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    Clinical Trial Results:
    A Phase IV Open-Label, Single-Cohort Study of the Long-Term Neurocognitive Outcomes in 4 to 5 Year-Old Children with Phenylketonuria Treated with Sapropterin Dihydrochloride (Kuvan®) for 7 Years.

    Summary
    EudraCT number
    		 2009-015844-41
    Trial protocol
    		 GB   DE   IT   ES  
    Global end of trial date
    04 Jan 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Nov 2023
    First version publication date
    26 Nov 2023
    Other versions
    Summary report(s)
    		 BMN 162-502_Endpoint_Screenshot

    Trial information

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    Trial identification
    Sponsor protocol code
    EMR700773-002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01965912
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    BioMarin Pharmaceutical Inc
    Sponsor organisation address
    105 Digital Drive, Novato, United States, 94949
    Public contact
    Clinical Trials Information, BioMarin Pharmaceutical Inc., MedInfo@bmrn.com
    Scientific contact
    Clinical Trials Information, BioMarin Pharmaceutical Inc., MedInfo@bmrn.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    04 Jan 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Jan 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Jan 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate the long-term neurocognitive (NC) outcomes in children with hyperphenylalaninemia (HPA) due to phenylketonuria (PKU) treated with Kuvan® and a phenylalanine (Phe)-restricted diet for 7 years.
    Protection of trial subjects
    The study was conducted in compliance with the protocol, with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP), and with all applicable Regulatory Authority requirements and national laws.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Oct 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    United Kingdom: 13
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Italy: 7
    Worldwide total number of subjects
    34
    EEA total number of subjects
    34
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    34
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a multi-center study conducted at 12 study centers in four countries Germany (2), Italy (3), Spain (3) and the United Kingdom (4).

    Pre-assignment
    Screening details
    		 A total of 50 subjects were screened to participate in the study, 16 subjects did not meet the eligibility criteria and were considered screen failures and 34 were enrolled in the study.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Kuvan
    Arm description
    		 Kuvan® oral soluble tablet will be administered once daily along with Phenylalanine-restricted diet for a period of 7 years. Dosage of Kuvan® could range from 5 to 20 milligram per kilogram per day (mg/kg/day), as per Summary of Product Characteristics (SmPC).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Kuvan
    Investigational medicinal product code
    Other name
    Sapropterin dihydrochloride
    Pharmaceutical forms
    Soluble tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Kuvan was administered dissolved in water orally once daily. During the study period, the Kuvan dose administered was adjusted between 5 and 20 mg/kg/day, following recommendations of the SmPC. The aim of the dose adjustment was to fulfill the therapeutic goal: maintain, by adjustment of dietary Phe intake and/or Kuvan dosage, the blood Phe levels within the recommended target range of ≥120 to <360 μmol/L. Total daily dose was adjusted according to body weight every 3 months if necessary.

    Number of subjects in period 1
    		Kuvan
    Started
    34
    Completed
    32
    Not completed
    2
         Consent withdrawn by subject
    1
         Due to Kuvan having no beneficial effect after 4 m
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial (overall period)
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial (overall period) Total
    Number of subjects
    		 34 34
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 4.91 ( 0.737 ) -
    Gender categorical
    Units: Subjects
        Female
    		 17 17
        Male
    		 17 17
    Race
    Units: Subjects
        White
    		 33 33
        Black or African American
    		 0 0
        Asian
    		 1 1
        American Indian or Alaska Native
    		 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0
        Other
    		 0 0
    Country
    Units: Subjects
        Germany
    		 3 3
        Italy
    		 7 7
        Spain
    		 11 11
        United Kingdom
    		 13 13
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 108.99 ( 6.540 ) -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 19.76 ( 3.928 ) -
    BMI
    Body Mass Index (BMI)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 16.50 ( 1.967 ) -
    Subject analysis sets

    Subject analysis set title
    Naive Subjects
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects that had taken at least one dose of study treatment (Kuvan) on or after Day 1 visit of study period were included in the ITT analysis set. Subjects were classified as naïve, if on the eCRF page “Medical History of PKU” [Item 7] “Was the subject pre-treated with BH4/Kuvan?” was recorded “No.”

    Subject analysis set title
    Previously Treated
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects were classified as previously treated, if on the eCRF page “Medical History of PKU” [Item 7] “Was the subject pre-treated with BH4/Kuvan?” was recorded “Yes.”

    Subject analysis sets values
    		 Naive Subjects Previously Treated
    Number of subjects
    11
    23
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    5.15 ( 0.800 )
    4.79 ( 0.692 )
    Gender categorical
    Units: Subjects
        Female
    6
    11
        Male
    5
    12
    Race
    Units: Subjects
        White
    10
    23
        Black or African American
    0
    0
        Asian
    1
    0
        American Indian or Alaska Native
    0
    0
        Native Hawaiian or Other Pacific Islander
    0
    0
        Other
    0
    0
    Country
    Units: Subjects
        Germany
    0
    3
        Italy
    3
    4
        Spain
    0
    11
        United Kingdom
    8
    5
    Height
    Units: cm
        arithmetic mean (standard deviation)
    111.96 ( 7.752 )
    107.57 ( 5.505 )
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    22.51 ( 4.671 )
    18.45 ( 2.766 )
    BMI
    Body Mass Index (BMI)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    17.81 ( 2.384 )
    15.88 ( 1.400 )

    End points

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    End points reporting groups
    Reporting group title
    Kuvan
    Reporting group description
    		 Kuvan® oral soluble tablet will be administered once daily along with Phenylalanine-restricted diet for a period of 7 years. Dosage of Kuvan® could range from 5 to 20 milligram per kilogram per day (mg/kg/day), as per Summary of Product Characteristics (SmPC).

    Subject analysis set title
    Naive Subjects
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects that had taken at least one dose of study treatment (Kuvan) on or after Day 1 visit of study period were included in the ITT analysis set. Subjects were classified as naïve, if on the eCRF page “Medical History of PKU” [Item 7] “Was the subject pre-treated with BH4/Kuvan?” was recorded “No.”

    Subject analysis set title
    Previously Treated
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects were classified as previously treated, if on the eCRF page “Medical History of PKU” [Item 7] “Was the subject pre-treated with BH4/Kuvan?” was recorded “Yes.”

    Primary: Mean Full Scale Intelligence Quotient (FSIQ) Score of the Wechsler Intelligence Scale for Children (WISC)-IV

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    End point title
    		 Mean Full Scale Intelligence Quotient (FSIQ) Score of the Wechsler Intelligence Scale for Children (WISC)-IV
    End point description
    IQ scores of the general population have a normal distribution and are standardized for age to have an average of 100 points (±15) (13;14). IQ between 85 and 115 and are considered to have a normal IQ, i.e., within 1 standard deviation (SD) of the norm. IQ scores between 70 and 85 are considered as borderline intellectual functioning, and mental retardation is diagnosed when IQ scores are below -2 SD (<70) (13;14). Overall: Year 2 Full Scale IQ (n=32), Year 4 Full Scale IQ (n=32), Year 7 Full Scale IQ (n=31) Naϊve Subjects: Year 2 Full Scale IQ (n=9), Year 4 Full Scale IQ (n=9), Year 7 Full Scale IQ (n=9) Previously Treated: Year 2 Full Scale IQ (n=23), Year 4 Full Scale IQ (n=23), Year 7 Full Scale IQ (n=22)
    End point type
    Primary
    End point timeframe
    Up to 7 Years.
    End point values
    		 Kuvan Naive Subjects Previously Treated
    Number of subjects analysed
    32
    9
    23
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Year 2 Full Scale IQ
    99.2 ( 12.92 )
    95.7 ( 16.24 )
    100.6 ( 11.49 )
        Year 4 Full Scale IQ
    101.9 ( 13.93 )
    99.7 ( 19.87 )
    102.7 ( 11.28 )
        Year 7 Full Scale IQ
    99.8 ( 14.63 )
    95.8 ( 20.10 )
    101.4 ( 11.92 )
    Statistical analysis title
    		 Change from BL in IQ scores- Last 2 yrs FSIQ diffe
    Statistical analysis description
    Last 2 years FSIQ Difference- ITT Analysis Set
    Comparison groups
    Naive Subjects v Previously Treated
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.028 [1]
    Method
    		 t-test, 2-sided
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.9
         upper limit
    		 -0.4
    Notes
    [1] - p-values obtained from a paired difference between the last two available FSIQ assessments that were at least two years apart for each subject.

    Secondary: Height compared to the 2006 World Health Organization (WHO) Growth Standards at each timepoint.

