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    Clinical Trial Results:
    A Phase 1/2, Multicenter, Open-Label, Dose-Escalation Study to Evaluate the Safety, Tolerability, and Efficacy of BMN 110 in Subjects with Mucopolysaccharidosis IVA (Morquio Syndrome)

    Summary
    EudraCT number
    		 2008-007365-23
    Trial protocol
    		 GB  
    Global end of trial date
    09 Feb 2011

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Jul 2018
    First version publication date
    25 Jul 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MOR-002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00884949
    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 Information, BioMarin Pharmaceutical Inc., clinicaltrials@bmrn.com
    Scientific contact
    Clinical Trials 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-000973-PIP01-10
    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
    24 Oct 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Feb 2011
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Feb 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety of weekly infusions of BMN 110 administered in escalating doses to subjects with MPS IVA.
    Protection of trial subjects
    The study was conducted in accordance with the principles of the Declaration of Helsinki including amendments in force up to and including the time the study was conducted. The study was conducted in compliance with the International Conference on Harmonization E6 Guideline for Good Clinical Practice, and is compliant with the European Union Clinical Trial Directive 2001/20/EC. The study was also conducted in compliance with the United States Food and Drug Administration regulations in 21 Code of Federal Regulations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Apr 2009
    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
    United Kingdom: 20
    Worldwide total number of subjects
    20
    EEA total number of subjects
    20
    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)
    16
    Adolescents (12-17 years)
    4
    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
    		 Twenty patients were enrolled in the study. This sample size was determined based upon the small number of sites and the rarity of the disease. The 12 male and 8 female patients ranged in age from 4 to 16 years. Due to the heterogeneity of the disease, patients had wide variation in their functional impairment and organ system involvement.

    Pre-assignment
    Screening details
    		 Screening was to take place within 14 days prior to Baseline. The informed consent was to be completed and signed prior to any screening procedures.

    Period 1
    Period 1 title
    Period 1 (weeks 1-12): 0.1 mg/kg/week
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 BMN 110 0.1 mg/kg/week
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    BMN 110
    Investigational medicinal product code
    Other name
    recombinant human N-acetylgalactosamine-6-sulfatase
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    BMN 110, was administered weekly as a 4- to 5-hour intravenous infusion over three consecutive 12-week dose-escalating intervals.

    Number of subjects in period 1
    		BMN 110 0.1 mg/kg/week
    Started
    20
    Completed
    18
    Not completed
    2
         Consent withdrawn by subject
    1
         Adverse event, non-fatal
    1
    Period 2
    Period 2 title
    Period 2: Weeks 13-24: 1.0 mg/kg/week
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 BMN 110 1.0 mg/kg/week
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    BMN 110
    Investigational medicinal product code
    Other name
    recombinant human N-acetylgalactosamine-6-sulfatase
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    BMN 110, was administered weekly as a 4- to 5-hour intravenous infusion over three consecutive 12-week dose-escalating intervals.

    Number of subjects in period 2
    		BMN 110 1.0 mg/kg/week
    Started
    18
    Completed
    18
    Period 3
    Period 3 title
    Period 3: Weeks 25-36: 2.0 mg/kg/week
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 BMN 110 2.0 mg/kg/week
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    BMN 110
    Investigational medicinal product code
    Other name
    recombinant human N-acetylgalactosamine-6-sulfatase
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    BMN 110, was administered weekly as a 4- to 5-hour intravenous infusion over three consecutive 12-week dose-escalating intervals.

    Number of subjects in period 3
    		BMN 110 2.0 mg/kg/week
    Started
    18
    Completed
    18
    Period 4
    Period 4 title
    Period 4: Continuation Period
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 BMN 110 1.0 mg/kg/week (Continuation)
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    BMN 110
    Investigational medicinal product code
    Other name
    recombinant human N-acetylgalactosamine-6-sulfatase
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    BMN 110, was administered weekly as a 4- to 5-hour intravenous infusion over three consecutive 12-week dose-escalating intervals.

