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    Clinical Trial Results:
    A Multicenter, Multinational, Open-Label, Extension Study to Evaluate the Long-Term Efficacy and Safety of BMN 110 in Patients with Mucopolysaccharidosis IVA (Morquio A Syndrome)

    Summary
    EudraCT number
    		 2010-021048-16
    Trial protocol
    		 GB  
    Global end of trial date
    11 Jul 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Dec 2018
    First version publication date
    02 Dec 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MOR-100
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01242111
    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
    23 Dec 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Jul 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Jul 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the long-term safety and efficacy of weekly infusions of 2.0 mg/kg of BMN 110, administered to subjects with mucopolysaccharidosis (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 Harmonisation 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
    22 Nov 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    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)
    18
    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
    		 MOR-100 is an extension study of MOR-002 conducted at 5 study centers in the United Kingdom (UK).

    Pre-assignment
    Screening details
    		 Of the 20 subjects enrolled into MOR-002, 18 subjects completed the study and 17 subjects continued receiving BMN 110 throughout the entire study duration of MOR-100.

    Period 1
    Period 1 title
    Overall (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 BMN110 2.0 mg/kg/week
    Arm description
    		 BMN110 at 2.0 mg/kg/week intravenous infusion, over a period of approximately 4 hours per infusion, for up to 168 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    BMN 110
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    BMN110 2.0 mg/kg/week intravenous infusion, over a period of approximately 4 hours per infusion

    Number of subjects in period 1
    		BMN110 2.0 mg/kg/week
    Started
    20
    Completed
    17
    Not completed
    3
         Consent withdrawn by subject
    1
         Adverse event, non-fatal
    1
         MOR-100 Follow-up Consent Refusal
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BMN110 2.0 mg/kg/week
    Reporting group description
    		 BMN110 at 2.0 mg/kg/week intravenous infusion, over a period of approximately 4 hours per infusion, for up to 168 weeks

    Reporting group values
    		 BMN110 2.0 mg/kg/week Total
    Number of subjects
    		 20 20
    Age categorical
    Units: Subjects
        >=4 to <8
    		 10 10
        >=8 to <10
    		 5 5
        >=10 to <=18
    		 5 5
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 8.4 ± 2.9 -
    Gender categorical
    Units: Subjects
        Female
    		 8 8
        Male
    		 12 12
    Race
    Units: Subjects
        Asian
    		 9 9
        White
    		 9 9
        Other
    		 2 2
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    		 20 20
    Region of Enrollment
    Units: Subjects
        United Kingdom
    		 20 20
    MOR-002 Baseline : Urine Keratan Sulfate
    Units: ug/mg
        arithmetic mean (standard deviation)
    		 26.4 ± 12.04 -
    MOR-002 Baseline : Maximum Voluntary Ventilation
    Units: L/min
        arithmetic mean (standard deviation)
    		 31.7 ± 30.45 -
    MOR-002 Baseline : Forced Vital Capacity
    Units: litre
        arithmetic mean (standard deviation)
    		 0.9 ± 0.86 -

    End points

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    End points reporting groups
    Reporting group title
    BMN110 2.0 mg/kg/week
    Reporting group description
    		 BMN110 at 2.0 mg/kg/week intravenous infusion, over a period of approximately 4 hours per infusion, for up to 168 weeks

    Primary: Number of subjects with adverse events (AEs)

