Trial Outcomes & Findings for Kuvan® in Phenylketonuria Patients Less Than 4 Years Old (NCT NCT01376908)

Last Updated: 2017-09-15

Results Overview

Phe tolerance was defined as the amount of dietary Phe prescribed (milligram per kilogram per day \[mg/kg/day\]) while maintaining blood Phe levels within the selected therapeutic target range (defined as greater than or equal to \[\>=\] 120 to less than \[\<\] 360 micromoles per liter \[mcmol/L\]).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

56 participants

Primary outcome timeframe

Week 26

Results posted on

2017-09-15

Participant Flow

Out of 109 subjects screened for the study, 77 pharmacogenetics (PGx) informed consent forms were signed and 73 samples were analyzed which were used as analysis population for outcome measure 11 "Number of samples with phenylalanine hydroxylase (PAH) gene mutations".

Participant milestones

Participant milestones
Measure	Kuvan® + Phe-restricted Diet Kuvan® (sapropterin dihydrochloride) tablets were administered orally at a dose of 10 milligram/kilogram/day (mg/kg/day). If after 4 weeks, there was less than 20 percent (%) increase in subject's Phe tolerance versus baseline, the dose was escalated to 20 mg/kg/day. Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.	Phe-restricted Diet Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.
Overall Study STARTED	27	29
Overall Study COMPLETED	25	26
Overall Study NOT COMPLETED	2	3

Reasons for withdrawal

Reasons for withdrawal
Measure	Kuvan® + Phe-restricted Diet Kuvan® (sapropterin dihydrochloride) tablets were administered orally at a dose of 10 milligram/kilogram/day (mg/kg/day). If after 4 weeks, there was less than 20 percent (%) increase in subject's Phe tolerance versus baseline, the dose was escalated to 20 mg/kg/day. Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.	Phe-restricted Diet Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.
Overall Study Protocol Violation	1	1
Overall Study Withdrawal by Subject	1	2

Baseline Characteristics

Kuvan® in Phenylketonuria Patients Less Than 4 Years Old

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Kuvan® + Phe-restricted Diet n=27 Participants Kuvan® (sapropterin dihydrochloride) tablets were administered orally at a dose of 10 milligram/kilogram/day (mg/kg/day). If after 4 weeks, there was less than 20 percent (%) increase in subject's Phe tolerance versus baseline, the dose was escalated to 20 mg/kg/day. Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.	Phe-restricted Diet n=29 Participants Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.	Total n=56 Participants Total of all reporting groups
Age, Continuous	21.1 months STANDARD_DEVIATION 12.3 • n=5 Participants	21.2 months STANDARD_DEVIATION 12.0 • n=7 Participants	21.2 months STANDARD_DEVIATION 12.1 • n=5 Participants
Sex: Female, Male Female	11 Participants n=5 Participants	15 Participants n=7 Participants	26 Participants n=5 Participants
Sex: Female, Male Male	16 Participants n=5 Participants	14 Participants n=7 Participants	30 Participants n=5 Participants

PRIMARY outcome

Timeframe: Week 26

Population: Intention-to-treat (ITT) population consisted of all the randomized subjects at the start of the study and were analyzed according to the group allocated.

Outcome measures

Outcome measures
Measure	Kuvan® + Phe-restricted Diet n=27 Participants Kuvan® (sapropterin dihydrochloride) tablets were administered orally at a dose of 10 milligram/kilogram/day (mg/kg/day). If after 4 weeks, there was less than 20 percent (%) increase in subject's Phe tolerance versus baseline, the dose was escalated to 20 mg/kg/day. Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.	Phe-restricted Diet n=29 Participants Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.	Population PK Analysis Set: Age Group 2 (>= 2 Years) All enrolled subjects for whom at least one adequately documented BH4 concentration value and dose record were included in the population PK analysis. This includes patients receiving either Kuvan® (sapropterin dihydrochloride) tablets were administered orally at a dose of 10 milligram/kilogram/day (mg/kg/day) in conjunction with a Phe-restricted diet, or diet alone. If after 4 weeks, there was less than 20 percent (%) increase in subject's Phe tolerance versus baseline, the Kuvan® dose was escalated to 20 mg/kg/day. Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.
Dietary Phenylalanine (Phe) Tolerance at Week 26	80.6 mg/kg/day Standard Error 4.2	50.1 mg/kg/day Standard Error 4.3	—

SECONDARY outcome

Timeframe: Baseline, Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, and 26

Population: Intention-to-treat (ITT) population consisted of all the randomized subjects at the start of the study and were analyzed according to the group allocated. 'n' signifies number of subjects evaluable for this measure at given time points for each reporting group respectively.

Mean blood phe levels were defined as the mean of blood phe levels assessed over each 2-week intervals

