PKU-015: Effect of Kuvan on Neurocognitive Function, Blood Phenylalanine Level, Safety, and Pharmacokinetics in Children With PKU

• Sponsor: BioMarin Pharmaceutical (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00838435
• Collaborator: (none)
• Enrollment: 95
• Locations: 19
• Arm: 1
• Duration (Months): 115.4
• Patients Per Site: 5
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This multicenter, open label study is designed to evaluate the safety of Kuvan® and its effect on neurocognitive function, blood Phe concentration, and growth in children with PKU who are 0-6 years old.

Condition or Disease	Intervention/Treatment	Phase
Phenylketonuria	Drug: sapropterin dihydrochloride	Phase 3

Detailed Description

Rigorous control of diet is typically advocated in children 4 years and under with PKU because brain sensitivity to high Phe concentrations is expected to be greatest during these years of rapid neurocognitive development.

Prolonged high blood Phe concentrations are neurotoxic and lead to impairment of intelligence and other brain functions (such as attentiveness). Reduction of blood Phe concentrations through dietary control is an important determinant of long-term neurologic outcome in PKU patients, and reduction of blood Phe concentrations in patients with PKU has been shown to decrease the long term risk of neurologic injury.

It is difficult for many patients to maintain reduced blood Phe, and many patients with PKU experience some degree of neurological impairment despite efforts to maintain dietary Phe control.

The strongest determinant of intelligence quotient (IQ) and cognitive function is compliance with blood Phe control. Several clinical studies with Kuvan have already demonstrated efficacy in reducing blood Phe in subjects older than 4 years. This study will examine whether addition of Kuvan to the standard of care at an early age in children with well controlled diets can lower blood Phe levels (ie, reach and maintain a goal of ≤ 240 micromole/L) and preserve neurocognitive functioning. In addition, this study will provide data on Kuvan exposure, rate of uptake, half life, and clearance in young children.

Study Design

• Study Type: Interventional
• Actual Enrollment: 95 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 3b Open-Label Study to Evaluate the Effect of Kuvan® on Neurocognitive Function, Maintenance of Blood Phenylalanine Concentrations, Safety, and Population Pharmacokinetics in Young Children With Phenylketonuria
• Study Start Date: Feb 1, 2009
• Actual Primary Completion Date: Sep 14, 2018
• Actual Study Completion Date: Sep 14, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: sapropterin dihydrochloride A dose of 20 mg/kg will be administered dissolved in water or apple juice, based on subject's age and ability, and taken orally once daily with food.	Drug: sapropterin dihydrochloride; A dose of 20 mg/kg will be administered dissolved in water or apple juice, based on subject's age and ability, and taken orally once daily with food.; Other Names: Kuvan Phenoptin BH4 6R BH4

Outcome Measures

Primary Outcome Measures

1. Full-Scale Intelligence Quotient (FSIQ) Score [Assessments through 84 months.]

   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.

Secondary Outcome Measures

1. Number of Subjects With Adverse Events (AEs) [Up to 7 years]

   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.

2. Change From Baseline in Growth Measurements - Height Z-Scores [Baseline and up to 84 months]

   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%.

3. Change From Baseline in Growth Measurements - Weight Z-Scores [Baseline and up to 84 months]

   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%.

4. Change From Baseline in Growth Measurements - Head Circumference Z-Scores [Baseline and up to 84 months]

   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%.

5. Change From Baseline in Bayley-III Scores - Neurocognitive Testing Results [At Month 6, 12, 18 and 24]

   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.

6. Baseline Concentration of Tetrahydrobiopterin (BH4)(C0) [At predose and postdose - 0.22, 3.2 and 7 hours]

   Baseline concentration of BH4(C0) with associated inter-individual variability.

