Trial Outcomes & Findings for Effect of Kuvan on Neurocognitive Function, Blood Phenylalanine Level, Safety, and Pharmacokinetics in Children With PKU (NCT NCT00838435)
NCT ID: NCT00838435
Last Updated: 2020-12-22
Results Overview
Full Scale Intelligence Quotient (FSIQ) is a score derived through administration of selected subtests from age appropriate Wechsler Intelligence assessments. Weschler Preschool and Primary Scale of Intelligence (WPPSI)-III is used for children \>30 months and ≤6 years; and Weschler Intelligence Scale for Children (WISC)-IV is used for children \>6 years old. The outcome variable will be the FSIQ score from WPPSI-III and/or WISC-IV tests. FSIQ results can range from 40 being the lowest and 160 being the highest. Higher scores are associated with higher intelligence quotient.
Recruitment status
COMPLETED
Study phase
PHASE3
Target enrollment
95 participants
Primary outcome timeframe
Assessments through 84 months.
Results posted on
2020-12-22
Participant Flow
This was a multicenter study conducted at 20 sites in the U.S. and Canada.
Participant milestones
| Measure |
Sapropterin Dihydrochloride
A dose of 20 mg/kg dissolved in water or apple juice, administered once daily orally, with food.
Part 1: 95 subjects participated in Part 1.
Pharmacokinetic (PK) Sub-Study: 94 subjects participated in the PK substudy, one subject declined participation.
6-month Safety/Efficacy Sub-Study: 65 subjects met the minimum required score of 80, Kuvan responders, all 65 subjects participated in Safety/Efficacy Substudy.
Part 2: 65 subjects met the minimum required score of 80 at baseline (Month 2) neurocognitive tests, all 65 subjects participated in Part 2.
|
|---|---|
|
Part 1 (4 Weeks)
STARTED
|
95
|
|
Part 1 (4 Weeks)
COMPLETED
|
95
|
|
Part 1 (4 Weeks)
NOT COMPLETED
|
0
|
|
PK Sub-Study 2 (4 Weeks)
STARTED
|
94
|
|
PK Sub-Study 2 (4 Weeks)
COMPLETED
|
93
|
|
PK Sub-Study 2 (4 Weeks)
NOT COMPLETED
|
1
|
|
Safety/Efficacy Sub-Study 1 (6 Months)
STARTED
|
65
|
|
Safety/Efficacy Sub-Study 1 (6 Months)
COMPLETED
|
63
|
|
Safety/Efficacy Sub-Study 1 (6 Months)
NOT COMPLETED
|
2
|
|
Part 2 (7 Years)
STARTED
|
65
|
|
Part 2 (7 Years)
COMPLETED
|
49
|
|
Part 2 (7 Years)
NOT COMPLETED
|
16
|
Reasons for withdrawal
| Measure |
Sapropterin Dihydrochloride
A dose of 20 mg/kg dissolved in water or apple juice, administered once daily orally, with food.
Part 1: 95 subjects participated in Part 1.
Pharmacokinetic (PK) Sub-Study: 94 subjects participated in the PK substudy, one subject declined participation.
6-month Safety/Efficacy Sub-Study: 65 subjects met the minimum required score of 80, Kuvan responders, all 65 subjects participated in Safety/Efficacy Substudy.
Part 2: 65 subjects met the minimum required score of 80 at baseline (Month 2) neurocognitive tests, all 65 subjects participated in Part 2.
|
|---|---|
|
PK Sub-Study 2 (4 Weeks)
no postdose blood sample
|
1
|
|
Safety/Efficacy Sub-Study 1 (6 Months)
Adverse Event
|
2
|
|
Part 2 (7 Years)
Adverse Event
|
2
|
|
Part 2 (7 Years)
Lost to Follow-up
|
2
|
|
Part 2 (7 Years)
Physician Decision
|
1
|
|
Part 2 (7 Years)
Sponsor Decision
|
6
|
|
Part 2 (7 Years)
Withdrawal by Subject
|
5
|
Baseline Characteristics
Effect of Kuvan on Neurocognitive Function, Blood Phenylalanine Level, Safety, and Pharmacokinetics in Children With PKU
Baseline characteristics by cohort
| Measure |
Sapropterin Dihydrochloride
n=95 Participants
A dose of 20 mg/kg dissolved in water or apple juice, administered once daily orally, with food.
|
|---|---|
|
Age, Continuous
|
3.2 years
STANDARD_DEVIATION 1.94 • n=5 Participants
|
|
Sex: Female, Male
Female
|
57 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
38 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Hispanic or Latino
|
6 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Not Hispanic or Latino
|
89 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Asian
|
5 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Black or African American
|
2 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
White
|
79 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Other
|
9 Participants
n=5 Participants
|
|
Weight
|
15.6 kg
STANDARD_DEVIATION 6.08 • n=5 Participants
|
|
Height
|
94.8 cm
STANDARD_DEVIATION 17.70 • n=5 Participants
|
PRIMARY outcome
Timeframe: Assessments through 84 months.Population: Efficacy population is based on all subjects from the enrolled population who have at least 2 WPPSI/ WISC assessments.
