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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multinational Clinical Study to Evaluate the Efficacy and Safety of 2.0 mg/kg/week and 2.0 mg/kg/every other week BMN 110 in Patients with Mucopolysaccharidosis IVA (Morquio A Syndrome)

    Summary
    EudraCT number
    		 2010-020198-18
    Trial protocol
    		 GB   NL   FR   DE   PT   IT   NO   DK  
    Global end of trial date
    23 Aug 2012

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

    Trial information

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    Trial identification
    Sponsor protocol code
    MOR-004
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01275066
    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 Aug 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Aug 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Aug 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the ability of 2.0 mg/kg/week BMN 110 and 2.0 mg/kg/qow BMN 110 compared with placebo to enhance endurance in patients with MPS IVA, as measured by an increase in the number of meters walked in the 6MW test from baseline to Week 24.
    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
    01 Feb 2011
    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
    Argentina: 2
    Country: Number of subjects enrolled
    Brazil: 21
    Country: Number of subjects enrolled
    Canada: 14
    Country: Number of subjects enrolled
    Colombia: 6
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    France: 20
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Italy: 10
    Country: Number of subjects enrolled
    Japan: 6
    Country: Number of subjects enrolled
    Netherlands: 6
    Country: Number of subjects enrolled
    Portugal: 3
    Country: Number of subjects enrolled
    Qatar: 2
    Country: Number of subjects enrolled
    Saudi Arabia: 7
    Country: Number of subjects enrolled
    Taiwan: 5
    Country: Number of subjects enrolled
    United Kingdom: 23
    Country: Number of subjects enrolled
    United States: 33
    Country: Number of subjects enrolled
    Korea, Republic of: 7
    Worldwide total number of subjects
    176
    EEA total number of subjects
    73
    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)
    93
    Adolescents (12-17 years)
    47
    Adults (18-64 years)
    36
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study was conducted at 33 study centers in 17 countries.

    Pre-assignment
    Screening details
    		 Total of 204 patients screened, 177 randomized and 175 subjects completed the study. One subject was excluded before treatment due to unconfirmed diagnosis of Mucopolysaccharidosis IVA (MPS IVA).

    Period 1
    Period 1 title
    Overall (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Intravenous infusion of placebo solution at a volume equivalent to that needed for 2.0 mg/kg dose of BMN 110 administered over a period of approximately 4 hours once a week.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous infusion of placebo solution at a volume equivalent to that needed for 2.0 mg/kg dose of BMN 110 administered over a period of approximately 4 hours once a week.

    Arm title
    		 BMN110 2.0 mg/kg/Qow
    Arm description
    		 Intravenous infusion of BMN 110 at a dose of 2.0 mg/kg administered over a period of approximately 4 hours every other week and infusions of placebo on alternating 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
    Intravenous infusion of BMN 110 at a dose of 2.0 mg/kg administered over a period of approximately 4 hours every other week and infusions of placebo on alternating weeks.

    Arm title
    		 BMN110 2.0 mg/kg/Week
    Arm description
    		 Intravenous infusion of BMN 110 at a dose of 2.0 mg/kg administered over a period of approximately 4 hours once a week.
    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
    Intravenous infusion of BMN 110 at a dose of 2.0 mg/kg administered over a period of approximately 4 hours once a week.

    Number of subjects in period 1
    		Placebo BMN110 2.0 mg/kg/Qow BMN110 2.0 mg/kg/Week
    Started
    59
    59
    58
    Completed
    59
    59
    57
    Not completed
    0
    0
    1
         Consent withdrawn by subject
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Intravenous infusion of placebo solution at a volume equivalent to that needed for 2.0 mg/kg dose of BMN 110 administered over a period of approximately 4 hours once a week.

    Reporting group title
    BMN110 2.0 mg/kg/Qow
    Reporting group description
    		 Intravenous infusion of BMN 110 at a dose of 2.0 mg/kg administered over a period of approximately 4 hours every other week and infusions of placebo on alternating weeks.

    Reporting group title
    BMN110 2.0 mg/kg/Week
    Reporting group description
    		 Intravenous infusion of BMN 110 at a dose of 2.0 mg/kg administered over a period of approximately 4 hours once a week.