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    End point title
    		 Number of subjects with adverse events (AEs) [1]
    End point description
    Safety population includes all subjects who received any amount of study drug in MOR-002 or MOR-100, and includes 2 subjects who discontinued treatment in MOR-002 at study Week 11 while receiving BMN 110 at 0.1 mg/kg/week and 1 subject who discontinued treatment during the MOR-002 continuation period, as well as all subjects in MOR-100. SAE (Serious Adverse Event). AE (CTCAE) Grade: 1=Mild, 2=Moderate, 3=Severe or Undesirable, 4=Life Threatening or Debilitating.
    End point type
    Primary
    End point timeframe
    Up to Week 168
    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 done for safety endpoints.
    End point values
    		 BMN110 2.0 mg/kg/week
    Number of subjects analysed
    20
    Units: Participants
        Any AE—Grade 1
    1
        Any AE—Grade 2
    5
        Any AE—Grade 3
    12
        Any AE—Grade 4
    2
        Any Study Drug-Related AE—Grade 1
    6
        Any Study Drug-Related AE—Grade 2
    10
        Any Study Drug-Related AE—Grade 3
    2
        Any Study Drug-Related AE—Grade 4
    1
        Any SAE—Grade 1
    0
        Any SAE—Grade 2
    6
        Any SAE—Grade 3
    11
        Any SAE—Grade 4
    2
        Any Study Drug-Related SAE—Grade 1
    0
        Any Study Drug-Related SAE—Grade 2
    6
        Any Study Drug-Related SAE—Grade 3
    2
        Any Study Drug-Related SAE—Grade 4
    1
        Any AE Leading to Study Discontinuation—Grade 4
    1
        Any AE Leading to Permanent Drug Disc—Grade 4
    1
        Death
    0
    No statistical analyses for this end point

    Primary: Change From Baseline in Endurance as Measured by the 6-minute Walk Test During the Pilot Trial (MOR-002) and Current Extension Trial (MOR-100)

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    End point title
    		 Change From Baseline in Endurance as Measured by the 6-minute Walk Test During the Pilot Trial (MOR-002) and Current Extension Trial (MOR-100) [2]
    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. The analysis was based on observed cases 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.
    End point type
    Primary
    End point timeframe
    Baseline and every 12 weeks for up to 72 weeks during the MOR-002 pilot trial and every 24 weeks for up to 192 weeks during the MOR-100 extension trial
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analyses are Descriptive statistics for continuous variables consist of mean, standard deviation, median, and range and also include count and percentage for categorical variables.
    End point values
    		 BMN110 2.0 mg/kg/week
    Number of subjects analysed
    20
    Units: Meters
    arithmetic mean (standard deviation)
        MOR-002 Baseline (n=20)
    266.9 ± 137.39
        MOR-002 Week 12 Change from Baseline (n=19)
    -20.7 ± 85.95
        MOR-002 Week 24 Change from Baseline (n=17)
    16.3 ± 71.74
        MOR-002 Week 36 Change from Baseline (n=17)
    13.8 ± 63.25
        MOR-002 Week 48 Change from Baseline (n=17)
    -4.8 ± 64.70
        MOR-002 Week 72 Change from Baseline (n=17)
    4.0 ± 87.24
        MOR-100 Week 0 Change from Baseline (n=16)
    15.7 ± 89.00
        MOR-100 Week 24 Change from Baseline (n=16)
    24.5 ± 101.23
        MOR-100 Week 48 Change from Baseline (n=16)
    6.8 ± 98.66
        MOR-100 Week 72 Change from Baseline (n=17)
    -49.8 ± 132.63
        MOR-100 Week 96 Change from Baseline (n=16)
    11.2 ± 85.24
        MOR-100 Week 120 Change from Baseline (n=16)
    4.2 ± 94.09
        MOR-100 Week 144 Change from Baseline (n=13)
    3.1 ± 106.82
        MOR-100 Week 192 Change from Baseline (n=9)
    -37.1 ± 103.96
    No statistical analyses for this end point

    Primary: Change in Baseline in Endurance as Measured by the 3 Minute Stair Climb During the Pilot Trial (MOR-002) and Current Extension Trial (MOR-100)

