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| Name | Class |
|---|---|
| BioMarin Pharmaceutical | INDUSTRY |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Kuvan® | Experimental | Kuvan® (sapropterin) will be administered to all subjects at 20 mg/kg/day for 16 weeks. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Kuvan® | Drug | Brand-name Kuvan® (sapropterin) will be administered to all subjects at a dose of 20 mg/kg/day for 16 weeks. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Clinical Global Impressions 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 (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 | 16 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Vineland Adaptive Behavior Scale, 2nd Edition | 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Glen R Elliott, PhD, MD | The Children's Health Council | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The Children's Health Council | Palo Alto | California | 94304 | United States |
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 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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | Kuvan Following Active Treatment |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Clinical Global Impressions 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 (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 | The number of participants analyzed included those who completed the open label extension of this study. | Posted | Number | # participants much - very much improved | 16 weeks |
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.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Changes in bowel movements | Gastrointestinal disorders | Systematic Assessment | Diarrhea |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Glen R. Elliott, Ph.D., MD | Children's Health Council | 650.688.3649 | gelliott@chconline.org |
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| ID | Term |
|---|---|
| D001321 | Autistic Disorder |
| ID | Term |
|---|---|
| D000067877 | Autism Spectrum Disorder |
| D002659 | Child Development Disorders, Pervasive |
| D065886 | Neurodevelopmental Disorders |
| D001523 | Mental Disorders |
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| ID | Term |
|---|---|
| C003402 | sapropterin |
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| 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). |
| Children's Yale Brown Obsessive Compulsive Scale | 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. | Weeks 8 & 16 |
| Parental Global Assessment | this is a measure of parents impression of improvement. | Weeks 8 & 16 |
| Preschool Language Scale, 4th Edition (PLS-4) | 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 | 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). |
| Connor's Preschool ADHD Questionnaire | This is a measure of behavioral symptomatology in children 2-6 years of age. The ADHD scale is one subdomain. | Weeks 8 & 16 |
| Aberrant Behavior Checklist (ABC) | 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 | 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). |
| Adverse Events Reporting | 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. | Cummulative throughout study |
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. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| ID | Title | Description |
|---|
| OG000 | 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. |
| OG001 | 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. |
|
|
|
| Secondary | Vineland Adaptive Behavior Scale, 2nd Edition | 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. | All participants who completed the open label extension were analyzed. | Posted | Mean | Standard Error | units on a scale | 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). |
|
|
|
| Secondary | Children's Yale Brown Obsessive Compulsive Scale | 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. | 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. | Posted | Weeks 8 & 16 |
|
|
| Secondary | Parental Global Assessment | this is a measure of parents impression of improvement. | 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. | Posted | Weeks 8 & 16 |
|
|
| Secondary | Preschool Language Scale, 4th Edition (PLS-4) | 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 | All participants completed the open label extension were analyzed in the study. | Posted | Mean | Standard Error | units on a scale | 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). |
|
|
|
| Secondary | Connor's Preschool ADHD Questionnaire | This is a measure of behavioral symptomatology in children 2-6 years of age. The ADHD scale is one subdomain. | 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. | Posted | Weeks 8 & 16 |
|
|
| Secondary | Aberrant Behavior Checklist (ABC) | 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 | all participants who completed the open label extension were analyzed. | Posted | Mean | Standard Error | units on a scale | 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). |
|
|
|
| Secondary | Adverse Events Reporting | 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. | 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. | Posted | Cummulative throughout study |
|
|
| 0 |
| 21 |
| 14 |
| 21 |
| EG001 | 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. | 0 | 20 | 13 | 20 |
| Irritability | Psychiatric disorders | Systematic Assessment | Increased irritability in a variety of settings |
|
| Difficulty Sleeping | Nervous system disorders | Systematic Assessment | Persistent changes in sleep, including onset insomnia, frequent wakening during the night, lightening of sleep |
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| Rash | Skin and subcutaneous tissue disorders | Systematic Assessment | Viral or autoimmune rash |
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| Hyperactivity | Nervous system disorders | Systematic Assessment | Persistent increase in overall activity level in a variety of settings |
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| Anxiety | Psychiatric disorders | Systematic Assessment | Increase in anxious symptoms |
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| Repetitive Behaviors | Nervous system disorders | Systematic Assessment | Sustained changes in or appearance of stereotypies or other odd, repetitive behaviors |
|
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