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    Clinical Trial Results:
    A phase IIb, open-label study to assess the efficacy, safety, pharmacodynamics and pharmacokinetics of multiple subcutaneous doses of PRO045 in subjects with Duchenne muscular dystrophy

    Summary
    EudraCT number
    		 2011-005040-10
    Trial protocol
    		 BE   GB   IT   FR  
    Global end of trial date
    31 Aug 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Mar 2017
    First version publication date
    23 Mar 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PRO045-CLIN-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01826474
    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 Trials, BioMarin Pharmaceutical Inc., clinicaltrials@bmrn.com
    Scientific contact
    Clinical Trials, 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-000136-PIP01-12
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    21 Oct 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Aug 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To assess the efficacy of PRO045 after 48 weeks treatment in ambulant subjects with Duchenne muscular dystrophy.
    Protection of trial subjects
    Not applicable
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Dec 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    United Kingdom: 3
    Worldwide total number of subjects
    15
    EEA total number of subjects
    15
    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)
    13
    Adolescents (12-17 years)
    2
    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
    		 Visit S1 will include confirmation of consent and evaluation of the full DNA diagnostic report and the inclusion and exclusion criteria. Visit S2 should not be conducted until enrolment into any given dose group is agreed. S2 will be conducted within 2 weeks prior to first dose. S2 will include evaluation of the inclusion and exclusion criteria.

    Period 1
    Period 1 title
    BMN045 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 BMN045 0.15 mg/kg
    Arm description
    		 BMN045 0.15 mg/kg
    Arm type
    		 Experimental

    Investigational medicinal product name
    BMN045
    Investigational medicinal product code
    BMN045
    Other name
    PRO045
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects will each receive a single dose of 0.15 mg/kg BMN 045 by subcutaneous injection once per week.

    Arm title
    		 BMN045 1.0 mg/kg
    Arm description
    		 BMN045 1.0 mg/kg
    Arm type
    		 Experimental

    Investigational medicinal product name
    BMN045
    Investigational medicinal product code
    BMN045
    Other name
    PRO045
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Subcutaneous use, Intravenous use
    Dosage and administration details
    Subjects will each receive one single dose of intravenous BMN 045 at the corresponding dose level (1mg/kg) to assess pharmacokinetic and bioavailability compared to the subcutaneous route. One week later, and for every subsequent week until dose up-titration, the same dose will be administered by subcutaneous injection. The first BMN 045 administration will be by IV infusion over three hours.

    Arm title
    		 BMN045 3.0 mg/kg
    Arm description
    		 BMN045 3.0 mg/kg
    Arm type
    		 Experimental

    Investigational medicinal product name
    BMN045
    Investigational medicinal product code
    BMN045
    Other name
    PRO045
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Subjects will each receive one single dose of intravenous BMN 045 at the corresponding dose level (3mg/kg) to assess pharmacokinetic and bioavailability compared to the subcutaneous route. One week later, and for every subsequent week until dose up-titration, the same dose will be administered by subcutaneous injection. The first BMN 045 administration will be by IV infusion over three hours.

    Arm title
    		 BMN045 6.0 mg/kg
    Arm description
    		 BMN045 6.0 mg/kg
    Arm type
    		 Experimental

    Investigational medicinal product name
    BMN045
    Investigational medicinal product code
    BMN045
    Other name
    PRO045
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Subjects will each receive one single dose of intravenous BMN 045 at the corresponding dose level (6mg/kg) to assess pharmacokinetic and bioavailability compared to the subcutaneous route. One week later, and for every subsequent week until dose up-titration, the same dose will be administered by subcutaneous injection. The first BMN 045 administration will be by IV infusion over three hours.

    Arm title
    		 BMN045 9.0 mg/kg
    Arm description
    		 BMN045 9.0 mg/kg
    Arm type
    		 Experimental

    Investigational medicinal product name
    BMN045
    Investigational medicinal product code
    BMN045
    Other name
    PRO045
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Subjects will each receive one single dose of intravenous BMN 045 at the corresponding dose level (9mg/kg) to assess pharmacokinetic and bioavailability compared to the subcutaneous route. One week later, and for every subsequent week until dose up-titration, the same dose will be administered by subcutaneous injection. The first BMN 045 administration will be by IV infusion over three hours.