Full Scale Intelligence Quotient (FSIQ) is a score derived through administration of selected subtests from age appropriate Wechsler Intelligence assessments. Weschler Preschool and Primary Scale of Intelligence (WPPSI)-III is used for children \>30 months and ≤6 years; and Weschler Intelligence Scale for Children (WISC)-IV is used for children \>6 years old. The outcome variable will be the FSIQ score from WPPSI-III and/or WISC-IV tests. FSIQ results can range from 40 being the lowest and 160 being the highest. Higher scores are associated with higher intelligence quotient.
Outcome measures
| Measure |
Kuvan 20 mg/kg Once Daily
n=63 Participants
A dose of 20 mg/kg dissolved in water or apple juice, administered once daily orally, with food.
Part 2 (7 years): Part 1 determined that 71 subjects were Kuvan responders, defined as a 30% average reduction in blood Phe concentration during the first 4 weeks .This included 8 subjects who had Phe reductions less than 30% but were granted exemptions to participate in Part 2 of the study.
Sixty-five of these 71 subjects were enrolled in Part 2. All 65 subjects met the minimum required FSIQ test score of ≥80 at baseline (Month 2).
|
|---|---|
|
Full-Scale Intelligence Quotient (FSIQ) Score
FSIQ Baseline
|
101.06 score on a scale
Standard Deviation 14.039
|
|
Full-Scale Intelligence Quotient (FSIQ) Score
FSIQ Month 12
|
103.64 score on a scale
Standard Deviation 13.202
|
|
Full-Scale Intelligence Quotient (FSIQ) Score
FSIQ Month 24
|
104.69 score on a scale
Standard Deviation 11.697
|
|
Full-Scale Intelligence Quotient (FSIQ) Score
FSIQ Month 36
|
103.78 score on a scale
Standard Deviation 12.759
|
|
Full-Scale Intelligence Quotient (FSIQ) Score
FSIQ Month 48
|
104.25 score on a scale
Standard Deviation 13.242
|
|
Full-Scale Intelligence Quotient (FSIQ) Score
FSIQ Month 60
|
100.76 score on a scale
Standard Deviation 14.280
|
|
Full-Scale Intelligence Quotient (FSIQ) Score
FSIQ Month 72
|
104.57 score on a scale
Standard Deviation 11.012
|
|
Full-Scale Intelligence Quotient (FSIQ) Score
FSIQ Month 84
|
104.22 score on a scale
Standard Deviation 12.236
|
SECONDARY outcome
Timeframe: Up to 7 yearsPopulation: Enrolled Population consists of all subjects who enter Part 2. This population involves subjects who respond to Kuvan and had a Bayley-III or IQ test score ≥80 within 6 weeks of determination of Kuvan responsiveness in Part 1. Kuvan 20 mg/kg once daily.
Adverse Event is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product, and that does not necessarily have a causal relationship with this treatment. Drug Related Adverse all noxious and unintended responses to a medical product related to any dose. This means that a causal relationship between a medicinal product and an AE is at least a reasonable possibility, ie, the relationship cannot be ruled out. A serious adverse event (SAE) is an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect.
Outcome measures
| Measure |
Kuvan 20 mg/kg Once Daily
n=65 Participants
A dose of 20 mg/kg dissolved in water or apple juice, administered once daily orally, with food.
Part 2 (7 years): Part 1 determined that 71 subjects were Kuvan responders, defined as a 30% average reduction in blood Phe concentration during the first 4 weeks .This included 8 subjects who had Phe reductions less than 30% but were granted exemptions to participate in Part 2 of the study.
