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    Clinical Trial Results:
    ENDURE: A Phase IV, prospective, open-label, uncontrolled, multi-centre cohort trial to assess the responsiveness of subjects with phenylketonuria (PKU) to treatment with Kuvan® 20 mg/kg/day for 28 days

    Summary
    EudraCT number
    		 2009-018168-81
    Trial protocol
    		 DK   NO  
    Global end of trial date
    02 May 2012

    Results information
    Results version number
    		 v2(current)
    This version publication date
    18 Sep 2017
    First version publication date
    24 Jul 2015
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Correction of full data set

    Trial information

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    Trial identification
    Sponsor protocol code
    EMR700773-503 (ENDURE)
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01082328
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck KGaA
    Sponsor organisation address
    Frankfurter Str. 250, Darmstadt, Germany, 64293
    Public contact
    Merck KGaA Communication Center, Merck KGaA, 49 6151 72 5200, service@merckgroup.com
    Scientific contact
    Merck KGaA Communication Center, Merck KGaA, 49 6151 72 5200, service@merckgroup.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
    02 May 2012
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 May 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to evaluate the proportion of responders (at least 30 percent [%] reduction from baseline in blood Phenylalanine [Phe] level) to 20 milligram per kilogram per day (mg/kg/day) Sapropterin dihydrochloride treatment at several time points during 28 +/- 1 days.
    Protection of trial subjects
    Subject protection was ensured by following high medical and ethical standards in accordance with the principles laid down in the Declaration of Helsinki, and that are consistent with Good Clinical Practice and applicable regulations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 May 2010
    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
    Denmark: 19
    Country: Number of subjects enrolled
    Norway: 40
    Worldwide total number of subjects
    59
    EEA total number of subjects
    59
    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)
    15
    Adolescents (12-17 years)
    13
    Adults (18-64 years)
    31
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 First subject in: 11 May 2010 Last subject in: 20 Mar 2012

    Pre-assignment
    Screening details
    		 A total of 61 subjects were screened and gave signed informed consent to participate in the study. Two subjects did not pass entry criteria and were withdrawn before the baseline visit, therefore 59 subjects were randomized and given treatment.

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

    Arms
    Arm title
    		 Kuvan
    Arm description
    		 Kuvan® (sapropterin dihydrochloride) oral solution 20 milligram per kilogram (mg/kg) once daily for 28 +/- 1 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sapropterin dihydrochloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Soluble tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received once daily oral soluble tablet of Kuvan® (100mg sapropterin dihydrochloride) for 28 +/- 1 days with meal.The dose were calculated based on subject's body weight.

    Number of subjects in period 1
    		Kuvan
    Started
    59
    Completed
    58
    Not completed
    1
         Adverse event
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    		 -

    Reporting group values
    		 Overall Study Total
    Number of subjects
    		 59 59
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 21 ( 12.1 ) -
    Gender categorical
    Units: Subjects
        Female
    		 34 34
        Male
    		 25 25

    End points

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    End points reporting groups
    Reporting group title
    Kuvan
    Reporting group description
    		 Kuvan® (sapropterin dihydrochloride) oral solution 20 milligram per kilogram (mg/kg) once daily for 28 +/- 1 days.

    Primary: Percentage of Subjects With at Least 30 Percent Reduction From Baseline in Blood Phenylalanine (Phe) Level

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    End point title
    		 Percentage of Subjects With at Least 30 Percent Reduction From Baseline in Blood Phenylalanine (Phe) Level [1]
    End point description
    Response to treatment was defined as 30 percent reduction from Baseline in blood Phe Level during the 28 +/- 1 days.Full analysis set (FAS) population included all the subjects with a valid Baseline blood Phe level measure and who received at least one dose of Kuvan®.
    End point type
    Primary
    End point timeframe
    Baseline up to Day 28 +/- 1
    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: No statistical hypothesis tests were planned for Percentage of Participants With at Least 30 Percent Reduction From Baseline in Blood Phenylalanine (Phe) Level
    End point values
    		 Kuvan
    Number of subjects analysed
    59
    Units: Percentage of subjects
        number (confidence interval 95%)
    75 (62 to 85)
    No statistical analyses for this end point