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    End point title
    		 Height compared to the 2006 World Health Organization (WHO) Growth Standards at each timepoint.
    End point description
    Absolute values represent the differences between WHO Growth Standards and study subjects. Results are expressed in standard deviation score (SDS, also referred to as Z-score). Baseline is defined as last value prior to or on first Kuvan treatment within study. End of Treatment (EOT) is defined as last post-Baseline value for subjects who terminated Kuvan treatment Standard Deviation Scores (SDS) calculated using 2006 WHO Child Growth Standards and the 2007 WHO SAS macro package. Baseline (BL) ITT Analysis Set population: Boys (n=17) and Girls (n=17).
    End point type
    Secondary
    End point timeframe
    Every 6 months from Baseline through the end of the study or ET. End of Treatment (ET).
    End point values
    		 Kuvan
    Number of subjects analysed
    34
    Units: SDS
    arithmetic mean (standard deviation)
        Height SDS: Baseline-Absolute: Boys (n=17)
    0.08 ( 1.095 )
        Height SDS: Month 6-Absolute: Boys (n=17)
    0.07 ( 1.035 )
        Height SDS: Month 6-Change from BL: Boys (n=17)
    -0.01 ( 0.472 )
        Height SDS: Month 12-Absolute: Boys (n=17)
    0.17 ( 0.947 )
        Height SDS: Month 12-Change from BL: Boys (n=17)
    0.09 ( 0.581 )
        Height SDS: Month 18-Absolute: Boys (n=16)
    0.16 ( 0.864 )
        Height SDS: Month 18-Change from BL: Boys (n=16)
    0.23 ( 0.439 )
        Height SDS: Month 24-Absolute: Boys (n=16)
    0.10 ( 0.855 )
        Height SDS: Month 24-Change from BL: Boys (n=16)
    0.16 ( 0.640 )
        Height SDS: Month 30-Absolute: Boys (n=16)
    -0.00 ( 0.961 )
        Height SDS: Month 30-Change from BL: Boys (n=16)
    0.06 ( 0.653 )
        Height SDS: Month 36-Absolute: Boys (n=16)
    0.10 ( 0.876 )
        Height SDS: Month 36-Change from BL: Boys (n=16)
    0.17 ( 0.668 )
        Height SDS: Month 42-Absolute: Boys (n=16)
    0.16 ( 0.906 )
        Height SDS: Month 42-Change from BL: Boys (n=16)
    0.22 ( 0.640 )
        Height SDS: Month 48-Absolute: Boys (n=16)
    0.14 ( 0.959 )
        Height SDS: Month 48-Change from BL: Boys (n=16)
    0.20 ( 0.671 )
        Height SDS: Month 54-Absolute: Boys (n=15)
    0.14 ( 0.887 )
        Height SDS: Month 54-Change from BL: Boys (n=15)
    0.22 ( 0.721 )
        Height SDS: Month 60-Absolute: Boys (n=15)
    0.20 ( 0.885 )
        Height SDS: Month 60-Change from BL: Boys (n=15)
    0.28 ( 0.760 )
        Height SDS: Month 66-Absolute: Boys (n=16)
    0.16 ( 0.827 )
        Height SDS: Month 66-Change from BL: Boys (n=16)
    0.22 ( 0.730 )
        Height SDS: Month 72-Absolute: Boys (n=12)
    0.01 ( 0.903 )
        Height SDS: Month 72-Change from BL: Boys (n=12)
    0.19 ( 0.720 )
        Height SDS: Month 78-Absolute: Boys (n=13)
    0.07 ( 0.809 )
        Height SDS: Month 78-Change from BL: Boys (n=13)
    0.14 ( 0.688 )
        Height SDS: Month 84-Absolute: Boys (n=15)
    0.31 ( 0.940 )
        Height SDS: Month 84-Change from BL: Boys (n=15)
    0.44 ( 0.759 )
        Height SDS: End of treatment-Absolute: Boys(n=17
    0.42 ( 1.041 )
        Height SDS: EOT-Change from Baseline: Boys (n=17
    0.34 ( 0.795 )
        Height SDS: Baseline-Absolute: Girls (n=17)
    -0.02 ( 0.818 )
        Height SDS: Month 6-Absolute: Girls (n=15)
    0.20 ( 0.865 )
        Height SDS: Month 6-Change from BL: Girls (n=15)
    0.26 ( 0.421 )
        Height SDS: Month 12-Absolute: Girls (n=16)
    0.15 ( 0.867 )
        Height SDS: Month 12-Change from BL: Girls (n=16
    0.24 ( 0.326 )
        Height SDS: Month 18-Absolute: Girls (n=16)
    0.20 ( 0.860 )
        Height SDS: Month 18-Change from BL: Girls (n=16
    0.29 ( 0.423 )
        Height SDS: Month 24-Absolute: Girls (n=16)
    0.16 ( 0.890 )
        Height SDS: Month 24-Change from BL: Girls (n=16
    0.25 ( 0.425 )
        Height SDS: Month 30-Absolute: Girls (n=16)
    0.23 ( 0.946 )
        Height SDS: Month 30-Change from BL: Girls (n=16
    0.32 ( 0.504 )
        Height SDS: Month 36-Absolute: Girls (n=16)
    0.16 ( 0.904 )
        Height SDS: Month 36-Change from BL: Girls (n=16
    0.25 ( 0.469 )
        Height SDS: Month 42-Absolute: Girls (n=16)
    0.12 ( 0.889 )
        Height SDS: Month 42-Change from BL: Girls (n=16
    0.21 ( 0.464 )
        Height SDS: Month 48-Absolute: Girls (n=16)
    0.08 ( 0.943 )
        Height SDS: Month 48-Change from BL: Girls (n=16
    0.17 ( 0.462 )
        Height SDS: Month 54-Absolute: Girls (n=15)
    -0.05 ( 0.814 )
        Height SDS: Month 54-Change from BL: Girls (n=15
    0.14 ( 0.520 )
        Height SDS: Month 60-Absolute: Girls (n=15)
    -0.12 ( 0.798 )
        Height SDS: Month 60-Change from BL: Girls (n=15
    0.07 ( 0.580 )
        Height SDS: Month 66-Absolute: Girls (n=16)
    0.06 ( 0.937 )
        Height SDS: Month 66-Change from BL: Girls (n=16
    0.16 ( 0.586 )
        Height SDS: Month 72-Absolute: Girls (n=14)
    0.15 ( 0.807 )
        Height SDS: Month 72-Change from BL: Girls (n=14
    0.10 ( 0.601 )
        Height SDS: Month 78-Absolute: Girls (n=14)
    0.42 ( 0.815 )
        Height SDS: Month 78-Change from BL: Girls (n=14
    0.45 ( 0.626 )
        Height SDS: Month 84-Absolute: Girls (n=16)
    0.20 ( 0.952 )
        Height SDS: Month 84-Change from BL: Girls (n=16)
    0.29 ( 0.624 )
        Height SDS:End of treatment-Absolute: Girls(n=17
    0.26 ( 0.960 )
        Height SDS: EOT-Change from Baseline: Girls(n=17)
    0.28 ( 0.606 )
    No statistical analyses for this end point

    Secondary: Weight compared to the 2006 World Health Organization (WHO) Growth Standards at each timepoint.

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    End point title
    		 Weight compared to the 2006 World Health Organization (WHO) Growth Standards at each timepoint.
    End point description
    ITT Analysis Set: Boys (n=17) & Girls (n=17). Refer attached file for Values of month 72, 78 and 84 for both boys and girls as number of subject analyzed is zero.
    End point type
    Secondary
    End point timeframe
    Upto 7 years
    End point values
    		 Kuvan
    Number of subjects analysed
    34
    Units: SDS
    arithmetic mean (standard deviation)
        Weight SDS: Baseline-Absolute: Boys (n=17)
    0.41 ( 1.192 )
        Weight SDS: Month 6-Absolute: Boys (n=17)
    0.47 ( 1.118 )
        Weight SDS: Month 6-Change from BL: Boys (n=17)
    0.07 ( 0.243 )
        Weight SDS: Month 12-Absolute: Boys (n=17)
    0.54 ( 1.095 )
        Weight SDS: Month 12-Change from BL: Boys (n=17)
    0.13 ( 0.334 )
        Weight SDS: Month 18-Absolute: Boys (n=16)
    0.50 ( 0.945 )
        Weight SDS: Month 18-Change from BL: Boys (n=16)
    0.29 ( 0.400 )
        Weight SDS: Month 24-Absolute: Boys (n=16)
    0.50 ( 0.967 )
        Weight SDS: Month 24-Change from BL: Boys (n=16)
    0.29 ( 0.558 )
        Weight SDS: Month 30-Absolute: Boys (n=16)
    0.46 ( 0.962 )
        Weight SDS: Month 30-Change from BL: Boys (n=16)
    0.25 ( 0.532 )
        Weight SDS: Month 36-Absolute: Boys (n=16)
    0.55 ( 0.918 )
        Weight SDS: Month 36-Change from BL: Boys (n=16)
    0.34 ( 0.550 )
        Weight SDS: Month 42-Absolute: Boys (n=16)
    0.70 ( 0.962 )
        Weight SDS: Month 42-Change from BL: Boys (n=16)
    0.49 ( 0.657 )
        Weight SDS: Month 48-Absolute: Boys (n=16)
    0.71 ( 0.976 )
        Weight SDS: Month 48-Change from BL: Boys (n=16)
    0.49 ( 0.695 )
        Weight SDS: Month 54-Absolute: Boys (n=11)
    0.62 ( 0.877 )
        Weight SDS: Month 54-Change from BL: Boys (n=11)
    0.82 ( 0.686 )
        Weight SDS: Month 60-Absolute: Boys (n=8)
    0.50 ( 1.119 )
        Weight SDS: Month 60-Change from BL: Boys (n=8)
    0.96 ( 0.795 )
        Weight SDS: Month 66-Absolute: Boys (n=7)
    0.46 ( 0.811 )
        Weight SDS: Month 66-Change from BL: Boys (n=7)
    0.71 ( 0.466 )
        Weight SDS: End of treatment-Absolute: Boys(n=17)
    1.01 ( 1.060 )
        Weight SDS: EOT-Change from Baseline: Boys (n=17)
    0.60 ( 0.684 )
        Weight SDS: Baseline-Absolute: Girls (n=17)
    0.60 ( 1.065 )
        Weight SDS: Month 6-Absolute: Girls (n=15)
    0.55 ( 1.014 )
        Weight SDS: Month 6-Change from BL: Girls (n=15)
    0.10 ( 0.217 )
        Weight SDS: Month 12-Absolute: Girls (n=16)
    0.69 ( 1.033 )
        Weight SDS: Month 12-Change from BL: Girls (n=16)
    0.20 ( 0.245 )
        Weight SDS: Month 18-Absolute: Girls (n=16)
    0.80 ( 0.963 )
        Weight SDS: Month 18-Change from BL: Girls (n=16)
    0.31 ( 0.337 )
        Weight SDS: Month 24-Absolute: Girls (n=16)
    0.76 ( 1.053 )
        Weight SDS: Month 24-Change from BL: Girls (n=16)
    0.28 ( 0.422 )
        Weight SDS: Month 30-Absolute: Girls (n=16)
    0.79 ( 1.064 )
        Weight SDS: Month 30-Change from BL: Girls (n=16)
    0.30 ( 0.516 )
        Weight SDS: Month 36-Absolute: Girls (n=16)
    0.74 ( 1.122 )
        Weight SDS: Month 36-Change from BL: Girls (n=16)
    0.25 ( 0.520 )
        Weight SDS: Month 42-Absolute: Girls (n=16)
    0.78 ( 1.165 )
        Weight SDS: Month 42-Change from BL: Girls (n=16)
    0.29 ( 0.539 )
        Weight SDS: Month 48-Absolute: Girls (n=14)
    0.67 ( 1.287 )
        Weight SDS: Month 48-Change from BL: Girls (n=14)
    0.25 ( 0.602 )
        Weight SDS: Month 54-Absolute: Girls (n=10)
    0.61 ( 0.490 )
        Weight SDS: Month 54-Change from BL: Girls (n=10)
    0.20 ( 0.590 )
        Weight SDS: Month 60-Absolute: Girls (n=8)
    0.61 ( 0.417 )
        Weight SDS: Month 60-Change from BL: Girls (n=8)
    0.16 ( 0.570 )
        Weight SDS: Month 66-Absolute: Girls (n=7)
    1.19 ( 1.046 )
        Weight SDS: Month 66-Change from BL: Girls (n=7)
    0.48 ( 0.666 )
        Weight SDS: End of treatment-Absolute: Girls(n=17)
    0.82 ( 1.112 )
        Weight SDS: EOT-Change from Baseline: Girls(n=17)
    0.22 ( 0.588 )
    No statistical analyses for this end point