Sixty-five of these 71 subjects were enrolled in Part 2. All 65 subjects met the minimum required FSIQ test score of ≥80 at baseline (Month 2).
|
|---|---|
|
Number of Subjects With Adverse Events (AEs)
Any Adverse Events (AEs)
|
65 Participants
|
|
Number of Subjects With Adverse Events (AEs)
Drug-Related Adverse Events
|
35 Participants
|
|
Number of Subjects With Adverse Events (AEs)
Drug-Related Serious Adverse Events
|
2 Participants
|
|
Number of Subjects With Adverse Events (AEs)
Any AEs causing study discontinuation
|
2 Participants
|
|
Number of Subjects With Adverse Events (AEs)
Drug-related AEs causing study discontinuation
|
2 Participants
|
|
Number of Subjects With Adverse Events (AEs)
Death
|
0 Participants
|
|
Number of Subjects With Adverse Events (AEs)
Any Serious Adverse Events
|
11 Participants
|
SECONDARY outcome
Timeframe: Baseline and up to 84 monthsPopulation: Efficacy Population
Z-scores of Height determined using World Health Organization(WHO) growth charts for children \<24 months and Centers for Disease Control and Prevention(CDC) clinical growth charts for children 24 months and older. A height z-score is a standardized height measure after considering important factors like age and gender, in which higher z-scores are associated with taller children. Z-scores (or standard deviation scores) describe how far a measurement is from the median (mean). A z-score of 0 is the same as a 50th percentile; a positive value is a factor of standard deviation (SD) unit above the 50%; and a negative value is a factor of SD unit below 50%.
Outcome measures
| Measure |
Kuvan 20 mg/kg Once Daily
n=63 Participants
A dose of 20 mg/kg dissolved in water or apple juice, administered once daily orally, with food.
Part 2 (7 years): Part 1 determined that 71 subjects were Kuvan responders, defined as a 30% average reduction in blood Phe concentration during the first 4 weeks .This included 8 subjects who had Phe reductions less than 30% but were granted exemptions to participate in Part 2 of the study.
Sixty-five of these 71 subjects were enrolled in Part 2. All 65 subjects met the minimum required FSIQ test score of ≥80 at baseline (Month 2).
|
|---|---|
|
Change From Baseline in Growth Measurements - Height Z-Scores
Baseline
|
0.4 Z-score change from baseline
Standard Deviation 0.97
|
|
Change From Baseline in Growth Measurements - Height Z-Scores
Change from Baseline Week 4
|
0.0 Z-score change from baseline
Standard Deviation 0.44
|
|
Change From Baseline in Growth Measurements - Height Z-Scores
Change from Baseline Month 3
|
0.1 Z-score change from baseline
Standard Deviation 0.57
|
|
Change From Baseline in Growth Measurements - Height Z-Scores
Change from Baseline Month 6
|
0.1 Z-score change from baseline
Standard Deviation 0.72
|
|
Change From Baseline in Growth Measurements - Height Z-Scores
Change from Baseline Month 12
|
-0.1 Z-score change from baseline
Standard Deviation 0.73
|
|
Change From Baseline in Growth Measurements - Height Z-Scores
Change from Baseline Month 18
|
0.0 Z-score change from baseline
Standard Deviation 0.78
|
|
Change From Baseline in Growth Measurements - Height Z-Scores
Change from Baseline Month 24
|
0.0 Z-score change from baseline
Standard Deviation 0.71
|
|
Change From Baseline in Growth Measurements - Height Z-Scores
Change from Baseline Month 30
|
-0.1 Z-score change from baseline
Standard Deviation 0.72
|
|
Change From Baseline in Growth Measurements - Height Z-Scores
Change from Baseline Month 36
|
-0.1 Z-score change from baseline
Standard Deviation 0.71
|
|
Change From Baseline in Growth Measurements - Height Z-Scores
Change from Baseline Month 42
|
-0.1 Z-score change from baseline
Standard Deviation 0.73
|
|
Change From Baseline in Growth Measurements - Height Z-Scores
Change from Baseline Month 48
|
-0.2 Z-score change from baseline
Standard Deviation 0.77
|
|
Change From Baseline in Growth Measurements - Height Z-Scores
Change from Baseline Month 54
|
-0.2 Z-score change from baseline
Standard Deviation 0.78
|
|
Change From Baseline in Growth Measurements - Height Z-Scores
Change from Baseline Month 60
|
-0.2 Z-score change from baseline
Standard Deviation 0.75
|
|
Change From Baseline in Growth Measurements - Height Z-Scores
Change from Baseline Month 66
|
-0.2 Z-score change from baseline
Standard Deviation 0.77
|
|
Change From Baseline in Growth Measurements - Height Z-Scores
Change from Baseline Month 72
|
-0.3 Z-score change from baseline
Standard Deviation 0.78
|
|
Change From Baseline in Growth Measurements - Height Z-Scores
Change from Baseline Month 78
|
-0.2 Z-score change from baseline
Standard Deviation 0.78
|
|
Change From Baseline in Growth Measurements - Height Z-Scores
Change from Baseline Month 84
|
-0.2 Z-score change from baseline
Standard Deviation 0.83
|
SECONDARY outcome
Timeframe: Baseline and up to 84 monthsPopulation: Efficacy Population
Z-scores of Weight determined using World Health Organization(WHO) growth charts for children \<24 months and Centers for Disease Control and Prevention(CDC) clinical growth charts for children 24 months or older. A weight z-score is a standardized weight measure after considering important factors like age and gender, in which higher z-scores are associated with heavier children. Z-scores (or standard deviation scores) describe how far a measurement is from the median (mean). A z-score of 0 is the same as a 50th percentile; a positive value is a factor of SD unit above the 50%; and a negative value is a factor of SD unit below 50%.