    Number of subjects in period 4
    		BMN 110 1.0 mg/kg/week (Continuation)
    Started
    18
    Completed
    18

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Period 1 (weeks 1-12): 0.1 mg/kg/week
    Reporting group description
    		 -

    Reporting group values
    		 Period 1 (weeks 1-12): 0.1 mg/kg/week Total
    Number of subjects
    		 20 20
    Age categorical
    Units: Subjects
        >=4 to <8 years
    		 10 10
        >=8 to <10 years
    		 6 6
        >=10 to <=18 years
    		 4 4
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 8.0 ( 2.89 ) -
    Gender categorical
    Units: Subjects
        Female
    		 8 8
        Male
    		 12 12
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 0
        Not Hispanic or Latino
    		 20 20
        Unknown or Not Reported
    		 0 0
    Race/Ethnicity
    Units: Subjects
        American Indian or Alaska Native
    		 0 0
        Asian
    		 9 9
        Native Hawaiian or Other Pacific Islander
    		 0 0
        Black or African American
    		 0 0
        White
    		 9 9
        Other
    		 2 2
    Maximum Voluntary Ventilation (MVV)
    Units: L/min
        arithmetic mean (standard deviation)
    		 31.7 ( 30.45 ) -
    Forced Vital Capacity (FVC)
    Units: Liter
        arithmetic mean (standard deviation)
    		 0.9 ( 0.86 ) -

    End points

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    End points reporting groups
    Reporting group title
    BMN 110 0.1 mg/kg/week
    Reporting group description
    		 -
    Reporting group title
    BMN 110 1.0 mg/kg/week
    Reporting group description
    		 -
    Reporting group title
    BMN 110 2.0 mg/kg/week
    Reporting group description
    		 -
    Reporting group title
    BMN 110 1.0 mg/kg/week (Continuation)
    Reporting group description
    		 -

    Subject analysis set title
    Entire Study: BMN 110
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Entire Study period includes both Dose-Escalation Period and Continuation Period.

    Primary: Number of subjects with Treatment Emergent Adverse Events (TEAEs)

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    End point title
    		 Number of subjects with Treatment Emergent Adverse Events (TEAEs) [1]
    End point description
    Safety Population.
    End point type
    Primary
    End point timeframe
    Up to Week 84 (Continuation Period)
    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 Analysis was performed for Safety Evaluation (Adverse Event).
    End point values
    		 BMN 110 0.1 mg/kg/week BMN 110 1.0 mg/kg/week BMN 110 2.0 mg/kg/week BMN 110 1.0 mg/kg/week (Continuation) Entire Study: BMN 110
    Number of subjects analysed
    20
    18
    18
    18
    20
    Units: Participants
        Any AEs
    18
    18
    17
    17
    20
        Any Study Drug-Related AEs
    12
    10
    7
    8
    14
        Any SAEs
    6
    2
    8
    6
    14
        Any Study Drug-Related SAEs
    2
    1
    2
    1
    4
        Any AEs During Infusion
    15
    13
    10
    15
    17
        Any SAEs During Infusion
    5
    0
    1
    1
    6
        Any AEs Causing Study Discontinuation
    1
    0
    0
    0
    1
        Any Study Drug-Related AE Causing Study Discont.
    1
    0
    0
    0
    1
        AEs Causing Permanent Study Drug Discontinuation
    1
    0
    0
    0
    1
        Drug-Related AE Causing Permanent StudyDrug Discon
    1
    0
    0
    0
    1
        Any SAEs Causing Study Discontinuation
    1
    0
    0
    0
    1
        Any SAEs Causing Permanent Study Drug Discont.
    1
    0
    0
    0
    1
        Study Drug-Related SAE Causing Study Discont.
    1
    0
    0
    0
    1
        StudyDrug-Related SAE Causing Permanent DrugDiscon
    1
    0
    0
    0
    1
        Death
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline in 6MWT