    Secondary: Blood levels of tyrosine & tryptophan compared to age-related norms.

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    End point title
    		 Blood levels of tyrosine & tryptophan compared to age-related norms.
    End point description
    Tyrosine (the precursor of dopamine and an essential amino-acid in PKU patients measured as part of standard-of-care to verify if dietary intake of Tyr is adequate). Tryptophan (an essential amino acid and precursor of the neurotransmitter serotonin).
    End point type
    Secondary
    End point timeframe
    Screening, Every 6 months and at ET Visit.
    End point values
    		 Kuvan
    Number of subjects analysed
    34
    Units: μmol/L
    arithmetic mean (standard deviation)
        Tyrosine: Baseline-Absolute (n=31)
    61.73 ( 41.353 )
        Tyrosine: Month 6-Absolute (n=31)
    65.39 ( 37.916 )
        Tyrosine: Month 6-Change from Baseline (n=28)
    4.31 ( 40.139 )
        Tyrosine: Month 12-Absolute (n=32)
    76.42 ( 48.715 )
        Tyrosine: Month 12-Change from Baseline (n=29)
    10.57 ( 36.377 )
        Tyrosine: Month 18-Absolute (31)
    69.12 ( 38.494 )
        Tyrosine: Month 18-Change from Baseline (n=29)
    8.54 ( 31.130 )
        Tyrosine: Month 24-Absolute (n=31)
    73.47 ( 48.148 )
        Tyrosine: Month 24-Change from Baseline (n=28)
    12.00 ( 35.216 )
        Tyrosine: Month 30-Absolute (n=30)
    72.73 ( 37.864 )
        Tyrosine: Month 30- Change from Baseline (n=27)
    10.30 ( 23.656 )
        Tyrosine: Month 36-Absolute (n=32)
    68.91 ( 39.842 )
        Tyrosine: Month 36- Change from Baseline (n=29)
    7.90 ( 37.220 )
        Tyrosine: Month 42-Absolute (n=31)
    71.54 ( 42.393 )
        Tyrosine: Month 42-Change from Baseline (n=28)
    9.67 ( 35.511 )
        Tyrosine: Month 48-Absolute (n=32)
    67.55 ( 37.065 )
        Tyrosine: Month 48-Change from Baseline (n=29)
    8.25 ( 30.397 )
        Tyrosine: Month 54-Absolute (n=29)
    58.52 ( 26.076 )
        Tyrosine: Month 54-Change from Baseline (n=28)
    4.99 ( 36.114 )
        Tyrosine: Month 60-Absolute (n=27)
    60.99 ( 24.068 )
        Tyrosine: Month 60-Change from Baseline (n=26)
    2.83 ( 32.292 )
        Tyrosine: Month 66-Absolute (n=28)
    61.00 ( 29.208 )
        Tyrosine: Month 66-Change from Baseline (n=26)
    4.36 ( 26.800 )
        Tyrosine: Month 72-Absolute (n=19)
    52.87 ( 23.427 )
        Tyrosine: Month 72-Change from Baseline (n=17)
    -3.78 ( 29.404 )
        Tyrosine: Month 78-Absolute (n=22)
    58.50 ( 21.035 )
        Tyrosine: Month 78-Change from Baseline (n=20)
    8.32 ( 27.904 )
        Tyrosine: Month 84-Absolute (n=25)
    62.85 ( 22.573 )
        Tyrosine: Month 84-Change from Baseline (n=22)
    7.59 ( 27.905 )
        Tyrosine: End of Treatment- Absolute (n=34)
    61.97 ( 24.186 )
        Tyrosine:End of Treatment-Change from BL (n=31)
    -1.56 ( 35.418 )
        Tryptophane: Baseline-Absolute (n=32)
    49.87 ( 21.437 )
        Tryptophane: Month 6-Absolute (n=31)
    58.39 ( 18.360 )
        Tryptophane: Month 6-Change from Baseline (n=29)
    6.90 ( 21.379 )
        Tryptophane: Month 12-Absolute (n=32)
    60.92 ( 18.717 )
        Tryptophane: Month 12-Change from Baseline (n=30)
    10.68 ( 16.924 )
        Tryptophane: Month 18-Absolute (n=31)
    56.75 ( 17.500 )
        Tryptophane: Month 18-Change from Baseline (n=30)
    8.05 ( 23.343 )
        Tryptophane: Month 24-Absolute (n=31)
    55.48 ( 15.640 )
        Tryptophane: Month 24-Change from Baseline (n=29)
    7.24 ( 19.228 )
        Tryptophane: Month 30-Absolute (n=30)
    57.38 ( 16.139 )
        Tryptophane: Month 30- Change from Baseline (n=28)
    7.74 ( 19.814 )
        Tryptophane: Month 36-Absolute (n=32)
    57.96 ( 14.691 )
        Tryptophane: Month 36- Change from Baseline (n=30)
    8.64 ( 21.998 )
        Tryptophane: Month 42-Absolute (n=31)
    58.48 ( 18.117 )
        Tryptophane: Month 42-Change from Baseline (n=29)
    8.79 ( 22.865 )
        Tryptophane: Month 48-Absolute (n=32)
    53.72 ( 12.888 )
        Tryptophane: Month 48-Change from Baseline (n=30)
    5.58 ( 20.633 )
        Tryptophane: Month 54-Absolute (n=29)
    51.76 ( 12.437 )
        Tryptophane: Month 54-Change from Baseline (n=29)
    5.11 ( 23.255 )
        Tryptophane: Month 60-Absolute (n=27)
    55.59 ( 11.446 )
        Tryptophane: Month 60-Change from Baseline (n=27)
    8.17 ( 21.023 )
        Tryptophane: Month 66-Absolute (n=28)
    51.96 ( 10.654 )
        Tryptophane: Month 66-Change from Baseline (n=27)
    3.11 ( 17.442 )
        Tryptophane: Month 72-Absolute ((n=19)
    50.28 ( 10.626 )
        Tryptophane: Month 72-Change from Baseline ((n=18)
    2.90 ( 18.653 )
        Tryptophane: Month 78-Absolute (n=22)
    54.59 ( 10.706 )
        Tryptophane: Month 78-Change from Baseline ((n=21)
    9.19 ( 16.714 )
        Tryptophane: Month 84-Absolute ((n=25)
    53.47 ( 12.106 )
        Tryptophane: Month 84-Change from Baseline (n=23)
    8.88 ( 19.700 )
        Tryptophane: End of Treatment-Absolute (n=34)
    55.45 ( 13.543 )
        Tryptophane:End of Treatment-Change from BL (n=32)
    5.12 ( 20.673 )
    No statistical analyses for this end point