Outcome measures

Outcome measures
Measure	Kuvan® + Phe-restricted Diet n=27 Participants Kuvan® (sapropterin dihydrochloride) tablets were administered orally at a dose of 10 milligram/kilogram/day (mg/kg/day). If after 4 weeks, there was less than 20 percent (%) increase in subject's Phe tolerance versus baseline, the dose was escalated to 20 mg/kg/day. Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.	Phe-restricted Diet n=29 Participants Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.	Population PK Analysis Set: Age Group 2 (>= 2 Years) All enrolled subjects for whom at least one adequately documented BH4 concentration value and dose record were included in the population PK analysis. This includes patients receiving either Kuvan® (sapropterin dihydrochloride) tablets were administered orally at a dose of 10 milligram/kilogram/day (mg/kg/day) in conjunction with a Phe-restricted diet, or diet alone. If after 4 weeks, there was less than 20 percent (%) increase in subject's Phe tolerance versus baseline, the Kuvan® dose was escalated to 20 mg/kg/day. Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.
Mean Blood Phe Levels Week 4 (n=27, 24)	202.1 micromol per liter (mmol/L) Standard Deviation 79.3	308.0 micromol per liter (mmol/L) Standard Deviation 122.2	—
Mean Blood Phe Levels Week 6 (n=25, 26)	248.0 micromol per liter (mmol/L) Standard Deviation 85.4	303.8 micromol per liter (mmol/L) Standard Deviation 87.4	—
Mean Blood Phe Levels Week 8 (n=26, 26)	268.7 micromol per liter (mmol/L) Standard Deviation 107.9	318.0 micromol per liter (mmol/L) Standard Deviation 108.9	—
Mean Blood Phe Levels Week 10 (n=24, 27)	271.1 micromol per liter (mmol/L) Standard Deviation 109.4	325.4 micromol per liter (mmol/L) Standard Deviation 106.2	—
Mean Blood Phe Levels Baseline (n=27, 29)	287.3 micromol per liter (mmol/L) Standard Deviation 166.6	352.9 micromol per liter (mmol/L) Standard Deviation 219.9	—
Mean Blood Phe Levels Week 2 (n=27, 26)	214.3 micromol per liter (mmol/L) Standard Deviation 89.3	321.3 micromol per liter (mmol/L) Standard Deviation 133.5	—
Mean Blood Phe Levels Week 12 (n=22, 22)	317.6 micromol per liter (mmol/L) Standard Deviation 106.0	328.9 micromol per liter (mmol/L) Standard Deviation 125.0	—
Mean Blood Phe Levels Week 14 (n=24, 26)	271.6 micromol per liter (mmol/L) Standard Deviation 79.0	311.2 micromol per liter (mmol/L) Standard Deviation 118.6	—
Mean Blood Phe Levels Week 16 (n=25, 26)	320.3 micromol per liter (mmol/L) Standard Deviation 112.2	356.3 micromol per liter (mmol/L) Standard Deviation 99.1	—
Mean Blood Phe Levels Week 18 (n=24, 26)	302.9 micromol per liter (mmol/L) Standard Deviation 122.7	325.4 micromol per liter (mmol/L) Standard Deviation 80.4	—
Mean Blood Phe Levels Week 20 (n=25, 25)	305.1 micromol per liter (mmol/L) Standard Deviation 116.1	326.3 micromol per liter (mmol/L) Standard Deviation 77.0	—
Mean Blood Phe Levels Week 22 (n=25, 24)	293.2 micromol per liter (mmol/L) Standard Deviation 86.8	346.9 micromol per liter (mmol/L) Standard Deviation 97.8	—
Mean Blood Phe Levels Week 24 (n=24, 25)	278.8 micromol per liter (mmol/L) Standard Deviation 77.2	326.1 micromol per liter (mmol/L) Standard Deviation 120.4	—
Mean Blood Phe Levels Week 26 (n=21, 22)	300.1 micromol per liter (mmol/L) Standard Deviation 115.2	343.3 micromol per liter (mmol/L) Standard Deviation 118.4	—

SECONDARY outcome

Timeframe: Baseline and at Week 26 (last observation carried-forward [LOCF])

Phe tolerance was defined as the amount of dietary Phe ingested (mg/kg/day) while maintaining blood Phe levels within the selected therapeutic target range (defined as \>=120 to \<360 mcmol/L).

Outcome measures

Outcome measures
Measure	Kuvan® + Phe-restricted Diet n=27 Participants Kuvan® (sapropterin dihydrochloride) tablets were administered orally at a dose of 10 milligram/kilogram/day (mg/kg/day). If after 4 weeks, there was less than 20 percent (%) increase in subject's Phe tolerance versus baseline, the dose was escalated to 20 mg/kg/day. Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.	Phe-restricted Diet n=29 Participants Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.	Population PK Analysis Set: Age Group 2 (>= 2 Years) All enrolled subjects for whom at least one adequately documented BH4 concentration value and dose record were included in the population PK analysis. This includes patients receiving either Kuvan® (sapropterin dihydrochloride) tablets were administered orally at a dose of 10 milligram/kilogram/day (mg/kg/day) in conjunction with a Phe-restricted diet, or diet alone. If after 4 weeks, there was less than 20 percent (%) increase in subject's Phe tolerance versus baseline, the Kuvan® dose was escalated to 20 mg/kg/day. Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.
Change From Baseline in Dietary Phe Tolerance After 26 Weeks Change at Week 26: LOCF (n=27, 27)	36.9 mg/kg/day Standard Error 27.3	13.1 mg/kg/day Standard Error 19.6	—
Change From Baseline in Dietary Phe Tolerance After 26 Weeks Baseline (n=27, 29)	37.1 mg/kg/day Standard Error 17.3	35.8 mg/kg/day Standard Error 20.9	—
Change From Baseline in Dietary Phe Tolerance After 26 Weeks Week 26:LOCF (n=27, 27)	74.0 mg/kg/day Standard Error 38.6	49.8 mg/kg/day Standard Error 24.2	—

SECONDARY outcome

Timeframe: From the first dose of study drug administration up to 31 days after the last dose of study drug administration

Population: Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.

An AE was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. A serious adverse event (SAE) was 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. Treatment-emergent are events between first dose of study treatment and up to 31 days after last dose that were absent before treatment or that worsened relative to pretreatment state.

Outcome measures

Outcome measures
Measure	Kuvan® + Phe-restricted Diet n=27 Participants Kuvan® (sapropterin dihydrochloride) tablets were administered orally at a dose of 10 milligram/kilogram/day (mg/kg/day). If after 4 weeks, there was less than 20 percent (%) increase in subject's Phe tolerance versus baseline, the dose was escalated to 20 mg/kg/day. Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.	Phe-restricted Diet n=27 Participants Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.	Population PK Analysis Set: Age Group 2 (>= 2 Years) All enrolled subjects for whom at least one adequately documented BH4 concentration value and dose record were included in the population PK analysis. This includes patients receiving either Kuvan® (sapropterin dihydrochloride) tablets were administered orally at a dose of 10 milligram/kilogram/day (mg/kg/day) in conjunction with a Phe-restricted diet, or diet alone. If after 4 weeks, there was less than 20 percent (%) increase in subject's Phe tolerance versus baseline, the Kuvan® dose was escalated to 20 mg/kg/day. Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.
Number of Subjects With Any TEAEs, AEs Related to Kuvan, Serious AEs, AEs Leading to Death, and AEs Leading to Discontinuation TEAEs	27 subjects	27 subjects	—
Number of Subjects With Any TEAEs, AEs Related to Kuvan, Serious AEs, AEs Leading to Death, and AEs Leading to Discontinuation AEs related to Kuvan	8 subjects	0 subjects	—
Number of Subjects With Any TEAEs, AEs Related to Kuvan, Serious AEs, AEs Leading to Death, and AEs Leading to Discontinuation SAEs	3 subjects	1 subjects	—
Number of Subjects With Any TEAEs, AEs Related to Kuvan, Serious AEs, AEs Leading to Death, and AEs Leading to Discontinuation AEs leading to death	0 subjects	0 subjects	—
Number of Subjects With Any TEAEs, AEs Related to Kuvan, Serious AEs, AEs Leading to Death, and AEs Leading to Discontinuation AEs Leading to discontinuation	0 subjects	0 subjects	—