7. Absorption Rate Constant (Ka) of Kuvan [At predose and postdose - 0.22, 3.2 and 7 hours]

   Population pharmacokinetic parameter, Absorption Rate Constant (Ka)

8. Apparent Volume of Distribution (V/F) of Kuvan [At predose and postdose - 0.22, 3.2 and 7 hours]

   Population pharmacokinetic parameter apparent volume of distribution (V/F)

9. Apparent Clearance (CL/F) of Kuvan [At predose and postdose - 0.22, 3.2 and 7 hours]

   Population pharmacokinetic parameter apparent clearance (CL/F)

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 6 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Established diagnosis of PKU with hyperphenylalaninemia (HPA) documented in the medical record by at least 2 blood Phe concentrations greater than or equal to 360 micromole/L (6 mg/dL) taken at least 3 days apart

• Documented blood Phe control (defined by the standard used at each treatment center) prior to study enrollment, if applicable (eg, the subject is old enough for these data to be collected); blood Phe concentrations for subjects < 6 months old at Screening must be considered controlled and stable by the Investigator

• Willing to adhere to a prescribed Phe restricted diet in order to maintain blood Phe concentrations within the recommended ranges established at the subject's study site

• Age 0 to 6 years old, inclusive, at Screening

• Parent(s) or guardian(s) willing and able to provide written, signed informed consent after the nature of the study has been explained, and prior to any research-related procedures

• Parent(s) or guardian(s) willing and able to comply with all study procedures

• Female subjects of childbearing potential (as determined by the investigator) and sexually mature male subjects willing to use a medically accepted method of contraception throughout the study. Female subjects of childbearing potential willing to undergo periodic pregnancy tests during the course of the study

Exclusion Criteria:

• Established diagnosis of primary tetrahydrobiopterin (BH4) deficiency

• Known hypersensitivity to Kuvan or its excipients

• History of organ transplantation

• Perceived to be unreliable or unavailable for study participation or to have parents or legal guardians who are perceived to be unreliable or unavailable

• Use of methotrexate or other medications that inhibit folate metabolism

• Serious neuropsychiatric illness (eg, major depression) not currently under medical control

• Use of Kuvan or any investigational agent within 30 days prior to Screening, or known requirement for any investigational agent prior to completion of all scheduled study assessments

• Concurrent disease or condition that would interfere with study participation or safety (eg, seizure disorder, oral steroid-dependent asthma or other condition requiring oral or parenteral corticosteroid administration, or insulin dependent diabetes)

• Any condition that, in the view of the Principal Investigator (PI), renders the subject at high risk for failure to comply with treatment or to complete the study

• Use of phosphodiesterase type 5 (PDE5) inhibitor.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		La Jolla	California	United States
2		Orange	California	United States
3		Tampa	Florida	United States
4		Chicago	Illinois	United States
5		Boston	Massachusetts	United States
6		Kansas City	Missouri	United States
7		Cleveland	Ohio	United States
8		Columbus	Ohio	United States
9		Hershey	Pennsylvania	United States
10		Nashville	Tennessee	United States
11		Salt Lake City	Utah	United States
12		Milwaukee	Wisconsin	United States
13		Edmonton	Alberta	Canada
14		Vancouver	British Columbia	Canada
15		Winnipeg	Manitoba	Canada
16		Hamilton	Ontario	Canada
17		Toronto	Ontario	Canada
18		Montreal	Quebec	Canada
19		Sainte-Foy	Quebec	Canada

Sponsors and Collaborators

• BioMarin Pharmaceutical

Investigators

• Study Director: Joshua Lilienstein, M.D., BioMarin Pharmaceutical

Study Documents (Full-Text)

• Study Protocol - Nov 30, 2010
• Statistical Analysis Plan - Apr 26, 2019

More Information

Publications

None provided.

• Responsible Party: BioMarin Pharmaceutical
• ClinicalTrials.gov Identifier: NCT00838435
• Other Study ID Numbers: PKU-015
• First Posted: Feb 6, 2009
• Last Update Posted: Dec 22, 2020
• Last Verified: Dec 1, 2020

• Keywords provided by BioMarin Pharmaceutical: Phenylketonuria; PKU; Kuvan; Phenoptin; Biopten; Neurocognitive Function; Phenylalanine
• Additional relevant MeSH terms: Phenylketonurias; Verapamil

Study Results

Participant Flow

Recruitment Details	This was a multicenter study conducted at 20 sites in the U.S. and Canada.