Outcome measures
| Measure |
Kuvan 20 mg/kg Once Daily
n=63 Participants
A dose of 20 mg/kg dissolved in water or apple juice, administered once daily orally, with food.
Part 2 (7 years): Part 1 determined that 71 subjects were Kuvan responders, defined as a 30% average reduction in blood Phe concentration during the first 4 weeks .This included 8 subjects who had Phe reductions less than 30% but were granted exemptions to participate in Part 2 of the study.
Sixty-five of these 71 subjects were enrolled in Part 2. All 65 subjects met the minimum required FSIQ test score of ≥80 at baseline (Month 2).
|
|---|---|
|
Change From Baseline in Growth Measurements - Weight Z-Scores
Baseline
|
0.4 Z-score change from baseline
Standard Deviation 0.84
|
|
Change From Baseline in Growth Measurements - Weight Z-Scores
Change from Baseline Week 4
|
0.0 Z-score change from baseline
Standard Deviation 0.24
|
|
Change From Baseline in Growth Measurements - Weight Z-Scores
Change from Baseline Month 3
|
0.0 Z-score change from baseline
Standard Deviation 0.26
|
|
Change From Baseline in Growth Measurements - Weight Z-Scores
Change from Baseline Month 42
|
0.0 Z-score change from baseline
Standard Deviation 0.75
|
|
Change From Baseline in Growth Measurements - Weight Z-Scores
Change from Baseline Month 48
|
0.0 Z-score change from baseline
Standard Deviation 0.79
|
|
Change From Baseline in Growth Measurements - Weight Z-Scores
Change from Baseline Month 54
|
0.0 Z-score change from baseline
Standard Deviation 0.84
|
|
Change From Baseline in Growth Measurements - Weight Z-Scores
Change from Baseline Month 60
|
0.0 Z-score change from baseline
Standard Deviation 0.91
|
|
Change From Baseline in Growth Measurements - Weight Z-Scores
Change from Baseline Month 66
|
0.0 Z-score change from baseline
Standard Deviation 0.85
|
|
Change From Baseline in Growth Measurements - Weight Z-Scores
Change from Baseline Month 6
|
0.0 Z-score change from baseline
Standard Deviation 0.36
|
|
Change From Baseline in Growth Measurements - Weight Z-Scores
Change from Baseline Month 12
|
0.1 Z-score change from baseline
Standard Deviation 0.45
|
|
Change From Baseline in Growth Measurements - Weight Z-Scores
Change from Baseline Month 18
|
0.1 Z-score change from baseline
Standard Deviation 0.59
|
|
Change From Baseline in Growth Measurements - Weight Z-Scores
Change from Baseline Month 24
|
0.1 Z-score change from baseline
Standard Deviation 0.62
|
|
Change From Baseline in Growth Measurements - Weight Z-Scores
Change from Baseline Month 30
|
0.1 Z-score change from baseline
Standard Deviation 0.68
|
|
Change From Baseline in Growth Measurements - Weight Z-Scores
Change from Baseline Month 36
|
0.1 Z-score change from baseline
Standard Deviation 0.71
|
|
Change From Baseline in Growth Measurements - Weight Z-Scores
Change from Baseline Month 72
|
0.0 Z-score change from baseline
Standard Deviation 0.77
|
|
Change From Baseline in Growth Measurements - Weight Z-Scores
Change from Baseline Month 78
|
0.0 Z-score change from baseline
Standard Deviation 0.81
|
|
Change From Baseline in Growth Measurements - Weight Z-Scores
Change from Baseline Month 84
|
0.0 Z-score change from baseline
Standard Deviation 0.85
|
SECONDARY outcome
Timeframe: Baseline and up to 84 monthsPopulation: Efficacy Population, subjects less than 36 months of age.