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    End point title
    		 Change in Baseline in Endurance as Measured by the 3 Minute Stair Climb During the Pilot Trial (MOR-002) and Current Extension Trial (MOR-100) [3]
    End point description
    In the 3-minute Stair Climb Test (3MSCT), 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. The analysis was based on observed cases. ITT population. One patient was developmentally unable to perform the 3MSCT and the test scores were set to missing.
    End point type
    Primary
    End point timeframe
    Baseline and every 12 weeks for up to 72 weeks during the MOR-002 pilot trial and every 24 weeks for up to 192 weeks during the MOR-100 extension trial
    Notes
    [3] - 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: Statistical analyses are Descriptive statistics for continuous variables consist of mean, standard deviation, median, and range and also include count and percentage for categorical variables.
    End point values
    		 BMN110 2.0 mg/kg/week
    Number of subjects analysed
    20
    Units: stairs/min
    arithmetic mean (standard deviation)
        MOR-002 Baseline (n=20)
    38.9 ± 25.39
        MOR-002 Week 12 Change from Baseline (n=19)
    0.3 ± 14.07
        MOR-002 Week 24 Change from Baseline (n=17)
    6.1 ± 8.66
        MOR-002 Week 36 Change from Baseline (n=17)
    7.8 ± 13.69
        MOR-002 Week 48 Change from Baseline (n=17)
    9.7 ± 14.42
        MOR-002 Week 72 Change from Baseline (n=17)
    9.7 ± 13.91
        MOR-100 Week 0 Change from Baseline (n=16)
    12.7 ± 13.96
        MOR-100 Week 24 Change from Baseline (n=16)
    13.4 ± 17.07
        MOR-100 Week 48 Change from Baseline (n=16)
    6.6 ± 16.87
        MOR-100 Week 72 Change from Baseline (n=16)
    -1.4 ± 21.11
        MOR-100 Week 96 Change from Baseline (n=16)
    9.9 ± 18.84
        MOR-100 Week 120 Change from Baseline (n=16)
    6.2 ± 14.41
        MOR-100 Week 144 Change from Baseline (n=12)
    5.4 ± 11.93
        MOR-100 Week 192 Change from Baseline (n=7)
    -0.2 ± 10.34
    No statistical analyses for this end point

    Primary: Percent Change From Baseline in Urine Keratan Sulfate (uKS) Levels During the Pilot Trial (MOR-002) and Current Extension Trial (MOR-100)

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    End point title
    		 Percent Change From Baseline in Urine Keratan Sulfate (uKS) Levels During the Pilot Trial (MOR-002) and Current Extension Trial (MOR-100) [4]
    End point description
    Percent change was calculated (Week X value - baseline value)/baseline value*100%. ITT population.
    End point type
    Primary
    End point timeframe
    Baseline and every 12 weeks for up to 72 weeks during the MOR-002 pilot trial and every 24 weeks for up to 168 weeks during the MOR-100 extension trial
    Notes
    [4] - 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: Statistical analyses are Descriptive statistics for continuous variables consist of mean, standard deviation, median, and range and also include count and percentage for categorical variables.
    End point values
    		 BMN110 2.0 mg/kg/week
    Number of subjects analysed
    20
    Units: Percentage change
    arithmetic mean (standard deviation)
        MOR-002 Wk 12 Percent Change from Baseline (n=19)
    -23.2 ± 19.04
        MOR-002 Wk 24 Percent Change from Baseline (n=18)
    -27.9 ± 17.92
        MOR-002 Wk 36 Percent Change from Baseline (n=18)
    -40.6 ± 20.16
        MOR-002 Wk 48 Percent Change from Baseline (n=18)
    -35.9 ± 13.09
        MOR-002 Wk 60 Percent Change from Baseline (n=16)
    -31.4 ± 17.51
        MOR-002 Wk 72 Percent Change from Baseline (n=17)
    -32.2 ± 17.10
        MOR-100 Wk 0 Percent Change from Baseline (n=17)
    -30.0 ± 19.23
        MOR-100 Wk 24 Percent Change from Baseline (n=17)
    -43.6 ± 19.56
        MOR-100 Wk 48 Percent Change from Baseline (n=16)
    -41.9 ± 19.29
        MOR-100 Wk 72 Percent Change from Baseline (n=12)
    -36.4 ± 36.70
        MOR-100 Wk 96 Percent Change from Baseline (n=17)
    -49.7 ± 19.93
        MOR-100 Wk 120 Percent Change from Baseline (n=16)
    -49.3 ± 22.28
        MOR-100 Wk 144 Percent Change from Baseline (n=16)
    -56.6 ± 19.54
        MOR-100 Wk 168 Percent Change from Baseline (n=15)
    -58.9 ± 16.02
    No statistical analyses for this end point