    Secondary: Blood levels of pre-albumin compared to age-related norms

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    End point title
    		 Blood levels of pre-albumin compared to age-related norms
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, every 6 months and end of treatment.
    End point values
    		 Kuvan
    Number of subjects analysed
    34
    Units: g/L
    arithmetic mean (standard deviation)
        Prealbumin: Baseline- Absolute (n=32)
    0.174 ( 0.0391 )
        Prealbumin: Month 6-Absolute (n=31)
    0.196 ( 0.0478 )
        Prealbumin: Month 6-Change from Baseline (n=29)
    0.024 ( 0.0521 )
        Prealbumin: Month 12-Absolute (n=32)
    0.198 ( 0.0341 )
        Prealbumin: Month 12-Change from Baseline (n=30)
    0.023 ( 0.0351 )
        Prealbumin: Month 18-Absolute (n=32)
    0.203 ( 0.0304 )
        Prealbumin: Month 18-Change from Baseline (n=30)
    0.030 ( 0.0376 )
        Prealbumin: Month 24-Absolute (n=30)
    0.193 ( 0.0321 )
        Prealbumin: Month 24-Change from Baseline (n=28)
    0.022 ( 0.0403 )
        Prealbumin: Month 30-Absolute (n=30)
    0.209 ( 0.0359 )
        Prealbumin: Month 30-Change from Baseline (n=28)
    0.036 ( 0.0334 )
        Prealbumin: Month 36-Absolute (n=32)
    0.203 ( 0.0302 )
        Prealbumin: Month 36-Change from Baseline (n=30)
    0.029 ( 0.0390 )
        Prealbumin: Month 42-Absolute (n=32)
    0.211 ( 0.0319 )
        Prealbumin: Month 42-Change from Baseline (n=30)
    0.038 ( 0.0451 )
        Prealbumin: Month 48-Absolute (n=31)
    0.205 ( 0.0284 )
        Prealbumin: Month 48-Change from Baseline (n=29)
    0.037 ( 0.0388 )
        Prealbumin: Month 54-Absolute (n=30)
    0.204 ( 0.0284 )
        Prealbumin: Month 54-Change from Baseline (n=30)
    0.033 ( 0.0389 )
        Prealbumin: Month 60-Absolute (n=27)
    0.208 ( 0.0327 )
        Prealbumin: Month 60-Change from Baseline (n=27)
    0.038 ( 0.0427 )
        Prealbumin: Month 66-Absolute (n=30)
    0.214 ( 0.0388 )
        Prealbumin: Month 66-Change from Baseline (n=28)
    0.036 ( 0.0359 )
        Prealbumin: Month 72-Absolute (n=20)
    0.220 ( 0.0369 )
        Prealbumin: Month 72-Change from Baseline (n=18)
    0.046 ( 0.0473 )
        Prealbumin: Month 78-Absolute (n=22)
    0.216 ( 0.0347 )
        Prealbumin: Month 78-Change from Baseline (n=20)
    0.046 ( 0.0429 )
        Prealbumin: Month 84-Absolute (n=27)
    0.226 ( 0.0332 )
        Prealbumin: Month 84-Change from Baseline (n=25)
    0.053 ( 0.0350 )
        Prealbumin: End of Treatment-Absolute (n=34)
    0.221 ( 0.0336 )
        Prealbumin: EOT-Change from Baseline (n=32)
    0.044 ( 0.0384 )
    No statistical analyses for this end point

    Secondary: Blood levels of methylmalonic acid compared to age-related norms.

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    End point title
    		 Blood levels of methylmalonic acid compared to age-related norms.
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 7 years.
    End point values
    		 Kuvan
    Number of subjects analysed
    34
    Units: nmol/L
    arithmetic mean (standard deviation)
        Methylmalonic acid: Baseline-Absolute (n=32)
    143.00 ( 50.931 )
        Methylmalonic acid: Month 6-Absolute (n=31)
    129.19 ( 51.688 )
        Methylmalonic acid: Month 6-Change from BL (n=29)
    -16.14 ( 44.051 )
        Methylmalonic acid: Month 12-Absolute (n=31)
    139.61 ( 50.302 )
        Methylmalonic acid: Month 12-Change from BL (n=29)
    -4.76 ( 49.530 )
        Methylmalonic acid: Month 18-Absolute (n=31)
    140.90 ( 58.793 )
        Methylmalonic acid: Month 18-Change from BL (n=30)
    -6.63 ( 52.901 )
        Methylmalonic acid: Month 24-Absolute (n=31)
    127.90 ( 49.556 )
        Methylmalonic acid: Month 24-Change from BL (n=29)
    -15.17 ( 42.777 )
        Methylmalonic acid: Month 30-Absolute (n=30)
    127.53 ( 45.890 )
        Methylmalonic acid: Month 30-Change from BL (n=28)
    -16.32 ( 45.622 )
        Methylmalonic acid: Month 36-Absolute (n=32)
    136.97 ( 55.907 )
        Methylmalonic acid: Month 36-Change from BL (n=30)
    -4.00 ( 53.718 )
        Methylmalonic acid: Month 42-Absolute (n=31)
    135.55 ( 46.326 )
        Methylmalonic acid: Month 42-Change from BL (n=29)
    -7.45 ( 53.348 )
        Methylmalonic acid: Month 48-Absolute (n=32)
    133.63 ( 48.463 )
        Methylmalonic acid: Month 48-Change from BL (n=30)
    -8.50 ( 50.078 )
        Methylmalonic acid: Month 54-Absolute (n=29)
    129.31 ( 38.843 )
        Methylmalonic acid: Month 54-Change from BL (n=29)
    -14.10 ( 49.861 )
        Methylmalonic acid: Month 60-Absolute (n=27)
    137.07 ( 45.473 )
        Methylmalonic acid: Month 60-Change from BL (n=27)
    -2.96 ( 53.840 )
        Methylmalonic acid: Month 66-Absolute (n=27)
    139.59 ( 45.487 )
        Methylmalonic acid: Month 66-Change from BL (n=26)
    -7.04 ( 48.962 )
        Methylmalonic acid: Month 72-Absolute (n=19)
    145.05 ( 80.098 )
        Methylmalonic acid: Month 72-Change from BL (n=18)
    7.17 ( 98.547 )
        Methylmalonic acid: Month 78-Absolute (n=22)
    153.05 ( 58.359 )
        Methylmalonic acid: Month 78-Change from BL (n=21)
    6.48 ( 82.927 )
        Methylmalonic acid: Month 84-Absolute (n=25)
    167.60 ( 69.135 )
        Methylmalonic acid: Month 84-Change from BL (n=23)
    24.87 ( 80.983 )
        Methylmalonic acid:End of Treatment-Absolute(n=34)
    162.50 ( 70.984 )
        Methylmalonic acid:EOT Change from Baseline (n=32)
    20.06 ( 87.214 )
    No statistical analyses for this end point

    Secondary: Intelligence Quotient (IQ) score and sub-scores such as, verbal IQ, performance IQ, Full Scale Intelligence Quotient (FSIQ) of Wechsler Preschool and Primary Scale of Intelligence (WPPSI)-III

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    End point title
    		 Intelligence Quotient (IQ) score and sub-scores such as, verbal IQ, performance IQ, Full Scale Intelligence Quotient (FSIQ) of Wechsler Preschool and Primary Scale of Intelligence (WPPSI)-III
    End point description
    WPPSITM-III (Wechsler Preschool and Primary Scale of Intelligence 3rd edition) for subjects >=4 and <6 years-old at baseline. Scores are: Full Scale IQ (overall score), Verbal IQ and Performance IQ . This validated test has two parts: Part 1 for children aged 2 years 6 months to 3 years 11 months and Part 2 for children 4 years to 7 years and 3 months. The second part of the WPPSITM-III will be used to assess baseline IQ. Baseline is defined as last value prior to or on first Kuvan treatment within study.
    End point type
    Secondary
    End point timeframe
    At Baseline.
    End point values
    		 Kuvan Naive Subjects Previously Treated
    Number of subjects analysed
    34
    11
    23
    Units: Score on a scale
    arithmetic mean (standard deviation)
        WPPSI-III: Full Scale IQ
    100.9 ( 13.03 )
    102.9 ( 12.86 )
    100.0 ( 13.29 )
        WPPSI-III: Verbal IQ
    104.2 ( 13.91 )
    103.9 ( 10.68 )
    104.4 ( 15.44 )
        WPPSI-III: Performance IQ
    95.9 ( 12.49 )
    96.0 ( 14.26 )
    95.8 ( 11.90 )
    No statistical analyses for this end point

    Secondary: Intelligence Quotient (IQ) score and sub-scores such as verbal comprehension, perceptual reasoning, working memory, and processing speed indexes and Full Scale Intelligence Quotient (FSIQ) of the Wechsler Intelligence Scale for Children (WISC)-IV