Z-scores of Head Circumference determined using World Health Organization(WHO) growth charts for children \<24 months and Centers for Disease Control and Prevention(CDC) clinical growth charts for children 24 months and older. A head circumference z-score is a standardized head circumference measure after considering important factors like age and gender, in which higher z-scores are associated with children with larger heads. Z-scores (or standard deviation scores) describe how far a measurement is from the median (mean). A z-score of 0 is the same as a 50th percentile; a positive value is a factor of SD unit above the 50%; and a negative value is a factor of SD unit below 50%.
Outcome measures
| Measure |
Kuvan 20 mg/kg Once Daily
n=33 Participants
A dose of 20 mg/kg dissolved in water or apple juice, administered once daily orally, with food.
Part 2 (7 years): Part 1 determined that 71 subjects were Kuvan responders, defined as a 30% average reduction in blood Phe concentration during the first 4 weeks .This included 8 subjects who had Phe reductions less than 30% but were granted exemptions to participate in Part 2 of the study.
Sixty-five of these 71 subjects were enrolled in Part 2. All 65 subjects met the minimum required FSIQ test score of ≥80 at baseline (Month 2).
|
|---|---|
|
Change From Baseline in Growth Measurements - Head Circumference Z-Scores
Baseline
|
0.2 Z-score change from baseline
Standard Deviation 0.95
|
|
Change From Baseline in Growth Measurements - Head Circumference Z-Scores
Change from Baseline Week 4
|
0.1 Z-score change from baseline
Standard Deviation 0.69
|
|
Change From Baseline in Growth Measurements - Head Circumference Z-Scores
Change from Baseline Month 3
|
0.0 Z-score change from baseline
Standard Deviation 0.40
|
|
Change From Baseline in Growth Measurements - Head Circumference Z-Scores
Change from Baseline Month 6
|
0.1 Z-score change from baseline
Standard Deviation 0.70
|
|
Change From Baseline in Growth Measurements - Head Circumference Z-Scores
Change from Baseline Month 12
|
0.1 Z-score change from baseline
Standard Deviation 0.56
|
|
Change From Baseline in Growth Measurements - Head Circumference Z-Scores
Change from Baseline Month 18
|
-0.1 Z-score change from baseline
Standard Deviation 1.00
|
|
Change From Baseline in Growth Measurements - Head Circumference Z-Scores
Change from Baseline Month 24
|
0.2 Z-score change from baseline
Standard Deviation 0.74
|
|
Change From Baseline in Growth Measurements - Head Circumference Z-Scores
Change from Baseline Month 30
|
0.8 Z-score change from baseline
Standard Deviation 0.81
|
SECONDARY outcome
Timeframe: At Month 6, 12, 18 and 24Population: Efficacy Population, analysis only comprised of subjects less than 30 months of age.
The Bayley-III is a tool for assessing all facets of development in infants within an age range of 12 to 30 months, with normative data available for infants as young as 16 days. Composite scores are derived for cognitive, language, and motor development and scaled to a metric, with a range of 40 to 160. Higher scores are a better outcome.
Outcome measures
| Measure |
Kuvan 20 mg/kg Once Daily
n=26 Participants
A dose of 20 mg/kg dissolved in water or apple juice, administered once daily orally, with food.
Part 2 (7 years): Part 1 determined that 71 subjects were Kuvan responders, defined as a 30% average reduction in blood Phe concentration during the first 4 weeks .This included 8 subjects who had Phe reductions less than 30% but were granted exemptions to participate in Part 2 of the study.
Sixty-five of these 71 subjects were enrolled in Part 2. All 65 subjects met the minimum required FSIQ test score of ≥80 at baseline (Month 2).