SECONDARY outcome

Timeframe: Baseline, Weeks 12, 26

Population: Intention-to-Treat (ITT) population consisted of all subjects who were randomized at the start of the Study Period and analyzed according to the group allocated. "n" signifies number of evaluable subjects in the specified categories, for each reporting group, respectively.

Subjects with normal neuromotor development were assessed by standardized developmental milestones using a parent/guardian report form in the following areas: fine motor, gross motor, language, and personal-social using DDS Test. DDS Test is a widely used to examine the developmental progress of 0-6 years of children. The scale reflects what percentage of a certain age group is able to perform a certain task. Tasks are grouped into 4 categories (social contact, fine motor skill, language, and gross motor skill) and include items such as smiles spontaneously (performed by 90% of three-month-olds), knocks 2 building blocks against each other (90% of 13-month-olds), speaks 3 words other than "mom" and "dad" (90% of 21-month-olds), or hops on 1 leg (90% of 5-year-olds). The more items a child fails to perform (passed by 90% of his/her peers), the more likely the child manifests a significant developmental problems.

Outcome measures

Outcome measures
Measure	Kuvan® + Phe-restricted Diet n=27 Participants Kuvan® (sapropterin dihydrochloride) tablets were administered orally at a dose of 10 milligram/kilogram/day (mg/kg/day). If after 4 weeks, there was less than 20 percent (%) increase in subject's Phe tolerance versus baseline, the dose was escalated to 20 mg/kg/day. Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.	Phe-restricted Diet n=29 Participants Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.	Population PK Analysis Set: Age Group 2 (>= 2 Years) All enrolled subjects for whom at least one adequately documented BH4 concentration value and dose record were included in the population PK analysis. This includes patients receiving either Kuvan® (sapropterin dihydrochloride) tablets were administered orally at a dose of 10 milligram/kilogram/day (mg/kg/day) in conjunction with a Phe-restricted diet, or diet alone. If after 4 weeks, there was less than 20 percent (%) increase in subject's Phe tolerance versus baseline, the Kuvan® dose was escalated to 20 mg/kg/day. Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.
Number of Subjects With Normal Neuromotor Developmental Milestones Assessed Using Denver Developmental Scale (DDS) Fine motor: Baseline (n=25, 26)	18 subjects	21 subjects	—
Number of Subjects With Normal Neuromotor Developmental Milestones Assessed Using Denver Developmental Scale (DDS) Fine motor: Week 12 (n=25, 25)	21 subjects	23 subjects	—
Number of Subjects With Normal Neuromotor Developmental Milestones Assessed Using Denver Developmental Scale (DDS) Fine motor: Week 26 (n=25, 25)	20 subjects	23 subjects	—
Number of Subjects With Normal Neuromotor Developmental Milestones Assessed Using Denver Developmental Scale (DDS) Gross motor: Baseline (n=25, 26)	23 subjects	23 subjects	—
Number of Subjects With Normal Neuromotor Developmental Milestones Assessed Using Denver Developmental Scale (DDS) Gross motor: Week 12 (n=25, 25)	21 subjects	20 subjects	—
Number of Subjects With Normal Neuromotor Developmental Milestones Assessed Using Denver Developmental Scale (DDS) Gross motor: Week 26 (n=25, 25)	20 subjects	19 subjects	—
Number of Subjects With Normal Neuromotor Developmental Milestones Assessed Using Denver Developmental Scale (DDS) Language: Baseline (n=25, 26)	22 subjects	20 subjects	—
Number of Subjects With Normal Neuromotor Developmental Milestones Assessed Using Denver Developmental Scale (DDS) Language: Week 12 (n=25, 25)	22 subjects	22 subjects	—
Number of Subjects With Normal Neuromotor Developmental Milestones Assessed Using Denver Developmental Scale (DDS) Language: Week 26 (n=25, 25)	16 subjects	20 subjects	—
Number of Subjects With Normal Neuromotor Developmental Milestones Assessed Using Denver Developmental Scale (DDS) Personal social: Baseline (n= 25, 26)	22 subjects	22 subjects	—
Number of Subjects With Normal Neuromotor Developmental Milestones Assessed Using Denver Developmental Scale (DDS) Personal social: Week 12 (n=25, 25)	22 subjects	21 subjects	—
Number of Subjects With Normal Neuromotor Developmental Milestones Assessed Using Denver Developmental Scale (DDS) Personal social: Week 26 (n=25, 25)	22 subjects	18 subjects	—

SECONDARY outcome

Timeframe: Baseline and Week 26

Neurodevelopmental assessments was done using the following age-dependent scales: Bayley III for subjects less than (\<) 3.5 years of age and WPPSI III for subjects greater than or equal to (\>=) 3.5 to \<4 years of age, based on following scores: adaptive behavior composite (ABC) score, cognitive composite (CC) score, language composite (LC) score, motor composite (MC) score., and social-emotional composite (SEC) score. Composite scores ranged from 40 (very poor) to 160 (excellent) and are classified as following: \>=115: accelerated performance; 85-114: development within normal limits; 70-84: mildly delayed development; less than or equal to (\<=) 69: significant delayed development.