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    End point title
    		 Intelligence Quotient (IQ) score and sub-scores such as verbal comprehension, perceptual reasoning, working memory, and processing speed indexes and Full Scale Intelligence Quotient (FSIQ) of the Wechsler Intelligence Scale for Children (WISC)-IV
    End point description
    WISC®-IV (Wechsler Intelligence Scale for Children 4th edition) for children for children aged 6 years to 16 years and 11 months at post-baseline visits. Year2 Full Scale IQ: Overall(n=32),Naive(n=9)&Previously Treated(n=23) Year2 Verbal Comprehension Index: Overall(n=32),Naive(n=9)&Previously Treated(n=23) Year2 Perceptual Reasoning Index: Overall (n=31),Naive (n=9)&Previously Treated(n=22) Year2 Working Memory Index: Overall (n=31),Naive (n=9)&Previously Treated(n=22) Year2 Processing Speed Index: Overall(n=32),Naive(n=9)&Previously Treated(n=23) Year4 Full Scale IQ, Verbal Comprehension Index, Perceptual Reasoning Index, Working Memory Index, Processing Speed Index: Overall (n=32),Naive (n=9)&Previously Treated(n=23). Year7 Full Scale IQ, Verbal Comprehension Index, Perceptual Reasoning Index, Working Memory Index, Processing Speed Index: Overall (n=31),Naive (n=9)&Previously Treated(n=22).
    End point type
    Secondary
    End point timeframe
    At 2, 4, 7 Years.
    End point values
    		 Kuvan Naive Subjects Previously Treated
    Number of subjects analysed
    34
    9
    23
    Units: Score on a scale
    arithmetic mean (standard deviation)
        WPPSI-IV: Year 2 Full Scale IQ
    99.2 ( 12.92 )
    95.7 ( 16.24 )
    100.6 ( 11.49 )
        WPPSI-IV: Year 2 Verbal Comprehension Index
    104.0 ( 12.36 )
    98.4 ( 13.91 )
    106.2 ( 11.28 )
        WPPSI-IV: Year 2 Perceptual Reasoning Index
    101.4 ( 12.74 )
    99.8 ( 16.05 )
    102.0 ( 11.50 )
        WPPSI-IV: Year 2 Working Memory Index
    93.9 ( 12.40 )
    91.2 ( 16.69 )
    95.0 ( 10.44 )
        WPPSI-IV: Year 2 Processing Speed Index
    94.1 ( 13.70 )
    94.0 ( 18.19 )
    94.1 ( 12.01 )
        WISC-IV : Year 4 Full Scale IQ
    101.9 ( 13.93 )
    99.7 ( 19.87 )
    102.7 ( 11.28 )
        WISC-IV : Year 4 Verbal Comprehension Index
    104.9 ( 12.19 )
    104.6 ( 18.36 )
    105.0 ( 9.31 )
        WISC-IV : Year 4 Perceptual Reasoning Index
    100.4 ( 12.82 )
    96.7 ( 15.16 )
    101.8 ( 11.85 )
        WISC-IV : Year 4 Working Memory Index
    99.0 ( 13.54 )
    95.3 ( 16.70 )
    100.4 ( 12.21 )
        WISC-IV : Year 4 Processing Speed Index
    98.8 ( 15.04 )
    99.0 ( 20.70 )
    98.8 ( 12.76 )
        WISC-IV : Year 7 Full Scale IQ
    99.8 ( 14.63 )
    95.8 ( 20.10 )
    101.4 ( 11.92 )
        WPPSI-IV: Year 7 Verbal Comprehension Index
    100.8 ( 15.51 )
    99.4 ( 22.42 )
    101.4 ( 12.29 )
        WISC-IV : Year 7 Perceptual Reasoning Index
    99.6 ( 13.94 )
    98.1 ( 22.00 )
    100.2 ( 9.60 )
        WISC-IV : Year 7 Working Memory Index
    98.2 ( 13.55 )
    93.1 ( 21.22 )
    100.2 ( 8.67 )
        WISC-IV : Year 7 Processing Speed Index
    99.2 ( 15.29 )
    94.2 ( 15.11 )
    101.2 ( 15.23 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in FSIQ score and Verbal IQ subscore at 2, 4, and 7 years

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    End point title
    		 Change from Baseline in FSIQ score and Verbal IQ subscore at 2, 4, and 7 years
    End point description
    ITT Analysis Set Year 2 Full Scale IQ : Overall (n=32), Naïve (n=9), & Previously Treated (n=23) Year 2 Verbal IQ: Overall (n=32), Naïve (n=9), & Previously Treated (n=23) Year 4 Full Scale IQ: Overall (n=32), Naïve (n=9), & Previously Treated (n=23) Year 4 Verbal IQ: Overall (n=32), Naïve (n=9), & Previously Treated (n=23) Year 7 Full Scale IQ: Overall (n=31), Naïve (n=9), & Previously Treated (n=22) Year 7 Verbal IQ: Overall (n=31), Naïve (n=9), & Previously Treated (n=22)
    End point type
    Secondary
    End point timeframe
    At 2, 4 and 7 years.
    End point values
    		 Kuvan Naive Subjects Previously Treated
    Number of subjects analysed
    32
    9
    23
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Year 2: Full Scale IQ
    -1.5 ( 12.87 )
    -6.9 ( 13.70 )
    0.6 ( 12.19 )
        Year 2: Verbal IQ
    -0.5 ( 16.13 )
    -6.2 ( 15.91 )
    1.8 ( 16.00 )
        Year 4: Full Scale IQ
    1.2 ( 14.40 )
    -2.9 ( 17.69 )
    2.7 ( 13.00 )
        Year 4: Verbal IQ
    0.4 ( 14.10 )
    -0.1 ( 17.10 )
    0.7 ( 13.18 )
        Year 7: Full Scale IQ
    -1.0 ( 14.31 )
    -6.8 ( 16.98 )
    1.4 ( 12.75 )
        Year 7: Verbal IQ
    -3.8 ( 16.81 )
    -5.2 ( 20.99 )
    -3.3 ( 15.32 )
    No statistical analyses for this end point

    Secondary: Dietary Phe tolerance over the 7-year period

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    End point title
    		 Dietary Phe tolerance over the 7-year period
    End point description
    Dietary Phe tolerance over the 7-year period, as represented by the average amount of dietary Phe (mg/kg/day) ingested while maintaining overall control of blood Phe levels within target range of >=120 to <360 µmol/L). The amount of dietary Phe ingested was estimated using the average daily Phe intake based on mean Phe prescription as well as the average daily intake calculated from the 3-day diary bi-annually. Overall, Naive, & Previously Treated: Phe Intake: Day 1 to M6 (n=33, 10, 23), Phe Intake: M6 to M12 (n=33, 10, 23), Phe Intake: M12 to M18 (n=31, 9, 22), Phe Intake: M18 to M24 (n=32, 9, 23), Phe Intake: M24 to M30 (n=31, 9, 22), Phe Intake: M30 to M36 (n=32, 9, 23), Phe Intake: M36 to M42 (n=31, 8, 23), Phe Intake: M42 to M48 (n=32, 9, 23), Phe Intake: M48 to M54 (n=32, 9, 23), Phe Intake: M54 to M60 (n=31, 8, 23), Phe Intake: M60 to M66 (n=30, 8, 22), Phe Intake: M66 to M72 (n=30, 8, 22), Phe Intake: M72 to M78 (n=31, 9, 22), Phe Intake: M78 to M84 (n=29, 8, 21).
    End point type
    Secondary
    End point timeframe
    Up to 7 years.
    End point values
    		 Kuvan Naive Subjects Previously Treated
    Number of subjects analysed
    34
    11
    23
    Units: mg/day
    arithmetic mean (standard deviation)
        Phe Intake: Day 1 to M6
    1053.2 ( 661.32 )
    871.4 ( 340.99 )
    1132.3 ( 753.01 )
        Phe Intake: M6 to M12
    1020.9 ( 598.42 )
    978.3 ( 314.70 )
    1039.4 ( 692.23 )
        Phe Intake: M12 to M18
    1188.1 ( 618.69 )
    907.9 ( 390.77 )
    1302.7 ( 664.25 )
        Phe Intake: M18 to M24
    1212.5 ( 560.49 )
    1006.0 ( 360.90 )
    1293.3 ( 609.11 )
        Phe Intake: M24 to M30
    1196.7 ( 651.83 )
    967.9 ( 502.57 )
    1290.4 ( 692.19 )
        Phe Intake: M30 to M36
    1217.1 ( 583.63 )
    995.2 ( 525.72 )
    1304.0 ( 592.83 )
        Phe Intake: M36 to M42
    1255.8 ( 614.52 )
    1131.5 ( 273.05 )
    1299.1 ( 695.46 )
        Phe Intake: M42 to M48
    1391.5 ( 734.53 )
    1146.0 ( 353.05 )
    1487.6 ( 824.99 )
        Phe Intake: M48 to M54
    1316.4 ( 709.48 )
    1125.1 ( 336.92 )
    1391.2 ( 804.48 )
        Phe Intake: M54 to M60
    1321.9 ( 662.06 )
    1205.3 ( 423.33 )
    1362.4 ( 730.78 )
        Phe Intake: M60 to M66
    1297.5 ( 735.47 )
    1140.3 ( 273.05 )
    1354.7 ( 842.18 )
        Phe Intake: M66 to M72
    1328.7 ( 772.85 )
    1134.5 ( 406.91 )
    1399.3 ( 866.06 )
        Phe Intake: M72 to M78
    1377.9 ( 774.21 )
    1279.8 ( 730.49 )
    1418.0 ( 804.49 )
        Phe Intake: M78 to M84
    1416.5 ( 795.58 )
    1369.6 ( 545.40 )
    1434.4 ( 883.63 )
    No statistical analyses for this end point