    Number of subjects in period 1
    		BMN045 0.15 mg/kg BMN045 1.0 mg/kg BMN045 3.0 mg/kg BMN045 6.0 mg/kg BMN045 9.0 mg/kg
    Started
    3
    6
    9
    12
    15
    Completed
    0
    0
    0
    0
    0
    Not completed
    3
    6
    9
    12
    15
         Other
    -
    -
    1
    1
    1
         Study Subject Withdrawal by Parent or Guardian
    3
    4
    4
    4
    5
         Study Terminated by Sponsor
    -
    2
    4
    7
    9

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BMN045 0.15 mg/kg
    Reporting group description
    		 BMN045 0.15 mg/kg

    Reporting group title
    BMN045 1.0 mg/kg
    Reporting group description
    		 BMN045 1.0 mg/kg

    Reporting group title
    BMN045 3.0 mg/kg
    Reporting group description
    		 BMN045 3.0 mg/kg

    Reporting group title
    BMN045 6.0 mg/kg
    Reporting group description
    		 BMN045 6.0 mg/kg

    Reporting group title
    BMN045 9.0 mg/kg
    Reporting group description
    		 BMN045 9.0 mg/kg

    Reporting group values
    		 BMN045 0.15 mg/kg BMN045 1.0 mg/kg BMN045 3.0 mg/kg BMN045 6.0 mg/kg BMN045 9.0 mg/kg Total
    Number of subjects
    		 3 6 9 12 15 15
    Age categorical
    Units: Subjects
        6 - 12
    		 3 6 9 12 15 15
    Age continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 10 ± 3.46 6.7 ± 1.15 8.3 ± 0.58 8.3 ± 1.53 9 ± 1.73 -
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0 0 0 0
        Male
    		 3 6 9 12 15 15
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 0 0 0 0
        Not Hispanic or Latino
    		 0 0 2 5 8 8
        Unknown or Not Reported
    		 3 6 7 7 7 7
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0 0
        Asian
    		 0 0 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0 0
        Black or African American
    		 0 0 0 0 0 0
        White
    		 0 0 0 0 0 0
        Other
    		 3 6 9 12 15 15
        Not Collected
    		 0 0 0 0 0 0
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 36.5 ± 13.115 25.83 ± 8.119 27.9 ± 6.092 28.57 ± 5.437 31.67 ± 9.074 -
    Length
    Units: cm
        arithmetic mean (standard deviation)
    		 1.226 ± 0.132 1.183 ± 0.059 1.277 ± 0.077 1.273 ± 0.058 1.263 ± 0.079 -

    End points

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    End points reporting groups
    Reporting group title
    BMN045 0.15 mg/kg
    Reporting group description
    		 BMN045 0.15 mg/kg

    Reporting group title
    BMN045 1.0 mg/kg
    Reporting group description
    		 BMN045 1.0 mg/kg

    Reporting group title
    BMN045 3.0 mg/kg
    Reporting group description
    		 BMN045 3.0 mg/kg

    Reporting group title
    BMN045 6.0 mg/kg
    Reporting group description
    		 BMN045 6.0 mg/kg

    Reporting group title
    BMN045 9.0 mg/kg
    Reporting group description
    		 BMN045 9.0 mg/kg

    Primary: 6 MWD

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    End point title
    		 6 MWD [1]
    End point description
    To assess the efficacy of BMN 045 after 48 weeks of treatment in ambulant subjects with DMD.
    End point type
    Primary
    End point timeframe
    48 weeks
    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: Due to the early termination of this study, no efficacy outcomes are reported.
    End point values
    		 BMN045 0.15 mg/kg BMN045 1.0 mg/kg BMN045 3.0 mg/kg BMN045 6.0 mg/kg BMN045 9.0 mg/kg
    Number of subjects analysed
    0 [2]
    0 [3]
    0 [4]
    0 [5]
    0 [6]
    Units: meter
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    ±
    ±
    Notes
    [2] - Due to the early termination of this study, no efficacy outcomes are reported.
    [3] - Due to the early termination of this study, no efficacy outcomes are reported.
    [4] - Due to the early termination of this study, no efficacy outcomes are reported.
    [5] - Due to the early termination of this study, no efficacy outcomes are reported.
    [6] - Due to the early termination of this study, no efficacy outcomes are reported.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Study Period
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    BMN045 0.15 mg/kg
    Reporting group description
    		 -

    Reporting group title
    BMN045 1.0 mg/kg
    Reporting group description
    		 -

    Reporting group title
    BMN045 3.0 mg/kg
    Reporting group description
    		 -

    Reporting group title
    BMN045 6.0 mg/kg
    Reporting group description
    		 -

    Reporting group title
    BMN045 9.0 mg/kg
    Reporting group description
    		 -

