## Protocol Section
### Identification Module
**NCT ID:** NCT00943579

**Brief Title:** Open-Label Extension Study of Kuvan for Autism

**Official Title:** Kuvan® (Sapropterin) as a Treatment for Autistic Disorder: An Open Label Extension Protocol

#### Organization Study ID Info
**ID:** CHC-0902
#### Organization
**Class:** OTHER
**Full Name:** The Children's Health Council
### Status Module
#### Completion Date
**Date:** 2012-03

**Type:** ACTUAL

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2018-05-02

**Type:** ACTUAL

**Last Update Submit Date:** 2018-04-30

**Overall Status:** COMPLETED

#### Primary Completion Date
**Date:** 2011-12

**Type:** ACTUAL

#### Results First Post Date
**Date:** 2013-07-04

**Type:** ESTIMATED

**Results First Submit Date:** 2013-01-16

**Results First Submit QC Date:** 2013-07-02

#### Start Date
**Date:** 2009-08

**Status Verified Date:** 2018-04

#### Study First Post Date
**Date:** 2009-07-22
**Type:** ESTIMATED
**Study First Submit Date:** 2009-07-20
**Study First Submit QC Date:** 2009-07-20
### Sponsor Collaborators Module

#### Collaborators

**Class:** INDUSTRY

**Name:** BioMarin Pharmaceutical

#### Lead Sponsor

**Class:** OTHER

**Name:** The Children's Health Council

#### Responsible Party

**Investigator Affiliation:** The Children's Health Council

**Investigator Full Name:** Glen R. Elliott

**Investigator Title:** Chief Psychiatrist and Medical Director

**Type:** PRINCIPAL_INVESTIGATOR

### Oversight Module

**Oversight Has DMC:** False

### Description Module

**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.

**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.

### Conditions Module

**Conditions:**

- Autistic Disorder

**Keywords:**

- autism

- autistic disorder

- tetrahydrobiopterin

- sapropterin

- treatment

### Design Module

#### Design Info

**Allocation:** NA

**Intervention Model:** SINGLE_GROUP

##### Masking Info

**Masking:** NONE

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 41

**Type:** ACTUAL

**Phases:**

- PHASE2

- PHASE3

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** Kuvan® (sapropterin) will be administered to all subjects at 20 mg/kg/day for 16 weeks.

**Intervention Names:**

- Drug: Kuvan®

**Label:** Kuvan®

**Type:** EXPERIMENTAL

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Kuvan®

**Description:** Brand-name Kuvan® (sapropterin) will be administered to all subjects at a dose of 20 mg/kg/day for 16 weeks.