    Secondary: Number of Subjects With Adverse Events (AEs), Treatment Emergent Adverse Events, Treatment Related Adverse Events and AEs Leading to Withdrawal

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    End point title
    		 Number of Subjects With Adverse Events (AEs), Treatment Emergent Adverse Events, Treatment Related Adverse Events and AEs Leading to Withdrawal
    End point description
    An Adverse Event (AE) is defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to Baseline during a clinical study with an investigational medicinal product (IMP), regardless of causal relationship and even if no IMP has been administered. Safety population included all the subjects with a valid baseline blood Phe level measure and who received at least one dose of Kuvan®.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 42 +/- 3
    End point values
    		 Kuvan
    Number of subjects analysed
    59
    Units: Subjects
        AEs
    58
        Treatment Emergent AEs
    57
        Treatment Related AEs
    36
        AEs leading to withdrawal
    1
    No statistical analyses for this end point

    Secondary: Percentage of Early-, Late-, Partial-Responders and Non-responders to Treatment With Kuvan®

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    End point title
    		 Percentage of Early-, Late-, Partial-Responders and Non-responders to Treatment With Kuvan®
    End point description
    Early responders defined as percentage of subjects with at least 30 percent reduction in Phe levels within the first seven days of treatment. Late responders defined as percentage of subjects with less than 30 percent reduction in Phe levels within first seven days of treatment, but at least 30 percent reduction in Phe levels within 28 +/- 1 days of treatment. Partial responders defined as percentage of participants with Phe levels reduction between 10 and 30 percent at any blood measurement within the 28 +/- 1 days of treatment. Non-responders defined as percentage of subjects with a Phe level reduction of less than 10 percent within 28 +/- 1 days. FAS population included all the subjects with a valid Baseline blood Phe level measure and who received at least one dose of Kuvan®.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 28 +/- 1
    End point values
    		 Kuvan
    Number of subjects analysed
    59
    Units: Percentage of subjects
    number (confidence interval 95%)
        Early Responders
    64.4 (50.9 to 76.4)
        Late Responders
    10.2 (3.8 to 20.8)
        Partial Responders
    25.4 (15 to 38.4)
        Non-responders
    0 (0 to 0)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Greater Than or Equal to (>=) 30 Percent, 20 to 30 Percent, 10 to 20 Percent and Less Than (<) 10 Percent Reduction in Blood Phe Levels According to Phenylketonuria (PKU) Phenotypes

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    End point title
    		 Percentage of Subjects With Greater Than or Equal to (>=) 30 Percent, 20 to 30 Percent, 10 to 20 Percent and Less Than (<) 10 Percent Reduction in Blood Phe Levels According to Phenylketonuria (PKU) Phenotypes
    End point description
    The Phenylketonuria (PKU) is categorized as per phenotype into classical PKU: (blood Phe levels greater than [>] 1200 micromole per liter [mcmol/l]), mild PKU (blood Phe levels 600 to 1200 mcmol/l), mild Hyperphenylalaninaemia (HPA) (blood Phe levels 300 to 600 mcmol/l). FAS population included all the subjects with a valid Baseline blood Phe level measure and who received at least one dose of Kuvan®. ‘n’ signifies number of subjects who were evaluable for specified categories at different time points.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 28 +/- 1
    End point values
    		 Kuvan
    Number of subjects analysed
    55 [2]
    Units: percentage of subjects
        Mild HPA: >= 30 percent (n=7)
    57
        Mild HPA: 20 to 30 percent (n=7)
    29
        Mild HPA: 10 to 20 percent (n=7)
    0
        Mild HPA: < 10 percent (n=7)
    14
        Mild PKU: >= 30 percent (n=26)
    69
        Mild PKU: 20 to 30 percent (n=26)
    8
        Mild PKU: 10 to 20 percent (n=26)
    4
        Mild PKU: < 10 percent (n=26)
    19
        Classical PKU: >= 30 percent (n=22)
    45
        Classical PKU: 20 to 30 percent (n=22)
    0
        Classical PKU: 10 to 20 percent (n=22)
    23
        Classical PKU: < 10 percent (n=22)
    32
    Notes
    [2] - 'N' (number of subjects analyzed) signifies subjects who were evaluable for this measure.
    No statistical analyses for this end point

