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    Clinical Trial Results:
    A Phase IIIb, Multicentre, Open-Label, Randomized, Controlled Study of the Efficacy, Safety, and Population Pharmacokinetics of Sapropterin Dihydrochloride (Kuvan®) in Phenylketonuria (PKU) Patients <4 Years Old

    Summary
    EudraCT number
    		 2009-015768-33
    Trial protocol
    		 GB   SK   DE   AT   CZ   PT   BE   NL   IT  
    Global end of trial date
    17 Feb 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Sep 2020
    First version publication date
    02 Sep 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EMR700773-003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01376908
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    BioMarin Pharmaceutical Inc.
    Sponsor organisation address
    105 Digital Drive, Novato, United States, CA 94949
    Public contact
    Clinical Trails Information, BioMarin Pharmaceutical Inc., clinicaltrials@bmrn.com
    Scientific contact
    Clinical Trails Information, BioMarin Pharmaceutical Inc., clinicaltrials@bmrn.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001476-PIP01-13
    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
    17 Feb 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Feb 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1. Evaluate the efficacy after 26 weeks of Kuvan® treatment + Phe-restricted diet therapy in increasing dietary Phe tolerance, as compared to dietary therapy alone in <4 year-old infants and children with phenylketonuria (PKU). Phe tolerance will be defined as the amount of dietary Phe (mg/kg/day) ingested while maintaining blood Phe levels within the range of 120-360 μmol/L (defined as ≥120 to < 360 μmol/L). 2. Evaluate the safety after 26 weeks of Kuvan® treatment in <4 year-old infants and children with PKU. 3. Evaluate BH4 (tetrahydrobiopterin; sapropterin) blood levels via scheduled PopPK samplings.
    Protection of trial subjects
    The trial was performed in accordance with the protocol and subsequent protocol amendments and with the ethical principles laid down in the Declaration of Helsinki, in accordance with the International Council for Harmonisation (ICH), Note for Guidance on Good Clinical Practice (GCP) (ICH Topic E6, 1996) and applicable regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Jun 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 3 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Czech Republic: 7
    Country: Number of subjects enrolled
    Germany: 17
    Country: Number of subjects enrolled
    Italy: 11
    Country: Number of subjects enrolled
    Slovakia: 2
    Country: Number of subjects enrolled
    United Kingdom: 7
    Country: Number of subjects enrolled
    Turkey: 5
    Country: Number of subjects enrolled
    Netherlands: 1
    Worldwide total number of subjects
    56
    EEA total number of subjects
    49
    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)
    33
    Children (2-11 years)
    23
    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
    		 -

    Pre-assignment
    Screening details
    		 Of the 56 subjects enrolled to study, 51 subjects remained through the end of the study.

    Period 1
    Period 1 title
    Kuvan Continuous Stage
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Kuvan® + Phe-restricted Diet - Continuous
    Arm description
    		 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.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Kuvan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Soluble tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg soluble Kuvan tablets (sapropterin dihydrochloride). The appropriate number of Kuvan tablets, based on the dose calculated according to the subject’s weight, were dissolved in the protocol-defined volume of water and given to the child during breakfast. The solution was to be ingested within 15 to 20 minutes after dissolution.

    Arm title
    		 Phe-restricted Diet - Continuous
    Arm description
    		 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. After 26 weeks, the starting dose of Kuvan will be 10 mg/kg/day, and the dose may be adjusted by the Investigator, if clinically indicated, but it may not exceed 20 mg/kg/day.
    Arm type
    		 Restricted diet

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Kuvan® + Phe-restricted Diet - Continuous Phe-restricted Diet - Continuous
    Started
    27
    29
    Completed
    25
    26
    Not completed
    2
    3
         Unknown
    2
    3
    Period 2
    Period 2 title
    Kuvan Extension Stage
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Kuvan® + Phe-restricted Diet - Extension
    Arm description
    		 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.After 26 weeks, the dose may be adjusted by the Investigator, if clinically indicated, but it may not exceed 20 mg/kg/day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Kuvan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Soluble tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Appropriate number of Kuvan® 100 mg soluble tablets (sapropterin dihydrochloride), based on the dose calculated according to the subject’s weight, were dissolved in the protocol-defined volume of water and given to the child during breakfast. The solution was to be ingested within 15 to 20 minutes after dissolution.

    Arm title
    		 Phe-restricted Diet - Extension
    Arm description
    		 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. After 26 weeks, the starting dose of Kuvan will be 10 mg/kg/day, and the dose may be adjusted by the Investigator, if clinically indicated, but it may not exceed 20 mg/kg/day.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		Kuvan® + Phe-restricted Diet - Extension Phe-restricted Diet - Extension
    Started
    25
    26
    Completed
    18
    15
    Not completed
    7
    11
         Unknown
    7
    10
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Kuvan® + Phe-restricted Diet - Continuous
    Reporting group description
    		 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.

    Reporting group title
    Phe-restricted Diet - Continuous
    Reporting group description
    		 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. After 26 weeks, the starting dose of Kuvan will be 10 mg/kg/day, and the dose may be adjusted by the Investigator, if clinically indicated, but it may not exceed 20 mg/kg/day.

    Reporting group values
    		 Kuvan® + Phe-restricted Diet - Continuous Phe-restricted Diet - Continuous Total
    Number of subjects
    		 27 29 56
    Age categorical
    Units: Subjects
        <12 Months
    		 7 8 15
        12 - <24 Months
    		 9 9 18
        24 - <48 Months
    		 11 12 23
    Age continuous
    Units: months
        arithmetic mean (standard deviation)
    		 21.1 ( 12.3 ) 21.2 ( 12.0 ) -
    Gender categorical
    Units: Subjects
        Female
    		 11 15 26
        Male
    		 16 14 30
    Race
    Units: Subjects
        White
    		 26 28 54
        Asian
    		 0 1 1
        Other
    		 1 0 1
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 82.0 ( 11.3 ) 82.3 ( 11.6 ) -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 11.3 ( 3.1 ) 11.3 ( 2.8 ) -
    Body Mass Index
    Units: kg/m*2
        arithmetic mean (standard deviation)
    		 16.5 ( 1.0 ) 16.5 ( 1.4 ) -

    End points

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    End points reporting groups
    Reporting group title
    Kuvan® + Phe-restricted Diet - Continuous
    Reporting group description
    		 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.

    Reporting group title
    Phe-restricted Diet - Continuous
    Reporting group description
    		 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. After 26 weeks, the starting dose of Kuvan will be 10 mg/kg/day, and the dose may be adjusted by the Investigator, if clinically indicated, but it may not exceed 20 mg/kg/day.
    Reporting group title
    Kuvan® + Phe-restricted Diet - Extension
    Reporting group description
    		 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.After 26 weeks, the dose may be adjusted by the Investigator, if clinically indicated, but it may not exceed 20 mg/kg/day.

    Reporting group title
    Phe-restricted Diet - Extension
    Reporting group description
    		 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. After 26 weeks, the starting dose of Kuvan will be 10 mg/kg/day, and the dose may be adjusted by the Investigator, if clinically indicated, but it may not exceed 20 mg/kg/day.

    Subject analysis set title
    Pharmacokinetic Population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    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.

    Subject analysis set title
    Pharmacogenetics
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Phenylalanine hydroxylase (gene or protein) gene mutation analysis in 73 DNA samples Phenylalanine hydroxylase genotype analysis had been performed prior to a subject being considered for the trial, all subjects were still to undergo sampling for PAH genotype analysis at Screening. The number of subjects in subject analysis set are ITT 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.