|
|---|---|
|
Change From Baseline in Bayley-III Scores - Neurocognitive Testing Results
Language: Baseline
|
100.73 score on a scale
Standard Deviation 12.914
|
|
Change From Baseline in Bayley-III Scores - Neurocognitive Testing Results
Language: Change from Baseline Month 6
|
2.59 score on a scale
Standard Deviation 10.966
|
|
Change From Baseline in Bayley-III Scores - Neurocognitive Testing Results
Language: Change from BaselineMonth 12
|
1.37 score on a scale
Standard Deviation 14.469
|
|
Change From Baseline in Bayley-III Scores - Neurocognitive Testing Results
Language: Change from Baseline Month 18
|
4.82 score on a scale
Standard Deviation 22.903
|
|
Change From Baseline in Bayley-III Scores - Neurocognitive Testing Results
Language: Change from Baseline Month 24
|
-3.00 score on a scale
Standard Deviation 18.407
|
|
Change From Baseline in Bayley-III Scores - Neurocognitive Testing Results
Motor: Baseline
|
104.96 score on a scale
Standard Deviation 11.837
|
|
Change From Baseline in Bayley-III Scores - Neurocognitive Testing Results
Motor: Change from Baseline Month 6
|
1.32 score on a scale
Standard Deviation 10.952
|
|
Change From Baseline in Bayley-III Scores - Neurocognitive Testing Results
Motor: Change from Baseline Month 12
|
2.11 score on a scale
Standard Deviation 12.297
|
|
Change From Baseline in Bayley-III Scores - Neurocognitive Testing Results
Motor: Change from Baseline Month 18
|
0.18 score on a scale
Standard Deviation 19.894
|
|
Change From Baseline in Bayley-III Scores - Neurocognitive Testing Results
Motor: Change from Baseline Month 24
|
7.50 score on a scale
Standard Deviation 18.512
|
|
Change From Baseline in Bayley-III Scores - Neurocognitive Testing Results
Cognitive: Baseline
|
102.31 score on a scale
Standard Deviation 9.081
|
|
Change From Baseline in Bayley-III Scores - Neurocognitive Testing Results
Cognitive: Change from Baseline Month 6
|
5.68 score on a scale
Standard Deviation 10.943
|
|
Change From Baseline in Bayley-III Scores - Neurocognitive Testing Results
Cognitive: Change from Baseline Month 12
|
2.11 score on a scale
Standard Deviation 13.157
|
|
Change From Baseline in Bayley-III Scores - Neurocognitive Testing Results
Cognitive: Change from Baseline Month 18
|
2.27 score on a scale
Standard Deviation 20.170
|
|
Change From Baseline in Bayley-III Scores - Neurocognitive Testing Results
Cognitive: Change from Baseline Month 24
|
0.83 score on a scale
Standard Deviation 23.962
|
SECONDARY outcome
Timeframe: At predose and postdose - 0.22, 3.2 and 7 hoursPopulation: Eighty patients were evaluable from PKU-015 PK Sub-Study.
Baseline concentration of BH4(C0) with associated inter-individual variability.
Outcome measures
| Measure |
Kuvan 20 mg/kg Once Daily
n=80 Participants
A dose of 20 mg/kg dissolved in water or apple juice, administered once daily orally, with food.
Part 2 (7 years): Part 1 determined that 71 subjects were Kuvan responders, defined as a 30% average reduction in blood Phe concentration during the first 4 weeks .This included 8 subjects who had Phe reductions less than 30% but were granted exemptions to participate in Part 2 of the study.
Sixty-five of these 71 subjects were enrolled in Part 2. All 65 subjects met the minimum required FSIQ test score of ≥80 at baseline (Month 2).
|
|---|---|
|
Baseline Concentration of Tetrahydrobiopterin (BH4)(C0)
|
16.6 µg/L
Standard Error 4.1
|
SECONDARY outcome
Timeframe: At predose and postdose - 0.22, 3.2 and 7 hoursPopulation: Eighty subjects were evaluable from PKU-015 PK Sub-Study.
Population pharmacokinetic parameter, Absorption Rate Constant (Ka)
Outcome measures
| Measure |
Kuvan 20 mg/kg Once Daily
n=80 Participants
A dose of 20 mg/kg dissolved in water or apple juice, administered once daily orally, with food.
Part 2 (7 years): Part 1 determined that 71 subjects were Kuvan responders, defined as a 30% average reduction in blood Phe concentration during the first 4 weeks .This included 8 subjects who had Phe reductions less than 30% but were granted exemptions to participate in Part 2 of the study.
Sixty-five of these 71 subjects were enrolled in Part 2. All 65 subjects met the minimum required FSIQ test score of ≥80 at baseline (Month 2).
|
|---|---|
|
Absorption Rate Constant (Ka) of Kuvan
|
0.235 l/hour
Standard Error 23.8
|
SECONDARY outcome
Timeframe: At predose and postdose - 0.22, 3.2 and 7 hoursPopulation: Eighty subjects were evaluable from PKU-015 PK Sub-Study.
Population pharmacokinetic parameter apparent volume of distribution (V/F)
Outcome measures
| Measure |
Kuvan 20 mg/kg Once Daily
n=80 Participants
A dose of 20 mg/kg dissolved in water or apple juice, administered once daily orally, with food.
Part 2 (7 years): Part 1 determined that 71 subjects were Kuvan responders, defined as a 30% average reduction in blood Phe concentration during the first 4 weeks .This included 8 subjects who had Phe reductions less than 30% but were granted exemptions to participate in Part 2 of the study.