    Primary: Percent Change From Baseline in Respiratory Function Test MVV During the Pilot Trial (MOR-002) and Current Extension Trial (MOR-100)

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    End point title
    		 Percent Change From Baseline in Respiratory Function Test MVV During the Pilot Trial (MOR-002) and Current Extension Trial (MOR-100) [5]
    End point description
    MVV (Maximum Voluntary Ventilation). ITT population. The analysis was based on observed cases.
    End point type
    Primary
    End point timeframe
    Baseline and every 12 weeks for up to 72 weeks during the MOR-002 pilot trial and every 24 weeks for up to 192 weeks during the MOR-100 extension trial
    Notes
    [5] - 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: Statistical analyses are Descriptive statistics for continuous variables consist of mean, standard deviation, median, and range and also include count and percentage for categorical variables.
    End point values
    		 BMN110 2.0 mg/kg/week
    Number of subjects analysed
    20
    Units: Percentage change
    arithmetic mean (standard deviation)
        MOR-002 Wk 12 Percent Change from Baseline (n=14)
    9.9 ± 21.29
        MOR-002 Wk 24 Percent Change from Baseline (n=13)
    11.0 ± 21.48
        MOR-002 Wk 36 Percent Change from Baseline (n=14)
    10.5 ± 17.43
        MOR-002 Wk 48 Percent Change from Baseline (n=12)
    18.1 ± 23.54
        MOR-002 Wk 72 Percent Change from Baseline (n=14)
    18.4 ± 20.77
        MOR-100 Wk 0 Percent Change from Baseline (n=13)
    11.1 ± 16.44
        MOR-100 Wk 24 Percent Change from Baseline (n=13)
    9.8 ± 22.25
        MOR-100 Wk 48 Percent Change from Baseline (n=12)
    3.5 ± 17.78
        MOR-100 Wk 72 Percent Change from Baseline (n=13)
    10.1 ± 27.83
        MOR-100 Wk 96 Percent Change from Baseline (n=12)
    -4.9 ± 35.53
        MOR-100 Wk 120 Percent Change from Baseline (n=13)
    -3.3 ± 28.35
        MOR-100 Wk 144 Percent Change from Baseline (n=11)
    -3.5 ± 34.61
        MOR-100 Wk 192 Percent Change from Baseline (n=6)
    28.2 ± 38.78
    No statistical analyses for this end point

    Primary: Percent Change From Baseline in Respiratory Function Test FVC During the Pilot Trial (MOR-002) and Current Extension Trial (MOR-100)

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    End point title
    		 Percent Change From Baseline in Respiratory Function Test FVC During the Pilot Trial (MOR-002) and Current Extension Trial (MOR-100) [6]
    End point description
    FVC (Forced Vital Capacity). ITT population. The analysis was based on observed cases.
    End point type
    Primary
    End point timeframe
    Baseline and every 12 weeks for up to 72 weeks during the MOR-002 pilot trial and every 24 weeks for up to 192 weeks during the MOR-100 extension trial
    Notes
    [6] - 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: Statistical analyses are Descriptive statistics for continuous variables consist of mean, standard deviation, median, and range and also include count and percentage for categorical variables.
    End point values
    		 BMN110 2.0 mg/kg/week
    Number of subjects analysed
    20
    Units: Percentage change
    arithmetic mean (standard deviation)
        MOR-002 Wk 12 Percent Change from Baseline (n=18)
    3.4 ± 10.85
        MOR-002 Wk 24 Percent Change from Baseline (n=16)
    0.2 ± 16.60
        MOR-002 Wk 36 Percent Change from Baseline (n=16)
    10.7 ± 20.81
        MOR-002 Wk 48 Percent Change from Baseline (n=14)
    11.2 ± 17.11
        MOR-002 Wk 72 Percent Change from Baseline (n=16)
    12.5 ± 14.88
        MOR-100 Wk 0 Percent Change from Baseline (n=15)
    11.8 ± 14.97
        MOR-100 Wk 24 Percent Change from Baseline (n=14)
    15.3 ± 16.31
        MOR-100 Wk 48 Percent Change from Baseline (n=13)
    15.8 ± 16.56
        MOR-100 Wk 72 Percent Change from Baseline (n=15)
    16.1 ± 21.96
        MOR-100 Wk 96 Percent Change from Baseline (n=14)
    14.8 ± 17.36
        MOR-100 Wk 120 Percent Change from Baseline (n=16)
    22.8 ± 21.14
        MOR-100 Wk 144 Percent Change from Baseline (n=12)
    17.5 ± 24.32
        MOR-100 Wk 192 Percent Change from Baseline (n=7)
    18.6 ± 30.98
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Week 168
    Adverse event reporting additional description
    Safety population.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    BMN110
    Reporting group description
    		 Safety population.