**Name:** Kuvan®

**Other Names:**

- sapropterin

- tetrahydrobiopterin

**Type:** DRUG

### Outcomes Module

#### Primary Outcomes

**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

**Measure:** Clinical Global Impressions Scale

**Time Frame:** 16 weeks

#### Secondary Outcomes

**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.

**Measure:** Vineland Adaptive Behavior Scale, 2nd Edition

**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).

**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.

**Measure:** Children's Yale Brown Obsessive Compulsive Scale

**Time Frame:** Weeks 8 & 16

**Description:** this is a measure of parents impression of improvement.

**Measure:** Parental Global Assessment

**Time Frame:** Weeks 8 & 16

**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

**Measure:** Preschool Language Scale, 4th Edition (PLS-4)

**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).

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

**Measure:** Connor's Preschool ADHD Questionnaire

**Time Frame:** Weeks 8 & 16

**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

**Measure:** Aberrant Behavior Checklist (ABC)

**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).

**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.

**Measure:** Adverse Events Reporting

**Time Frame:** Cummulative throughout study

### Eligibility Module

**Eligibility Criteria:** 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)

**Maximum Age:** 6 Years

**Minimum Age:** 3 Years

**Sex:** ALL

**Standard Ages:**

- CHILD

### Contacts Locations Module

#### Locations

**Location 1:**

**City:** Palo Alto

**Country:** United States

**Facility:** The Children's Health Council

**State:** California

**Zip:** 94304

#### Overall Officials

**Official 1:**

**Affiliation:** The Children's Health Council

**Name:** Glen R Elliott, PhD, MD

**Role:** PRINCIPAL_INVESTIGATOR

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000067877

- Term: Autism Spectrum Disorder

- ID: D000002659

- Term: Child Development Disorders, Pervasive

- ID: D000065886

- Term: Neurodevelopmental Disorders

- ID: D000001523

- Term: Mental Disorders

### Condition Browse Module - Browse Branches

- Abbrev: BXM

- Name: Behaviors and Mental Disorders

- Abbrev: All

- Name: All Conditions

### Condition Browse Module - Browse Leaves

- ID: M4623

- Name: Autistic Disorder

- Relevance: HIGH

- As Found: Autistic Disorder

- ID: M206

- Name: Autism Spectrum Disorder

- Relevance: LOW

- As Found: Unknown

- ID: M5903

- Name: Child Development Disorders, Pervasive

- Relevance: LOW

- As Found: Unknown

- ID: M5902

- Name: Developmental Disabilities

- Relevance: LOW

- As Found: Unknown

- ID: M30644

- Name: Neurodevelopmental Disorders

- Relevance: LOW

- As Found: Unknown

- ID: M4815

- Name: Mental Disorders

- Relevance: LOW

- As Found: Unknown

- ID: M14473

- Name: Psychotic Disorders

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000001321

- Term: Autistic Disorder

### Misc Info Module

- Version Holder: 2024-05-24

## Results Section

### Adverse Events Module

**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.

#### Event Groups

**Group ID:** EG000

**Title:** Kuvan Following Placebo

**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.

**ID:** EG000

**Other Num Affected:** 14

**Other Num at Risk:** 21

**Serious Number At Risk:** 21

**Title:** Kuvan Following Placebo

**Group ID:** EG001

**Title:** Kuvan Following Active Treatment

**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 active medication.

**ID:** EG001

**Other Num Affected:** 13

**Other Num at Risk:** 20

**Serious Number At Risk:** 20

**Title:** Kuvan Following Active Treatment

**Frequency Threshold:** 1

#### Other Events

**Term:** Changes in bowel movements

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Notes:** Diarrhea

**Organ System:** Gastrointestinal disorders

**Source Vocabulary:** 

**Term:** Irritability

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Notes:** Increased irritability in a variety of settings

**Organ System:** Psychiatric disorders

**Source Vocabulary:** 

**Term:** Difficulty Sleeping

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Notes:** Persistent changes in sleep, including onset insomnia, frequent wakening during the night, lightening of sleep

**Organ System:** Nervous system disorders

**Source Vocabulary:** 

**Term:** Rash

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Notes:** Viral or autoimmune rash

**Organ System:** Skin and subcutaneous tissue disorders

**Source Vocabulary:** 

**Term:** Hyperactivity

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Notes:** Persistent increase in overall activity level in a variety of settings

**Organ System:** Nervous system disorders

**Source Vocabulary:** 

**Term:** Anxiety

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Notes:** Increase in anxious symptoms

**Organ System:** Psychiatric disorders

**Source Vocabulary:** 

**Term:** Repetitive Behaviors

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Notes:** Sustained changes in or appearance of stereotypies or other odd, repetitive behaviors