    Reporting group values
    		 Placebo BMN110 2.0 mg/kg/Qow BMN110 2.0 mg/kg/Week Total
    Number of subjects
    		 59 59 58 176
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 15.0 ± 11.30 15.3 ± 10.79 13.1 ± 8.10 -
    Gender categorical
    Units: Subjects
        Female
    		 32 25 32 89
        Male
    		 27 34 26 87
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 13 16 9 38
        Not Hispanic or Latino
    		 46 43 49 138
    Race
    Units: Subjects
        Asian
    		 11 15 14 40
        Black or African American
    		 0 2 2 4
        White
    		 44 35 36 115
        Other
    		 4 7 6 17
    Walk Category
    Units: Subjects
        <= 200m
    		 23 24 23 70
        > 200m
    		 36 35 35 106
    Normalized Urine Keratan Sulfate
    Baseline
    Units: ug/mg
        arithmetic mean (standard deviation)
    		 26.1 ± 15.43 28.6 ± 21.17 26.9 ± 14.11 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Intravenous infusion of placebo solution at a volume equivalent to that needed for 2.0 mg/kg dose of BMN 110 administered over a period of approximately 4 hours once a week.

    Reporting group title
    BMN110 2.0 mg/kg/Qow
    Reporting group description
    		 Intravenous infusion of BMN 110 at a dose of 2.0 mg/kg administered over a period of approximately 4 hours every other week and infusions of placebo on alternating weeks.

    Reporting group title
    BMN110 2.0 mg/kg/Week
    Reporting group description
    		 Intravenous infusion of BMN 110 at a dose of 2.0 mg/kg administered over a period of approximately 4 hours once a week.

    Primary: Change From Baseline in Endurance as Measured by the 6-minute Walk Test

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    End point title
    		 Change From Baseline in Endurance as Measured by the 6-minute Walk Test
    End point description
    Intention to treat (ITT) population consist of all subjects who were randomized to study treatment and received at least one dose of study drug. Two missing outcomes at Week 24 were imputed using method of multiple imputation.
    End point type
    Primary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Placebo BMN110 2.0 mg/kg/Qow BMN110 2.0 mg/kg/Week
    Number of subjects analysed
    59
    59
    58
    Units: Meters
    arithmetic mean (standard deviation)
        Baseline
    211.9 ± 69.88
    205.7 ± 81.19
    203.9 ± 76.32
        Week 24
    225.4 ± 83.22
    219.9 ± 87.60
    240.0 ± 86.61
        Change from Baseline to Week 24
    13.5 ± 50.63
    14.2 ± 40.82
    36.0 ± 58.11
    Statistical analysis title
    		 Placebo vs BMN110 2.0 mg/kg/Week
    Comparison groups
    Placebo v BMN110 2.0 mg/kg/Week
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0174
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Placebo vs BMN110 2.0 mg/kg/Qow
    Comparison groups
    Placebo v BMN110 2.0 mg/kg/Qow
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9542
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change From Baseline in Endurance as Measured by the 3-minute Stair Climb Test

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    End point title
    		 Change From Baseline in Endurance as Measured by the 3-minute Stair Climb Test
    End point description
    ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Placebo BMN110 2.0 mg/kg/Qow BMN110 2.0 mg/kg/Week
    Number of subjects analysed
    59
    59
    58
    Units: Stairs/minute
    arithmetic mean (standard deviation)
        Baseline
    30.0 ± 14.05
    27.1 ± 15.8
    29.6 ± 16.44
        Week 24
    33.6 ± 18.36
    30.4 ± 17.77
    34.3 ± 18.7
        Change from Baseline to Week 24
    3.6 ± 8.51
    3.2 ± 10.29
    4.7 ± 7.99
    Statistical analysis title
    		 Placebo vs BMN110 2.0 mg/kg/Week
    Comparison groups
    Placebo v BMN110 2.0 mg/kg/Week
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4935
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Placebo vs BMN110 2.0 mg/kg/Qow
    Comparison groups
    BMN110 2.0 mg/kg/Qow v Placebo
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7783
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Percent Change From Baseline in Normalized Urine Keratan Sulfate