    Serious adverse events
    		 BMN110
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 20 (95.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Procedural pain
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skull fracture
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Jugular vein distension
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Poor venous access
         subjects affected / exposed
    8 / 20 (40.00%)
         occurrences causally related to treatment / all
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Abscess drainage
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Bone operation
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Knee operation
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Central venous catheterisation
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Medical device implantation
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Medical device removal
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Orthopaedic procedure
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Cervical cord compression
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Gait disturbance
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infusion site inflammation
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infusion site reaction
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Type I hypersensitivity
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary oedema
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Panic attack
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Knee deformity
         subjects affected / exposed
    6 / 20 (30.00%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abscess limb
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Device related infection
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Catheter site infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infusion site infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Otitis media
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia mycoplasmal
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Viral infection
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 BMN110
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 20 (100.00%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    6
    Hot flush
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Poor venous access
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    6
    Hypotension
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    3
    Hypertension
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    6
    Thrombosis
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Surgical and medical procedures
    Catheter removal
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Cautery to nose
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Central venous catheterisation
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Ear tube insertion
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Medical device removal
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    4
    Thrombectomy
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    General disorders and administration site conditions
    Application site reaction
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Application site vesicles
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Catheter site erythema
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    9
    Catheter site extravasation
         subjects affected / exposed
    7 / 20 (35.00%)
         occurrences all number
    12
    Catheter site inflammation
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Catheter site rash
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Catheter site pain
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    5
    Catheter site oedema
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Catheter site swelling
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    6
    Catheter site scab
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Catheter site related reaction
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    3
    Chest pain
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Chills
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Device expulsion
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Device dislocation
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Device connection issue
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Device leakage
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Device malfunction
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Device occlusion
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Extravasation
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    3
    Fatigue
         subjects affected / exposed
    7 / 20 (35.00%)
         occurrences all number
    11
    Feeling hot
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Influenza like illness
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Gait disturbance
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    3
    Infusion site pain
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Infusion site erythema
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Infusion site extravasation
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Infusion site reaction
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    3
    Injection site reaction
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Medical device complication
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    4
    Malaise
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    8
    Local swelling
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    3
    Medical device site reaction
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Pain
         subjects affected / exposed
    6 / 20 (30.00%)
         occurrences all number
    12
    Pyrexia
         subjects affected / exposed
    16 / 20 (80.00%)
         occurrences all number
    101
    Vaccination site pain
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Seasonal allergy
         subjects affected / exposed
    5 / 20 (25.00%)
         occurrences all number
    8
    Reproductive system and breast disorders
    Balanitis
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Genital ulceration
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Dysmenorrhoea
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    3
    Menorrhagia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Penile pain
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Scrotal erythema
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Perineal ulceration
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Vulvovaginal pruritus
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    3
    Cough
         subjects affected / exposed
    18 / 20 (90.00%)
         occurrences all number
    81
    Dry throat
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Dysphonia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Dyspnoea
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    5
    Dyspnoea exertional
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Nasal congestion
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    3
    Epistaxis
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    12
    Nasal obstruction
         subjects affected / exposed
    5 / 20 (25.00%)
         occurrences all number
    6
    Pharyngeal disorder