    Secondary: Percentage of Early-, Late- and Partial-Responders According to Phenotype

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    End point title
    		 Percentage of Early-, Late- and Partial-Responders According to Phenotype
    End point description
    The PKU is categorized as per phenotype into classical PKU: (blood Phe levels > 1200 mcmol/l), mild PKU (blood Phe levels 600 to 1200 mcmol/l), mild HPA (blood Phe levels 300 to 600 mcmol/l). Early responders defined as percentage of subjects with at least 30 % reduction in Phe levels within the first 7 days of treatment. Late responders defined as percentage of subjects with < 30 % reduction in Phe levels within first seven days of treatment, but at least 30 % reduction in Phe levels within 28 +/- 1 days of treatment. Partial responders defined as percentage of subjects with Phe levels reduction between 10 and 30 % at any blood measurement within the 28 +/- 1 days of treatment. FAS population included all the subjects with a valid baseline blood Phe level measure and who received at least one dose of Kuvan®. 'n' signifies number of subjects who were evaluable for specified categories at different time points.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 28 +/- 1
    End point values
    		 Kuvan
    Number of subjects analysed
    56 [3]
    Units: percentage of subjects
        Mild HPA: Early Responders (n=7)
    86
        Mild HPA: Late Responders (n=7)
    0
        Mild HPA: Partial Responders (n=7)
    14
        Mild PKU: Early Responders (n=26)
    85
        Mild PKU: Late Responders (n=26)
    4
        Mild PKU: Partial Responders (n=26)
    12
        Classical PKU: Early Responders (n=23)
    39
        Classical PKU: Late Responders (n=23)
    17
        Classical PKU: Partial Responders (n=23)
    43
    Notes
    [3] - 'N' (number of subjects analyzed) signifies subjects who were evaluable for this measure.
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in Blood Phenylalanine-to-tyrosine Ratio

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    End point title
    		 Mean Change From Baseline in Blood Phenylalanine-to-tyrosine Ratio
    End point description
    Phenylalanine-to-tyrosine ratio is the best indicator of dopamine availability in PKU. The change in blood phenylalanine-to-tyrosine ratio at Day 28 was calculated as blood phenylalanine-to-tyrosine ratio at Day 28 minus blood phenylalanine-to-tyrosine ratio at Baseline. FAS population included all the subjects with a valid Baseline blood Phe level measure and who received at least one dose of Kuvan®. ‘n’ signifies number of subjects who were evaluable for specified categories at different time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 28
    End point values
    		 Kuvan
    Number of subjects analysed
    59
    Units: ratio
    arithmetic mean (standard deviation)
        Baseline (n=59)
    10.978 ( 5.978 )
        Change at Day 28 (n=58)
    -2.316 ( 3.948 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to Day 42 +/- 3
    Adverse event reporting additional description
    An adverse event is defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to Baseline during a clinical study with an IMP, regardless of causal relationship and even if no IMP has been administered.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Kuvan
    Reporting group description
    		 Kuvan® (sapropterin dihydrochloride) oral solution 20 milligram per kilogram (mg/kg) once daily for 28 +/- 1 days.

