Trial Outcomes & Findings for Open-Label Extension Study of Kuvan for Autism (NCT NCT00943579)

Results Overview

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

Recruitment status

COMPLETED

Study phase

PHASE2/PHASE3

Target enrollment

41 participants

Primary outcome timeframe

16 weeks

Results posted on

2018-05-02

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	Kuvan Following 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 placebo.	Kuvan Following Active Treatment 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 Study STARTED	21	20
Overall Study COMPLETED	15	15
Overall Study NOT COMPLETED	6	5

Reasons for withdrawal

Reasons for withdrawal
Measure	Kuvan Following 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 placebo.	Kuvan Following Active Treatment 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 Study Adverse Event	4	3
Overall Study Lack of Efficacy	2	2

Baseline Characteristics

Open-Label Extension Study of Kuvan for Autism

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Kuvan Following Placebo n=21 Participants 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 Following Active Treatment n=20 Participants 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 n=41 Participants Total of all reporting groups
Age, Categorical <=18 years	21 Participants n=93 Participants	20 Participants n=4 Participants	41 Participants n=27 Participants
Age, Categorical Between 18 and 65 years	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Age, Categorical >=65 years	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Age, Continuous	5 years STANDARD_DEVIATION 1 • n=93 Participants	5 years STANDARD_DEVIATION 1 • n=4 Participants	5 years STANDARD_DEVIATION 1 • n=27 Participants
Sex: Female, Male Female	5 Participants n=93 Participants	5 Participants n=4 Participants	10 Participants n=27 Participants
Sex: Female, Male Male	16 Participants n=93 Participants	15 Participants n=4 Participants	31 Participants n=27 Participants
Region of Enrollment United States	21 participants n=93 Participants	20 participants n=4 Participants	41 participants n=27 Participants

PRIMARY outcome

Timeframe: 16 weeks

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

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

Outcome measures

Outcome measures
Measure	Kuvan Following Placebo n=15 Participants 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 Following Active Treatment n=15 Participants 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.
Clinical Global Impressions Scale	3 # participants much - very much improved	3 # participants much - very much improved

SECONDARY outcome

Timeframe: 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).

Population: All participants who completed the open label extension were analyzed.

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.

Outcome measures

Outcome measures
Measure	Kuvan Following Placebo n=15 Participants 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 Following Active Treatment n=15 Participants 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.
Vineland Adaptive Behavior Scale, 2nd Edition	275 units on a scale Standard Error 10.77	321 units on a scale Standard Error 10.78

SECONDARY outcome

Timeframe: Weeks 8 & 16

Population: 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.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Weeks 8 & 16

Population: 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.

this is a measure of parents impression of improvement.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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).

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

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

Outcome measures

Outcome measures
Measure	Kuvan Following Placebo n=15 Participants 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 Following Active Treatment n=15 Participants 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.
Preschool Language Scale, 4th Edition (PLS-4)	57.24 units on a scale Standard Error 5.48	77.83 units on a scale Standard Error 5.27

SECONDARY outcome

Timeframe: Weeks 8 & 16

Population: 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.

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

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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).

Population: all participants who completed the open label extension were analyzed.

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

Outcome measures

Outcome measures
Measure	Kuvan Following Placebo n=15 Participants 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 Following Active Treatment n=15 Participants 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.
Aberrant Behavior Checklist (ABC)	16.84 units on a scale Standard Error 1.68	9.70 units on a scale Standard Error 1.73

SECONDARY outcome

Timeframe: Cummulative throughout study

Population: 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.

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.

Outcome measures

Outcome data not reported

Adverse Events

Kuvan Following Placebo

Serious events: 0 serious events

Other events: 14 other events

Deaths: 0 deaths

Kuvan Following Active Treatment

Serious events: 0 serious events

Other events: 13 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Kuvan Following Placebo n=21 participants at risk 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 Following Active Treatment n=20 participants at risk 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.
Gastrointestinal disorders Changes in bowel movements	23.8% 5/21 • Adverse events were monitored for the length of the study, i.e., 16 weeks. 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.	25.0% 5/20 • Adverse events were monitored for the length of the study, i.e., 16 weeks. 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.
Psychiatric disorders Irritability	14.3% 3/21 • Adverse events were monitored for the length of the study, i.e., 16 weeks. 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.	20.0% 4/20 • Adverse events were monitored for the length of the study, i.e., 16 weeks. 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.
Nervous system disorders Difficulty Sleeping	28.6% 6/21 • Adverse events were monitored for the length of the study, i.e., 16 weeks. 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.	25.0% 5/20 • Adverse events were monitored for the length of the study, i.e., 16 weeks. 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.
Skin and subcutaneous tissue disorders Rash	4.8% 1/21 • Adverse events were monitored for the length of the study, i.e., 16 weeks. 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.	0.00% 0/20 • Adverse events were monitored for the length of the study, i.e., 16 weeks. 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.
Nervous system disorders Hyperactivity	14.3% 3/21 • Adverse events were monitored for the length of the study, i.e., 16 weeks. 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.	0.00% 0/20 • Adverse events were monitored for the length of the study, i.e., 16 weeks. 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.
Psychiatric disorders Anxiety	9.5% 2/21 • Adverse events were monitored for the length of the study, i.e., 16 weeks. 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.	0.00% 0/20 • Adverse events were monitored for the length of the study, i.e., 16 weeks. 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.
Nervous system disorders Repetitive Behaviors	14.3% 3/21 • Adverse events were monitored for the length of the study, i.e., 16 weeks. 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.	25.0% 5/20 • Adverse events were monitored for the length of the study, i.e., 16 weeks. 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.

Additional Information

Glen R. Elliott, Ph.D., MD

Children's Health Council

Phone: 650.688.3649

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place