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Oropharyngeal pain
         subjects affected / exposed
    15 / 20 (75.00%)
         occurrences all number
    31
    Pharyngeal erythema
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Pharyngeal oedema
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Productive cough
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    3
    Rales
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Respiratory failure
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Rhinitis allergic
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Rhinorrhoea
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    6
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Wheezing
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    6
    Tachypnoea
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    3
    Anxiety
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Aspiration joint
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Blood cholesterol increased
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Blood immunoglobulin G decreased
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Blood immunoglobulin E increased
         subjects affected / exposed
    6 / 20 (30.00%)
         occurrences all number
    6
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Blood pressure systolic increased
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Blood sodium increased
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Body temperature increased
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    6
    Breath sounds abnormal
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Cardiac murmur
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    3
    Computerised tomogram
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Electrocardiogram T wave amplitude decreased
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Liver palpable subcostal
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Eosinophil percentage increased
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Eosinophil count increased
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    3
    Nuclear magnetic resonance imaging spinal
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Oxygen saturation decreased
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    3
    Nuclear magnetic resonance imaging
         subjects affected / exposed
    6 / 20 (30.00%)
         occurrences all number
    8
    Protein total abnormal
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Respiratory rate increased
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Protein urine
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Ultrasound scan abnormal
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Weight increased
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    4
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    5
    Arthropod sting
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Contusion
         subjects affected / exposed
    6 / 20 (30.00%)
         occurrences all number
    8
    Ear injury
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Excoriation
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    4
    Eye contusion
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Fall
         subjects affected / exposed
    8 / 20 (40.00%)
         occurrences all number
    20
    Face injury
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Head injury
         subjects affected / exposed
    8 / 20 (40.00%)
         occurrences all number
    14
    Injury
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Infusion related reaction
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Laceration
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Ligament sprain
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Limb injury
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    4
    Lip injury
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Neck injury
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Post procedural complication
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Periorbital contusion
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Occupational exposure to radiation
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Procedural headache
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Scar
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Procedural vomiting
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Procedural pain
         subjects affected / exposed
    7 / 20 (35.00%)
         occurrences all number
    7
    Scratch
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Skeletal injury
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Sunburn
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Thermal burn
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Upper limb fracture
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Wound complication
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Congenital, familial and genetic disorders
    Congenital heart valve disorder
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Cardiac disorders
    Aortic valve incompetence
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Diastolic dysfunction
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Mitral valve disease
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Mitral valve incompetence
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Pulmonary valve incompetence
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Tachycardia
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    6
    Tricuspid valve incompetence
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Nervous system disorders
    Areflexia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Ageusia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Cervical cord compression
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Clonus
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    4
    Lethargy
         subjects affected / exposed
    5 / 20 (25.00%)
         occurrences all number
    5
    Headache
         subjects affected / exposed
    16 / 20 (80.00%)
         occurrences all number
    100
    Dizziness
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    7
    Migraine
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Neuralgia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Paraesthesia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Spinal cord compression
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Reflexes abnormal
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    5
    Eosinophilia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Cerumen impaction
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Deafness
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Ear canal erythema
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Deafness neurosensory
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Ear discomfort
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Ear disorder
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Ear pain
         subjects affected / exposed
    12 / 20 (60.00%)
         occurrences all number
    41
    Ear pruritus
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Hyperacusis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Hypoacusis
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    4
    Middle ear disorder