Outcome measures

Outcome measures
Measure	Kuvan® + Phe-restricted Diet n=27 Participants Kuvan® (sapropterin dihydrochloride) tablets were administered orally at a dose of 10 milligram/kilogram/day (mg/kg/day). If after 4 weeks, there was less than 20 percent (%) increase in subject's Phe tolerance versus baseline, the dose was escalated to 20 mg/kg/day. Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.	Phe-restricted Diet n=29 Participants Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.	Population PK Analysis Set: Age Group 2 (>= 2 Years) All enrolled subjects for whom at least one adequately documented BH4 concentration value and dose record were included in the population PK analysis. This includes patients receiving either Kuvan® (sapropterin dihydrochloride) tablets were administered orally at a dose of 10 milligram/kilogram/day (mg/kg/day) in conjunction with a Phe-restricted diet, or diet alone. If after 4 weeks, there was less than 20 percent (%) increase in subject's Phe tolerance versus baseline, the Kuvan® dose was escalated to 20 mg/kg/day. Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.
Neurodevelopmental Status Assessed Using Bayley III Scales of Infant and Toddler Development ABC score: Baseline (n=15, 18)	106.5 Units on a scale Standard Deviation 14.2	96.2 Units on a scale Standard Deviation 14.6	—
Neurodevelopmental Status Assessed Using Bayley III Scales of Infant and Toddler Development ABC score: Week 26 (n=19, 18)	102.4 Units on a scale Standard Deviation 16.4	93.4 Units on a scale Standard Deviation 14.1	—
Neurodevelopmental Status Assessed Using Bayley III Scales of Infant and Toddler Development CC score: Baseline (n=19, 20)	100.0 Units on a scale Standard Deviation 11.8	101.2 Units on a scale Standard Deviation 15.9	—
Neurodevelopmental Status Assessed Using Bayley III Scales of Infant and Toddler Development CC score: Week 26 (n=20, 19)	102.8 Units on a scale Standard Deviation 12.9	100.8 Units on a scale Standard Deviation 13.0	—
Neurodevelopmental Status Assessed Using Bayley III Scales of Infant and Toddler Development LS score: Baseline (n=18, 19)	96.7 Units on a scale Standard Deviation 12.4	97.7 Units on a scale Standard Deviation 19.5	—
Neurodevelopmental Status Assessed Using Bayley III Scales of Infant and Toddler Development LS score: Week 26 (n=20, 19)	98.3 Units on a scale Standard Deviation 11.9	93.6 Units on a scale Standard Deviation 12.1	—
Neurodevelopmental Status Assessed Using Bayley III Scales of Infant and Toddler Development MC score: Baseline (n=19, 20)	97.8 Units on a scale Standard Deviation 13.7	94.9 Units on a scale Standard Deviation 13.6	—
Neurodevelopmental Status Assessed Using Bayley III Scales of Infant and Toddler Development MC score: Week 26 (n=20, 19)	100.6 Units on a scale Standard Deviation 15.2	98.7 Units on a scale Standard Deviation 9.5	—
Neurodevelopmental Status Assessed Using Bayley III Scales of Infant and Toddler Development SEC score: Baseline (n=17, 18)	102.9 Units on a scale Standard Deviation 11.3	106.0 Units on a scale Standard Deviation 16.3	—
Neurodevelopmental Status Assessed Using Bayley III Scales of Infant and Toddler Development SEC score: Week 26 (n=19, 18)	106.3 Units on a scale Standard Deviation 19.1	102.5 Units on a scale Standard Deviation 13.2	—

SECONDARY outcome

Timeframe: Baseline, Weeks 4, 8, 12, 16, 20, and 26

Growth assessment was performed by monitoring body mass index, height (or length), weight, and maximal occipital-frontal head circumference (MOFHC). Supine length was measured up to 2 years of age thereafter standing height was measured unless subject was unable to stand upright, in which case supine length was measured. Respective parameter SDS was calculated as the value of parameter minus reference mean value of parameter divided by standard deviation of the reference population.