Arm/Group Title	Sapropterin Dihydrochloride
Arm/Group Description	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.
Period Title: Part 1 (4 Weeks)
STARTED	95
COMPLETED	95
NOT COMPLETED	0
Period Title: Part 1 (4 Weeks)
STARTED	94
COMPLETED	93
NOT COMPLETED	1
Period Title: Part 1 (4 Weeks)
STARTED	65
COMPLETED	63
NOT COMPLETED	2
Period Title: Part 1 (4 Weeks)
STARTED	65
COMPLETED	49
NOT COMPLETED	16

Baseline Characteristics

Arm/Group Title	Sapropterin Dihydrochloride
Arm/Group Description	A dose of 20 mg/kg dissolved in water or apple juice, administered once daily orally, with food.
Overall Participants	95
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	3.2 (1.94)
Sex: Female, Male (Count of Participants)
Female	57 60%
Male	38 40%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	6 6.3%
Not Hispanic or Latino	89 93.7%
Unknown or Not Reported	0 0%
Race/Ethnicity, Customized (Count of Participants)
Asian	5 5.3%
Black or African American	2 2.1%
White	79 83.2%
Other	9 9.5%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	15.6 (6.08)
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	94.8 (17.70)

Outcome Measures

1. Primary Outcome

Title	Full-Scale Intelligence Quotient (FSIQ) Score
Description	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.
Time Frame	Assessments through 84 months.

Outcome Measure Data

Analysis Population Description

Efficacy population is based on all subjects from the enrolled population who have at least 2 WPPSI/ WISC assessments.

Arm/Group Title	Kuvan 20 mg/kg Once Daily
Arm/Group Description	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).
Measure Participants	63
FSIQ Baseline	101.06 (14.039)
FSIQ Month 12	103.64 (13.202)
FSIQ Month 24	104.69 (11.697)
FSIQ Month 36	103.78 (12.759)
FSIQ Month 48	104.25 (13.242)
FSIQ Month 60	100.76 (14.280)
FSIQ Month 72	104.57 (11.012)
FSIQ Month 84	104.22 (12.236)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Kuvan 20 mg/kg Once Daily
	Comments	A random coefficient model was used to calculate the slope (per year) of FSIQ over the entire study period. Factors in the model included visit and testing sequence, with change in FSIQ score as the dependent variable. Random terms include both intercept and visit. The treatment was considered successful if the lower 95% confidence limit of the mean change excluded a decline of greater than 5 points over a 2-year window.
	Type of Statistical Test	Other
	Comments	Coefficient estimates from a random coefficient model and associated p-values.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	-0.5768
	Confidence Interval	(2-Sided) 95%; -1.6004 to 0.4468
	Parameter Dispersion	Type: Value:
	Estimation Comments	The slope shown above is based on a 2-year window.

2. Secondary Outcome

Title	Number of Subjects With Adverse Events (AEs)
Description	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.
Time Frame	Up to 7 years

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Part 2
Arm/Group Description	A dose of 20 mg/kg dissolved in water or apple juice, administered once daily orally, with food. Part 2 (7 years): Sixty-five of the 71 subjects that were determined to be Kuvan responders in Part 1 were enrolled in Part 2. All 65 subjects met the minimum required IQ test score of ≥80 at baseline (Month 2).
Measure Participants	65
Any Adverse Events (AEs)	65 68.4%
Drug-Related Adverse Events	35 36.8%
Any Serious Adverse Events	11 11.6%
Drug-Related Serious Adverse Events	2 2.1%
Any AEs causing study discontinuation	2 2.1%
Drug-related AEs causing study discontinuation	2 2.1%
Death	0 0%

3. Secondary Outcome

Title	Change From Baseline in Growth Measurements - Height Z-Scores
Description	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%.
Time Frame	Baseline and up to 84 months