    Secondary: Monthly blood Phe levels and Phe levels on the day of the IQ test

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    End point title
    		 Monthly blood Phe levels and Phe levels on the day of the IQ test
    End point description
    Overall, Naïve & Previously Trt BL Ab 33,10,23; M3 Ab 33,11,22 & Ch 32,10,22; M6 Ab 33,10,23 & Ch 32,9,23; M9 Ab 33,10,23 & Ch 32,9,23; M12 Ab 33,10,23 & Ch 32,9,23; M15 Ab 32,9,23 & Ch 31,8,23; M18 Ab 32,9,23 & Ch 31,8,23; M21 Ab 32,9,23 & Ch 31,8,23; M24 Ab 32,9,23 & Ch 31,8,23; M27 Ab 30,9,21 & Ch 29,8,21; M30 Ab 31,9,22 & Ch 30,8,22; M33 Ab 32,9,23 & Ch 31,8,23; M36 Ab 32,9,23 & Ch 31,8,23; M39 Ab 32,9,23 & Ch 31,8,23; M42 Ab 32,9,23 & Ch 31,8,23; M45 Ab 32,9,23 & Ch 31,8,23; M48 Ab 32,9,23 & Ch 31,8,23; M51 Ab 31,9,22 & Ch 30,8,22; M54 Ab 32,9,23 & Ch 31,8,23; M57 Ab 32,9,23 & Ch 31,8,23; M60 Ab 31,9,22 & Ch 30,8,22; M63 Ab 31,9,22 & Ch 30,8,22; M66 Ab 32,9,23 & Ch 31,8,23; M69 Ab 31,8,23 & Ch 30,7,23; M72 Ab 32,9,23 & Ch 31,8,23; M75 Ab 30,8,22 & Ch 29,7,22; M78 Ab 30,9,21 & Ch 29,8,21; M81 Ab 29,8,21 & Ch 28,7,21; M84 Ab 31,9,22 & Ch 30,8,22 Refer attached file for Values of M1 Ab 11,11,0 & Ch 10,10,0; End of Treatment Ab 2,2,0 & Ch 2,2,0 as number of sub analyzed is zero.
    End point type
    Secondary
    End point timeframe
    Up to End of treatment.
    End point values
    		 Kuvan Naive Subjects Previously Treated
    Number of subjects analysed
    34
    11
    23
    Units: µmol/L
    arithmetic mean (standard deviation)
        Baseline: Absolute
    306.09 ( 153.427 )
    371.68 ( 188.509 )
    277.57 ( 129.988 )
        Month 3: Absolute
    265.30 ( 82.688 )
    252.72 ( 99.698 )
    271.59 ( 74.573 )
        Month 3: Change from Baseline
    -43.26 ( 131.026 )
    -109.84 ( 156.693 )
    -12.99 ( 108.397 )
        Month 6: Absolute
    286.42 ( 88.241 )
    251.35 ( 112.817 )
    301.66 ( 72.918 )
        Month 6: Change from Baseline
    -11.12 ( 175.910 )
    -101.11 ( 250.877 )
    24.09 ( 126.915 )
        Month 9: Absolute
    308.06 ( 114.398 )
    337.30 ( 170.552 )
    295.35 ( 81.107 )
        Month 9: Change from Baseline
    4.06 ( 178.331 )
    -31.00 ( 277.636 )
    17.77 ( 126.817 )
        Month 12: Absolute
    309.93 ( 91.657 )
    281.35 ( 103.565 )
    322.36 ( 85.433 )
        Month 12: Change from Baseline
    13.43 ( 155.953 )
    -66.71 ( 202.314 )
    44.79 ( 125.424 )
        Month 15: Absolute
    332.33 ( 96.575 )
    276.97 ( 75.748 )
    353.99 ( 96.498 )
        Month 15: Change from Baseline
    40.43 ( 53.626 )
    -63.04 ( 213.923 )
    76.41 ( 111.245 )
        Month 18: Absolute
    303.78 ( 83.069 )
    306.28 ( 102.022 )
    302.80 ( 77.039 )
        Month 18: Change from Baseline
    12.84 ( 158.723 )
    -22.76 ( 220.177 )
    25.23 ( 135.307 )
        Month 21: Absolute
    315.37 ( 94.663 )
    292.85 ( 94.431 )
    324.19 ( 95.372 )
        Month 21: Change from Baseline
    22.74 ( 154.798 )
    -45.90 ( 232.377 )
    46.61 ( 114.829 )
        Month 24: Absolute
    330.02 ( 84.348 )
    348.39 ( 126.451 )
    322.83 ( 63.393 )
        Month 24: Change from Baseline
    37.41 ( 144.485 )
    14.82 ( 215.842 )
    45.26 ( 115.732 )
        Month 27: Absolute
    295.54 ( 86.691 )
    302.59 ( 123.464 )
    292.52 ( 69.051 )
        Month 27: Change from Baseline
    4.88 ( 158.412 )
    -45.83 ( 247.722 )
    24.20 ( 110.605 )
        Month 30: Absolute
    327.44 ( 112.803 )
    329.82 ( 173.921 )
    326.46 ( 81.555 )
        Month 30: Change from Baseline
    35.30 ( 194.754 )
    1.94 ( 294.156 )
    47.43 ( 151.517 )
        Month 33: Absolute
    308.09 ( 107.417 )
    301.11 ( 115.997 )
    310.83 ( 106.480 )
        Month 33: Change from Baseline
    14.91 ( 153.253 )
    -37.81 ( 202.131 )
    33.25 ( 132.909 )
        Month 36: Absolute
    325.35 ( 82.485 )
    364.05 ( 92.755 )
    310.21 ( 74.875 )
        Month 36: Change from Baseline
    30.02 ( 148.388 )
    22.51 ( 197.266 )
    32.63 ( 132.728 )
        Month 39: Absolute
    328.81 ( 85.429 )
    317.88 ( 106.494 )
    333.08 ( 78.049 )
        Month 39: Change from Baseline
    32.92 ( 47.577 )
    -32.03 ( 200.693 )
    55.51 ( 121.719 )
        Month 42: Absolute
    360.77 ( 91.288 )
    357.01 ( 110.227 )
    362.25 ( 85.536 )
        Month 42: Change from Baseline
    68.94 ( 165.132 )
    23.71 ( 191.138 )
    84.67 ( 156.707 )
        Month 45: Absolute
    348.22 ( 112.540 )
    323.70 ( 107.009 )
    357.82 ( 115.500 )
        Month 45: Change from Baseline
    53.47 ( 156.523 )
    -23.50 ( 157.352 )
    80.24 ( 150.420 )
        Month 48: Absolute
    354.78 ( 97.902 )
    351.87 ( 96.801 )
    355.92 ( 100.466 )
        Month 48: Change from Baseline
    59.49 ( 165.697 )
    5.28 ( 166.705 )
    78.35 ( 164.792 )
        Month 51: Absolute
    361.97 ( 103.328 )
    360.21 ( 131.235 )
    362.69 ( 93.218 )
        Month 51: Change from Baseline
    64.92 ( 158.105 )
    13.41 ( 159.469 )
    83.65 ( 157.049 )
        Month 54: Absolute
    398.53 ( 131.917 )
    395.27 ( 140.048 )
    399.80 ( 131.845 )
        Month 54: Change from Baseline
    107.52 ( 198.359 )
    65.24 ( 220.428 )
    122.23 ( 193.178 )
        Month 57: Absolute
    418.99 ( 175.828 )
    375.45 ( 153.167 )
    436.03 ( 184.263 )
        Month 57: Change from Baseline
    126.75 ( 246.010 )
    35.61 ( 288.487 )
    158.45 ( 227.984 )
        Month 60: Absolute
    387.58 ( 87.746 )
    364.20 ( 92.929 )
    397.14 ( 85.903 )
        Month 60: Change from Baseline
    95.48 ( 162.098 )
    11.42 ( 188.929 )
    126.05 ( 143.934 )
        Month 63: Absolute
    408.53 ( 145.820 )
    414.51 ( 226.952 )
    406.09 ( 103.600 )
        Month 63: Change from Baseline
    121.72 ( 198.224 )
    81.80 ( 317.316 )
    136.24 ( 140.963 )
        Month 66: Absolute
    394.47 ( 112.065 )
    396.22 ( 102.756 )
    393.79 ( 117.707 )
        Month 66: Change from Baseline
    101.67 ( 167.822 )
    59.87 ( 177.148 )
    116.21 ( 166.024 )
        Month 69: Absolute
    410.79 ( 102.230 )
    394.86 ( 139.266 )
    416.33 ( 89.195 )
        Month 69: Change from Baseline
    119.60 ( 165.888 )
    56.65 ( 213.392 )
    138.76 ( 149.033 )
        Month 72: Absolute
    404.23 ( 97.686 )
    396.93 ( 57.880 )
    407.09 ( 110.443 )
        Month 72: Change from Baseline
    110.54 ( 158.739 )
    55.97 ( 191.676 )
    129.52 ( 145.641 )
        Month 75: Absolute
    440.01 ( 132.362 )
    493.48 ( 154.273 )
    420.57 ( 121.554 )
        Month 75: Change from Baseline
    145.33 ( 195.980 )
    157.26 ( 298.757 )
    141.54 ( 160.146 )
        Month 78: Absolute
    436.43 ( 149.454 )
    518.06 ( 124.610 )
    401.44 ( 147.960 )
        Month 78: Change from Baseline
    139.27 ( 206.550 )
    187.68 ( 247.979 )
    120.83 ( 192.122 )
        Month 81: Absolute
    438.00 ( 156.075 )
    470.35 ( 105.872 )
    425.67 ( 172.052 )
        Month 81: Change from Baseline
    147.15 ( 218.779 )
    153.43 ( 268.978 )
    145.06 ( 207.108 )
        Month 84: Absolute
    479.07 ( 181.230 )
    505.69 ( 188.972 )
    468.17 ( 181.351 )
        Month 84: Change from Baseline
    186.17 ( 252.675 )
    177.97 ( 335.507 )
    189.15 ( 224.967 )
    No statistical analyses for this end point

    Secondary: Ratio of Phe/Tyr levels at Baseline and every 6 months.