Outcome measures

Outcome measures
Measure	Kuvan® + Phe-restricted Diet n=27 Participants Kuvan® (sapropterin dihydrochloride) tablets were administered orally at a dose of 10 milligram/kilogram/day (mg/kg/day). If after 4 weeks, there was less than 20 percent (%) increase in subject's Phe tolerance versus baseline, the dose was escalated to 20 mg/kg/day. Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.	Phe-restricted Diet n=29 Participants Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.	Population PK Analysis Set: Age Group 2 (>= 2 Years) All enrolled subjects for whom at least one adequately documented BH4 concentration value and dose record were included in the population PK analysis. This includes patients receiving either Kuvan® (sapropterin dihydrochloride) tablets were administered orally at a dose of 10 milligram/kilogram/day (mg/kg/day) in conjunction with a Phe-restricted diet, or diet alone. If after 4 weeks, there was less than 20 percent (%) increase in subject's Phe tolerance versus baseline, the Kuvan® dose was escalated to 20 mg/kg/day. Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.
Growth Parameters Standard Deviation Scores (SDS) Body mass index SDS: Baseline (n=27, 29)	0.37 SDS Standard Deviation 0.84	0.34 SDS Standard Deviation 0.99	—
Growth Parameters Standard Deviation Scores (SDS) Body mass index SDS: Week 4 (n=26, 27)	0.33 SDS Standard Deviation 0.92	0.36 SDS Standard Deviation 0.95	—
Growth Parameters Standard Deviation Scores (SDS) Body mass index SDS: Week 8 (n=25, 26)	0.47 SDS Standard Deviation 0.93	0.38 SDS Standard Deviation 0.82	—
Growth Parameters Standard Deviation Scores (SDS) Body mass index SDS: Week 12 (n=25, 26)	0.37 SDS Standard Deviation 1.02	0.48 SDS Standard Deviation 0.91	—
Growth Parameters Standard Deviation Scores (SDS) Body mass index SDS: Week 16 (n=25, 26)	0.34 SDS Standard Deviation 0.95	0.39 SDS Standard Deviation 0.93	—
Growth Parameters Standard Deviation Scores (SDS) Body mass index SDS: Week 20 (n=25, 27)	0.46 SDS Standard Deviation 0.93	0.44 SDS Standard Deviation 0.86	—
Growth Parameters Standard Deviation Scores (SDS) Body mass index SDS: Week 26 (n=25, 26)	0.58 SDS Standard Deviation 0.83	0.41 SDS Standard Deviation 0.81	—
Growth Parameters Standard Deviation Scores (SDS) Height SDS: Baseline (n=27, 29)	-0.19 SDS Standard Deviation 1.17	-0.21 SDS Standard Deviation 1.03	—
Growth Parameters Standard Deviation Scores (SDS) Height SDS: Week 4 (n=26, 27)	-0.19 SDS Standard Deviation 1.08	-0.25 SDS Standard Deviation 1.00	—
Growth Parameters Standard Deviation Scores (SDS) Height SDS: Week 8 (n=25, 26)	-0.22 SDS Standard Deviation 1.08	-0.13 SDS Standard Deviation 1.05	—
Growth Parameters Standard Deviation Scores (SDS) Height SDS: Week 12 (n=25, 26)	0.02 SDS Standard Deviation 1.62	-0.14 SDS Standard Deviation 1.11	—
Growth Parameters Standard Deviation Scores (SDS) Height SDS: Week 16 (n=25, 26)	0.05 SDS Standard Deviation 1.36	-0.05 SDS Standard Deviation 1.05	—
Growth Parameters Standard Deviation Scores (SDS) Height SDS: Week 20 (n=25, 27)	-0.08 SDS Standard Deviation 1.21	-0.11 SDS Standard Deviation 0.95	—
Growth Parameters Standard Deviation Scores (SDS) Height SDS: Week 26 (n=25, 26)	-0.11 SDS Standard Deviation 1.16	-0.06 SDS Standard Deviation 0.92	—
Growth Parameters Standard Deviation Scores (SDS) MOFHC SDS: Baseline (n=27, 29)	0.37 SDS Standard Deviation 1.38	0.07 SDS Standard Deviation 1.10	—
Growth Parameters Standard Deviation Scores (SDS) MOFHC SDS: Week 4 (n=25, 26)	0.48 SDS Standard Deviation 1.41	0.21 SDS Standard Deviation 1.03	—
Growth Parameters Standard Deviation Scores (SDS) MOFHC SDS: Week 8 (n=25, 26)	0.51 SDS Standard Deviation 1.40	0.35 SDS Standard Deviation 1.05	—
Growth Parameters Standard Deviation Scores (SDS) MOFHC SDS: Week 12 (n=25, 26)	0.43 SDS Standard Deviation 1.23	0.20 SDS Standard Deviation 1.19	—
Growth Parameters Standard Deviation Scores (SDS) MOFHC SDS: Week 16 (n=25, 26)	0.58 SDS Standard Deviation 1.26	0.25 SDS Standard Deviation 1.18	—
Growth Parameters Standard Deviation Scores (SDS) MOFHC SDS: Week 20 (n=25, 26)	0.41 SDS Standard Deviation 1.30	0.18 SDS Standard Deviation 1.24	—
Growth Parameters Standard Deviation Scores (SDS) MOFHC SDS: Week 26 (n=25, 26)	0.43 SDS Standard Deviation 1.34	0.15 SDS Standard Deviation 1.26	—
Growth Parameters Standard Deviation Scores (SDS) Weight SDS: Baseline (n=27, 29)	0.12 SDS Standard Deviation 0.81	0.12 SDS Standard Deviation 0.66	—
Growth Parameters Standard Deviation Scores (SDS) Weight SDS: Week 4 (n=26, 27)	0.11 SDS Standard Deviation 0.86	0.12 SDS Standard Deviation 0.64	—
Growth Parameters Standard Deviation Scores (SDS) Weight SDS: Week 8 (n=25, 27)	0.18 SDS Standard Deviation 0.88	0.18 SDS Standard Deviation 0.66	—
Growth Parameters Standard Deviation Scores (SDS) Weight SDS: Week 12 (n=25, 26)	0.23 SDS Standard Deviation 0.91	0.25 SDS Standard Deviation 0.65	—
Growth Parameters Standard Deviation Scores (SDS) Weight SDS: Week 16 (n=25, 26)	0.23 SDS Standard Deviation 0.97	0.25 SDS Standard Deviation 0.74	—
Growth Parameters Standard Deviation Scores (SDS) Weight SDS: Week 20 (n=25, 27)	0.25 SDS Standard Deviation 0.95	0.24 SDS Standard Deviation 0.67	—
Growth Parameters Standard Deviation Scores (SDS) Weight SDS: Week 26 (n=25, 26)	0.32 SDS Standard Deviation 0.93	0.19 SDS Standard Deviation 0.67	—

SECONDARY outcome

Timeframe: Week 26

Population: Safety population consisted of all subjects who had some safety assessment data available (at least one visit in vital signs, AE or laboratory results) in the Study Period and who received at least one dose of Kuvan in the Study Period, or who were randomized to Phe-restricted diet alone.

Hypophenylalanemia is defined as the condition of blood Phe levels \<120 mcmol/L.

Outcome measures

Outcome measures
Measure	Kuvan® + Phe-restricted Diet n=27 Participants Kuvan® (sapropterin dihydrochloride) tablets were administered orally at a dose of 10 milligram/kilogram/day (mg/kg/day). If after 4 weeks, there was less than 20 percent (%) increase in subject's Phe tolerance versus baseline, the dose was escalated to 20 mg/kg/day. Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.	Phe-restricted Diet n=27 Participants Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.	Population PK Analysis Set: Age Group 2 (>= 2 Years) All enrolled subjects for whom at least one adequately documented BH4 concentration value and dose record were included in the population PK analysis. This includes patients receiving either Kuvan® (sapropterin dihydrochloride) tablets were administered orally at a dose of 10 milligram/kilogram/day (mg/kg/day) in conjunction with a Phe-restricted diet, or diet alone. If after 4 weeks, there was less than 20 percent (%) increase in subject's Phe tolerance versus baseline, the Kuvan® dose was escalated to 20 mg/kg/day. Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.
Number of Subjects With Hypophenylalanemia	10 Subjects	9 Subjects	—

SECONDARY outcome

Timeframe: Every 6 months during 3 year extension period or until product is commercially approved

Population: The extension period of this study is ongoing. Data will be provided after completion of extension period i.e first quarter 2017

Phe tolerance was defined as the amount of dietary Phe ingested (mg/kg/day) while maintaining blood Phe levels within the selected therapeutic target range (defined as \>=120 to \<360 mcmol/L).