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    End point title
    		 Change From Baseline in 6MWT
    End point description
    As a measure of endurance, a 6-minute walk test (6MWT) was performed according to the American Thoracic Society Guidelines. Patients were instructed to walk as far as possible in 6 minutes. Intent-to-Treat (ITT) population includes all subjects who enrolled in the study. Two patients were either physically (score was designated as 0 m) or developmentally (score was set to missing) unable to perform the 6MWT. The analysis was based on observed cases.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, 24, 36, 48, and 72
    End point values
    		 Entire Study: BMN 110
    Number of subjects analysed
    20
    Units: Meters
    arithmetic mean (standard deviation)
        Baseline
    266.9 ( 137.39 )
        Week 12 Change from Baseline (n=19)
    -20.7 ( 85.95 )
        Week 24 Change from Baseline (n=17)
    16.3 ( 71.74 )
        Week 36 Change from Baseline (n=17)
    13.8 ( 63.25 )
        Week 48 Change from Baseline (n=17)
    -4.8 ( 64.70 )
        Week 72 Change from Baseline (n=17)
    4.0 ( 87.24 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in 3MSCT

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    End point title
    		 Change From Baseline in 3MSCT
    End point description
    Change from baseline in the 3-minute Stair Climb Test. Patients walked up stairs that have a railing, which could be used for support, for 3 minutes, with the number of stairs climbed recorded. The test result was the number of steps climbed per minute. ITT population. One patient was developmentally unable to perform the 3MSCT and the test scores were set to missing. The analysis was based on observed cases.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, 24, 36, 48 and 72
    End point values
    		 Entire Study: BMN 110
    Number of subjects analysed
    20
    Units: Steps/min
    arithmetic mean (standard deviation)
        Baseline
    38.9 ( 25.39 )
        Week 12 Change from Baseline (n=19)
    0.3 ( 14.07 )
        Week 24 Change from Baseline (n=17)
    6.1 ( 8.66 )
        Week 36 Change from Baseline (n=17)
    7.8 ( 13.69 )
        Week 48 Change from Baseline (n=17)
    9.7 ( 14.42 )
        Week 72 Change from Baseline (n=17)
    9.7 ( 13.91 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Urine Keratan Sulfate (uKS)

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    End point title
    		 Change From Baseline in Urine Keratan Sulfate (uKS)
    End point description
    Change was calculated as: Week X value - baseline value)/baseline value ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, 24, 36 and 72
    End point values
    		 Entire Study: BMN 110
    Number of subjects analysed
    20
    Units: ug/mg
    arithmetic mean (standard deviation)
        Baseline (n=20)
    26.4 ( 12.04 )
        Week 12 (n=19)
    20.3 ( 7.63 )
        Week 24 (n=18)
    19.6 ( 5.40 )
        Week 36 (n=18)
    15.7 ( 4.10 )
        Week 72 (n=17)
    18.7 ( 5.63 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Maximum Voluntary Ventilation (MVV)

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    End point title
    		 Percent Change From Baseline in Maximum Voluntary Ventilation (MVV)
    End point description
    ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, 24, 36 and 72
    End point values
    		 Entire Study: BMN 110
    Number of subjects analysed
    18 [2]
    Units: Percentage of MVV
    arithmetic mean (standard deviation)
        Week 12 Percent Change from Baseline (n=14)
    9.9 ( 21.29 )
        Week 24 Percent Change from Baseline (n=13)
    11.0 ( 21.48 )
        Week 36 Percent Change from Baseline (n=14)
    10.5 ( 17.43 )
        Week 72 Percent Change from Baseline (n=14)
    18.4 ( 20.77 )
    Notes
    [2] - Two patients were either physically or developmentally unable to perform.
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Forced Vital Capacity (FVC)