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    End point title
    		 Ratio of Phe/Tyr levels at Baseline and every 6 months.
    End point description
    Overall: Baseline (n=30), Month 6 (n=31), Month 12 (n=32), Month 18 (n=31), Month 24 (n=31), Month 30 (n=30), Month 36 (n=32), Month 42 (n=31), Month 48 (n=32), Month 54 (n=29), Month 60 (n=26), Month 66 (n=28), Month 72 (n=19), Month 78 (n=22), Month 84 (n=25), & End of Treatment (n=34) Naive: Baseline (n=8), Month 6 (n=9), Month 12 (n=10), Month 18 (n=8), Month 24 (n=9), Month 30 (n=9), Month 36 (n=9), Month 42 (n=9), Month 48 (n=9), Month 54 (n=6), Month 60 (n=6), Month 66 (n=7), Month 72 (n=6), Month 78 (n=5), Month 84 (n=7), & End of Treatment (n=11) Previously Treated : Baseline (n=22), Month 6 (n=22), Month 12 (n=22), Month 18 (n=23), Month 24 (n=22), Month 30 (n=21), Month 36 (n=23), Month 42 (n=22), Month 48 (n=23), Month 54 (n=23), Month 60 (n=20), Month 66 (n=21), Month 72 (n=13), Month 78 (n=17), Month 84 (n=18), & End of Treatment (n=23)
    End point type
    Secondary
    End point timeframe
    Baseline and every 6 months.
    End point values
    		 Kuvan Naive Subjects Previously Treated
    Number of subjects analysed
    34
    11
    23
    Units: Ratio
    arithmetic mean (standard deviation)
        Baseline
    7.71 ( 5.839 )
    8.01 ( 8.540 )
    7.61 ( 4.767 )
        Month 6
    6.51 ( 3.440 )
    5.62 ( 4.477 )
    6.87 ( 2.965 )
        Month 12
    6.67 ( 4.178 )
    5.70 ( 4.971 )
    7.11 ( 3.812 )
        Month 18
    6.65 ( 3.780 )
    5.73 ( 3.539 )
    6.96 ( 3.884 )
        Month 24
    5.84 ( 2.964 )
    5.10 ( 3.447 )
    6.15 ( 2.774 )
        Month 30
    6.39 ( 4.390 )
    5.65 ( 5.072 )
    6.70 ( 4.160 )
        Month 36
    6.46 ( 3.573 )
    6.49 ( 4.697 )
    6.45 ( 3.157 )
        Month 42
    7.03 ( 5.177 )
    4.17 ( 2.583 )
    8.20 ( 5.549 )
        Month 48
    7.08 ( 3.980 )
    6.33 ( 4.156 )
    7.37 ( 3.965 )
        Month 54
    7.13 ( 3.823 )
    7.31 ( 5.390 )
    7.08 ( 3.462 )
        Month 60
    6.75 ( 4.326 )
    7.05 ( 6.882 )
    6.66 ( 3.481 )
        Month 66
    5.89 ( 3.731 )
    5.77 ( 3.479 )
    5.93 ( 3.893 )
        Month 72
    6.94 ( 3.843 )
    7.68 ( 5.637 )
    6.60 ( 2.917 )
        Month 78
    6.18 ( 2.864 )
    8.11 ( 3.032 )
    5.62 ( 2.639 )
        Month 84
    5.66 ( 3.585 )
    4.28 ( 2.888 )
    6.19 ( 3.758 )
        End of Treatment
    5.95 ( 3.729 )
    4.61 ( 2.869 )
    6.60 ( 3.972 )
    No statistical analyses for this end point

    Secondary: Index of Dietary Control (IDC)

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    End point title
    		 Index of Dietary Control (IDC)
    End point description
    IDC (Index of Dietary Control) = half-year Phe level medians averaged from baseline to 2, 4, and 7 years).
    End point type
    Secondary
    End point timeframe
    From baseline to 2, 4 and 7 years. 
    End point values
    		 Kuvan Naive Subjects Previously Treated
    Number of subjects analysed
    34
    11
    23
    Units: mg/dL
    median (full range (min-max))
        Baseline to Month 24
    316.6 (157 to 436)
    302.1 (189 to 436)
    316.8 (157 to 425)
        Baseline to Month 48
    319.0 (196 to 436)
    326.6 (202 to 436)
    317.6 (196 to 427)
        Baseline to Month 84
    348.5 (239 to 481)
    380.4 (255 to 478)
    343.0 (239 to 481)
    No statistical analyses for this end point

    Secondary: Adherence to Kuvan Treatment

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    End point title
    		 Adherence to Kuvan Treatment
    End point description
    Adherence to Kuvan treatment is defined as the percentage of actual Kuvan dose administered compared to the Kuvan dose prescribed. Overall: Day 1 to M12 (n=34), M12 to M24 (n=33), M24 to M36 (n=32), M36 to M48 (n=32), M48 to M60 (n=32), M60 to M72 (n=32), & M72 to M84 (n=32). Naïve Subjects: Day 1 to M12 (n=11), M12 to M24 (n=10), M24 to M36 (n=9), M36 to M48 (n=9), M48 to M60 (n=9), M60 to M72 (n=9), & M72 to M84 (n=9) Previously Treated: Day 1 to M12 (n=23), M12 to M24 (n=23), M24 to M36 (n=23), M36 to M48 (n=23), M48 to M60 (n=23), M60 to M72 (n=23), & M72 to M84 (n=23). Overall: Overall (n=34), Naive (n=11), Previously Treated (n=23)
    End point type
    Secondary
    End point timeframe
    Yearly (up to 7 years)
    End point values
    		 Kuvan Naive Subjects Previously Treated
    Number of subjects analysed
    34
    11
    23
    Units: Percentage
    arithmetic mean (standard deviation)
        Day 1 to M12
    98.5 ( 30.27 )
    89.5 ( 49.56 )
    102.8 ( 14.06 )
        M12 to M24
    98.2 ( 16.33 )
    104.5 ( 8.10 )
    95.4 ( 18.30 )
        M24 to M36
    102.4 ( 17.53 )
    99.7 ( 5.48 )
    103.4 ( 20.45 )
        M36 to M48
    101.2 ( 8.98 )
    100.1 ( 5.46 )
    101.7 ( 10.10 )
        M48 to M60
    104.2 ( 8.78 )
    104.3 ( 3.95 )
    104.2 ( 10.15 )
        M60 to M72
    97.8 ( 11.89 )
    104.0 ( 4.55 )
    95.4 ( 13.04 )
        M72 to M84
    94.6 ( 21.52 )
    96.5 ( 17.30 )
    93.9 ( 23.28 )
        Overall
    98.7 ( 8.97 )
    97.4 ( 12.88 )
    99.4 ( 6.63 )
    No statistical analyses for this end point

    Secondary: Adherence to Dietary Phe Prescription

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    End point title
    		 Adherence to Dietary Phe Prescription
    End point description
    Adherence to dietary Phe prescription is defined as the percentage of actual dietary Phe intake compared to prescribed dietary Phe intake. To assess adherence, the dietician calculated several dietary nutrients such as total protein (g/day), total kilocalories (kcal/day), actual Phe intake per day (mg/day), etc., and compared those parameters with the Phe prescription. Day 1 to M12: Overall (n=34), Naive (n=11), Previously Treated (n=23) M12 to M24: Overall (n=32), Naive (n=10), Previously Treated (n=22) M24 to M36: Overall (n=31), Naive (n=9), Previously Treated (n=22) M36 to M48: Overall (n=31), Naive (n=9), Previously Treated (n=22) M48 to M60: Overall (n=31), Naive (n=9), Previously Treated (n=22) M60 to M72: Overall (n=31), Naive (n=9), Previously Treated (n=22) M72 to M84: Overall (n=30), Naive (n=9), Previously Treated (n=21) Overall: Overall (n=34), Naive (n=11), Previously Treated (n=23)
    End point type
    Secondary
    End point timeframe
    Yearly (up to 7 years)
    End point values
    		 Kuvan Naive Subjects Previously Treated
    Number of subjects analysed
    34
    11
    23
    Units: Percentage
    arithmetic mean (standard deviation)
        Day 1 to M12
    102.8 ( 31.50 )
    121.3 ( 28.72 )
    94.0 ( 29.33 )
        M12 to M24
    106.1 ( 29.62 )
    101.7 ( 20.18 )
    108.2 ( 33.26 )
        M24 to M36
    104.3 ( 24.81 )
    95.5 ( 24.44 )
    107.9 ( 24.59 )
        M36 to M48
    112.9 ( 53.05 )
    106.3 ( 22.29 )
    115.7 ( 61.68 )
        M48 to M60
    107.1 ( 41.52 )
    105.5 ( 14.67 )
    107.7 ( 48.77 )
        M60 to M72
    101.9 ( 27.93 )
    101.7 ( 18.17 )
    101.9 ( 31.45 )
        M72 to M84
    107.7 ( 21.51 )
    109.2 ( 24.00 )
    107.0 ( 20.95 )
        Overall
    107.6 ( 20.57 )
    106.3 ( 14.79 )
    108.2 ( 23.11 )
    No statistical analyses for this end point

    Secondary: Adherence to Diet+Kuvan Treatment: defined as the percentage of monthly mean blood Phe levels within target blood Phe levels: >=120 to <360 μmol/L