    Primary: Dietary Phe Tolerance - Kuvan Continuous Study

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    End point title
    		 Dietary Phe Tolerance - Kuvan Continuous Study [1]
    End point description
    Phe tolerance is 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]). Dietary Phe tolerance after 26 weeks (6 months) of treatment with Kuvan®+ a Phe-restricted diet, as compared to just a Phe-restricted diet alone. 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.
    End point type
    Primary
    End point timeframe
    Week 26
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The following null hypothesis regarding the primary endpoint for the Extension Period was tested: H0: The mean dietary Phe tolerance with Kuvan along with dietary therapy does not differ over time vs H1: The mean dietary Phe tolerance with Kuvan along with dietary therapy differs over time
    End point values
    		 Kuvan® + Phe-restricted Diet - Continuous Phe-restricted Diet - Continuous
    Number of subjects analysed
    27
    29
    Units: mg/kg/day
        arithmetic mean (standard error)
    80.6 ( 4.2 )
    50.1 ( 4.3 )
    No statistical analyses for this end point

    Primary: Dietary Phe Tolerance - Kuvan Extension Study

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    End point title
    		 Dietary Phe Tolerance - Kuvan Extension Study [2]
    End point description
    Dietary Phe Tolerance (mg/kg/day) over time by Age Group (ITTE Population)
    End point type
    Primary
    End point timeframe
    Baseline, Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33 and 36 (End of Extension Period)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The following null hypothesis regarding the primary endpoint for the Extension Period was tested: H0: The mean dietary Phe tolerance with Kuvan along with dietary therapy does not differ over time vs H1: The mean dietary Phe tolerance with Kuvan along with dietary therapy differs over time
    End point values
    		 Kuvan® + Phe-restricted Diet - Extension Phe-restricted Diet - Extension
    Number of subjects analysed
    18
    15
    Units: mg/kg/day
    arithmetic mean (standard deviation)
        Baseline (<12M) (n=25, n=26)
    44.25 ( 11.00 )
    59.00 ( 28.51 )
        Baseline (12 - <24M) (n=25, n=26)
    48.63 ( 23.65 )
    49.25 ( 18.63 )
        Baseline (24 - <48M) (n=25, n=26)
    25.80 ( 8.41 )
    45.90 ( 24.85 )
        Month 3 (<12M) (n=25, n=26)
    92.20 ( 36.05 )
    61.86 ( 23.81 )
        Month 3 (12 - <24M) (n=25, n=26)
    102.25 ( 25.46 )
    59.33 ( 22.74 )
        Month 3 (24 - <48M) (n=25, n=26)
    64.75 ( 22.21 )
    46.00 ( 11.31 )
        Month 6 (<12M) (n=25, n=26)
    79.50 ( 33.24 )
    67.75 ( 27.32 )
        Month 6 (12 - <24M) (n=25, n=26)
    71.00 ( 46.29 )
    61.63 ( 17.15 )
        Month 6 (24 - <48M) (n=25, n=26)
    59.88 ( 24.26 )
    48.13 ( 11.04 )
        Month 9 (<12M) (n=25, n=26)
    94.00 ( 37.33 )
    66.50 ( 25.33 )
        Month 9 (12 - <24M) (n=25, n=26)
    90.60 ( 36.40 )
    61.60 ( 24.76 )
        Month 9 (24 - <48M) (n=25, n=26)
    54.80 ( 18.43 )
    55.40 ( 11.84 )
        Month 12 (<12M) (n=25, n=26)
    83.60 ( 39.06 )
    67.67 ( 29.33 )
        Month 12 (12 - <24M) (n=25, n=26)
    80.17 ( 37.62 )
    65.80 ( 25.88 )
        Month 12 (24 - <48M) (n=25, n=26)
    70.50 ( 32.96 )
    55.29 ( 14.01 )
        Month 15 (<12M) (n=25, n=26)
    82.33 ( 36.16 )
    74.80 ( 39.52 )
        Month 15 (12 - <24M) (n=25, n=26)
    83.86 ( 34.02 )
    60.17 ( 32.54 )
        Month 15 (24 - <48M) (n=25, n=26)
    48.00 ( 19.50 )
    54.75 ( 13.39 )
        Month 18 (<12M) (n=25, n=26)
    81.57 ( 31.88 )
    65.14 ( 31.82 )
        Month 18 (12 - <24M) (n=25, n=26)
    87.33 ( 24.58 )
    86.80 ( 33.53 )
        Month 18 (24 - <48M) (n=25, n=26)
    57.00 ( 17.13 )
    58.60 ( 16.83 )
        Month 21 (<12M) (n=25, n=26)
    78.86 ( 37.02 )
    63.33 ( 36.00 )
        Month 21 (12 - <24M) (n=25, n=26)
    78.71 ( 35.09 )
    64.60 ( 34.53 )
        Month 21 (24 - <48M) (n=25, n=26)
    49.20 ( 14.43 )
    59.00 ( 17.80 )
        Month 24 (<12M) (n=25, n=26)
    83.33 ( 30.63 )
    51.50 ( 38.02 )
        Month 24 (12 - <24M) (n=25, n=26)
    67.80 ( 36.34 )
    61.00 ( 26.01 )
        Month 24 (24 - <48M) (n=25, n=26)
    57.75 ( 5.25 )
    46.00 ( 4.58 )
        Month 27 (<12M) (n=25, n=26)
    86.80 ( 31.41 )
    58.67 ( 27.65 )
        Month 27 (12 - <24M) (n=25, n=26)
    82.20 ( 28.15 )
    62.50 ( 22.04 )
        Month 27 (24 - <48M) (n=25, n=26)
    42.00 ( 23.52 )
    55.75 ( 12.42 )
        Month 30 (<12M) (n=25, n=26)
    84.43 ( 46.10 )
    61.43 ( 34.49 )
        Month 30 (12 - <24M) (n=25, n=26)
    76.50 ( 28.22 )
    56.80 ( 26.77 )
        Month 30 (24 - <48M) (n=25, n=26)
    40.33 ( 22.50 )
    46.67 ( 4.16 )
        Month 33 (<12M) (n=25, n=26)
    70.80 ( 31.85 )
    59.71 ( 35.18 )
        Month 33 (12 - <24M) (n=25, n=26)
    73.75 ( 33.03 )
    56.80 ( 28.92 )
        Month 33 (24 - <48M) (n=25, n=26)
    44.00 ( 16.37 )
    46.00 ( 5.66 )
        End of Extension Period (EOS) (<12M) (n=25, n=26)
    97.40 ( 48.00 )
    54.80 ( 33.82 )
        End of Extension Period(EOS)(12 - <24M)(n=25,n=26)
    78.20 ( 34.10 )
    63.25 ( 34.41 )
        End of Extension Period(EOS)(24 - <48M)(n=25,n=26)
    44.33 ( 23.71 )
    49.67 ( 7.51 )
    No statistical analyses for this end point