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    End point title
    		 Percent Change From Baseline in Forced Vital Capacity (FVC)
    End point description
    ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, 24, 36 and 72
    End point values
    		 Entire Study: BMN 110
    Number of subjects analysed
    20
    Units: Percentage of FVC
    arithmetic mean (standard deviation)
        Week 12 Percent Change from Baseline (n=18)
    3.4 ( 10.85 )
        Week 24 Percent Change from Baseline (n=16)
    0.2 ( 16.60 )
        Week 36 Percent Change from Baseline (n=16)
    10.7 ( 20.82 )
        Week 72 Percent Change from Baseline (n=16)
    12.5 ( 14.88 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Week 84 (Continuation Period)
    Adverse event reporting additional description
    Safety Population.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12.0
    Reporting groups
    Reporting group title
    Dose Escalation (weeks 1-12): BMN 110 0.1 mg/kg/week
    Reporting group description
    		 BMN 110 0.1 mg/kg/week (4- to 5-hour intravenous infusion weekly) in Dose-Escalation Period (weeks 1-12)

    Reporting group title
    Dose Escalation (weeks 13-24): BMN 110 1.0 mg/kg/week
    Reporting group description
    		 BMN 110 1.0 mg/kg/week (4- to 5-hour intravenous infusion weekly) in Dose-Escalation Period (weeks 13-24)

    Reporting group title
    Dose Escalation (weeks 25-36): BMN 110 2.0 mg/kg/week
    Reporting group description
    		 BMN 110 2.0 mg/kg/week (4- to 5-hour intravenous infusion weekly) in Dose-Escalation Period (weeks 25-36)

    Reporting group title
    Continuation Period (weeks 36-48): BMN 110 1.0 mg/kg/week
    Reporting group description
    		 Subjects continuing on treatment after the Dose-Escalation period will receive BMN 110 1.0 mg/kg/week (4- to 5-hour intravenous infusion weekly) for 36 to 48 weeks.

    Reporting group title
    Entire Study
    Reporting group description
    		 Entire Study period includes both Dose-Escalation Period and Continuation Period.