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    End point title
    		 Percent Change From Baseline in Normalized Urine Keratan Sulfate
    End point description
    ITT population. Normalized urine keratan sulfate is calculated as urine keratan sulfate divided by urine creatinine. Nine missing outcomes at Week 24 were imputed using method of multiple imputation.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Placebo BMN110 2.0 mg/kg/Qow BMN110 2.0 mg/kg/Week
    Number of subjects analysed
    59
    59
    58
    Units: ug/mg
    arithmetic mean (standard deviation)
        Percent Change From Baseline
    -3.6 ± 27.41
    -35.3 ± 20.74
    -43.7 ± 22.29
    Statistical analysis title
    		 Placebo vs BMN110 2.0 mg/kg/Week
    Comparison groups
    Placebo v BMN110 2.0 mg/kg/Week
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Placebo vs BMN110 2.0 mg/kg/Qow
    Comparison groups
    Placebo v BMN110 2.0 mg/kg/Qow
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Week 24
    Adverse event reporting additional description
    Safety Population: Consisted of all subjects who received any study drug (either BMN 110 or placebo).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    BMN110 2.0 mg/kg/Qow
    Reporting group description
    		 -

    Reporting group title
    BMN110 2.0 mg/kg/Week
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo BMN110 2.0 mg/kg/Qow BMN110 2.0 mg/kg/Week
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 59 (3.39%)
    4 / 59 (6.78%)
    9 / 58 (15.52%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Surgical and medical procedures
    Suture removal
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 59 (1.69%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cervical cord compression
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 59 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Infusion site pain
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 59 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 59 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction 
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 59 (1.69%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 59 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 59 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 59 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Dengue fever
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 59 (1.69%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 59 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 59 (1.69%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 59 (0.00%)
    2 / 58 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 59 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo BMN110 2.0 mg/kg/Qow BMN110 2.0 mg/kg/Week
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    57 / 59 (96.61%)
    59 / 59 (100.00%)
    56 / 58 (96.55%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    1 / 59 (1.69%)
    4 / 59 (6.78%)
    3 / 58 (5.17%)
         occurrences all number
    1
    6
    3
    Hypertension
         subjects affected / exposed
    4 / 59 (6.78%)
    4 / 59 (6.78%)
    3 / 58 (5.17%)
         occurrences all number
    13
    18
    6
    Hypotension
         subjects affected / exposed
    1 / 59 (1.69%)
    2 / 59 (3.39%)
    3 / 58 (5.17%)
         occurrences all number
    1
    3
    3
    Flushing
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 59 (1.69%)
    5 / 58 (8.62%)
         occurrences all number
    0
    1
    7
    Poor venous access
         subjects affected / exposed
    4 / 59 (6.78%)
    1 / 59 (1.69%)
    3 / 58 (5.17%)
         occurrences all number
    8
    1
    4
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    17 / 59 (28.81%)
    22 / 59 (37.29%)
    25 / 58 (43.10%)
         occurrences all number
    29
    35
    47
    Fatigue
         subjects affected / exposed
    15 / 59 (25.42%)
    8 / 59 (13.56%)
    9 / 58 (15.52%)
         occurrences all number
    24
    10
    17
    Chills
         subjects affected / exposed
    1 / 59 (1.69%)
    6 / 59 (10.17%)
    6 / 58 (10.34%)
         occurrences all number
    1
    7
    7
    Infusion site extravasation
         subjects affected / exposed
    2 / 59 (3.39%)
    4 / 59 (6.78%)
    2 / 58 (3.45%)
         occurrences all number
    2
    4
    2
    Infusion site pain
         subjects affected / exposed