    Secondary: Mean Blood Phe Levels - Kuvan Continuous Study

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    End point title
    		 Mean Blood Phe Levels - Kuvan Continuous Study
    End point description
    Mean blood phe levels were defined as the mean of blood phe levels assessed over each 2-week intervals. 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.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, and 26
    End point values
    		 Kuvan® + Phe-restricted Diet - Continuous Phe-restricted Diet - Continuous
    Number of subjects analysed
    27
    29
    Units: micromole(s)/litre
    arithmetic mean (standard deviation)
        Baseline (n=27, 29)
    287.3 ( 166.6 )
    352.9 ( 219.9 )
        Week 2 (n=27, 26)
    214.3 ( 89.3 )
    321.3 ( 133.5 )
        Week 4 (n=27, 24)
    202.1 ( 79.3 )
    308.0 ( 122.2 )
        Week 6 (n=25, 26)
    248.0 ( 85.4 )
    303.8 ( 87.4 )
        Week 8 (n=26, 26)
    268.7 ( 107.9 )
    318.0 ( 108.9 )
        Week 10 (n=24, 27)
    271.1 ( 109.4 )
    325.4 ( 106.2 )
        Week 12 (n=22, 22)
    317.6 ( 106.0 )
    328.9 ( 125.0 )
        Week 14 (n=24, 26)
    271.6 ( 79.0 )
    311.2 ( 118.6 )
        Week 16 (n=25, 26)
    320.3 ( 112.2 )
    356.3 ( 99.1 )
        Week 18 (n=24, 26)
    302.9 ( 122.7 )
    325.4 ( 80.4 )
        Week 20 (n=25, 25)
    305.1 ( 116.1 )
    326.3 ( 77.0 )
        Week 22 (n=25, 24)
    293.2 ( 86.8 )
    346.9 ( 97.8 )
        Week 24 (n=24, 25)
    278.8 ( 77.2 )
    326.1 ( 120.4 )
        Week 26 (n=21, 22)
    300.1 ( 115.2 )
    343.3 ( 118.4 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Dietary Phe Tolerance After 26 Weeks - Kuvan Continuous Study

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    End point title
    		 Change From Baseline in Dietary Phe Tolerance After 26 Weeks - Kuvan Continuous Study
    End point description
    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).
    End point type
    Secondary
    End point timeframe
    Baseline and at Week 26 (last observation carried-forward [LOCF]) 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 subject
    End point values
    		 Kuvan® + Phe-restricted Diet - Continuous Phe-restricted Diet - Continuous
    Number of subjects analysed
    27
    29
    Units: mg/kg/day
    arithmetic mean (standard error)
        Baseline (n=27, 29)
    37.1 ( 17.3 )
    35.8 ( 20.9 )
        Week 26: LOCF (n=27, 27)
    74.0 ( 38.6 )
    49.8 ( 24.2 )
        Change at Week 26: LOCF (n=27, 27)
    36.9 ( 27.3 )
    13.1 ( 19.6 )
    No statistical analyses for this end point

    Secondary: Number of Subjects With Any TEAEs, AEs Related to Kuvan, Serious AEs, AEs Leading to Death, and AEs Leading to Discontinuation - Kuvan Continuous Study

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    End point title
    		 Number of Subjects With Any TEAEs, AEs Related to Kuvan, Serious AEs, AEs Leading to Death, and AEs Leading to Discontinuation - Kuvan Continuous Study
    End point description
    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. 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.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug administration up to 31 days after the last dose of study drug administration.
    End point values
    		 Kuvan® + Phe-restricted Diet - Continuous Phe-restricted Diet - Continuous
    Number of subjects analysed
    27
    27
    Units: Subjects
    number (not applicable)
        Treatment-emergent adverse events
    27
    27
        Adverse events related to Kuvan
    8
    0
        Serious adverse events
    3
    1
        Related serious adverse events
    0
    0
        Adverse events leading to death
    0
    0
        Adverse events Leading to discontinuation
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Neuromotor Developmental Milestones Assessed Using Denver Developmental Scale (DDS) - Kuvan Continuous Study

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    End point title
    		 Number of Subjects With Neuromotor Developmental Milestones Assessed Using Denver Developmental Scale (DDS) - Kuvan Continuous Study
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, 26
    End point values
    		 Kuvan® + Phe-restricted Diet - Continuous Phe-restricted Diet - Continuous
    Number of subjects analysed
    27
    29
    Units: Subjects
    number (not applicable)
        Fine motor:Baseline-Normal(n=25,26)
    18
    21
        Fine motor:Baseline-Abnormal(n=25,26)
    7
    5
        Fine motor:Week 12-Normal(n=25,25)
    21
    23
        Fine motor:Week 12-Abnormal(n=25,25)
    4
    2
        Fine motor:Week 26-Normal (n=25,25)
    20
    23
        Fine motor:Week 26-Abnormal(n=25,25)
    5
    2
        Gross motor:Baseline-Normal(n=25,26)
    23
    23
        Gross motor:Baseline-Abnormal(n=25,26)
    2
    3
        Gross motor:Week 12-Normal(n=25,25)
    21
    20
        Gross motor:Week 12-Abnormal(n=25,25)
    4
    5
        Gross motor:Week 26-Normal(n=25,25)
    20
    19
        Gross motor:Week 26-Abnormal(n=25,25)
    5
    6
        Language:Baseline-Normal(n=25,26)
    22
    20
        Language:Baseline-Abnormal(n=25,26)
    3
    6
        Language:Week 12-Normal(n=25,25)
    22
    22
        Language:Week 12-Abnormal(n=25,25)
    3
    3
        Language:Week 26-Normal(n=25,25)
    16
    20
        Language:Week 26-Abnormal(n=25,25)
    9
    5
        Personal social:Baseline-Normal(n=25,26)
    22
    22
        Personal social:Baseline-Abnormal(n=25,26)
    3
    4
        Personal social:Week 12-Normal(n=25,25)
    22
    21
        Personal social:Week 12-Abnormal(n=25,25)
    3
    4
        Personal social:Week 26-Normal(n=25,25)
    22
    18
        Personal social:Week 26-Abnormal(n=25,25)
    3
    7
    No statistical analyses for this end point

    Secondary: Neurodevelopmental Status Assessed Using Bayley III Scales of Infant and Toddler Development - Kuvan Continuous Study

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    End point title
    		 Neurodevelopmental Status Assessed Using Bayley III Scales of Infant and Toddler Development - Kuvan Continuous Study
    End point description
    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. 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.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 26
    End point values
    		 Kuvan® + Phe-restricted Diet - Continuous Phe-restricted Diet - Continuous
    Number of subjects analysed
    27
    29
    Units: Units on a scale
    arithmetic mean (standard deviation)
        ABC score: Baseline (n=15, 18)
    106.5 ( 14.2 )
    96.2 ( 14.6 )
        ABC score: Week 26 (n=19, 18)
    102.4 ( 16.4 )
    93.4 ( 14.1 )
        CC score: Baseline (n=19, 20)
    100.0 ( 11.8 )
    101.2 ( 15.9 )
        CC score: Week 26 (n=20, 19)
    102.8 ( 12.9 )
    100.8 ( 13.0 )
        LS score: Baseline (n=18, 19)
    96.7 ( 12.4 )
    97.7 ( 19.5 )
        LS score: Week 26 (n=20, 19)
    98.3 ( 11.9 )
    93.6 ( 12.1 )
        MC score: Baseline (n=19, 20)
    97.8 ( 13.7 )
    94.9 ( 13.6 )
        MC score: Week 26 (n=20, 19)
    100.6 ( 15.2 )
    98.7 ( 9.5 )
        SEC score: Baseline (n=17, 18)
    102.9 ( 11.3 )
    106.0 ( 16.3 )
        SEC score: Week 26 (n=19, 18)
    106.3 ( 19.1 )
    102.5 ( 13.2 )
    No statistical analyses for this end point

    Secondary: Growth Parameters Standard Deviation Scores (SDS) - Kuvan Continuous Study