Outcome Measure Data

Analysis Population Description

Efficacy Population

Arm/Group Title	Sapropterin Dihydrochloride
Arm/Group Description	A dose of 20 mg/kg dissolved in water or apple juice, administered once daily orally, with food. Part 2 (7 years): Sixty-five of the 71 subjects that were determined to be Kuvan responders in Part 1 were enrolled in Part 2. All 65 subjects met the minimum required IQ test score of ≥80 at baseline (Month 2).
Measure Participants	63
Baseline	0.4 (0.97)
Change from Baseline Week 4	0.0 (0.44)
Change from Baseline Month 3	0.1 (0.57)
Change from Baseline Month 6	0.1 (0.72)
Change from Baseline Month 12	-0.1 (0.73)
Change from Baseline Month 18	0.0 (0.78)
Change from Baseline Month 24	0.0 (0.71)
Change from Baseline Month 30	-0.1 (0.72)
Change from Baseline Month 36	-0.1 (0.71)
Change from Baseline Month 42	-0.1 (0.73)
Change from Baseline Month 48	-0.2 (0.77)
Change from Baseline Month 54	-0.2 (0.78)
Change from Baseline Month 60	-0.2 (0.75)
Change from Baseline Month 66	-0.2 (0.77)
Change from Baseline Month 72	-0.3 (0.78)
Change from Baseline Month 78	-0.2 (0.78)
Change from Baseline Month 84	-0.2 (0.83)

4. Secondary Outcome

Title	Change From Baseline in Growth Measurements - Weight Z-Scores
Description	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%.
Time Frame	Baseline and up to 84 months

Outcome Measure Data

Analysis Population Description

Efficacy Population

Arm/Group Title	Sapropterin Dihydrochloride
Arm/Group Description	A dose of 20 mg/kg dissolved in water or apple juice, administered once daily orally, with food. Part 2 (7 years): Sixty-five of the 71 subjects that were determined to be Kuvan responders in Part 1 were enrolled in Part 2. All 65 subjects met the minimum required IQ test score of ≥80 at baseline (Month 2).
Measure Participants	63
Baseline	0.4 (0.84)
Change from Baseline Week 4	0.0 (0.24)
Change from Baseline Month 3	0.0 (0.26)
Change from Baseline Month 6	0.0 (0.36)
Change from Baseline Month 12	0.1 (0.45)
Change from Baseline Month 18	0.1 (0.59)
Change from Baseline Month 24	0.1 (0.62)
Change from Baseline Month 30	0.1 (0.68)
Change from Baseline Month 36	0.1 (0.71)
Change from Baseline Month 42	0.0 (0.75)
Change from Baseline Month 48	0.0 (0.79)
Change from Baseline Month 54	0.0 (0.84)
Change from Baseline Month 60	0.0 (0.91)
Change from Baseline Month 66	0.0 (0.85)
Change from Baseline Month 72	0.0 (0.77)
Change from Baseline Month 78	0.0 (0.81)
Change from Baseline Month 84	0.0 (0.85)

5. Secondary Outcome

Title	Change From Baseline in Growth Measurements - Head Circumference Z-Scores
Description	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%.
Time Frame	Baseline and up to 84 months

Outcome Measure Data

Analysis Population Description

Efficacy Population, subjects less than 36 months of age.

Arm/Group Title	Sapropterin Dihydrochloride
Arm/Group Description	A dose of 20 mg/kg dissolved in water or apple juice, administered once daily orally, with food. Part 2 (7 years): Sixty-five of the 71 subjects that were determined to be Kuvan responders in Part 1 were enrolled in Part 2. All 65 subjects met the minimum required IQ test score of ≥80 at baseline (Month 2).
Measure Participants	33
Baseline	0.2 (0.95)
Change from Baseline Week 4	0.1 (0.69)
Change from Baseline Month 3	0.0 (0.40)
Change from Baseline Month 6	0.1 (0.70)
Change from Baseline Month 12	0.1 (0.56)
Change from Baseline Month 18	-0.1 (1.00)
Change from Baseline Month 24	0.2 (0.74)
Change from Baseline Month 30	0.8 (0.81)

6. Secondary Outcome

Title	Change From Baseline in Bayley-III Scores - Neurocognitive Testing Results
Description	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.
Time Frame	At Month 6, 12, 18 and 24

Outcome Measure Data

Analysis Population Description

Efficacy Population, analysis only comprised of subjects less than 30 months of age.