    0 / 59 (0.00%)
    4 / 59 (6.78%)
    4 / 58 (6.90%)
         occurrences all number
    0
    7
    4
    Oedema peripheral
         subjects affected / exposed
    2 / 59 (3.39%)
    4 / 59 (6.78%)
    1 / 58 (1.72%)
         occurrences all number
    2
    6
    1
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 59 (0.00%)
    3 / 59 (5.08%)
    1 / 58 (1.72%)
         occurrences all number
    0
    3
    1
    Puncture site pain
         subjects affected / exposed
    2 / 59 (3.39%)
    3 / 59 (5.08%)
    1 / 58 (1.72%)
         occurrences all number
    2
    3
    1
    Device occlusion
         subjects affected / exposed
    1 / 59 (1.69%)
    2 / 59 (3.39%)
    3 / 58 (5.17%)
         occurrences all number
    1
    2
    4
    Chest discomfort
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 59 (1.69%)
    3 / 58 (5.17%)
         occurrences all number
    0
    1
    3
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 59 (1.69%)
    4 / 59 (6.78%)
    3 / 58 (5.17%)
         occurrences all number
    1
    7
    3
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    2 / 59 (3.39%)
    3 / 59 (5.08%)
    1 / 58 (1.72%)
         occurrences all number
    2
    3
    1
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    7 / 59 (11.86%)
    9 / 59 (15.25%)
    12 / 58 (20.69%)
         occurrences all number
    8
    12
    14
    Cough
         subjects affected / exposed
    21 / 59 (35.59%)
    17 / 59 (28.81%)
    16 / 58 (27.59%)
         occurrences all number
    28
    29
    20
    Dyspnoea
         subjects affected / exposed
    3 / 59 (5.08%)
    6 / 59 (10.17%)
    7 / 58 (12.07%)
         occurrences all number
    4
    8
    12
    Nasal congestion
         subjects affected / exposed
    5 / 59 (8.47%)
    5 / 59 (8.47%)
    5 / 58 (8.62%)
         occurrences all number
    8
    7
    7
    Rhinorrhoea
         subjects affected / exposed
    4 / 59 (6.78%)
    4 / 59 (6.78%)
    5 / 58 (8.62%)
         occurrences all number
    6
    9
    5
    Asthma
         subjects affected / exposed
    0 / 59 (0.00%)
    3 / 59 (5.08%)
    1 / 58 (1.72%)
         occurrences all number
    0
    3
    1
    Epistaxis
         subjects affected / exposed
    3 / 59 (5.08%)
    2 / 59 (3.39%)
    3 / 58 (5.17%)
         occurrences all number
    5
    2
    3
    Tonsillar hypertrophy
         subjects affected / exposed
    3 / 59 (5.08%)
    0 / 59 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    3
    0
    0
    Throat irritation
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 59 (0.00%)
    3 / 58 (5.17%)
         occurrences all number
    0
    0
    4
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 59 (0.00%)
    2 / 59 (3.39%)
    3 / 58 (5.17%)
         occurrences all number
    0
    2
    3
    Investigations
    Oxygen saturation decreased
         subjects affected / exposed
    6 / 59 (10.17%)
    7 / 59 (11.86%)
    6 / 58 (10.34%)
         occurrences all number
    19
    8
    10
    Blood pressure diastolic increased
         subjects affected / exposed
    2 / 59 (3.39%)
    3 / 59 (5.08%)
    2 / 58 (3.45%)
         occurrences all number
    5
    4
    2
    Blood pressure systolic increased
         subjects affected / exposed
    2 / 59 (3.39%)
    3 / 59 (5.08%)
    1 / 58 (1.72%)
         occurrences all number
    5
    16
    1
    Body temperature increased
         subjects affected / exposed
    2 / 59 (3.39%)
    2 / 59 (3.39%)
    4 / 58 (6.90%)
         occurrences all number
    10
    2
    24
    Respiratory rate increased
         subjects affected / exposed
    3 / 59 (5.08%)
    1 / 59 (1.69%)
    1 / 58 (1.72%)
         occurrences all number
    3
    1
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 59 (1.69%)
    4 / 59 (6.78%)
    0 / 58 (0.00%)
         occurrences all number
    1
    5
    0
    Head injury
         subjects affected / exposed
    0 / 59 (0.00%)
    3 / 59 (5.08%)
    2 / 58 (3.45%)
         occurrences all number
    0
    3
    2
    Ligament sprain
         subjects affected / exposed
    3 / 59 (5.08%)
    0 / 59 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    3
    0
    0
    Cardiac disorders
    Tricuspid valve incompetence
         subjects affected / exposed
    3 / 59 (5.08%)
    7 / 59 (11.86%)
    4 / 58 (6.90%)
         occurrences all number
    3
    7