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    End point title
    		 Growth Parameters Standard Deviation Scores (SDS) - Kuvan Continuous Study
    End point description
    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. 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.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 8, 12, 16, 20, and 26
    End point values
    		 Kuvan® + Phe-restricted Diet - Continuous Phe-restricted Diet - Continuous
    Number of subjects analysed
    27
    29
    Units: Standard Deviation Scores (SDS)
    arithmetic mean (standard deviation)
        Body mass index SDS: Baseline (n=27, 29)
    0.37 ( 0.84 )
    0.34 ( 0.99 )
        Body mass index SDS: Week 4 (n=26, 27)
    0.33 ( 0.92 )
    0.36 ( 0.95 )
        Body mass index SDS: Week 8 (n=25, 26)
    0.47 ( 0.93 )
    0.38 ( 0.82 )
        Body mass index SDS: Week 12 (n=25, 26)
    0.37 ( 1.02 )
    0.48 ( 0.91 )
        Body mass index SDS: Week 16 (n=25, 26)
    0.34 ( 0.95 )
    0.39 ( 0.93 )
        Body mass index SDS: Week 20 (n=25, 27)
    0.46 ( 0.93 )
    0.44 ( 0.86 )
        Body mass index SDS: Week 26 (n=25, 26)
    0.58 ( 0.83 )
    0.41 ( 0.81 )
        Height SDS: Baseline (n=27, 29)
    -0.19 ( 1.17 )
    -0.21 ( 1.03 )
        Height SDS: Week 4 (n=26, 27)
    -0.19 ( 1.08 )
    -0.25 ( 1.00 )
        Height SDS: Week 8 (n=25, 26)
    -0.22 ( 1.08 )
    -0.13 ( 1.05 )
        Height SDS: Week 12 (n=25, 26)
    0.02 ( 1.62 )
    -0.14 ( 1.11 )
        Height SDS: Week 16 (n=25, 26)
    0.05 ( 1.36 )
    -0.05 ( 1.05 )
        Height SDS: Week 20 (n=25, 27)
    -0.08 ( 1.21 )
    -0.11 ( 0.95 )
        Height SDS: Week 26 (n=25, 26)
    -0.11 ( 1.16 )
    -0.06 ( 0.92 )
        MOFHC SDS: Baseline (n=27, 29)
    0.37 ( 1.38 )
    0.07 ( 1.10 )
        MOFHC SDS: Week 4 (n=25, 26)
    0.48 ( 1.41 )
    0.21 ( 1.03 )
        MOFHC SDS: Week 8 (n=25, 26)
    0.51 ( 1.40 )
    0.35 ( 1.05 )
        MOFHC SDS: Week 12 (n=25, 26)
    0.43 ( 1.23 )
    0.20 ( 1.19 )
        MOFHC SDS: Week 16 (n=25, 26)
    0.58 ( 1.26 )
    0.25 ( 1.18 )
        MOFHC SDS: Week 20 (n=25, 26)
    0.41 ( 1.30 )
    0.18 ( 1.24 )
        MOFHC SDS: Week 26 (n=25, 26)
    0.43 ( 1.34 )
    0.15 ( 1.26 )
        Weight SDS: Baseline (n=27, 29)
    0.12 ( 0.81 )
    0.12 ( 0.66 )
        Weight SDS: Week 4 (n=26, 27)
    0.11 ( 0.86 )
    0.12 ( 0.64 )
        Weight SDS: Week 8 (n=25, 27)
    0.18 ( 0.88 )
    0.18 ( 0.66 )
        Weight SDS: Week 12 (n=25, 26)
    0.23 ( 0.91 )
    0.25 ( 0.65 )
        Weight SDS: Week 16 (n=25, 26)
    0.23 ( 0.97 )
    0.25 ( 0.74 )
        Weight SDS: Week 20 (n=25, 27)
    0.25 ( 0.95 )
    0.24 ( 0.67 )
        Weight SDS: Week 26 (n=25, 26)
    0.32 ( 0.93 )
    0.19 ( 0.67 )
    No statistical analyses for this end point

    Secondary: Number of Subjects With Hypophenylalanemia - Kuvan Continuous Study

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    End point title
    		 Number of Subjects With Hypophenylalanemia - Kuvan Continuous Study
    End point description
    Hypophenylalanemia is defined as the condition of blood Phe levels <120 mcmol/L. 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.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    		 Kuvan® + Phe-restricted Diet - Continuous Phe-restricted Diet - Continuous
    Number of subjects analysed
    27
    27
    Units: Subjects
        number (not applicable)
    10
    9
    No statistical analyses for this end point

    Secondary: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) - Kuvan Continuous Study

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    End point title
    		 Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) - Kuvan Continuous Study
    End point description
    Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) 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.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 8, 12, 16, 20, and 26
    End point values
    		 Kuvan® + Phe-restricted Diet - Continuous Phe-restricted Diet - Continuous
    Number of subjects analysed
    27
    29
    Units: mmHg
    arithmetic mean (standard deviation)
        SBP: Baseline (n=25, 25)
    93.5 ( 11.0 )
    93.1 ( 14.4 )
        SBP: Week 4 (n=22, 25)
    95.9 ( 14.6 )
    101.5 ( 17.6 )
        SBP: Week 8 (n=23, 25)
    95.9 ( 17.5 )
    95.7 ( 17.9 )
        SBP: Week 12 (n=23, 26)
    97.0 ( 13.2 )
    95.2 ( 9.8 )
        SBP: Week 16 (n=23, 26)
    95.0 ( 14.5 )
    98.2 ( 12.3 )
        SBP: Week 20 (n=21, 27)
    95.6 ( 14.1 )
    98.4 ( 12.6 )
        SBP: Week 26 (n=22, 25)
    97.5 ( 11.1 )
    96.8 ( 8.7 )
        DBP: Baseline (n=25, 25)
    55.8 ( 9.0 )
    57.1 ( 8.1 )
        DBP: Week 4 (n=22, 25)
    59.8 ( 9.8 )
    59.0 ( 13.3 )
        DBP: Week 8 (n=23, 25)
    59.1 ( 7.8 )
    55.2 ( 8.7 )
        DBP: Week 12 (n=23, 26)
    58.5 ( 6.2 )
    57.4 ( 9.7 )
        DBP: Week 16 (n=23, 26)
    57.7 ( 12.1 )
    58.5 ( 11.2 )
        DBP: Week 20 (n=21, 27)
    57.5 ( 12.1 )
    58.4 ( 6.3 )
        DBP: Week 26 (n=22, 25)
    59.0 ( 7.0 )
    59.2 ( 9.4 )
    No statistical analyses for this end point

    Secondary: Number of Samples With Phenylalanine Hydroxylase (PAH) Gene Mutations - Kuvan Continuous Study

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    End point title
    		 Number of Samples With Phenylalanine Hydroxylase (PAH) Gene Mutations - Kuvan Continuous Study
    End point description
    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 and Sanger sequenced. 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. 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.
    End point type
    Secondary
    End point timeframe
    Screening (within 42 days prior to Day 1 of the 26-week study period)
    End point values
    		 Pharmacogenetics
    Number of subjects analysed
    73
    Units: Sample
        number (not applicable)
    73
    No statistical analyses for this end point

    Secondary: Population Pharmacokinetic (PK) Parameter: Apparent Clearance (CL/f) - Kuvan Continuous Study

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    End point title
    		 Population Pharmacokinetic (PK) Parameter: Apparent Clearance (CL/f) - Kuvan Continuous Study
    End point description
    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. 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® 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.
    End point type
    Secondary
    End point timeframe
    Weeks 5 to 12
    End point values
    		 Pharmacokinetic Population
    Number of subjects analysed
    52
    Units: litre per hour
        arithmetic mean (standard error)
    2780 ( 2 )
    No statistical analyses for this end point

    Secondary: Population PK Parameter: Apparent Volume of Distribution (V/f) - Kuvan Continuous Study

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    End point title
    		 Population PK Parameter: Apparent Volume of Distribution (V/f) - Kuvan Continuous Study
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    Weeks 5 to 12
    End point values
    		 Pharmacokinetic Population
    Number of subjects analysed
    52
    Units: litre(s)
        arithmetic mean (standard error)
    3870 ( 5.9 )
    No statistical analyses for this end point