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    End point title
    		 Adherence to Diet+Kuvan Treatment: defined as the percentage of monthly mean blood Phe levels within target blood Phe levels: >=120 to <360 μmol/L
    End point description
    Overall, Naïve & Previously Treated D1 to M6: n=34,11,23; M6 to M12: n=33,10,23; Day1 to M12: n=34,11,23; M12 to M18: n=33,10,23; M18 to M24: n=32,9,23; M12 to 24: n=33,10,23; M24 to M30: n=31,9,22; M30 to M36: n=32,9,23; M24 to M36: n=32,9,23; M36 to M42: n=32,9,23; M42 to M48: n=32,9,23; M36 to M48: n=32,9,23; M48 to M54: n=32,9,23; M54 to M60: n=32,9,23; M48 to M60: n=32,9,23; M60 to M66: n=32,9,23; M66 to M72: n=32,9,23; M60 to M72: n=32,9,23; M72 to M78: n=31,9,22; M78 to M84: n=31,9,22; M72 to M84: n=32,9,23; Overall: n=34,11,23
    End point type
    Secondary
    End point timeframe
    Yearly and per 6 months.
    End point values
    		 Kuvan Naive Subjects Previously Treated
    Number of subjects analysed
    34
    11
    23
    Units: Percentage
    arithmetic mean (standard deviation)
        Day 1 to M6
    84.3 ( 23.90 )
    78.8 ( 26.97 )
    87.0 ( 22.45 )
        M6 to M12
    66.7 ( 38.86 )
    60.0 ( 39.44 )
    69.6 ( 39.14 )
        Day 1 to M12
    75.7 ( 22.89 )
    70.3 ( 19.86 )
    78.3 ( 24.20 )
        M12 to M18
    69.7 ( 39.41 )
    75.0 ( 42.49 )
    67.4 ( 38.76 )
        M18 to M24
    70.3 ( 30.74 )
    66.7 ( 25.00 )
    71.7 ( 33.12 )
        M12 to M24
    70.5 ( 23.76 )
    72.5 ( 24.86 )
    69.6 ( 23.78 )
        M24 to M30
    75.8 ( 33.84 )
    61.1 ( 41.67 )
    81.8 ( 29.05 )
        M30 to M36
    71.9 ( 33.45 )
    66.7 ( 43.30 )
    73.9 ( 29.66 )
        M24 to M36
    74.2 ( 26.55 )
    63.9 ( 35.60 )
    78.3 ( 21.72 )
        M36 to M42
    56.3 ( 39.66 )
    50.0 ( 43.30 )
    58.7 ( 38.88 )
        M42 to M48
    56.3 ( 43.53 )
    61.1 ( 48.59 )
    54.3 ( 42.41 )
        M36 to M48
    56.3 ( 35.92 )
    55.6 ( 39.09 )
    56.5 ( 35.53 )
        M48 to M54
    46.9 ( 43.88 )
    50.0 ( 43.30 )
    45.7 ( 45.01 )
        M54 to M60
    40.6 ( 39.02 )
    50.0 ( 43.30 )
    37.0 ( 37.59 )
        M48 to M60
    44.5 ( 35.46 )
    50.0 ( 35.36 )
    42.4 ( 36.05 )
        M60 to M66
    37.5 ( 40.16 )
    33.3 ( 43.30 )
    39.1 ( 39.76 )
        M66 to M72
    31.3 ( 35.36 )
    27.8 ( 36.32 )
    32.6 ( 35.70 )
        M60 to M72
    34.6 ( 33.41 )
    31.5 ( 36.98 )
    35.9 ( 32.71 )
        M72 to M78
    27.4 ( 38.38 )
    5.6 ( 16.67 )
    36.4 ( 41.35 )
        M78 to M84
    27.4 ( 40.49 )
    16.7 ( 35.36 )
    31.8 ( 42.39 )
        M72 to M84
    26.6 ( 32.34 )
    11.1 ( 18.16 )
    32.6 ( 34.90 )
        Overall
    55.5 ( 21.39 )
    53.3 ( 24.09 )
    56.6 ( 20.47 )
    No statistical analyses for this end point

    Secondary: Number of subjects with Adverse Events and Serious Adverse Events

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    End point title
    		 Number of subjects with Adverse Events and Serious Adverse Events
    End point description
    End point type
    Secondary
    End point timeframe
    Up to Safety Follow-Up (approximately 96 months).
    End point values
    		 Kuvan
    Number of subjects analysed
    34
    Units: Number of participants
        Any Adverse Event
    33
        Any Treatment-Emergent Adverse Event
    33
        Any Treatment-Emergent Adverse Event related to St
    0
        Any Severe Treatment-Emergent Adverse Event
    1
        Any Serious Adverse Events
    0
        Any Serious Adverse Events related to Study Treatm
    0
        Any Adverse Events leading to regimen modification
    1
        Any Adverse Events leading to dose reduction
    0
        Any Adverse Events leading to temporary treatment
    6
        Any Adverse Events leading to permanent treatment
    0
        Any Adverse Events leading to trial discontinuatio
    0
        Any Adverse Events leading to death
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Safety Follow-Up (approximately 96 months).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Kuvan
    Reporting group description
    		 Safety analysis set: All enrolled subjects taking at least one dose of study treatment (Kuvan) and having some safety assessment data available were included in the safety analysis set. all subjects who were part of the ITT analysis set were included in the safety analysis set, as it could be assumed that all treated subjects would have safety data available (i.e., a 1-month safety follow-up visit was mandatory for all subjects).

    Serious adverse events
    		 Kuvan
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 34 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Kuvan
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    33 / 34 (97.06%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    4 / 34 (11.76%)
         occurrences all number
    6
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    16 / 34 (47.06%)
         occurrences all number
    58
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    3 / 34 (8.82%)
         occurrences all number
    4
    Hypersensitivity
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences all number
    2
    Reproductive system and breast disorders
    Balanoposthitis
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences all number
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    12 / 34 (35.29%)
         occurrences all number
    23
    Oropharyngeal pain
         subjects affected / exposed
    9 / 34 (26.47%)
         occurrences all number
    11
    Asthma
         subjects affected / exposed
    3 / 34 (8.82%)
         occurrences all number
    12
    Rhinorrhoea
         subjects affected / exposed
    3 / 34 (8.82%)
         occurrences all number
    7
    Investigations
    Body temperature increased
         subjects affected / exposed
    4 / 34 (11.76%)
         occurrences all number
    4
    Amino acid level decreased
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences all number
    4
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    3 / 34 (8.82%)
         occurrences all number
    3
    Arthropod sting
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences all number
    4
    Fall
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences all number
    2
    Skin laceration
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences all number
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    10 / 34 (29.41%)
         occurrences all number
    16
    Syncope
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences all number
    2
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    6 / 34 (17.65%)
         occurrences all number
    6
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    14 / 34 (41.18%)
         occurrences all number
    50
    Diarrhoea
         subjects affected / exposed
    11 / 34 (32.35%)
         occurrences all number
    14
    Abdominal pain
         subjects affected / exposed
    4 / 34 (11.76%)
         occurrences all number
    7
    Dental caries
         subjects affected / exposed
    3 / 34 (8.82%)
         occurrences all number
    3
    Abdominal pain upper
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    3 / 34 (8.82%)
         occurrences all number
    3
    Eczema
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences all number
    5
    Erythema
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences all number
    2
    Rash erythematous
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences all number
    2
    Urticaria
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences all number
    2
    Pain in extremity
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences all number
    13
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    17 / 34 (50.00%)
         occurrences all number
    75
    Gastroenteritis
         subjects affected / exposed
    12 / 34 (35.29%)
         occurrences all number
    22
    Upper respiratory tract infection
         subjects affected / exposed
    12 / 34 (35.29%)
         occurrences all number
    45
    Corona virus infection
         subjects affected / exposed
    8 / 34 (23.53%)
         occurrences all number
    9
    Conjunctivitis
         subjects affected / exposed
    5 / 34 (14.71%)
         occurrences all number
    6
    Pharyngitis
         subjects affected / exposed
    5 / 34 (14.71%)
         occurrences all number
    10
    Viral infection
         subjects affected / exposed
    5 / 34 (14.71%)
         occurrences all number
    10
    Viral upper respiratory tract infection
         subjects affected / exposed
    5 / 34 (14.71%)
         occurrences all number
    15
    Ear infection
         subjects affected / exposed
    4 / 34 (11.76%)
         occurrences all number
    5
    Lower respiratory tract infection
         subjects affected / exposed
    4 / 34 (11.76%)
         occurrences all number
    4
    Rhinitis
         subjects affected / exposed
    4 / 34 (11.76%)
         occurrences all number
    4
    Varicella
         subjects affected / exposed
    4 / 34 (11.76%)
         occurrences all number
    4
    Bronchitis
         subjects affected / exposed
    3 / 34 (8.82%)
         occurrences all number
    7
    Impetigo
         subjects affected / exposed
    3 / 34 (8.82%)
         occurrences all number
    3
    Influenza
         subjects affected / exposed
    3 / 34 (8.82%)
         occurrences all number
    6
    Molluscum contagiosum
         subjects affected / exposed
    3 / 34 (8.82%)
         occurrences all number
    3
    Respiratory tract infection
         subjects affected / exposed
    3 / 34 (8.82%)
         occurrences all number
    4
    Gastroenteritis viral
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences all number
    2
    Lice infestation
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences all number
    3
    Oral herpes
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences all number
    3
    Otitis media
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences all number
    2
    Tonsillitis
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences all number
    7
    Urinary tract infection
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences all number
    3
    Metabolism and nutrition disorders
    Obesity
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Nov 2015
    • Added BioMarin study identifier in cover page • Updated coordinating investigator information in cover page • Updated Sponsor and Medical Responsible in cover page • Updated confidentiality statement in cover page • Updated medical monitor in Signature of medical monitor section • Removed protocol lead information • Updated coordinating investigator information in Coordinating investigator signature page • Removal of further responsible persons information in Further responsible Persons section • BioMarin study identifier included in Synopsis and Trial Number section • Updated Sponsor details in Synopsis and Sponsor section • Updated Sponsor responsibility information in Synopsis, trial design and plan sections • Updated Sponsor details in Sections 2, 3.2.3.2 and 5.2.3 • Updated Diary card instruction in Section 6.5.1 • Updated Capillary blood sampling instruction in Sections 7.1.2.7, 7.1.3 and 7.1.4 • Updated diary instructions in Section 7.4.2 • Updated Sponsor details in Sections 7.8 and 9.4 • Updated Capillary blood sampling instruction in Appendix II • Included BioMarin study identifier in page header

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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