Sixty-five of these 71 subjects were enrolled in Part 2. All 65 subjects met the minimum required FSIQ test score of ≥80 at baseline (Month 2).
|
|---|---|
|
Apparent Volume of Distribution (V/F) of Kuvan
|
1209 L
Standard Error 56.4
|
SECONDARY outcome
Timeframe: At predose and postdose - 0.22, 3.2 and 7 hoursPopulation: Eighty subjects were evaluable from PKU-015 PK Sub-Study.
Population pharmacokinetic parameter apparent clearance (CL/F)
Outcome measures
| Measure |
Kuvan 20 mg/kg Once Daily
n=80 Participants
A dose of 20 mg/kg dissolved in water or apple juice, administered once daily orally, with food.
Part 2 (7 years): Part 1 determined that 71 subjects were Kuvan responders, defined as a 30% average reduction in blood Phe concentration during the first 4 weeks .This included 8 subjects who had Phe reductions less than 30% but were granted exemptions to participate in Part 2 of the study.
Sixty-five of these 71 subjects were enrolled in Part 2. All 65 subjects met the minimum required FSIQ test score of ≥80 at baseline (Month 2).
|
|---|---|
|
Apparent Clearance (CL/F) of Kuvan
|
815 L/hour
Standard Error 50.9
|
Adverse Events
Safety Population
Serious events: 12 serious events
Other events: 90 other events
Deaths: 0 deaths
Serious adverse events
| Measure |
Safety Population
n=95 participants at risk
All subjects who enrolled in the study (Full Analysis Set) and received any study drug.
|
|---|---|
|
Congenital, familial and genetic disorders
Phenylketonuria
|
1.1%
1/95 • Up to 7 years
|
|
Gastrointestinal disorders
Colitis ulcerative
|
1.1%
1/95 • Up to 7 years
|
|
Gastrointestinal disorders
Constipation
|
2.1%
2/95 • Up to 7 years
|
|
Gastrointestinal disorders
Diarrhoea
|
1.1%
1/95 • Up to 7 years
|
|
Infections and infestations
Croup infectious
|
1.1%
1/95 • Up to 7 years
|
|
Infections and infestations
Gastroenteritis
|
2.1%
2/95 • Up to 7 years
|
|
Infections and infestations
Pneumonia
|
1.1%
1/95 • Up to 7 years
|
|
Injury, poisoning and procedural complications
Airway complication of anaesthesia
|
1.1%
1/95 • Up to 7 years
|
|
Injury, poisoning and procedural complications
Concussion
|
1.1%
1/95 • Up to 7 years
|
|
Injury, poisoning and procedural complications
Injury
|
1.1%
1/95 • Up to 7 years
|
|
Nervous system disorders
Convulsion
|
2.1%
2/95 • Up to 7 years
|
|
Psychiatric disorders
Autism spectrum disorder
|
1.1%
1/95 • Up to 7 years
|
|
Social circumstances
Diet noncompliance
|
1.1%
1/95 • Up to 7 years
|
Other adverse events
| Measure |
Safety Population
n=95 participants at risk
All subjects who enrolled in the study (Full Analysis Set) and received any study drug.
|
|---|---|
|
Blood and lymphatic system disorders
Lymphadenopathy
|
13.7%
13/95 • Up to 7 years
|
|
Ear and labyrinth disorders
Ear pain
|
7.4%
7/95 • Up to 7 years
|
|
Eye disorders
Conjunctivitis
|
9.5%
9/95 • Up to 7 years
|
|
Eye disorders
Myopia
|
5.3%
5/95 • Up to 7 years
|
|
Gastrointestinal disorders
Abdominal discomfort
|
8.4%
8/95 • Up to 7 years
|
|
Gastrointestinal disorders
Abdominal pain
|
14.7%
14/95 • Up to 7 years
|
|
Gastrointestinal disorders
Abdominal pain upper
|
17.9%
17/95 • Up to 7 years
|
|
Gastrointestinal disorders
Constipation
|
11.6%
11/95 • Up to 7 years
|
|
Gastrointestinal disorders
Diarrhoea
|
41.1%
39/95 • Up to 7 years
|
|
Gastrointestinal disorders
Nausea
|
5.3%
5/95 • Up to 7 years
|
|
Gastrointestinal disorders
Teething
|
5.3%
5/95 • Up to 7 years
|
|
Gastrointestinal disorders
Toothache
|
6.3%
6/95 • Up to 7 years
|
|
Gastrointestinal disorders
Vomiting
|
55.8%
53/95 • Up to 7 years
|
|
General disorders
Pain
|
6.3%
6/95 • Up to 7 years
|
|
General disorders