    Secondary: Population PK Parameter: Area Under the Plasma Concentration Curve, Time 0 to Infinity (AUC [0-infinity]) - Kuvan Continuous Study

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    End point title
    		 Population PK Parameter: Area Under the Plasma Concentration Curve, Time 0 to Infinity (AUC [0-infinity]) - Kuvan Continuous Study
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    Weeks 5 to 12
    End point values
    		 Pharmacokinetic Population
    Number of subjects analysed
    52
    Units: microgram*hour/litre
    arithmetic mean (standard deviation)
        Population PK Analysis Set: Age Group 1 (< 1 Year)
    234.89 ( 89.82 )
        Population PK Analysis Set: Age Group 2 (1-2 Yrs)
    215.74 ( 63.88 )
        Population PK Analysis Set: Age Group 2 (>= 2 Yrs)
    206.22 ( 103.24 )
    No statistical analyses for this end point

    Secondary: Population PK Parameter: Terminal Elimination Half-life (t1/2) - Kuvan Continuous Study

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    End point title
    		 Population PK Parameter: Terminal Elimination Half-life (t1/2) - Kuvan Continuous Study
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    Weeks 5 to 12
    End point values
    		 Pharmacokinetic Population
    Number of subjects analysed
    52
    Units: hour
        number (not applicable)
    0.96
    No statistical analyses for this end point

    Secondary: Change from Baseline of Dietary Phe Tolerance - Kuvan Extension study

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    End point title
    		 Change from Baseline of Dietary Phe Tolerance - Kuvan Extension study
    End point description
    Change from Baseline of Dietary Phe Tolerance (mg/kg/day) Over Time by Age Group (ITTE Population)
    End point type
    Secondary
    End point timeframe
    Baseline value, Month 12 - Baseline, Month 24 - Baseline, End of Extension Period (EOS) – Baseline
    End point values
    		 Kuvan® + Phe-restricted Diet - Extension Phe-restricted Diet - Extension
    Number of subjects analysed
    18
    15
    Units: mg/kg/day
    arithmetic mean (standard deviation)
        Baseline value (<12M) (n=25, n=26)
    42.86 ( 9.19 )
    59.00 ( 28.51 )
        Baseline value (12 - <24M) (n=25, n=26)
    46.00 ( 23.48 )
    49.25 ( 18.63 )
        Baseline value (24 - <48M) (n=25, n=26)
    23.89 ( 6.70 )
    45.90 ( 24.85 )
        Month 12 – Baseline (<12M) (n=25, n=26)
    38.20 ( 37.04 )
    6.00 ( 16.70 )
        Month 12 – Baseline (12 - <24M) (n=25, n=26)
    38.67 ( 19.94 )
    14.20 ( 21.22 )
        Month 12 – Baseline (24 - <48M) (n=25, n=26)
    46.00 ( 25.97 )
    6.57 ( 31.18 )
        Month 24 – Baseline (<12M) (n=25, n=26)
    40.50 ( 30.24 )
    -11.50 ( 33.39 )
        Month 24 – Baseline (12 - <24M) (n=25, n=26)
    26.60 ( 19.84 )
    6.50 ( 17.71 )
        Month 24 – Baseline (24 - <48M) (n=25, n=26)
    34.25 ( 9.74 )
    6.67 ( 7.02 )
        EOS – Baseline (<12M) (n=25, n=26)
    53.60 ( 52.20 )
    -4.00 ( 14.53 )
        EOS – Baseline (12 - <24M) (n=25, n=26)
    35.20 ( 22.68 )
    10.25 ( 17.75 )
        EOS – Baseline (24 - <48M) (n=25, n=26)
    23.67 ( 18.23 )
    2.33 ( 4.04 )
    No statistical analyses for this end point

    Secondary: Change from Baseline over Time in Blood Pressure - Kuvan Extension Study

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    End point title
    		 Change from Baseline over Time in Blood Pressure - Kuvan Extension Study
    End point description
    Change from Baseline over Time in Blood Pressure (mmHg) - Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) by Age Group (ITTE Population)
    End point type
    Secondary
    End point timeframe
    Baseline value, Month 12 - Baseline, Month 24 - Baseline, EOS - Baseline
    End point values
    		 Kuvan® + Phe-restricted Diet - Extension Phe-restricted Diet - Extension
    Number of subjects analysed
    18
    15
    Units: mmHg
    arithmetic mean (standard deviation)
        SBP - Baseline value (<12M) (n=25, n=26)
    94.86 ( 13.55 )
    96.25 ( 7.30 )
        SBP - Baseline value (12 - <24M) (n=25, n=26)
    87.71 ( 7.41 )
    97.50 ( 9.99 )
        SBP - Baseline value (24 - <48M) (n=25, n=26)
    104.44 ( 16.97 )
    95.30 ( 10.02 )
        SBP - Month 12 – Baseline (<12M) (n=25, n=26)
    2.50 ( 19.42 )
    11.43 ( 15.40 )
        SBP - Month 12 – Baseline (12 - <24M) (n=25, n=26)
    2.00 ( 12.15 )
    2.00 ( 12.90 )
        SBP - Month 12 – Baseline (24 - <48M) (n=25, n=26)
    -1.78 ( 13.51 )
    5.14 ( 13.99 )
        SBP - Month 24 – Baseline (<12M) (n=25, n=26)
    1.40 ( 14.74 )
    -1.50 ( 10.45 )
        SBP - Month 24 – Baseline (12 - <24M) (n=25, n=26)
    12.00 ( 10.02 )
    4.57 ( 15.90 )
        SBP - Month 24 – Baseline (24 - <48M) (n=25, n=26)
    2.33 ( 11.64 )
    2.83 ( 8.33 )
        SBP - EOS – Baseline (<12M) (n=25, n=26)
    -1.29 ( 16.31 )
    -4.00 ( 10.30 )
        SBP - EOS – Baseline (12 - <24M) (n=25, n=26)
    10.00 ( 9.35 )
    6.00 ( 23.16 )
        SBP - EOS – Baseline (24 - <48M) (n=25, n=26)
    18.25 ( 10.28 )
    8.33 ( 2.89 )
        DBP - Baseline value (<12M) (n=25, n=26)
    57.43 ( 13.88 )
    58.63 ( 10.88 )
        DBP - Baseline value (12 - <24M) (n=25, n=26)
    53.86 ( 6.09 )
    58.63 ( 8.72 )
        DBP - Baseline value (24 - <48M) (n=25, n=26)
    68.44 ( 13.00 )
    58.80 ( 10.14 )
        DBP - Month 12 – Baseline (<12M) (n=25, n=26)
    -1.17 ( 23.83 )
    10.29 ( 16.27 )
        DBP - Month 12 – Baseline (12 - <24M) (n=25, n=26)
    4.29 ( 6.16 )
    2.29 ( 8.36 )
        DBP - Month 12 – Baseline (24 - <48M) (n=25, n=26)
    -10.56 ( 13.59 )
    1.14 ( 12.77 )
        DBP - Month 24 – Baseline (<12M) (n=25, n=26)
    -1.40 ( 5.94 )
    -3.38 ( 10.35 )
        DBP - Month 24 – Baseline (12 - <24M) (n=25, n=26)
    6.50 ( 10.45 )
    2.00 ( 10.58 )
        DBP - Month 24 – Baseline (24 - <48M) (n=25, n=26)
    -7.83 ( 7.25 )
    -1.00 ( 10.30 )
        DBP - EOS – Baseline (<12M) (n=25, n=26)
    3.71 ( 15.68 )
    -4.14 ( 10.07 )
        DBP - EOS – Baseline (12 - <24M) (n=25, n=26)
    5.00 ( 5.29 )
    1.60 ( 7.47 )
        DBP - EOS – Baseline (24 - <48M) (n=25, n=26)
    7.25 ( 7.59 )
    10.00 ( 5.00 )
    No statistical analyses for this end point