    Serious adverse events
    		 Kuvan
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 59 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Kuvan
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    58 / 59 (98.31%)
    Vascular disorders
    Migraine
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences all number
    1
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences all number
    1
    Asthenia
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences all number
    1
    Discomfort
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences all number
    1
    Fatigue
         subjects affected / exposed
    5 / 59 (8.47%)
         occurrences all number
    5
    Influenza like illness
         subjects affected / exposed
    2 / 59 (3.39%)
         occurrences all number
    2
    Listless
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences all number
    1
    Malaise
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences all number
    1
    Pain
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    5 / 59 (8.47%)
         occurrences all number
    5
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    4 / 59 (6.78%)
         occurrences all number
    4
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    10 / 59 (16.95%)
         occurrences all number
    10
    Dyspnoea
         subjects affected / exposed
    2 / 59 (3.39%)
         occurrences all number
    2
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences all number
    1
    Oropharyngeal pain
         subjects affected / exposed
    4 / 59 (6.78%)
         occurrences all number
    4
    Psychiatric disorders
    Irritability
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences all number
    1
    Somatoform disorder
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences all number
    1
    Investigations
    Amino acid level decreased
         subjects affected / exposed
    21 / 59 (35.59%)
         occurrences all number
    21
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences all number
    1
    Fall
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    3
    Joint injury
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences all number
    1
    Injury
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences all number
    1
    Road traffic accident
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences all number
    1
    Muscle strain
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences all number
    1
    Cardiac disorders
    Dizziness
         subjects affected / exposed
    2 / 59 (3.39%)
         occurrences all number
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    24 / 59 (40.68%)
         occurrences all number
    24
    Psychomotor hyperactivity
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences all number
    1
    Eye disorders
    Dry eye
         subjects affected / exposed
    2 / 59 (3.39%)
         occurrences all number
    2
    Eye pruritus
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    6 / 59 (10.17%)
         occurrences all number
    6
    Abdominal pain
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    3
    Diarrhoea
         subjects affected / exposed
    14 / 59 (23.73%)
         occurrences all number
    14
    Aphthous stomatitis
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences all number
    1
    Dyspepsia
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    3
    Flatulence
         subjects affected / exposed
    2 / 59 (3.39%)
         occurrences all number
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences all number
    1
    Gastroenteritis
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences all number
    1
    Gingival pruritus
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    14 / 59 (23.73%)
         occurrences all number
    14
    Tongue blistering
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    2 / 59 (3.39%)
         occurrences all number
    2
    Sinusitis
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences all number
    1
    Eczema
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences all number
    1
    Rash maculo-papular
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences all number
    1
    Rash
         subjects affected / exposed
    2 / 59 (3.39%)
         occurrences all number
    2
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 59 (3.39%)
         occurrences all number
    2
    Back pain
         subjects affected / exposed
    2 / 59 (3.39%)
         occurrences all number
    2
    Joint lock
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences all number
    1
    Myalgia
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences all number
    1
    Muscle spasms
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences all number
    1
    Neck pain
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences all number
    1
    Tendon pain
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences all number
    1
    Infections and infestations
    Influenza
         subjects affected / exposed
    2 / 59 (3.39%)
         occurrences all number
    2
    Pharyngitis
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences all number
    1
    Oral herpes
         subjects affected / exposed
    2 / 59 (3.39%)
         occurrences all number
    2
    Rhinitis
         subjects affected / exposed
    2 / 59 (3.39%)
         occurrences all number
    2
    Urinary tract infection
         subjects affected / exposed
    2 / 59 (3.39%)
         occurrences all number
    2
    Viral infection
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences all number
    1
    Iron deficiency
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Feb 2010
    Laboratory assessment were modified to be performed prior to the Kuvan treatment initiation. Blood Phe and tyrosine levels assessment was to be performed at 0, 8, 16 and 24 hours.
    08 Nov 2011
    The number of subjects (Earlier N=150; Now N=70) planned in the study and the number of recruiting sites were reduced. Consequently, the statistical section has been amended, since the reduction in sample size impacts the statistical method used. The reduction in sample size also impacts the precision of the primary endpoint. Considering the descriptive nature of the study, the precision is considered as acceptable. The treatment period with Kuvan® is amended to 28±1 days rather than 28 days. The method of administration of Kuvan was clarified (must be taken with water) and the definition of Kuvan overdose was clarified in this amendment.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/19261295
    http://www.ncbi.nlm.nih.gov/pubmed/17693179
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