    4
    Mitral valve incompetence
         subjects affected / exposed
    4 / 59 (6.78%)
    3 / 59 (5.08%)
    3 / 58 (5.17%)
         occurrences all number
    4
    3
    3
    Tachycardia
         subjects affected / exposed
    6 / 59 (10.17%)
    2 / 59 (3.39%)
    3 / 58 (5.17%)
         occurrences all number
    7
    6
    8
    Pulmonary valve incompetence
         subjects affected / exposed
    2 / 59 (3.39%)
    1 / 59 (1.69%)
    3 / 58 (5.17%)
         occurrences all number
    2
    1
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    21 / 59 (35.59%)
    24 / 59 (40.68%)
    24 / 58 (41.38%)
         occurrences all number
    38
    52
    69
    Dizziness
         subjects affected / exposed
    3 / 59 (5.08%)
    4 / 59 (6.78%)
    7 / 58 (12.07%)
         occurrences all number
    3
    6
    10
    Paraesthesia
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 59 (0.00%)
    3 / 58 (5.17%)
         occurrences all number
    0
    0
    6
    Somnolence
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 59 (0.00%)
    3 / 58 (5.17%)
         occurrences all number
    0
    0
    3
    Hyperreflexia
         subjects affected / exposed
    3 / 59 (5.08%)
    1 / 59 (1.69%)
    0 / 58 (0.00%)
         occurrences all number
    6
    3
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    5 / 59 (8.47%)
    8 / 59 (13.56%)
    3 / 58 (5.17%)
         occurrences all number
    6
    11
    3
    Eye disorders
    Corneal opacity
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 59 (0.00%)
    5 / 58 (8.62%)
         occurrences all number
    1
    0
    5
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    21 / 59 (35.59%)
    21 / 59 (35.59%)
    26 / 58 (44.83%)
         occurrences all number
    42
    44
    61
    Nausea
         subjects affected / exposed
    12 / 59 (20.34%)
    14 / 59 (23.73%)
    18 / 58 (31.03%)
         occurrences all number
    13
    22
    37
    Diarrhoea
         subjects affected / exposed
    7 / 59 (11.86%)
    12 / 59 (20.34%)
    12 / 58 (20.69%)
         occurrences all number
    8
    14
    14
    Abdominal pain
         subjects affected / exposed
    5 / 59 (8.47%)
    8 / 59 (13.56%)
    14 / 58 (24.14%)
         occurrences all number
    5
    14
    23
    Abdominal pain upper
         subjects affected / exposed
    5 / 59 (8.47%)
    4 / 59 (6.78%)
    9 / 58 (15.52%)
         occurrences all number
    6
    4
    22
    Abdominal discomfort
         subjects affected / exposed
    1 / 59 (1.69%)
    3 / 59 (5.08%)
    2 / 58 (3.45%)
         occurrences all number
    1
    4
    4
    Dyspepsia
         subjects affected / exposed
    4 / 59 (6.78%)
    1 / 59 (1.69%)
    1 / 58 (1.72%)
         occurrences all number
    4
    1
    1
    Flatulence
         subjects affected / exposed
    3 / 59 (5.08%)
    1 / 59 (1.69%)
    0 / 58 (0.00%)
         occurrences all number
    4
    1
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    5 / 59 (8.47%)
    6 / 59 (10.17%)
    6 / 58 (10.34%)
         occurrences all number
    6
    7
    9
    Urticaria
         subjects affected / exposed
    0 / 59 (0.00%)
    4 / 59 (6.78%)
    4 / 58 (6.90%)
         occurrences all number
    0
    5
    6
    Petechiae
         subjects affected / exposed
    0 / 59 (0.00%)
    3 / 59 (5.08%)
    0 / 58 (0.00%)
         occurrences all number
    0
    3
    0
    Pruritus
         subjects affected / exposed
    2 / 59 (3.39%)
    3 / 59 (5.08%)
    4 / 58 (6.90%)
         occurrences all number
    2
    5
    4
    Eczema
         subjects affected / exposed
    3 / 59 (5.08%)
    1 / 59 (1.69%)
    1 / 58 (1.72%)
         occurrences all number
    3
    1
    2
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    9 / 59 (15.25%)
    14 / 59 (23.73%)
    9 / 58 (15.52%)
         occurrences all number
    13
    24
    16
    Back pain
         subjects affected / exposed
    6 / 59 (10.17%)
    10 / 59 (16.95%)
    7 / 58 (12.07%)
         occurrences all number
    7
    17
    10
    Arthralgia
         subjects affected / exposed
    17 / 59 (28.81%)
    9 / 59 (15.25%)
    10 / 58 (17.24%)
         occurrences all number
    27
    14
    14
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 59 (1.69%)
    3 / 59 (5.08%)
    0 / 58 (0.00%)
         occurrences all number
    1
    3
    0
    Neck pain
         subjects affected / exposed