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Otorrhoea
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Motion sickness
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    9
    Tinnitus
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Tympanic membrane perforation
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Tympanic membrane hyperaemia
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Tympanic membrane disorder
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    4
    Dry eye
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Eye discharge
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Eye pain
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Eye pruritus
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Eye swelling
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    3
    Ocular hyperaemia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Eyelid cyst
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Abdominal pain upper
         subjects affected / exposed
    11 / 20 (55.00%)
         occurrences all number
    33
    Abdominal pain
         subjects affected / exposed
    12 / 20 (60.00%)
         occurrences all number
    27
    Constipation
         subjects affected / exposed
    5 / 20 (25.00%)
         occurrences all number
    5
    Dental caries
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    5
    Dental plaque
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Dyspepsia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Diarrhoea
         subjects affected / exposed
    12 / 20 (60.00%)
         occurrences all number
    28
    Faecal incontinence
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    3
    Gingival hyperpigmentation
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Glossodynia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Haematemesis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Lip disorder
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Mouth ulceration
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Lip pain
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Nausea
         subjects affected / exposed
    5 / 20 (25.00%)
         occurrences all number
    8
    Retching
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    3
    Tongue discolouration
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Tooth deposit
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Tooth disorder
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Toothache
         subjects affected / exposed
    5 / 20 (25.00%)
         occurrences all number
    8
    Vomiting
         subjects affected / exposed
    16 / 20 (80.00%)
         occurrences all number
    92
    Hepatobiliary disorders
    Hepatomegaly
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Dermatitis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Dermatitis contact
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Dermatitis diaper
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Dry skin
         subjects affected / exposed
    5 / 20 (25.00%)
         occurrences all number
    6
    Eczema
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    3
    Erythema
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    43
    Eczema asteatotic
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Lichen planus
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Miliaria
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Onychomadesis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Pain of skin
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Pigmentation disorder
         subjects affected / exposed
    6 / 20 (30.00%)
         occurrences all number
    14
    Petechiae
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Papule
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Rash
         subjects affected / exposed
    11 / 20 (55.00%)
         occurrences all number
    34
    Psoriasis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    3
    Pruritus
         subjects affected / exposed
    5 / 20 (25.00%)
         occurrences all number
    11
    Rash erythematous
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Rash generalised
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Rash maculo-papular
         subjects affected / exposed
    5 / 20 (25.00%)
         occurrences all number
    35
    Skin depigmentation
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Skin discolouration
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Skin mass
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    4
    Skin exfoliation
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Skin disorder
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    5
    Urticaria
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    53
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Polyuria
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Incontinence
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    3
    Enuresis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    3
    Urinary incontinence
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Endocrine disorders
    Autoimmune thyroiditis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Atlantoaxial instability
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Arthralgia
         subjects affected / exposed
    12 / 20 (60.00%)
         occurrences all number
    58
    Axillary mass
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Back pain
         subjects affected / exposed
    9 / 20 (45.00%)
         occurrences all number
    17
    Bursitis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Joint stiffness
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Joint instability
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Joint swelling
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Knee deformity
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Mobility decreased
         subjects affected / exposed
    5 / 20 (25.00%)
         occurrences all number
    6
    Muscle spasms
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    3
    Muscular weakness
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    3
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Musculoskeletal pain
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    3
    Myalgia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Pain in extremity
         subjects affected / exposed
    16 / 20 (80.00%)
         occurrences all number
    75
    Neck pain
         subjects affected / exposed
    8 / 20 (40.00%)
         occurrences all number
    12
    Pain in jaw
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Catheter site infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Eye infection
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Ear infection
         subjects affected / exposed
    6 / 20 (30.00%)
         occurrences all number
    15
    Fungal infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Fungal skin infection
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Furuncle
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    4
    Gingivitis
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Gastroenteritis viral
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Helminthic infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Herpes simplex
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Herpes zoster