    Serious adverse events
    		 BMN045 0.15 mg/kg BMN045 1.0 mg/kg BMN045 3.0 mg/kg BMN045 6.0 mg/kg BMN045 9.0 mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Infections and infestations
    Respiratory tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 BMN045 0.15 mg/kg BMN045 1.0 mg/kg BMN045 3.0 mg/kg BMN045 6.0 mg/kg BMN045 9.0 mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    6 / 6 (100.00%)
    7 / 9 (77.78%)
    12 / 12 (100.00%)
    15 / 15 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Influenza like illness
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    1 / 12 (8.33%)
    1 / 15 (6.67%)
         occurrences all number
    2
    0
    1
    2
    1
    Injection site laceration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Injection site pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Injection site vesicles
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Malaise
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    2
    0
    0
    0
    4
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    3 / 12 (25.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    1
    4
    5
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    2 / 12 (16.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    Cough
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    3 / 12 (25.00%)
    3 / 15 (20.00%)
         occurrences all number
    1
    1
    0
    3
    3
    Nasal obstruction
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    0
    1
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    2
    1
    Rhinorrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Anxiety
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Delusion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Insomnia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    0
    1
    2
    Activated partial thromboplastin time shortened
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    2
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    2 / 12 (16.67%)
    3 / 15 (20.00%)
         occurrences all number
    0
    0
    0
    2
    3
    Alpha 1 microglobulin increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    2 / 12 (16.67%)
    3 / 15 (20.00%)
         occurrences all number
    0
    0
    0
    2
    6
    Blood fibrinogen decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Blood immunoglobulin g decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    C-reactive protein increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Complement factor c3 decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    6 / 12 (50.00%)
    11 / 15 (73.33%)
         occurrences all number
    0
    0
    1
    15
    22
    Complement factor decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Cystatin c increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    0
    0
    2
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    3 / 12 (25.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    3
    1
    Glomerular filtration rate increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Glutamate dehydrogenase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    3 / 12 (25.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Monocyte chemotactic protein-1 increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    4
    Platelet count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    9 / 12 (75.00%)
    9 / 15 (60.00%)
         occurrences all number
    0
    2
    0
    30
    22
    Platelet count increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Protein urine
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    3 / 9 (33.33%)
    10 / 12 (83.33%)
    12 / 15 (80.00%)
         occurrences all number
    0
    4
    10
    87
    43
    Protein urine present
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    3 / 12 (25.00%)
    3 / 15 (20.00%)
         occurrences all number
    1
    0
    0
    9
    8
    Serum ferritin increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Urinary casts
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    0
    0
    3
    Urine protein/creatinine ratio increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    6 / 12 (50.00%)
    7 / 15 (46.67%)
         occurrences all number
    0
    0
    0
    13
    14
    White blood cells urine positive
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    2 / 12 (16.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Fall
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    2 / 12 (16.67%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    0
    2
    5
    Foot fracture
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    0
    1
    Head injury
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Joint injury
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Ligament sprain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Post procedural complication
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Post procedural contusion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Procedural complication
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Procedural pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    0
    0
    3
    Headache
         subjects affected / exposed
    2 / 3 (66.67%)
    2 / 6 (33.33%)
    1 / 9 (11.11%)
    3 / 12 (25.00%)
    2 / 15 (13.33%)
         occurrences all number
    7
    3
    2
    11
    11
    Lethargy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Syncope
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Platelet disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    0
    0
    3
    Eye disorders
    Conjunctival hyperaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Eye irritation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    4 / 12 (33.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    6
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    3 / 12 (25.00%)
    4 / 15 (26.67%)
         occurrences all number
    0
    0
    0
    5
    6
    Anal fissure
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Breath odour
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Constipation
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    2 / 12 (16.67%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    0
    2
    1
    Diarrhoea
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    2 / 15 (13.33%)
         occurrences all number
    1
    1
    0
    10
    3
    Food poisoning
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Gastritis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Nausea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    0
    0
    2
    Noninfective gingivitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Stomatitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Tooth disorder
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Tooth impacted
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Vomiting
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    0
    1
    4
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Angioedema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Decubitus ulcer
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Ecchymosis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Drug eruption
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Erythema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    1 / 12 (8.33%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    2
    1
    Ingrowing nail
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Pruritus
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Petechiae
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Rash
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    0
    1
    1
    Rash erythematous
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Spider naevus
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    2
    0
    Urticaria
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    2 / 12 (16.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Back pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    2
    Haemarthrosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Joint instability
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Muscle spasms
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    2
    Musculoskeletal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Myalgia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    0
    0
    1
    Neck pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    2 / 12 (16.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Cystitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Ear infection
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Fungal skin infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 9 (11.11%)
    2 / 12 (16.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    2
    2
    0
    Helminthic infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Gastrointestinal infection
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Influenza
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    0
    1
    2
    Localised infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    1 / 9 (11.11%)
    4 / 12 (33.33%)
    6 / 15 (40.00%)
         occurrences all number
    0
    2
    2
    4
    8
    Oropharyngeal candidiasis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Rhinitis
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    4
    0
    0
    0
    0
    Tonsillitis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    2 / 12 (16.67%)
    1 / 15 (6.67%)
         occurrences all number
    4
    0
    2
    3
    4
    Viral infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Dec 2012
    Prot Amt 1
    16 Aug 2013
    Prot Amt 2
    07 Jan 2016
    Prot Amt 3

    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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