    0 / 59 (0.00%)
    3 / 59 (5.08%)
    5 / 58 (8.62%)
         occurrences all number
    0
    5
    6
    Osteopenia
         subjects affected / exposed
    3 / 59 (5.08%)
    3 / 59 (5.08%)
    0 / 58 (0.00%)
         occurrences all number
    3
    3
    0
    Musculoskeletal pain
         subjects affected / exposed
    3 / 59 (5.08%)
    2 / 59 (3.39%)
    3 / 58 (5.17%)
         occurrences all number
    4
    2
    4
    Myalgia
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 59 (1.69%)
    3 / 58 (5.17%)
         occurrences all number
    0
    1
    4
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    9 / 59 (15.25%)
    12 / 59 (20.34%)
    10 / 58 (17.24%)
         occurrences all number
    12
    13
    11
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 59 (15.25%)
    10 / 59 (16.95%)
    10 / 58 (17.24%)
         occurrences all number
    14
    13
    15
    Gastroenteritis
         subjects affected / exposed
    4 / 59 (6.78%)
    8 / 59 (13.56%)
    7 / 58 (12.07%)
         occurrences all number
    4
    10
    8
    Viral infection
    Additional description: Safety population
         subjects affected / exposed
    1 / 59 (1.69%)
    6 / 59 (10.17%)
    3 / 58 (5.17%)
         occurrences all number
    1
    6
    3
    Influenza
         subjects affected / exposed
    3 / 59 (5.08%)
    5 / 59 (8.47%)
    2 / 58 (3.45%)
         occurrences all number
    4
    5
    3
    Otitis media
         subjects affected / exposed
    4 / 59 (6.78%)
    5 / 59 (8.47%)
    9 / 58 (15.52%)
         occurrences all number
    4
    6
    10
    Rhinitis
         subjects affected / exposed
    6 / 59 (10.17%)
    4 / 59 (6.78%)
    5 / 58 (8.62%)
         occurrences all number
    8
    8
    8
    Viral upper respiratory tract infection
         subjects affected / exposed
    3 / 59 (5.08%)
    4 / 59 (6.78%)
    2 / 58 (3.45%)
         occurrences all number
    5
    5
    4
    Pharyngitis
         subjects affected / exposed
    7 / 59 (11.86%)
    3 / 59 (5.08%)
    4 / 58 (6.90%)
         occurrences all number
    7
    3
    4
    Ear infection
         subjects affected / exposed
    1 / 59 (1.69%)
    2 / 59 (3.39%)
    5 / 58 (8.62%)
         occurrences all number
    1
    2
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Oct 2010
    •Study design modified to include a third treatment arm(2.0mg/kg/every other week) •Total number of patients increased from 120(60 patients per treatment arm) to 162 •Number of study centers increased from approximately 20 to approximately 40 •Randomization stratification factors were revised. Stratification by age group(5-11,12-18&≥19yrs old)was added. Randomization will be stratified by screening 6MW test categories(≤200m&>200m)& age group •PK sample size revised from 60(30 per treatment arm) to 54(18 per treatment arm) •PK time point at 180 min after start of infusion deleted & a new PK time point at 180 min post infusion added •PK assessment at Week 1 deleted.PK assessment for Week 23 moved to Week 22 •Immunogenicity testing deleted at Week 1&23 •Definition of infusion associated reaction(IAR) modified to include more thorough description of potential symptoms & to be inclusive of all reactions occurring after onset of infusion/within 1day following end of infusion regardless of investigator’s assessment of whether or not event was related to study drug administration •Immunogenicity testing in event of a severe IAR/IAR requiring cessation of infusion revised to include C4. CH50 deleted from testing •Allergic Reaction Review Board(ARRB) added to review severe/serious infusion associated reactions •Thyroid panel moved from Baseline to Screening •Schedule for 6MW test & 3MSC test revised from every 6 wks to every 12 wks •Cervical spine & lumbar spine radiographs deleted from Week 24&Early Termination Visit(ETV) •Audiometry examinations added to Baseline & Week 24 assessments for selected sites. Change in hearing assessments will be evaluated as a tertiary objective •Echocardiogram assessments will include evaluation for presence/absence of valve stenosis/regurgitation & clinical significance at Screening & Week 24 •Corneal clouding examinations added as part of physical examination at Screening, Week 12&Week 24 assessments

    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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