    Secondary: Change from Baseline over Time in Growth Parameters - Kuvan Extension Study

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    End point title
    		 Change from Baseline over Time in Growth Parameters - Kuvan Extension Study
    End point description
    Change from Baseline over Time in Growth Parameters (Body Mass Index (BMI), Maximal Occipital-Frontal Head Circumference (MOFHC), Height and Weight) by Age Group (ITTE Population).
    End point type
    Secondary
    End point timeframe
    Baseline value, Month 12 - Baseline, Month 24 - Baseline, EOS – Baseline
    End point values
    		 Kuvan® + Phe-restricted Diet - Extension Phe-restricted Diet - Extension
    Number of subjects analysed
    18
    15
    Units: Standard Deviation Scores
    arithmetic mean (standard deviation)
        BMI SDS: Baseline value (<12M) (n=25, n=26)
    -0.39 ( 0.90 )
    0.26 ( 0.87 )
        BMI SDS: Baseline value (12 - <24M) (n=25, n=26)
    0.56 ( 0.49 )
    0.70 ( 0.91 )
        BMI SDS: Baseline value (24 - <48M) (n=25, n=26)
    0.78 ( 0.55 )
    0.30 ( 0.69 )
        BMI SDS: Month 12-Baseline (<12M) (n=25, n=26)
    0.96 ( 0.91 )
    0.21 ( 0.68 )
        BMI SDS: Month 12-Baseline (12 - <24M)(n=25, n=26)
    0.21 ( 0.94 )
    0.23 ( 0.80 )
        BMI SDS: Month 12-Baseline (24 - <48M)(n=25, n=26)
    0.17 ( 0.42 )
    -0.02 ( 0.50 )
        BMI SDS: Month 24-Baseline (<12M) (n=25, n=26)
    0.46 ( 0.56 )
    0.47 ( 0.75 )
        BMI SDS: Month 24-Baseline (12 - <24M)(n=25, n=26)
    -0.03 ( 0.74 )
    -0.11 ( 0.41 )
        BMI SDS: Month 24-Baseline (24 - <48M)(n=25, n=26)
    -0.16 ( 0.46 )
    -0.23 ( 0.51 )
        BMI SDS: EOS - Baseline (<12M) (n=25, n=26)
    0.45 ( 0.91 )
    0.53 ( 0.89 )
        BMI SDS: EOS - Baseline (12 - <24M) (n=25, n=26)
    0.47 ( 0.74 )
    -0.37 ( 0.07 )
        MOFHC SDS: Baseline value (<12M) (n=25, n=26)
    42.56 ( 2.52 )
    45.75 ( 1.89 )
        MOFHC SDS: Baseline value (12-<24M) (n=25, n=26)
    47.83 ( 2.25 )
    48.75 ( 2.92 )
        MOFHC SDS: Baseline value (24-<48M) (n=25, n=26)
    49.33 ( 2.42 )
    48.88 ( 1.65 )
        MOFHC SDS: Month 12-Baseline (<12M) (n=25, n=26)
    6.09 ( 2.06 )
    2.96 ( 1.59 )
        MOFHC SDS: Month 12-Baseline (12-<24M) (n=25,n=26)
    1.66 ( 1.23 )
    1.31 ( 1.39 )
        MOFHC SDS: Month 12-Baseline (24-<48M) (n=25,n=26)
    1.33 ( 0.98 )
    0.93 ( 2.62 )
        MOFHC SDS: Month 24-Baseline (<12M) (n=25, n=26)
    6.77 ( 2.44 )
    3.59 ( 1.01 )
        MOFHC SDS: Month 24-Baseline (12-<24M) (n=25,n=26)
    2.86 ( 0.80 )
    1.80 ( 1.10 )
        MOFHC SDS: Month 24-Baseline (24-<48M) (n=25,n=26)
    1.67 ( 1.03 )
    2.18 ( 1.61 )
        MOFHC SDS: EOS - Baseline (<12M) (n=25, n=26)
    7.95 ( 2.06 )
    4.47 ( 1.23 )
        MOFHC SDS: EOS-Baseline (12-<24M) (n=25, n=26)
    3.54 ( 1.09 )
    1.36 ( 0.84 )
        MOFHC SDS: EOS-Baseline (24-<48M) (n=25, n=26)
    2.68 ( 1.64 )
    2.63 ( 1.41 )
        Height SDS: Baseline value (<12M) (n=25, n=26)
    0.43 ( 0.94 )
    0.11 ( 1.03 )
        Height SDS: Baseline value (12-<24M) (n=25, n=26)
    -0.28 ( 1.42 )
    -0.19 ( 0.66 )
        Height SDS: Baseline value (24-<48M) (n=25, n=26)
    -0.49 ( 1.13 )
    -0.35 ( 1.03 )
        Height SDS: Month 12-Baseline (<12M) (n=25, n=26)
    -0.38 ( 0.58 )
    0.01 ( 0.65 )
        Height SDS:Month 12-Baseline (12-<24M) (n=25,n=26)
    -0.09 ( 0.80 )
    0.11 ( 0.48 )
        Height SDS:Month 12-Baseline (24-<48M) (n=25,n=26)
    0.12 ( 0.66 )
    0.10 ( 0.57 )
        Height SDS: Month 24-Baseline (<12M) (n=25, n=26)
    -0.46 ( 0.67 )
    -0.16 ( 0.75 )
        Height SDS:Month 24-Baseline (12-<24M) (n=25,n=26)
    0.28 ( 0.53 )
    0.19 ( 0.74 )
        Height SDS:Month 24-Baseline (24-<48M) (n=25,n=26)
    -0.37 ( 0.92 )
    0.11 ( 0.52 )
        Height SDS: EOS-Baseline (<12M) (n=25, n=26)
    -0.39 ( 0.81 )
    -0.18 ( 0.55 )
        Height SDS: EOS-Baseline (12-<24M) (n=25, n=26)
    -0.12 ( 0.62 )
    0.31 ( 0.62 )
        Weight SDS: Baseline value (<12M) (n=25, n=26)
    -0.04 ( 0.74 )
    0.25 ( 0.71 )
        Weight SDS: Baseline value (12-<24M) (n=25, n=26)
    0.21 ( 0.95 )
    0.38 ( 0.63 )
        Weight SDS: Baseline value (24-<48M) (n=25, n=26)
    0.22 ( 0.73 )
    -0.01 ( 0.67 )
        Weight SDS: Month 12-Baseline (<12M) (n=25, n=26)
    0.48 ( 0.48 )
    0.14 ( 0.36 )
        Weight SDS:Month 12-Baseline (12-<24M) (n=25,n=26)
    0.06 ( 0.60 )
    0.21 ( 0.38 )
        Weight SDS:Month 12-Baseline (24-<48M) (n=25,n=26)
    0.19 ( 0.31 )
    0.03 ( 0.25 )
        Weight SDS: Month 24 - Baseline (<12M) (n=25,n=26)
    0.10 ( 0.50 )
    0.22 ( 0.61 )
        Weight SDS:Month 24-Baseline (12-<24M) (n=25,n=26)
    -0.01 ( 0.67 )
    0.01 ( 0.33 )
        Weight SDS:Month 24-Baseline (24-<48M) (n=25,n=26)
    -0.34 ( 0.65 )
    -0.10 ( 0.11 )
        Weight SDS: EOS - Baseline (<12M) (n=25, n=26)
    0.12 ( 0.34 )
    0.22 ( 0.66 )
        Weight SDS: EOS - Baseline (12-<24M) (n=25, n=26)
    0.15 ( 0.83 )
    -0.10 ( 0.39 )
    No statistical analyses for this end point