Pyrexia
|
58.9%
56/95 • Up to 7 years
|
|
Immune system disorders
Seasonal allergy
|
11.6%
11/95 • Up to 7 years
|
|
Infections and infestations
Bronchitis
|
11.6%
11/95 • Up to 7 years
|
|
Infections and infestations
Conjunctivitis infective
|
7.4%
7/95 • Up to 7 years
|
|
Infections and infestations
Croup infectious
|
9.5%
9/95 • Up to 7 years
|
|
Infections and infestations
Ear infection
|
27.4%
26/95 • Up to 7 years
|
|
Infections and infestations
Gastroenteritis
|
29.5%
28/95 • Up to 7 years
|
|
Infections and infestations
Gastroenteritis viral
|
11.6%
11/95 • Up to 7 years
|
|
Infections and infestations
Hand-foot-and-mouth disease
|
7.4%
7/95 • Up to 7 years
|
|
Infections and infestations
Influenza
|
21.1%
20/95 • Up to 7 years
|
|
Infections and infestations
Lower respiratory tract infection
|
5.3%
5/95 • Up to 7 years
|
|
Infections and infestations
Nasopharyngitis
|
44.2%
42/95 • Up to 7 years
|
|
Infections and infestations
Otitis media
|
23.2%
22/95 • Up to 7 years
|
|
Infections and infestations
Pharyngitis
|
8.4%
8/95 • Up to 7 years
|
|
Infections and infestations
Pharyngitis streptococcal
|
20.0%
19/95 • Up to 7 years
|
|
Infections and infestations
Pneumonia
|
6.3%
6/95 • Up to 7 years
|
|
Infections and infestations
Rhinitis
|
6.3%
6/95 • Up to 7 years
|
|
Infections and infestations
Sinusitis
|
13.7%
13/95 • Up to 7 years
|
|
Infections and infestations
Streptococcal infection
|
7.4%
7/95 • Up to 7 years
|
|
Infections and infestations
Upper respiratory tract infection
|
57.9%
55/95 • Up to 7 years
|
|
Infections and infestations
Urinary tract infection
|
6.3%
6/95 • Up to 7 years
|
|
Infections and infestations
Viral infection
|
18.9%
18/95 • Up to 7 years
|
|
Injury, poisoning and procedural complications
Fall
|
6.3%
6/95 • Up to 7 years
|
|
Injury, poisoning and procedural complications
Laceration
|
7.4%
7/95 • Up to 7 years
|
|
Injury, poisoning and procedural complications
Ligament sprain
|
5.3%
5/95 • Up to 7 years
|
|
Injury, poisoning and procedural complications
Procedural pain
|
5.3%
5/95 • Up to 7 years
|
|
Investigations
Red blood cell sedimentation rate increased
|
5.3%
5/95 • Up to 7 years
|
|
Metabolism and nutrition disorders
Decreased appetite
|
11.6%
11/95 • Up to 7 years
|
|
Musculoskeletal and connective tissue disorders
Arthralgia
|
7.4%
7/95 • Up to 7 years
|
|
Musculoskeletal and connective tissue disorders
Pain in extremity
|
5.3%
5/95 • Up to 7 years
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma
|
5.3%
5/95 • Up to 7 years
|
|
Nervous system disorders
Headache
|
26.3%
25/95 • Up to 7 years
|
|
Psychiatric disorders
Anxiety
|
6.3%
6/95 • Up to 7 years
|
|
Psychiatric disorders
Attention deficit/hyperactivity disorder
|
9.5%
9/95 • Up to 7 years
|
|
Respiratory, thoracic and mediastinal disorders
Cough
|
45.3%
43/95 • Up to 7 years
|
|
Respiratory, thoracic and mediastinal disorders
Nasal congestion
|
16.8%
16/95 • Up to 7 years
|
|
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
|
17.9%
17/95 • Up to 7 years
|
|
Respiratory, thoracic and mediastinal disorders
Rhinorrhoea
|
31.6%
30/95 • Up to 7 years
|
|
Skin and subcutaneous tissue disorders
Dry skin
|
6.3%
6/95 • Up to 7 years
|
|
Skin and subcutaneous tissue disorders
Eczema
|
5.3%
5/95 • Up to 7 years
|
|
Skin and subcutaneous tissue disorders
Rash
|
15.8%
15/95 • Up to 7 years
|
|
Skin and subcutaneous tissue disorders
Urticaria
|
5.3%
5/95 • Up to 7 years
|
Additional Information
Joshua Lilienstein/Medical Director, Global Medical Affairs
BioMarin Pharmaceutical Inc.
Phone: 651.523.0310
Email: [email protected]
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place