/21 (66.67%)   13/20 (65.00%) 
Gastrointestinal disorders     
Changes in bowel movements  [1]  5/21 (23.81%)  5/20 (25.00%) 
Nervous system disorders     
Difficulty Sleeping  [2]  6/21 (28.57%)  5/20 (25.00%) 
Hyperactivity  [3]  3/21 (14.29%)  0/20 (0.00%) 
Repetitive Behaviors  [4]  3/21 (14.29%)  5/20 (25.00%) 
Psychiatric disorders     
Irritability  [5]  3/21 (14.29%)  4/20 (20.00%) 
Anxiety  [6]  2/21 (9.52%)  0/20 (0.00%) 
Skin and subcutaneous tissue disorders     
Rash  [7]  1/21 (4.76%)  0/20 (0.00%) 
Indicates events were collected by systematic assessment
[1]
Diarrhea
[2]
Persistent changes in sleep, including onset insomnia, frequent wakening during the night, lightening of sleep
[3]
Persistent increase in overall activity level in a variety of settings
[4]
Sustained changes in or appearance of stereotypies or other odd, repetitive behaviors
[5]
Increased irritability in a variety of settings
[6]
Increase in anxious symptoms
[7]
Viral or autoimmune rash
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Glen R. Elliott, Ph.D., MD
Organization: Children's Health Council
Phone: 650.688.3649
EMail: gelliott@chconline.org
Layout table for additonal information
Responsible Party: Glen R. Elliott, The Children's Health Council
ClinicalTrials.gov Identifier: NCT00943579    
Other Study ID Numbers: CHC-0902
First Submitted: July 20, 2009
First Posted: July 22, 2009
Results First Submitted: January 16, 2013
Results First Posted: July 4, 2013
Last Update Posted: May 2, 2018