**Organ System:** Nervous system disorders

**Source Vocabulary:** 

**Time Frame:** Adverse events were monitored for the length of the study, i.e., 16 weeks.

## Results Section - Baseline Characteristics Module

### Denomination Counts

**Group ID:** BG000

**Value:** 21

**Group ID:** BG001

**Value:** 20

**Group ID:** BG002

**Value:** 41

**Units:** Participants

### Group

**ID:** BG000

**Title:** Kuvan Following Placebo

**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.

### Group

**ID:** BG001

**Title:** Kuvan Following Active Treatment

**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 active medication.

### Group

**ID:** BG002

**Title:** Total

**Description:** Total of all reporting groups

### Measure

#### Measurement

**Group ID:** BG000

**Value:** 21

#### Measurement

**Group ID:** BG001

**Value:** 20

#### Measurement

**Group ID:** BG002

**Value:** 41

**Category Title:** <=18 years

#### Measurement

**Group ID:** BG000

**Value:** 0

#### Measurement

**Group ID:** BG001

**Value:** 0

#### Measurement

**Group ID:** BG002

**Value:** 0

**Category Title:** Between 18 and 65 years

#### Measurement

**Group ID:** BG000

**Value:** 0

#### Measurement

**Group ID:** BG001

**Value:** 0

#### Measurement

**Group ID:** BG002

**Value:** 0

**Category Title:** >=65 years

**Class Title:** 

### Measure

#### Measurement

**Group ID:** BG000

**Spread:** 1

**Value:** 5

#### Measurement

**Group ID:** BG001

**Spread:** 1

**Value:** 5

#### Measurement

**Group ID:** BG002

**Spread:** 1

**Value:** 5

**Class Title:** 

### Measure

#### Measurement

**Group ID:** BG000

**Value:** 5

#### Measurement

**Group ID:** BG001

**Value:** 5

#### Measurement

**Group ID:** BG002

**Value:** 10

**Category Title:** Female

#### Measurement

**Group ID:** BG000

**Value:** 16

#### Measurement

**Group ID:** BG001

**Value:** 15

#### Measurement

**Group ID:** BG002

**Value:** 31

**Category Title:** Male

**Class Title:** 

### Measure

#### Measurement

**Group ID:** BG000

**Value:** 21

#### Measurement

**Group ID:** BG001

**Value:** 20

#### Measurement

**Group ID:** BG002

**Value:** 41

**Class Title:** United States

**Denomination Units Selected:** 

## Results Section - Baseline Characteristics Module

### Measure 1
**Parameter Type:** COUNT_OF_PARTICIPANTS
**Title:** Age, Categorical
**Unit of Measure:** Participants
### Measure 2
**Dispersion Type:** STANDARD_DEVIATION
**Parameter Type:** MEAN
**Title:** Age, Continuous
**Unit of Measure:** years
### Measure 3
**Parameter Type:** COUNT_OF_PARTICIPANTS
**Title:** Sex: Female, Male
**Unit of Measure:** Participants
### Measure 4
**Parameter Type:** NUMBER
**Title:** Region of Enrollment
**Unit of Measure:** participants
## Results Section - More Information Module
### Certain Agreement
**PI Sponsor Employee:** True
### Point of Contact
**Email:** gelliott@chconline.org
**Organization:** Children's Health Council
**Phone:** 650.688.3649
**Title:** Glen R. Elliott, Ph.D., MD
## Results Section - Outcome Measures Module
### Outcome Measure 1
#### Analysis
**CI Lower Limit:** 
**CI Number of Sides:** 
**CI Percentage Value:** 95
**CI Upper Limit:** 
**CI Upper Limit Comment:** 
**Dispersion Type:** 
**Dispersion Value:** 
**Estimate Comment:** 
**Group Description:** Chi-square analyses were used to assess CGI-I scores. there were no transformations.
**Non-Inferiority Comment:** 
**Non-Inferiority Type:** SUPERIORITY_OR_OTHER
**Other Analysis Description:** 
**P-Value:** >.05
**P-Value Comment:** 
**Parameter Type:** 
**Parameter Value:** 
**Statistical Comment:** 
**Statistical Method:** Chi-squared
**Tested Non-Inferiority:** 
### Outcome Measure 2
### Outcome Measure 3
### Outcome Measure 4
### Outcome Measure 5
### Outcome Measure 6
### Outcome Measure 7
### Outcome Measure 8
## Results Section
### Outcome Measures Module
#### Outcome Measure 1
**Class:**
##### Category
**Measurements:**
- **Comment:** 
- **Group ID:** OG000
- **Lower Limit:** 
- **Spread:** 
- **Upper Limit:** 
- **Value:** 3
- **Comment:** 
- **Group ID:** OG001
- **Lower Limit:** 
- **Spread:** 
- **Upper Limit:** 
- **Value:** 3
**Title:** 
#### Outcome Measure 2
**Class:**
##### Category
**Measurements:**
- **Comment:** 
- **Group ID:** OG000
- **Lower Limit:** 
- **Spread:** 10.77
- **Upper Limit:** 
- **Value:** 275
- **Comment:** 
- **Group ID:** OG001
- **Lower Limit:** 
- **Spread:** 10.78
- **Upper Limit:** 
- **Value:** 321
**Title:** 
#### Outcome Measure 3
#### Outcome Measure 4
#### Outcome Measure 5
**Class:**
##### Category
**Measurements:**
- **Comment:** 
- **Group ID:** OG000
- **Lower Limit:** 
- **Spread:** 5.48
- **Upper Limit:** 
- **Value:** 57.24
- **Comment:** 
- **Group ID:** OG001
- **Lower Limit:** 
- **Spread:** 5.27
- **Upper Limit:** 
- **Value:** 77.83
**Title:** 
#### Outcome Measure 6
#### Outcome Measure 7
**Class:**
##### Category
**Measurements:**
- **Comment:** 
- **Group ID:** OG000
- **Lower Limit:** 
- **Spread:** 1.68
- **Upper Limit:** 
- **Value:** 16.84
- **Comment:** 
- **Group ID:** OG001
- **Lower Limit:** 
- **Spread:** 1.73
- **Upper Limit:** 
- **Value:** 9.70