    Secondary: Neuromotor Developmental Milestones (ITTE population) - Kuvan Extension Study

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    End point title
    		 Neuromotor Developmental Milestones (ITTE population) - Kuvan Extension Study
    End point description
    Neurodevelopmental Status Assessment by Age Group in Subjects ≥42 Months at End of Year 1, 2, and 3 (Wechsler Preschool and Primary Scale of Intelligence) - ITTE Population
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, Month 24 and EOS (Month 36 -End of Extension Period)
    End point values
    		 Kuvan® + Phe-restricted Diet - Extension Phe-restricted Diet - Extension
    Number of subjects analysed
    18
    15
    Units: Standard Deviation Scores (SDS)
    arithmetic mean (standard deviation)
        Full Scale IQ:Month12-Baseline(24-<48M)(n=25,n=26)
    110.44 ( 17.58 )
    111.43 ( 26.22 )
        Full Scale IQ:Month24-Baseline(12-<24M)(n=25,n=26)
    98.00 ( 20.07 )
    94.40 ( 19.69 )
        Full Scale IQ:Month24-Baseline(24-<48M)(n=25,n=26)
    105.50 ( 12.12 )
    115.25 ( 7.27 )
        Full Scale IQ: EOS - Baseline (<12M) (n=25, n=26)
    120.67 ( 14.67 )
    108.60 ( 14.81 )
        Full Scale IQ: EOS-Baseline (24-<48M) (n=25,n=26)
    95.25 ( 8.26 )
    108.20 ( 14.75 )
        Performance IQ:Month12Baseline(24-<48M)(n=25,n=26)
    104.33 ( 19.76 )
    96.43 ( 20.26 )
        Performance IQ:Month24Baseline(12-<24M)(n=25,n=26)
    92.33 ( 22.01 )
    95.40 ( 22.79 )
        Performance IQ:Month24Baseline(24-<48M)(n=25,n=26)
    105.25 ( 4.99 )
    111.00 ( 12.19 )
        Performance IQ:EOS-Baseline(<12M)(n=25, n=26)
    116.33 ( 15.28 )
    96.80 ( 13.41 )
        Performance IQ:EOS-Baseline(24-<48M)(n=25,n=26)
    93.75 ( 11.24 )
    103.40 ( 18.17 )
        Verbal IQ: Month12-Baseline (24-<48M)(n=25,n=26)
    114.89 ( 17.29 )
    117.57 ( 22.27 )
        Verbal IQ: Month24-Baseline (12-<24M)(n=25,n=26)
    101.33 ( 18.23 )
    95.40 ( 14.03 )
        Verbal IQ: Month24-Baseline (24-<48M)(n=25,n=26)
    110.00 ( 15.56 )
    115.75 ( 6.85 )
        Verbal IQ: EOS-Baseline (<12M) (n=25, n=26)
    111.50 ( 13.11 )
    109.80 ( 12.17 )
        Verbal IQ: EOS-Baseline (24-<48M) (n=25, n=26)
    101.50 ( 9.04 )
    115.60 ( 11.95 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of study drug administration up to 31 days after the last dose of study drug administration
    Adverse event reporting additional description
    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.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Kuvan® + Phe-restricted Diet - Continuous
    Reporting group description
    		 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.

    Reporting group title
    Phe-restricted Diet - Continuous
    Reporting group description
    		 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. After 26 weeks, the starting dose of Kuvan will be 10 mg/kg/day, and the dose may be adjusted by the Investigator, if clinically indicated, but it may not exceed 20 mg/kg/day.

    Reporting group title
    Kuvan® + Phe-restricted Diet - Extension
    Reporting group description
    		 -

    Reporting group title
    Phe-restricted Diet - Extension
    Reporting group description
    		 -