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline, Weeks 4, 8, 12, 16, 20, and 26

Population: Intention-to-treat (ITT) population consisted of all the randomized subjects at the start of the study and were analyzed according to the group allocated. "n" signifies number of evaluable subjects in the specified categories for each reporting group, respectively.

Outcome measures

Outcome measures
Measure	Kuvan® + Phe-restricted Diet n=27 Participants Kuvan® (sapropterin dihydrochloride) tablets were administered orally at a dose of 10 milligram/kilogram/day (mg/kg/day). If after 4 weeks, there was less than 20 percent (%) increase in subject's Phe tolerance versus baseline, the dose was escalated to 20 mg/kg/day. Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.	Phe-restricted Diet n=29 Participants Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.	Population PK Analysis Set: Age Group 2 (>= 2 Years) All enrolled subjects for whom at least one adequately documented BH4 concentration value and dose record were included in the population PK analysis. This includes patients receiving either Kuvan® (sapropterin dihydrochloride) tablets were administered orally at a dose of 10 milligram/kilogram/day (mg/kg/day) in conjunction with a Phe-restricted diet, or diet alone. If after 4 weeks, there was less than 20 percent (%) increase in subject's Phe tolerance versus baseline, the Kuvan® dose was escalated to 20 mg/kg/day. Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP: Baseline (n=25, 25)	93.5 mmHg Standard Deviation 11.0	93.1 mmHg Standard Deviation 14.4	—
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP: Week 4 (n=22, 25)	95.9 mmHg Standard Deviation 14.6	101.5 mmHg Standard Deviation 17.6	—
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP: Week 8 (n=23, 25)	95.9 mmHg Standard Deviation 17.5	95.7 mmHg Standard Deviation 17.9	—
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP: Week 12 (n=23, 26)	97.0 mmHg Standard Deviation 13.2	95.2 mmHg Standard Deviation 9.8	—
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP: Week 16 (n=23, 26)	95.0 mmHg Standard Deviation 14.5	98.2 mmHg Standard Deviation 12.3	—
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP: Week 20 (n=21, 27)	95.6 mmHg Standard Deviation 14.1	98.4 mmHg Standard Deviation 12.6	—
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) SBP: Week 26 (n=22, 25)	97.5 mmHg Standard Deviation 11.1	96.8 mmHg Standard Deviation 8.7	—
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP: Baseline (n=25, 25)	55.8 mmHg Standard Deviation 9.0	57.1 mmHg Standard Deviation 8.1	—
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP: Week 4 (n=22, 25)	59.8 mmHg Standard Deviation 9.8	59.0 mmHg Standard Deviation 13.3	—
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP: Week 8 (n=23, 25)	59.1 mmHg Standard Deviation 7.8	55.2 mmHg Standard Deviation 8.7	—
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP: Week 12 (n=23, 26)	58.5 mmHg Standard Deviation 6.2	57.4 mmHg Standard Deviation 9.7	—
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP: Week 16 (n=23, 26)	57.7 mmHg Standard Deviation 12.1	58.5 mmHg Standard Deviation 11.2	—
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP: Week 20 (n=21, 27)	57.5 mmHg Standard Deviation 12.1	58.4 mmHg Standard Deviation 6.3	—
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) DBP: Week 26 (n=22, 25)	59.0 mmHg Standard Deviation 7.0	59.2 mmHg Standard Deviation 9.4	—

SECONDARY outcome

Timeframe: Screening (within 42 days prior to Day 1 of the 26-week study period)

Population: Analysis population included subjects who signed pharmacogenetics (PGx) informed consent and whose samples were available for analysis. Out of 109 subjects screened for the study, 77 PGx informed consent forms were signed and 73 samples were analyzed.

The DNA samples received were quantified by using a nanophotometer, and were aliquoted to a concentration of 20 nanogram/microliter DNA and aliquots from each sample were distributed to one 96-well plate. All samples were Sanger sequenced regarding exons 1 to 13 of the PAH gene in forward direction using the DNAs in the 96-well plate. All samples showing variants were Sanger sequenced regarding the concerned exon in reverse direction using DNA from the original tube. All samples showing a homozygous mutation were analyzed by MLPA. All samples showing only 1 mutation were analyzed by MLPA. All samples showing only 1 or no mutation were resequenced completely (exons 1 to 13) in both directions.

Outcome measures

Outcome measures
Measure	Kuvan® + Phe-restricted Diet n=73 Participants Kuvan® (sapropterin dihydrochloride) tablets were administered orally at a dose of 10 milligram/kilogram/day (mg/kg/day). If after 4 weeks, there was less than 20 percent (%) increase in subject's Phe tolerance versus baseline, the dose was escalated to 20 mg/kg/day. Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.	Phe-restricted Diet Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.	Population PK Analysis Set: Age Group 2 (>= 2 Years) All enrolled subjects for whom at least one adequately documented BH4 concentration value and dose record were included in the population PK analysis. This includes patients receiving either Kuvan® (sapropterin dihydrochloride) tablets were administered orally at a dose of 10 milligram/kilogram/day (mg/kg/day) in conjunction with a Phe-restricted diet, or diet alone. If after 4 weeks, there was less than 20 percent (%) increase in subject's Phe tolerance versus baseline, the Kuvan® dose was escalated to 20 mg/kg/day. Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.
Number of Samples With Phenylalanine Hydroxylase (PAH) Gene Mutations	73 Sample	—	—

SECONDARY outcome

Timeframe: Weeks 5 to 12

Population: All enrolled subjects for whom at least one adequately documented BH4 concentration value and dose record were included in the population PK analysis. 'N' (number of subjects analyzed) =subjects evaluable for this outcome measure.