Arm/Group Title	Sapropterin Dihydrochloride
Arm/Group Description	A dose of 20 mg/kg dissolved in water or apple juice, administered once daily orally, with food. Part 2 (7 years): Sixty-five of the 71 subjects that were determined to be Kuvan responders in Part 1 were enrolled in Part 2. All 65 subjects met the minimum required IQ test score of ≥80 at baseline (Month 2).
Measure Participants	26
Cognitive: Baseline	102.31 (9.081)
Cognitive: Change from Baseline Month 6	5.68 (10.943)
Cognitive: Change from Baseline Month 12	2.11 (13.157)
Cognitive: Change from Baseline Month 18	2.27 (20.170)
Cognitive: Change from Baseline Month 24	0.83 (23.962)
Language: Baseline	100.73 (12.914)
Language: Change from Baseline Month 6	2.59 (10.966)
Language: Change from BaselineMonth 12	1.37 (14.469)
Language: Change from Baseline Month 18	4.82 (22.903)
Language: Change from Baseline Month 24	-3.00 (18.407)
Motor: Baseline	104.96 (11.837)
Motor: Change from Baseline Month 6	1.32 (10.952)
Motor: Change from Baseline Month 12	2.11 (12.297)
Motor: Change from Baseline Month 18	0.18 (19.894)
Motor: Change from Baseline Month 24	7.50 (18.512)

7. Secondary Outcome

Title	Baseline Concentration of Tetrahydrobiopterin (BH4)(C0)
Description	Baseline concentration of BH4(C0) with associated inter-individual variability.
Time Frame	At predose and postdose - 0.22, 3.2 and 7 hours

Outcome Measure Data

Analysis Population Description

Eighty patients were evaluable from PKU-015 PK Sub-Study.

Arm/Group Title	Sapropterin Dihydrochloride
Arm/Group Description	A dose of 20 mg/kg dissolved in water or apple juice, administered once daily orally, with food. Substudy 2 (Pharmacokinetics Substudy): 94 subjects participated in the PK substudy, one subject declined participation.
Measure Participants	80
Least Squares Mean (Standard Error) [µg/L]	16.6 (4.1)

8. Secondary Outcome

Title	Absorption Rate Constant (Ka) of Kuvan
Description	Population pharmacokinetic parameter, Absorption Rate Constant (Ka)
Time Frame	At predose and postdose - 0.22, 3.2 and 7 hours

Outcome Measure Data

Analysis Population Description

Eighty subjects were evaluable from PKU-015 PK Sub-Study.

Arm/Group Title	Sapropterin Dihydrochloride
Arm/Group Description	A dose of 20 mg/kg dissolved in water or apple juice, administered once daily orally, with food. Substudy 2 (Pharmacokinetics Substudy): 94 subjects participated in the PK substudy, one subject declined participation.
Measure Participants	80
Least Squares Mean (Standard Error) [l/hour]	0.235 (23.8)

9. Secondary Outcome

Title	Apparent Volume of Distribution (V/F) of Kuvan
Description	Population pharmacokinetic parameter apparent volume of distribution (V/F)
Time Frame	At predose and postdose - 0.22, 3.2 and 7 hours

Outcome Measure Data

Analysis Population Description

Eighty subjects were evaluable from PKU-015 PK Sub-Study.

Arm/Group Title	Sapropterin Dihydrochloride
Arm/Group Description	A dose of 20 mg/kg dissolved in water or apple juice, administered once daily orally, with food. Substudy 2 (Pharmacokinetics Substudy): 94 subjects participated in the PK substudy, one subject declined participation.
Measure Participants	80
Mean (Standard Error) [L]	1209 (56.4)

10. Secondary Outcome

Title	Apparent Clearance (CL/F) of Kuvan
Description	Population pharmacokinetic parameter apparent clearance (CL/F)
Time Frame	At predose and postdose - 0.22, 3.2 and 7 hours

Outcome Measure Data

Analysis Population Description

Eighty subjects were evaluable from PKU-015 PK Sub-Study.