    Serious adverse events
    		 Kuvan® + Phe-restricted Diet - Continuous Phe-restricted Diet - Continuous Kuvan® + Phe-restricted Diet - Extension Phe-restricted Diet - Extension
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 27 (11.11%)
    1 / 27 (3.70%)
    6 / 25 (24.00%)
    7 / 26 (26.92%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Overdose
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Animal bite
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clavicle Fracture
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    0 / 25 (0.00%)
    2 / 26 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Febrile Convulsion
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Immune Thrombocytopenic
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Stomatitis
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 27 (0.00%)
    0 / 25 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Balanoposthitis
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Adenoidal Hypertrophy
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchiolitis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
    0 / 25 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis Media
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral Infection
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    0 / 25 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Kuvan® + Phe-restricted Diet - Continuous Phe-restricted Diet - Continuous Kuvan® + Phe-restricted Diet - Extension Phe-restricted Diet - Extension
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 27 (100.00%)
    27 / 27 (100.00%)
    25 / 25 (100.00%)
    24 / 26 (92.31%)
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    17 / 27 (62.96%)
    18 / 27 (66.67%)
    23 / 25 (92.00%)
    22 / 26 (84.62%)
         occurrences all number
    32
    37
    127
    86
    Fatigue
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    3 / 25 (12.00%)
    3 / 26 (11.54%)
         occurrences all number
    0
    0
    5
    3
    Immune system disorders
    House Dust Allergy
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Reproductive system and breast disorders
    Balanoposthitis
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    13 / 27 (48.15%)
    13 / 27 (48.15%)
    19 / 25 (76.00%)
    15 / 26 (57.69%)
         occurrences all number
    29
    25
    97
    52
    Rhinorrhoea
         subjects affected / exposed
    2 / 27 (7.41%)
    8 / 27 (29.63%)
    5 / 25 (20.00%)
    8 / 26 (30.77%)
         occurrences all number
    8
    17
    26
    31
    Nasal Congestion
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 27 (7.41%)
    0 / 25 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    3 / 25 (12.00%)
    4 / 26 (15.38%)
         occurrences all number
    0
    0
    3
    6
    Psychiatric disorders
    Irritability
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    0
    2
    3
    Investigations
    Body Temperature Increased
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    0
    4
    3
    Cardiac Murmur
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    2
    1
    Cardiac Murmur Functional
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Amino Acid Level Decreased
         subjects affected / exposed
    12 / 27 (44.44%)
    11 / 27 (40.74%)
    11 / 25 (44.00%)
    3 / 26 (11.54%)
         occurrences all number
    43
    29
    45
    6
    Amino Acid Level Increased
         subjects affected / exposed
    10 / 27 (37.04%)
    9 / 27 (33.33%)
    3 / 25 (12.00%)
    3 / 26 (11.54%)
         occurrences all number
    39
    22
    6
    19
    Amino Acid Level Abnormal
         subjects affected / exposed
    1 / 27 (3.70%)
    4 / 27 (14.81%)
    0 / 25 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    15
    0
    0
    Injury, poisoning and procedural complications
    Arthropod Bite
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Clavicle Fracture
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    0 / 25 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    0
    0
    2
    Face Injury
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    2
    1
    Lip Injury
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Fall
         subjects affected / exposed
    2 / 27 (7.41%)
    3 / 27 (11.11%)
    4 / 25 (16.00%)
    1 / 26 (3.85%)
         occurrences all number
    3
    3
    5
    1
    Contusion
         subjects affected / exposed
    3 / 27 (11.11%)
    1 / 27 (3.70%)
    4 / 25 (16.00%)
    1 / 26 (3.85%)
         occurrences all number
    3
    1
    4
    1
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    8
    2
    Nervous system disorders
    Hyperreflexia
         subjects affected / exposed
    2 / 27 (7.41%)
    3 / 27 (11.11%)
    0 / 25 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    2
    5
    0
    5
    Headache
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 27 (7.41%)
    1 / 25 (4.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    4
    3
    2
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    4 / 25 (16.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    0
    4
    2
    Ear and labyrinth disorders
    Ear Pain
         subjects affected / exposed
    1 / 27 (3.70%)
    3 / 27 (11.11%)
    4 / 25 (16.00%)
    8 / 26 (30.77%)
         occurrences all number
    4
    4
    11
    12
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    2 / 27 (7.41%)
    3 / 27 (11.11%)
    6 / 25 (24.00%)
    6 / 26 (23.08%)
         occurrences all number
    3
    3
    7
    8
    Gastrointestinal disorders
    Dental Caries
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    0 / 25 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    0
    0
    2
    Enteritis
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Stomatitis
         subjects affected / exposed
    3 / 27 (11.11%)
    1 / 27 (3.70%)
    2 / 25 (8.00%)
    1 / 26 (3.85%)
         occurrences all number
    3
    1
    2
    1
    Teething
         subjects affected / exposed
    1 / 27 (3.70%)
    2 / 27 (7.41%)
    2 / 25 (8.00%)
    2 / 26 (7.69%)
         occurrences all number
    3
    5
    4
    12
    Toothache
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    0 / 25 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    0
    0
    2
    Vomiting
         subjects affected / exposed
    10 / 27 (37.04%)
    9 / 27 (33.33%)
    17 / 25 (68.00%)
    16 / 26 (61.54%)
         occurrences all number
    18
    12
    59
    33
    Diarrhoea
         subjects affected / exposed
    9 / 27 (33.33%)
    6 / 27 (22.22%)
    12 / 25 (48.00%)
    11 / 26 (42.31%)
         occurrences all number
    14
    13
    29
    19
    Abdominal Pain
         subjects affected / exposed
    3 / 27 (11.11%)
    2 / 27 (7.41%)
    4 / 25 (16.00%)
    4 / 26 (15.38%)
         occurrences all number
    7
    2
    12
    5
    Constipation
         subjects affected / exposed
    2 / 27 (7.41%)
    1 / 27 (3.70%)
    4 / 25 (16.00%)
    1 / 26 (3.85%)
         occurrences all number
    2
    2
    5
    3
    Abdominal pain upper
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    0
    1
    2
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    6 / 27 (22.22%)
    2 / 27 (7.41%)
    2 / 25 (8.00%)
    0 / 26 (0.00%)
         occurrences all number
    8
    4
    2
    0
    Eczema
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 27 (0.00%)
    0 / 25 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    2
    0
    0
    3
    Rash
         subjects affected / exposed
    8 / 27 (29.63%)
    6 / 27 (22.22%)
    7 / 25 (28.00%)
    3 / 26 (11.54%)
         occurrences all number
    13
    9
    9
    5
    Dry Skin
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 27 (7.41%)
    0 / 25 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 27 (0.00%)
    0 / 25 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Infections and infestations
    Coxsackie Viral Infection
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Exanthema Subitum
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 27 (7.41%)
    0 / 25 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    2
    0
    2
    Laryngitis
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Lower Respiratory Tract Infection
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Otitis Media Acute
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    0 / 25 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    0
    0
    3
    Respiratory Tract Infection
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    3
    7
    Nasopharyngitis
         subjects affected / exposed
    13 / 27 (48.15%)
    11 / 27 (40.74%)
    17 / 25 (68.00%)
    12 / 26 (46.15%)
         occurrences all number
    30
    27
    99
    64
    Rhinitis
         subjects affected / exposed
    8 / 27 (29.63%)
    6 / 27 (22.22%)
    13 / 25 (52.00%)
    6 / 26 (23.08%)
         occurrences all number
    9
    10
    39
    27
    Pharyngitis
         subjects affected / exposed
    7 / 27 (25.93%)
    3 / 27 (11.11%)
    13 / 25 (52.00%)
    3 / 26 (11.54%)
         occurrences all number
    10
    3
    20
    6
    Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 27 (3.70%)
    6 / 27 (22.22%)
    4 / 25 (16.00%)
    4 / 26 (15.38%)
         occurrences all number
    1
    7
    7
    9
    Gastroenteritis
         subjects affected / exposed
    4 / 27 (14.81%)
    3 / 27 (11.11%)
    6 / 25 (24.00%)
    8 / 26 (30.77%)
         occurrences all number
    4
    3
    11
    12
    Otitis Media
         subjects affected / exposed
    2 / 27 (7.41%)
    3 / 27 (11.11%)
    5 / 25 (20.00%)
    4 / 26 (15.38%)
         occurrences all number
    2
    5
    7
    7
    Bronchitis
         subjects affected / exposed
    2 / 27 (7.41%)
    2 / 27 (7.41%)
    6 / 25 (24.00%)
    5 / 26 (19.23%)
         occurrences all number
    2
    5
    18
    6
    Acute Tonsillitis
         subjects affected / exposed
    2 / 27 (7.41%)
    1 / 27 (3.70%)
    2 / 25 (8.00%)
    2 / 26 (7.69%)
         occurrences all number
    2
    1
    2
    2
    Ear infection
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    4 / 25 (16.00%)
    7 / 26 (26.92%)
         occurrences all number
    0
    0
    6
    8
    Hand-foot-and-mouth disease
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
    3 / 26 (11.54%)
         occurrences all number
    0
    0
    1
    3
    Influenza
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
    3 / 26 (11.54%)
         occurrences all number
    0
    0
    2
    3
    Pharyngotonsillitis
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    3 / 25 (12.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    0
    3
    2
    Scarlet fever
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
    5 / 26 (19.23%)
         occurrences all number
    0
    0
    2
    6
    Varicella
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    7 / 25 (28.00%)
    3 / 26 (11.54%)
         occurrences all number
    0
    0
    9
    4
    Viral infection
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)
    3 / 25 (12.00%)
    3 / 26 (11.54%)
         occurrences all number
    0
    0
    5
    3
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 27 (7.41%)
    3 / 25 (12.00%)
    3 / 26 (11.54%)
         occurrences all number
    0
    3
    6
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Sep 2009
    (UK only) To specifically define the duration of treatment in the Extension Period as requested by the Medicines and Healthcare Products Regulatory Agency.
    26 Apr 2011
    1. To add a new safety visit at Month 1 in the 3 year Extension Period only for subjects who did not receive Kuvan treatment during the preceding 26-week Study Period 2. To clarify what constitutes an ‘overdose’ with regards to each daily Kuvan administration 3. To clarify the preparation and timing of each Kuvan dose with regards to administration with meals and in the event a preferred morning administration time is missed 4. To document that a Steering Committee has been established
    31 Oct 2011
    1. To clarify inclusion criterion number 6 with regard to the number of blood Phe values and the period during which these values are assessed prior to screening. 2. To increase the screening period time in order to facilitate the BH4 testing procedure for subjects who have not undergone such a test prior to screening.
    23 Jan 2013
    1. To increase the maximum number of enrolled subjects aged <12 months from 10 to 20. 2. Administrative changes
    08 Apr 2014
    1. Amendment of PGx ICF 2. Deletion of central diary reading 3. Administrative changes
    17 Oct 2014
    (Czech Republic only) To prolong the Extension Period for trial participants in the Czech Republic.
    09 Nov 2015
    To modify the Sponsor information and responsible individuals to reflect the updated Sponsor, BioMarin International Ltd.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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