**Title:** 
#### Outcome Measure 8
## Results Section
### Outcome Measures Module
#### Outcome Measure 1
**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
**Parameter Type:** NUMBER
**Population Description:** The number of participants analyzed included those who completed the open label extension of this study.
**Reporting Status:** POSTED
**Time Frame:** 16 weeks
**Title:** Clinical Global Impressions Scale
**Type:** PRIMARY
**Unit of Measure:** # participants much - very much improved
##### 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.
**ID:** OG000
**Title:** Kuvan Following Placebo
##### 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 active medication.
**ID:** OG001
**Title:** Kuvan Following Active Treatment
#### Outcome Measure 2
**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.
**Dispersion Type:** Standard Error
**Parameter Type:** MEAN
**Population Description:** All participants who completed the open label extension were analyzed.
**Reporting Status:** POSTED
**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).
**Title:** Vineland Adaptive Behavior Scale, 2nd Edition
**Type:** SECONDARY
**Unit of Measure:** units on a scale
##### Group
**ID:** OG000
**Title:** Kuvan Following Placebo
##### Group
**ID:** OG001
**Title:** Kuvan Following Active Treatment
#### Outcome Measure 3
**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.
**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.
**Reporting Status:** POSTED
**Time Frame:** Weeks 8 & 16
**Title:** Children's Yale Brown Obsessive Compulsive Scale
**Type:** SECONDARY
##### 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.
**ID:** OG000
**Title:** Kuvan®
#### Outcome Measure 4
**Description:** this is a measure of parents impression of improvement.
**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.
**Reporting Status:** POSTED
**Time Frame:** Weeks 8 & 16
**Title:** Parental Global Assessment
**Type:** SECONDARY
##### 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.
**ID:** OG000
**Title:** Kuvan Following Placebo
##### 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 active medication.
**ID:** OG001
**Title:** Kuvan Following Active Treatment
#### Outcome Measure 5
**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
**Dispersion Type:** Standard Error
**Parameter Type:** MEAN
**Population Description:** All participants completed the open label extension were analyzed in the study.
**Reporting Status:** POSTED
**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).
**Title:** Preschool Language Scale, 4th Edition (PLS-4)
**Type:** SECONDARY
**Unit of Measure:** units on a scale
##### 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.
**ID:** OG000
**Title:** Kuvan Following Placebo
##### 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 active medication.
**ID:** OG001
**Title:** Kuvan Following Active Treatment
#### Outcome Measure 6
**Description:** This is a measure of behavioral symptomatology in children 2-6 years of age. The ADHD scale is one subdomain.
**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.
**Reporting Status:** POSTED
**Time Frame:** Weeks 8 & 16
**Title:** Connor's Preschool ADHD Questionnaire
**Type:** SECONDARY
##### 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.
**ID:** OG000
**Title:** Kuvan Following Placebo
##### 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 active medication.
**ID:** OG001
**Title:** Kuvan Following Active Treatment
#### Outcome Measure 7
**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
**Dispersion Type:** Standard Error
**Parameter Type:** MEAN
**Population Description:** all participants who completed the open label extension were analyzed.
**Reporting Status:** POSTED
**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).
**Title:** Aberrant Behavior Checklist (ABC)
**Type:** SECONDARY
**Unit of Measure:** units on a scale
##### 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.
**ID:** OG000
**Title:** Kuvan Following Placebo
##### 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 active medication.
**ID:** OG001
**Title:** Kuvan Following Active Treatment
#### Outcome Measure 8
**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.
**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.
**Reporting Status:** POSTED
**Time Frame:** Cummulative throughout study
**Title:** Adverse Events Reporting
**Type:** SECONDARY
##### 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.
**ID:** OG000
**Title:** Kuvan Following Placebo
##### 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 active medication.
**ID:** OG001
**Title:** Kuvan Following Active Treatment
### Participant Flow Module
#### 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.
**ID:** FG000
**Title:** Kuvan Following Placebo
#### 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 active medication.
**ID:** FG001
**Title:** Kuvan Following Active Treatment
#### Period
**Title:** Overall Study
##### Withdraw
**Type:** Adverse Event
###### Reason
**Group ID:** FG000
**Number of Subjects:** 4
###### Reason
**Group ID:** FG001
**Number of Subjects:** 3
##### Withdraw
**Type:** Lack of Efficacy
###### Reason
**Group ID:** FG000
**Number of Subjects:** 2
###### Reason
**Group ID:** FG001
**Number of Subjects:** 2
##### Milestone
**Type:** STARTED
###### Achievement
**Group ID:** FG000
**Number of Subjects:** 21
###### Achievement
**Group ID:** FG001
**Number of Subjects:** 20
##### Milestone
**Type:** COMPLETED
###### Achievement
**Group ID:** FG000
**Number of Subjects:** 15
###### Achievement
**Group ID:** FG001
**Number of Subjects:** 15
##### Milestone
**Type:** NOT COMPLETED
###### Achievement
**Group ID:** FG000
**Number of Subjects:** 6
###### Achievement
**Group ID:** FG001
**Number of Subjects:** 5
**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.
**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.
**Has Results:** True