Trial Outcomes & Findings for Sapropterin as a Treatment for Autistic Disorder (NCT NCT00850070)

Results Overview

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

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

46 participants

Primary outcome timeframe

Weekly for 4 weeks, then monthly, with 16-week end point. Primary outcome assessment used two time points, baseline and 16 weeks.

Results posted on

2018-05-01

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	Sapropterin 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).	Placebo sugar pill; matched identical tablet, dosage was 20mg/kg/day administered once per day orally in tablet form. Pills could be crushed and mixed with a variety of food substances (e.g., liquids or solids).
Overall Study STARTED	23	23
Overall Study COMPLETED	20	22
Overall Study NOT COMPLETED	3	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Sapropterin 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).	Placebo sugar pill; matched identical tablet, dosage was 20mg/kg/day administered once per day orally in tablet form. Pills could be crushed and mixed with a variety of food substances (e.g., liquids or solids).
Overall Study Lack of Efficacy	1	1
Overall Study Adverse Event	2	0

Baseline Characteristics

Sapropterin as a Treatment for Autistic Disorder

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Sapropterin n=23 Participants tetrahydrobiopterin (BH4)	Placebo n=23 Participants sugar pill	Total n=46 Participants Total of all reporting groups
Age, Categorical <=18 years	23 Participants n=5 Participants	23 Participants n=7 Participants	46 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Continuous	5 years STANDARD_DEVIATION 1 • n=5 Participants	5 years STANDARD_DEVIATION 1 • n=7 Participants	5 years STANDARD_DEVIATION 1 • n=5 Participants
Sex: Female, Male Female	3 Participants n=5 Participants	5 Participants n=7 Participants	8 Participants n=5 Participants
Sex: Female, Male Male	20 Participants n=5 Participants	18 Participants n=7 Participants	38 Participants n=5 Participants
Region of Enrollment United States	23 participants n=5 Participants	23 participants n=7 Participants	46 participants n=5 Participants

PRIMARY outcome

Timeframe: Weekly for 4 weeks, then monthly, with 16-week end point. Primary outcome assessment used two time points, baseline and 16 weeks.

Population: 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.

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

Outcome measures

Outcome measures
Measure	Sapropterin n=23 Participants sapropterin 20 mg/kg/day	Placebo n=23 Participants sugar pill
Clinical Global Impression -- Improvement (CGI-I) Scale	5 participants	3 participants

PRIMARY outcome

Timeframe: Baseline, 8 weeks, and 16 weeks. Primary outcome assessment used 2 time points, baseline and 16 weeks.

Population: 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.

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

Outcome measures

Outcome measures
Measure	Sapropterin n=23 Participants sapropterin 20 mg/kg/day	Placebo n=23 Participants sugar pill
Clinical Global Impression -- Severity (CGI-S) Scale	3 participants	1 participants

SECONDARY outcome

Timeframe: Primary outcome assessment examined the difference in scores between baseline and week 16.

Population: Intent-to-treat analysis; all subjects included. Difference in scores between baseline and 16 weeks was used as treatment outcome.

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.

Outcome measures

Outcome measures
Measure	Sapropterin n=23 Participants sapropterin 20 mg/kg/day	Placebo n=23 Participants sugar pill
Preschool Language Scale-Fourth Edition (PLS-4). Assesses Expressive and Receptive Language Skills in Ages Birth Through 6 Years, 11 Months.	84 units on a scale Standard Deviation 29	60 units on a scale Standard Deviation 25

SECONDARY outcome

Timeframe: Primary outcome assessment used two time points, baseline and 16 weeks.

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

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.

Outcome measures

Outcome measures
Measure	Sapropterin n=23 Participants sapropterin 20 mg/kg/day	Placebo n=23 Participants sugar pill
Vineland Adaptive Behavior Scale-II.	344.76 units on a scale Standard Deviation 50.0	294.9 units on a scale Standard Deviation 70.1

Adverse Events

Sapropterin

Serious events: 2 serious events

Other events: 10 other events

Deaths: 0 deaths

Placebo

Serious events: 1 serious events

Other events: 14 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Sapropterin n=23 participants at risk sapropterin 20 mg/kg/day	Placebo n=23 participants at risk sugar pill
Skin and subcutaneous tissue disorders transient viral rash	8.7% 2/23 • Adverse events were monitored for the length of the study, i.e., 16 weeks.	0.00% 0/23 • Adverse events were monitored for the length of the study, i.e., 16 weeks.
Nervous system disorders seizure disorder	0.00% 0/23 • Adverse events were monitored for the length of the study, i.e., 16 weeks.	4.3% 1/23 • Adverse events were monitored for the length of the study, i.e., 16 weeks.

Other adverse events

Other adverse events
Measure	Sapropterin n=23 participants at risk sapropterin 20 mg/kg/day	Placebo n=23 participants at risk sugar pill
Psychiatric disorders irritablity	21.7% 5/23 • Adverse events were monitored for the length of the study, i.e., 16 weeks.	17.4% 4/23 • Adverse events were monitored for the length of the study, i.e., 16 weeks.
Nervous system disorders difficulty sleeping	8.7% 2/23 • Adverse events were monitored for the length of the study, i.e., 16 weeks.	17.4% 4/23 • Adverse events were monitored for the length of the study, i.e., 16 weeks.
Gastrointestinal disorders Change in Bowel Habits	0.00% 0/23 • Adverse events were monitored for the length of the study, i.e., 16 weeks.	17.4% 4/23 • Adverse events were monitored for the length of the study, i.e., 16 weeks.
Nervous system disorders repetitive behaviors	4.3% 1/23 • Adverse events were monitored for the length of the study, i.e., 16 weeks.	8.7% 2/23 • Adverse events were monitored for the length of the study, i.e., 16 weeks.
Nervous system disorders hyperactivity	8.7% 2/23 • Adverse events were monitored for the length of the study, i.e., 16 weeks.	4.3% 1/23 • Adverse events were monitored for the length of the study, i.e., 16 weeks.

Additional Information

Glen R. Elliott, Ph.D., M.D.

The 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