    Serious adverse events
    		 Dose Escalation (weeks 1-12): BMN 110 0.1 mg/kg/week Dose Escalation (weeks 13-24): BMN 110 1.0 mg/kg/week Dose Escalation (weeks 25-36): BMN 110 2.0 mg/kg/week Continuation Period (weeks 36-48): BMN 110 1.0 mg/kg/week Entire Study
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 20 (30.00%)
    2 / 18 (11.11%)
    8 / 18 (44.44%)
    6 / 18 (33.33%)
    14 / 20 (70.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Road traffic accident
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Poor venous access
         subjects affected / exposed
    3 / 20 (15.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    4 / 20 (20.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Abscess drainage
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Catheterisation venous
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    3 / 18 (16.67%)
    0 / 18 (0.00%)
    3 / 20 (15.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Gait disturbance
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Type I hypersensitivity
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug eruption
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash generalised
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Knee deformity
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    2 / 18 (11.11%)
    2 / 18 (11.11%)
    5 / 20 (25.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Implant site infection
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    2 / 18 (11.11%)
    3 / 20 (15.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    2 / 20 (10.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         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
    		 Dose Escalation (weeks 1-12): BMN 110 0.1 mg/kg/week Dose Escalation (weeks 13-24): BMN 110 1.0 mg/kg/week Dose Escalation (weeks 25-36): BMN 110 2.0 mg/kg/week Continuation Period (weeks 36-48): BMN 110 1.0 mg/kg/week Entire Study
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 20 (90.00%)
    18 / 18 (100.00%)
    17 / 18 (94.44%)
    17 / 18 (94.44%)
    20 / 20 (100.00%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 18 (11.11%)
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    3 / 20 (15.00%)
         occurrences all number
    0
    2
    1
    1
    4
    Hot flush
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Hypotension
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Poor venous access
         subjects affected / exposed
    3 / 20 (15.00%)
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    5 / 20 (25.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Surgical and medical procedures
    Cautery to nose
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Induction of anaesthesia
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Catheterisation venous
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    3 / 18 (16.67%)
    0 / 18 (0.00%)
    3 / 20 (15.00%)
         occurrences all number
    0
    0
    3
    0
    3
    Abscess drainage
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    0
    0
    1
    General disorders and administration site conditions
    Application site vesicles
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Catheter site erythema
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    0
    1
    2
    Catheter site pain
         subjects affected / exposed
    3 / 20 (15.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    3 / 20 (15.00%)
         occurrences all number
    3
    1
    0
    0
    4
    Chills
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Extravasation
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    2
    0
    0
    0
    2
    Feeling hot
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    2 / 20 (10.00%)
         occurrences all number
    0
    0
    1
    1
    2
    Gait disturbance
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    2
    0
    0
    0
    2
    Implant site erythema
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    4
    4
    Implant site extravasation
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Implant site rash
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Influenza like illness
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Infusion site erythema
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    1
    2
    Infusion site inflammation
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Infusion site oedema
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Injection site pain
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 18 (11.11%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    0
    0
    2
    Injection site reaction
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Malaise
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    0
    2
    3
    Pyrexia
         subjects affected / exposed
    6 / 20 (30.00%)
    9 / 18 (50.00%)
    5 / 18 (27.78%)
    10 / 18 (55.56%)
    14 / 20 (70.00%)
         occurrences all number
    6
    12
    8
    20
    46
    Infusion related reaction
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    1
    1
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Hypersensitivity
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Type I hypersensitivity
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Reproductive system and breast disorders
    Balanitis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Penile pain
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 20 (5.00%)
    5 / 18 (27.78%)
    3 / 18 (16.67%)
    10 / 18 (55.56%)
    13 / 20 (65.00%)
         occurrences all number
    1
    7
    3
    18
    29
    Dry throat
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Dyspnoea
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Epistaxis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Nasal congestion
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    3 / 20 (15.00%)
         occurrences all number
    1
    0
    2
    1
    4
    Oropharyngeal pain
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    4 / 18 (22.22%)
    6 / 20 (30.00%)
         occurrences all number
    0
    1
    1
    4
    6
    Pharyngeal oedema
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Productive cough