CL/f is the rate at which a drug is removed from the body via renal, hepatic and other clearance pathways.The reason for pooling subjects receiving Kuvan and subjects with Phe-restricted Diet was to facilitate the estimation of baseline endogenous value of BH4 which can only be observed in subjects not receiving the treatment. Ignoring this baseline endogenous value would have led to biased stimated of the Kuvan PK parameters. This pooling assumes that the addition of Kuvan does not confound the BH4 measurements in these analyses as a consequence the population PK parameters describing the PK of BH4 are the same for the 2 arms and so cannot be presented in terms of per arm/per treatment group based as per the planned analysis.

Outcome measures

Outcome measures
Measure	Kuvan® + Phe-restricted Diet n=52 Participants Kuvan® (sapropterin dihydrochloride) tablets were administered orally at a dose of 10 milligram/kilogram/day (mg/kg/day). If after 4 weeks, there was less than 20 percent (%) increase in subject's Phe tolerance versus baseline, the dose was escalated to 20 mg/kg/day. Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.	Phe-restricted Diet Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.	Population PK Analysis Set: Age Group 2 (>= 2 Years) All enrolled subjects for whom at least one adequately documented BH4 concentration value and dose record were included in the population PK analysis. This includes patients receiving either Kuvan® (sapropterin dihydrochloride) tablets were administered orally at a dose of 10 milligram/kilogram/day (mg/kg/day) in conjunction with a Phe-restricted diet, or diet alone. If after 4 weeks, there was less than 20 percent (%) increase in subject's Phe tolerance versus baseline, the Kuvan® dose was escalated to 20 mg/kg/day. Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.
Population Pharmacokinetic (PK) Parameter: Apparent Clearance (CL/f)	2780 liter per hour Standard Error 2	—	—

SECONDARY outcome

Timeframe: Weeks 5 to 12

V/f is defined as the distribution of a medication between the plasma and the rest of the body after the dose. It is the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of the drug. The reason for pooling subjects receiving Kuvan and subjects with Phe-restricted Diet was to facilitate the estimation of baseline endogenous value of BH4 which can only be observed in subjects not receiving the treatment. Ignoring this baseline endogenous value would have led to biased stimated of the Kuvan PK parameters. This pooling assumes that the addition of Kuvan does not confound the BH4 measurements in these analyses as a consequence the population PK parameters describing the PK of BH4 are the same for the 2 arms and so cannot be presented in terms of per arm/per treatment group based as per the planned analysis.

Outcome measures

Outcome measures
Measure	Kuvan® + Phe-restricted Diet n=52 Participants Kuvan® (sapropterin dihydrochloride) tablets were administered orally at a dose of 10 milligram/kilogram/day (mg/kg/day). If after 4 weeks, there was less than 20 percent (%) increase in subject's Phe tolerance versus baseline, the dose was escalated to 20 mg/kg/day. Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.	Phe-restricted Diet Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.	Population PK Analysis Set: Age Group 2 (>= 2 Years) All enrolled subjects for whom at least one adequately documented BH4 concentration value and dose record were included in the population PK analysis. This includes patients receiving either Kuvan® (sapropterin dihydrochloride) tablets were administered orally at a dose of 10 milligram/kilogram/day (mg/kg/day) in conjunction with a Phe-restricted diet, or diet alone. If after 4 weeks, there was less than 20 percent (%) increase in subject's Phe tolerance versus baseline, the Kuvan® dose was escalated to 20 mg/kg/day. Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.
Population PK Parameter: Apparent Volume of Distribution (V/f)	3870 liter Standard Error 5.9	—	—

SECONDARY outcome

Timeframe: Weeks 5 to 12

AUC \[0-infinity\] was estimated by determining total area under the curve of the concentration versus time curve extrapolated to infinity. Since AUC could not be obtained from non-compartmental analysis because of sparse data, AUC = Dose/(CL/F); CL/F was population apparent clearance estimated from the population PK model, \& Dose the actual total dose received by the patient on one dosing interval. The reason for pooling subjects receiving Kuvan \&subjects with Phe-restricted Diet was to facilitate estimation of baseline endogenous value of BH4 which can only be observed in subjects not receiving treatment. Ignoring this baseline endogenous value would have led to biased estimated of Kuvan PK parameters. This pooling assumes that the the addition of Kuvan does not confound the BH4 measurements in these analyses as a consequence the population PK parameters describing the PK of BH4 were same for the 2 arms and cannot be presented per arm/per treatment group as per planned analysis.

Outcome measures

Outcome measures
Measure	Kuvan® + Phe-restricted Diet n=14 Participants Kuvan® (sapropterin dihydrochloride) tablets were administered orally at a dose of 10 milligram/kilogram/day (mg/kg/day). If after 4 weeks, there was less than 20 percent (%) increase in subject's Phe tolerance versus baseline, the dose was escalated to 20 mg/kg/day. Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.	Phe-restricted Diet n=18 Participants Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.	Population PK Analysis Set: Age Group 2 (>= 2 Years) n=20 Participants All enrolled subjects for whom at least one adequately documented BH4 concentration value and dose record were included in the population PK analysis. This includes patients receiving either Kuvan® (sapropterin dihydrochloride) tablets were administered orally at a dose of 10 milligram/kilogram/day (mg/kg/day) in conjunction with a Phe-restricted diet, or diet alone. If after 4 weeks, there was less than 20 percent (%) increase in subject's Phe tolerance versus baseline, the Kuvan® dose was escalated to 20 mg/kg/day. Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.
Population PK Parameter: Area Under the Plasma Concentration Curve, Time 0 to Infinity (AUC [0-infinity])	234.89 microgramhour per liter(mcghour/liter) Standard Deviation 89.82	215.74 microgramhour per liter(mcghour/liter) Standard Deviation 63.88	206.22 microgramhour per liter(mcghour/liter) Standard Deviation 103.24