Arm/Group Title	Sapropterin Dihydrochloride
Arm/Group Description	A dose of 20 mg/kg dissolved in water or apple juice, administered once daily orally, with food. Substudy 2 (Pharmacokinetics Substudy): 94 subjects participated in the PK substudy, one subject declined participation.
Measure Participants	80
Mean (Standard Error) [L/hour]	815 (50.9)

Adverse Events

Time Frame	Up to 7 years
Arm/Group Title	Safety Population
Arm/Group Description	All subjects who enrolled in the study (Full Analysis Set) and received any study drug.
All Cause Mortality
	Safety Population
	Affected / at Risk (%)	# Events
Total	0/95 (0%)
Serious Adverse Events
	Safety Population
	Affected / at Risk (%)	# Events
Total	12/95 (12.6%)
Congenital, familial and genetic disorders
Phenylketonuria	1/95 (1.1%)
Gastrointestinal disorders
Colitis ulcerative	1/95 (1.1%)
Constipation	2/95 (2.1%)
Diarrhoea	1/95 (1.1%)
Infections and infestations
Croup infectious	1/95 (1.1%)
Gastroenteritis	2/95 (2.1%)
Pneumonia	1/95 (1.1%)
Injury, poisoning and procedural complications
Airway complication of anaesthesia	1/95 (1.1%)
Concussion	1/95 (1.1%)
Injury	1/95 (1.1%)
Nervous system disorders
Convulsion	2/95 (2.1%)
Psychiatric disorders
Autism spectrum disorder	1/95 (1.1%)
Social circumstances
Diet noncompliance	1/95 (1.1%)
Other (Not Including Serious) Adverse Events
	Safety Population
	Affected / at Risk (%)	# Events
Total	90/95 (94.7%)
Blood and lymphatic system disorders
Lymphadenopathy	13/95 (13.7%)
Ear and labyrinth disorders
Ear pain	7/95 (7.4%)
Eye disorders
Conjunctivitis	9/95 (9.5%)
Myopia	5/95 (5.3%)
Gastrointestinal disorders
Abdominal discomfort	8/95 (8.4%)
Abdominal pain	14/95 (14.7%)
Abdominal pain upper	17/95 (17.9%)
Constipation	11/95 (11.6%)
Diarrhoea	39/95 (41.1%)
Nausea	5/95 (5.3%)
Teething	5/95 (5.3%)
Toothache	6/95 (6.3%)
Vomiting	53/95 (55.8%)
General disorders
Pain	6/95 (6.3%)
Pyrexia	56/95 (58.9%)
Immune system disorders
Seasonal allergy	11/95 (11.6%)
Infections and infestations
Bronchitis	11/95 (11.6%)
Conjunctivitis infective	7/95 (7.4%)
Croup infectious	9/95 (9.5%)
Ear infection	26/95 (27.4%)
Gastroenteritis	28/95 (29.5%)
Gastroenteritis viral	11/95 (11.6%)
Hand-foot-and-mouth disease	7/95 (7.4%)
Influenza	20/95 (21.1%)
Lower respiratory tract infection	5/95 (5.3%)
Nasopharyngitis	42/95 (44.2%)
Otitis media	22/95 (23.2%)
Pharyngitis	8/95 (8.4%)
Pharyngitis streptococcal	19/95 (20%)
Pneumonia	6/95 (6.3%)
Rhinitis	6/95 (6.3%)
Sinusitis	13/95 (13.7%)
Streptococcal infection	7/95 (7.4%)
Upper respiratory tract infection	55/95 (57.9%)
Urinary tract infection	6/95 (6.3%)
Viral infection	18/95 (18.9%)
Injury, poisoning and procedural complications
Fall	6/95 (6.3%)
Laceration	7/95 (7.4%)
Ligament sprain	5/95 (5.3%)
Procedural pain	5/95 (5.3%)
Investigations
Red blood cell sedimentation rate increased	5/95 (5.3%)
Metabolism and nutrition disorders
Decreased appetite	11/95 (11.6%)
Musculoskeletal and connective tissue disorders
Arthralgia	7/95 (7.4%)
Pain in extremity	5/95 (5.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma	5/95 (5.3%)
Nervous system disorders
Headache	25/95 (26.3%)
Psychiatric disorders
Anxiety	6/95 (6.3%)
Attention deficit/hyperactivity disorder	9/95 (9.5%)
Respiratory, thoracic and mediastinal disorders
Cough	43/95 (45.3%)
Nasal congestion	16/95 (16.8%)
Oropharyngeal pain	17/95 (17.9%)
Rhinorrhoea	30/95 (31.6%)
Skin and subcutaneous tissue disorders
Dry skin	6/95 (6.3%)
Eczema	5/95 (5.3%)
Rash	15/95 (15.8%)
Urticaria	5/95 (5.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.