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Rales
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Wheezing
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Blood immunoglobulin E increased
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Blood immunoglobulin G decreased
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Blood sodium increased
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Cardiac murmur
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Computerised tomogram
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Echocardiogram abnormal
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Electrocardiogram T wave amplitude decreased
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Eosinophil count increased
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    2 / 20 (10.00%)
         occurrences all number
    1
    0
    0
    1
    2
    Nuclear magnetic resonance imaging
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 18 (11.11%)
    0 / 18 (0.00%)
    4 / 18 (22.22%)
    6 / 20 (30.00%)
         occurrences all number
    1
    2
    0
    4
    7
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    3
    0
    0
    3
    Protein total abnormal
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Respiratory rate increased
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Weight increased
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Arthropod sting
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Contusion
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    2 / 18 (11.11%)
    2 / 20 (10.00%)
         occurrences all number
    0
    1
    1
    2
    4
    Device migration
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    2 / 18 (11.11%)
    2 / 20 (10.00%)
         occurrences all number
    1
    0
    0
    2
    3
    Excoriation
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Eye injury
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Face injury
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    2
    2
    Fall
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 18 (0.00%)
    2 / 18 (11.11%)
    1 / 18 (5.56%)
    5 / 20 (25.00%)
         occurrences all number
    3
    0
    2
    2
    7
    Head injury
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    4 / 20 (20.00%)
         occurrences all number
    3
    2
    1
    1
    7
    Injury
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    2 / 20 (10.00%)
         occurrences all number
    1
    0
    0
    1
    2
    Joint injury
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Medical device complication
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    2 / 18 (11.11%)
    2 / 20 (10.00%)
         occurrences all number
    0
    0
    0
    2
    2
    Mouth injury
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Procedural pain
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    2 / 18 (11.11%)
    2 / 20 (10.00%)
         occurrences all number
    0
    0
    0
    2
    2
    Procedural vomiting
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Thermal burn
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Road traffic accident
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Cardiac disorders
    Mitral valve disease
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    2 / 18 (11.11%)
    0 / 18 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    0
    2
    0
    2
    Tachycardia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Nervous system disorders
    Ageusia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Clonus
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Dizziness
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    3
    0
    0
    0
    3
    Headache
         subjects affected / exposed
    4 / 20 (20.00%)
    2 / 18 (11.11%)
    1 / 18 (5.56%)
    6 / 18 (33.33%)
    9 / 20 (45.00%)
         occurrences all number
    8
    3
    8
    16
    35
    Lethargy
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Spinal cord compression
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 18 (11.11%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    0
    0
    2
    Ear and labyrinth disorders
    Cerumen impaction
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Deafness neurosensory
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Ear canal erythema
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Ear disorder
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Ear pain
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    5 / 18 (27.78%)
    5 / 20 (25.00%)
         occurrences all number
    1
    2
    3
    10
    16
    External ear disorder
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Hyperacusis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Hypoacusis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    2 / 20 (10.00%)
         occurrences all number
    1
    0
    0
    1
    2
    Inner ear disorder
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Motion sickness
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Otorrhoea
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Tinnitus
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    2 / 20 (10.00%)
         occurrences all number
    1
    0
    0
    1
    2
    Eye discharge
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Eyelid cyst
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 20 (15.00%)
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    4 / 20 (20.00%)
         occurrences all number
    3
    2
    3
    2
    10
    Abdominal pain upper
         subjects affected / exposed
    4 / 20 (20.00%)
    1 / 18 (5.56%)
    3 / 18 (16.67%)
    4 / 18 (22.22%)
    8 / 20 (40.00%)
         occurrences all number
    8
    2
    6
    4
    20
    Constipation
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    3 / 20 (15.00%)
         occurrences all number
    1
    1
    0
    1
    3
    Dental caries
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    2 / 18 (11.11%)
    2 / 20 (10.00%)
         occurrences all number
    0
    0
    0
    2
    2
    Diarrhoea
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 18 (11.11%)
    3 / 18 (16.67%)
    1 / 18 (5.56%)
    6 / 20 (30.00%)
         occurrences all number
    0
    2
    4
    2