SECONDARY outcome

Timeframe: Weeks 5 to 12

The t1/2 was defined as the time required for plasma concentration of drug to decrease 50 percent (%) in the final stage of elimination. Since t1/2 could not be obtained from non-compartmental analysis because of sparse data, t1/2 was estimated as Log(2)\*(V/F)/(CL/F), where V/F \& CL/F were the population apparent central Volume \& clearance, estimated from population PK model. The reason for pooling subjects receiving Kuvan \& subjects with Phe-restricted Diet was to facilitate the estimation of baseline endogenous value of BH4 which can only observed in subjects not receiving treatment. Ignoring this baseline endogenous value would have led biased stimated of the Kuvan PK parameters. This pooling assumes that the addition of Kuvan does not confound the BH4 measurements in these analyses as a consequence the population PK parameters describing the PK of BH4 are the same for the 2 arms and so cannot be presented in terms of per arm/per treatment group based as per the planned analysis.

Outcome measures

Outcome measures
Measure	Kuvan® + Phe-restricted Diet n=52 Participants Kuvan® (sapropterin dihydrochloride) tablets were administered orally at a dose of 10 milligram/kilogram/day (mg/kg/day). If after 4 weeks, there was less than 20 percent (%) increase in subject's Phe tolerance versus baseline, the dose was escalated to 20 mg/kg/day. Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.	Phe-restricted Diet Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.	Population PK Analysis Set: Age Group 2 (>= 2 Years) All enrolled subjects for whom at least one adequately documented BH4 concentration value and dose record were included in the population PK analysis. This includes patients receiving either Kuvan® (sapropterin dihydrochloride) tablets were administered orally at a dose of 10 milligram/kilogram/day (mg/kg/day) in conjunction with a Phe-restricted diet, or diet alone. If after 4 weeks, there was less than 20 percent (%) increase in subject's Phe tolerance versus baseline, the Kuvan® dose was escalated to 20 mg/kg/day. Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.
Population PK Parameter: Terminal Elimination Half-life (t1/2)	0.96 hours	—	—

SECONDARY outcome

Timeframe: Up to Week 26

Population: Cmax could not be calculated from the model derived parameters because shrinkage was over 20% for V/f and interindividual variability could not be estimated for absorption rate constant (Ka).

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Up to Week 26

Population: Tmax could not be calculated from the model derived parameters because shrinkage was over 20% for V/F and interindividual variability could not be estimated for Ka.

Outcome measures

Outcome data not reported

Adverse Events

Kuvan® + Phe-restricted Diet

Serious events: 3 serious events

Other events: 26 other events

Deaths: 0 deaths

Phe-restricted Diet

Serious events: 1 serious events

Other events: 26 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Kuvan® + Phe-restricted Diet n=27 participants at risk Kuvan® (sapropterin dihydrochloride) tablets were administered orally at a dose of 10 milligram/kilogram/day (mg/kg/day). If after 4 weeks, there was less than 20 percent (%) increase in subject's Phe tolerance versus baseline, the dose was escalated to 20 mg/kg/day. Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.	Phe-restricted Diet n=27 participants at risk Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.
Infections and infestations Gastroenteritis	3.7% 1/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.	0.00% 0/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.
Skin and subcutaneous tissue disorders Rash	3.7% 1/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.	0.00% 0/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.
Injury, poisoning and procedural complications Overdose	3.7% 1/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.	0.00% 0/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.
Gastrointestinal disorders Stomatitis	3.7% 1/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.	0.00% 0/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.
Infections and infestations Bronchiolitis	0.00% 0/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.	3.7% 1/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.
Infections and infestations Bronchopneumonia	0.00% 0/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.	3.7% 1/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.

Other adverse events

Additional Information

Medical Information Services

BioMarin Pharmaceutical Inc.

Phone: +1-800-983-4587

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: OTHER

Measure	Kuvan® + Phe-restricted Diet n=27 participants at risk Kuvan® (sapropterin dihydrochloride) tablets were administered orally at a dose of 10 milligram/kilogram/day (mg/kg/day). If after 4 weeks, there was less than 20 percent (%) increase in subject's Phe tolerance versus baseline, the dose was escalated to 20 mg/kg/day. Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.	Phe-restricted Diet n=27 participants at risk Phenylalanine (Phe)-restricted diet was adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.
Infections and infestations Nasopharyngitis	48.1% 13/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.	40.7% 11/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.
Infections and infestations Rhinitis	29.6% 8/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.	22.2% 6/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.
Infections and infestations Pharyngitis	25.9% 7/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.	11.1% 3/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.
Infections and infestations Gastroenteritis	11.1% 3/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.	11.1% 3/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.
Infections and infestations Otitis media	7.4% 2/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.	11.1% 3/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.
Infections and infestations Bronchitis	7.4% 2/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.	7.4% 2/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.
General disorders Pyrexia	63.0% 17/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.	66.7% 18/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.
Respiratory, thoracic and mediastinal disorders Cough	48.1% 13/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.	48.1% 13/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	7.4% 2/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.	29.6% 8/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.
Gastrointestinal disorders Vomiting	37.0% 10/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.	33.3% 9/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.
Gastrointestinal disorders Diarrhoea	33.3% 9/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.	22.2% 6/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.
Gastrointestinal disorders Abdominal Pain	11.1% 3/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.	7.4% 2/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.
Investigations Amino acid level decreased	37.0% 10/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.	33.3% 9/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.
Skin and subcutaneous tissue disorders Rash	18.5% 5/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.	7.4% 2/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.
Eye disorders Conjunctivitis	7.4% 2/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.	11.1% 3/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.
Injury, poisoning and procedural complications Fall	7.4% 2/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.	11.1% 3/27 • From the first dose of study drug administration up to 31 days after the last dose of study drug administration Safety population included all subjects who either received at least one dose of Kuvan in the study period, or were randomized to Phe-restricted diet alone and who had some safety assessment data available.