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Impetigo
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    3
    Infection
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Influenza
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Localised infection
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Lice infestation
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Nail infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Molluscum contagiosum
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Lower respiratory tract infection
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    8
    Nasopharyngitis
         subjects affected / exposed
    17 / 20 (85.00%)
         occurrences all number
    53
    Otitis externa
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Otitis media
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Paronychia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Oral candidiasis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Postoperative wound infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Pharyngitis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Rash pustular
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Skin infection
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Rhinitis
         subjects affected / exposed
    5 / 20 (25.00%)
         occurrences all number
    8
    Subcutaneous abscess
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Tinea pedis
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    4
    Tonsillitis
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    5
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 20 (25.00%)
         occurrences all number
    5
    Urinary tract infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Varicella
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Viral infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Wound infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Appetite disorder
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Decreased appetite
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    3
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Dehydration
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Vitamin D deficiency
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Jul 2010
    1. Removed text that the study may be terminated if the study drug becomes commercially available. Rationale: The United Kingdom Medicines and Healthcare products Regulatory Agency (MHRA) stated that commercial availability of BMN 110 is not an appropriate scientific endpoint and should be deleted. 2. The frequency of X-rays of the lumbar spine and lower extremity has been reduced from every 48 weeks to every 18 months from the previous examination. For subjects completing an Early Termination Visit (ETV), X-rays of the lumbar spine and lower extremity will be performed if the previous set was at least 12-18 months prior to ETV. Rationale: The frequency of the X-rays should be decreased to limit radiation exposure, particularly as the population includes children. 3. Language has been added to describe views of cervical spine, lumbar spine, and lower extremity X-rays. Rationale: A description of X-ray views is included for clarity. 4. Minor changes have been made for clarity and consistency throughout the protocol.
    16 Mar 2011
    1. Infusion reaction (IR) has been more specifically termed infusion-associated-reaction (IAR). In addition, the definition of IAR has been modified to include a more thorough description of potential symptoms, and to be inclusive of all reactions occurring after the onset of the infusion, within one day following the end of the infusion, regardless of the investigator’s assessment of relatedness to study drug administration. 2. Immunogenicity testing, in the event of a severe IAR or an IAR requiring cessation of infusion, was revised to include complement component 4 (C4). CH50 was deleted from testing. No blood draws were added or eliminated. 3. Text has been added to further describe the Allergic Reaction Review Board (ARRB). The ARRB will serve as a consultant to the clinical team and medical monitor. The ARRB may make recommendations regarding the appropriate management of IARs. 4. Duplicate testing for the 6-minute walk (6MW) and 3-meter stair climb (3MSC) tests was eliminated. 5. The schedule for obtaining cervical spine radiographs was lengthened to every 72 weeks, similar to the schedule for obtaining lumbar spine and lower extremity radiographs. 6. The lower extremity radiographs will only be performed for patients ≤ 20 years old. 7. Corneal clouding examinations were added as part of the physical examination at the Baseline and Every 12 week assessments. 8. Removed the option for patients, who enrolled and participated in MOR-004, to enroll in this long-term extension study and added participation in MOR-004 as an exclusion criterion. 9. Additional immunogenicity, total IgE, urine keratan sulfate, and urine creatinine assessments have been added during the time of the transition from Phase 1/2 to Phase 3 products. 10. Minor changes have been made throughout the protocol to improve the clarity and consistency of the protocol, update contact information for the Medical Monitor, and to include updated information from the ongoing MOR-002 study.
    21 Jun 2013
    1. An internal Data Monitoring Committee (DMC) has been added to act in an advisory capacity to monitor the safety of BMN 110 in patients who participate in MOR-100. 2. Language regarding oversight by the Allergic Reaction Review Board (ARRB) has been modified. 3. The frequency and extent of study assessments have been changed. 4. Time windows were added to vital signs assessments to decrease the number of minor protocol deviations and improve study site compliance without posing any material risk to patient safety. 5. The dose rationale and study background information were updated to include the results from the Phase 3 studies, MOR-004 and MOR-005. 6. Language was added permitting biomarker, pharmacogenetic, and pharmacodynamics testing of leftover research samples, and pharmacogenetic analysis to confirm diagnosis of MPS IVA in patients who had not had genetic testing previously. The testing in all cases was intended to permit a better understanding of the correlation between genotype and the varying patient responses to BMN 110. 7. Language regarding study drug administration was modified to make it clear that subjects did not have to return to an infusion center for dosing, thereby opening up the possibility of home infusion.
    30 Jan 2014
    A summary of major changes covered by Amendment 4 to the protocol is provided below. 1. A patient-reported outcomes (PRO) questionnaire and validated health utility scores (HUS) score (EQ-5D-5L) have been added to the study. Rationale: Patient Reported Outcomes (PRO) and Health Utility Scores (HUS) are essential tools to assess the overall effectiveness of a drug on disease burden as observed and experienced by patients and/or caregivers. PRO and HUS data will be collected at a single visit utilizing a health questionnaire and a validated HUS score (EQ5D-5L). Information on perceived disease burden at a given time point and at that point compared with the past will be collected to analyze the changes in disease burden during treatment over a period of 4 years or more.

    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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