    8
    Faecal incontinence
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Glossodynia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Nausea
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    2 / 18 (11.11%)
    3 / 20 (15.00%)
         occurrences all number
    1
    1
    0
    3
    5
    Retching
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    1
    0
    2
    Salivary gland enlargement
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Toothache
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 18 (11.11%)
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    4 / 20 (20.00%)
         occurrences all number
    1
    2
    1
    1
    5
    Vomiting
         subjects affected / exposed
    2 / 20 (10.00%)
    7 / 18 (38.89%)
    4 / 18 (22.22%)
    12 / 18 (66.67%)
    13 / 20 (65.00%)
         occurrences all number
    3
    7
    6
    26
    42
    Hepatobiliary disorders
    Hepatomegaly
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    2 / 20 (10.00%)
         occurrences all number
    1
    1
    0
    1
    3
    Skin and subcutaneous tissue disorders
    Dermatitis diaper
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Dry skin
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    2 / 20 (10.00%)
         occurrences all number
    0
    1
    0
    1
    2
    Erythema
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    2 / 18 (11.11%)
    2 / 20 (10.00%)
         occurrences all number
    0
    0
    0
    2
    2
    Petechiae
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Pruritus
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Psoriasis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Rash
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    3 / 18 (16.67%)
    4 / 20 (20.00%)
         occurrences all number
    1
    1
    0
    4
    6
    Rash generalised
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    2 / 18 (11.11%)
    3 / 20 (15.00%)
         occurrences all number
    0
    2
    0
    1
    3
    Rash maculo-papular
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    3
    3
    Rash papular
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    3
    0
    0
    3
    Rash pruritic
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    3 / 20 (15.00%)
         occurrences all number
    1
    1
    0
    2
    4
    Skin disorder
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    2
    2
    Skin lesion
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Skin ulcer
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Drug eruption
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Renal and urinary disorders
    Enuresis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Incontinence
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    3
    0
    0
    3
    Urinary incontinence
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    2 / 18 (11.11%)
    2 / 20 (10.00%)
         occurrences all number
    0
    0
    0
    2
    2
    Endocrine disorders
    Autoimmune thyroiditis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 20 (15.00%)
    3 / 18 (16.67%)
    0 / 18 (0.00%)
    4 / 18 (22.22%)
    8 / 20 (40.00%)
         occurrences all number
    3
    4
    0
    4
    11
    Back pain
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    3 / 18 (16.67%)
    4 / 20 (20.00%)
         occurrences all number
    1
    0
    0
    4
    5
    Bursitis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Mobility decreased
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    3 / 20 (15.00%)
         occurrences all number
    1
    0
    1
    1
    3
    Muscular weakness
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Neck pain
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Pain in extremity
         subjects affected / exposed
    4 / 20 (20.00%)
    3 / 18 (16.67%)
    1 / 18 (5.56%)
    5 / 18 (27.78%)
    11 / 20 (55.00%)
         occurrences all number
    6
    3
    1
    5
    15
    Pain in jaw
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Catheter site infection
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    2 / 18 (11.11%)
    0 / 18 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Ear infection
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    3 / 18 (16.67%)
    5 / 20 (25.00%)
         occurrences all number
    1
    1
    0
    4
    6
    Gastroenteritis viral
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Helminthic infection
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Impetigo
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    3
    3
    Infection
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Lice infestation
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    1
    2
    Localised infection
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    2 / 18 (11.11%)
    3 / 20 (15.00%)
         occurrences all number
    0
    0
    0
    2
    2
    Nail infection
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Nasopharyngitis
         subjects affected / exposed
    2 / 20 (10.00%)
    3 / 18 (16.67%)
    1 / 18 (5.56%)
    4 / 18 (22.22%)
    8 / 20 (40.00%)
         occurrences all number
    3
    3
    1
    6
    13
    Otitis externa
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Pharyngitis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    2 / 18 (11.11%)
    2 / 20 (10.00%)
         occurrences all number
    0
    0
    0
    2
    2
    Rhinitis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    2 / 18 (11.11%)
    2 / 20 (10.00%)
         occurrences all number
    0
    0
    0
    2
    2
    Skin infection
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Subcutaneous abscess
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Tinea pedis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Tonsillitis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Varicella
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    Otitis media
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    2
    0
    0
    0
    2
    Abscess limb
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Implant site infection
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Pneumonia
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Eye infection
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    2 / 20 (10.00%)
         occurrences all number
    0
    1
    0
    1
    2
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    0
    0
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Feb 2009
    1. The original study design was a 2-part study with a 36-week Dose-Escalation Period and an optional Extension Period lasting until the investigational product is commercially available or the study is terminated. In this amendment, the 36- week Dose-Escalation Period remains the same, but the Extension Period has been replaced with an optional bridging period of 36 weeks (referred to as the Continuation Period) that allows for the minimum time required to transition patients to a separate long-term treatment protocol and avoid any interruption to treatment. The total duration of this study will be 72 weeks of treatment for each subject (36-week Dose-Escalation Period plus an optional 36-week Continuation Period). 2. In the Extension Period, subjects were to be treated with an initial dose of 1.0 mg/kg/week with possible dose adjustment after analysis of the data from the Dose-Escalation Period. The protocol has been amended so that subjects who opt to continue treatment after the Dose-Escalation Period will be treated at a dose of 1.0 mg/kg/week; no dose adjustments will be made based on data analysis. 3. An Interim Analysis plan was incorporated to analyze the following three parameters at each dose level: safety (adverse events and laboratory analyses), total drug exposure as determined by PK assessments, and the percent reduction from Baseline in plasma and/or urine KS concentrations. This interim analysis will occur after the last patient completes the 36-week Dose-Escalation period and will be used to determine an optimal dose for a separate long-term treatment protocol. The following additional changes were made: 4. The design of the Dose-Escalation period was clarified to be a within-patient dose escalation. 5. The inclusion criteria for confirming diagnosis of MPS IVA was clarified to include results of molecular genetic testing. 6. Minor editorial changes were made for clarity and consistency throughout the protocol.
    08 Sep 2009
    1. Treatment prior to administration of study drug has been added. a. For all subjects, pretreatment with appropriate doses of anti-histamine and anti-pyretic will be administered prior to infusion of study drug. Non-sedating antihistamines, such as cetirizine or loratadine, are preferred. b. For subjects who have a history of infusion reactions or other risk factors (eg, history of allergies), a sedating antihistamine (eg, diphenhydramine or chlorpheniramine) may be administered, and premedication with additional agents such as H2 blockers, montelukast sodium, or steroids may be considered. 2. To mitigate the risk of infusion reactions (IRs), the study drug infusion rate information has been revised; additional details have been added. The increase in infusion rate has been slowed, with gradual rate increases every 15 minutes. The minimum infusion duration remains approximately 4 hours. 3. Information regarding the management of allergic reactions (Section 10.3) and site-specific guidelines have been added (Section 24.2) to provide further guidance regarding the management of hypersensitivity reactions. 4. Information regarding an independent Allergic Reaction Review Board (ARRB) has been added. The ARRB will review severe or serious IRs during the study. 5. For subjects who have a severe IR or experience an IR requiring cessation of infusion, additional blood samples will be taken to assess for CH50, total immunoglobulin E (IgE), and serum tryptase level. In addition, a sample will be obtained for testing of drug specific antibody levels. The Schedule of Events (Table 2.1.1) and Study Procedures (Section 12) have been revised to incorporate the additional sampling. 6. Safety information has been updated in the Summary of Overall Risks and Benefits (Section 7.5). Information regarding a subject who experienced a serious adverse event of Type I hypersensitivity during the study has been added. 7. Minor changes have been made for clarity and consistency
    01 Jul 2010
    The following additional measures with regard to managing and monitoring subject safety: 1. Extended the Continuation Period to allow up to 12 additional weeks on a subject- by-subject basis until enrollment in the long-term open label treatment study (MOR-100) is available or the subject decides to discontinue. This will extend the total duration of the study from 72 weeks up to a maximum of 84 weeks. 2. Allow subjects who discontinue receiving study drug to remain in the study. Rationale: There is little information available on the natural history of MPS IVA. Allowing these subjects to remain on study and continue to perform study assessments will help to characterize the progression of MPS IVA once enzyme replacement therapy is discontinued. Ongoing collection of clinical assessment data in subjects off therapy will allow a more complete understanding of the relative clinical impact of therapy. The safety burden of continued assessments is anticipated to be minimal. 3. Additional blood may be taken when subjects experience infusion reactions. Rationale: To allow further characterization of possibly related adverse events, including serious adverse events, the Investigator may need to order additional safety related laboratory testing. Capturing this data will improve understanding of these events and help to better define the risks of treatment with enzyme replacement therapy for all MPS IVA patients. 4. Guidance for the allowed number of missed infusions during the Continuation Period has been added. Rationale: Guidance to investigators is needed regarding missed infusions during the final 48 weeks of the study (Continuation Period). Guidelines are based on knowledge from related therapies while ensuring latitude for an individual subject. 5. Updated Section 7.2 (Nonclinical Studies). Rationale: To accurately report new nonclinical information since previous amendment. 6. Updated Sections 7.5 (Summary of Overall Risks and Benefits) and 7.5.1 (Infus

    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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