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    Clinical Trial Results:
    A Phase 1/2 Open-label Study of the Safety, Tolerability, Pharmacokinetics, Pharmacodynamic and Preliminary Efficacy of BMN 701 (GILT-tagged Recombinant human GAA) in Patients with Late-onset Pompe Disease

    Summary
    EudraCT number
    		 2010-023561-22
    Trial protocol
    		 GB   DE  
    Global end of trial date
    06 Mar 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Apr 2018
    First version publication date
    04 Apr 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    POM-001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01230801
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    BioMarin Pharmaceutical Inc.
    Sponsor organisation address
    105 Digital Drive, Novato, United States, 94949
    Public contact
    BMN701 Clinical Program Management, BioMarin Europe Ltd., +01 415-455-7448, slava.titov@bmrn.com
    Scientific contact
    BMN701 Clinical Program Management, BioMarin Europe Ltd., +01 415-455-7448, slava.titov@bmrn.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    03 Apr 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Mar 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Mar 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of the study are: • To evaluate the safety and tolerability of BMN 701
    Protection of trial subjects
    The Investigator supplied the following FDA or region-appropriate Regulatory Authority approved products and/or medications (generic or branded) to be used, as needed, for IP reconstitution or pre-medication to prevent or minimize infusion-associated reactions (IARs), with costs reimbursed by BioMarin: • Sterile water for reconstitution of IP. • 0.9% sodium chloride solution. • diphenhydramine or other antihistamine preparations. • acetaminophen or other anti-pyretic preparations. • methylprednisolone sodium succinate or other corticosteroid preparations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Dec 2010
    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
    Australia: 4
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    United States: 9
    Worldwide total number of subjects
    22
    EEA total number of subjects
    9
    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)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    22
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 22 subjects were enrolled.

    Pre-assignment
    Screening details
    		 Subjects aged 13 years or older with late-onset Pompe disease were selected to participate in this study, if they (or their legal guardian) had provided written informed consent, were enzyme replacement therapy naïve, and met requirements for muscular and pulmonary function. Subjects were required to be at least 18 years old in Germany and France.

    Period 1
    Period 1 title
    0-24 weeks (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 5 mg/kg
    Arm description
    		 5 mg/kg
    Arm type
    		 BMN701-5 mg/kg

    Investigational medicinal product name
    BMN 701
    Investigational medicinal product code
    BMN 701
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    5 mg/kg, it is for intravenous use

    Arm title
    		 10 mg/kg
    Arm description
    		 10 mg/kg
    Arm type
    		 BMN701-10 mg/kg

    Investigational medicinal product name
    BMN 701
    Investigational medicinal product code
    BMN 701
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    10 mg/kg, it is for intravenous use

    Arm title
    		 20 mg/kg
    Arm description
    		 20 mg/kg
    Arm type
    		 BMN701-20 mg/kg

    Investigational medicinal product name
    BMN 701
    Investigational medicinal product code
    BMN 701
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    20 mg/kg, it is for intravenous use

    Number of subjects in period 1
    		5 mg/kg 10 mg/kg 20 mg/kg
    Started
    3
    3
    16
    Completed
    3
    3
    15
    Not completed
    0
    0
    1
         Physician decision
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    5 mg/kg
    Reporting group description
    		 5 mg/kg

    Reporting group title
    10 mg/kg
    Reporting group description
    		 10 mg/kg

    Reporting group title
    20 mg/kg
    Reporting group description
    		 20 mg/kg

    Reporting group values
    		 5 mg/kg 10 mg/kg 20 mg/kg Total
    Number of subjects
    		 3 3 16 22
    Age categorical
    Units: Subjects
        18-65
    		 3 3 16 22
    Age continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 51.7 ± 6.81 42.3 ± 12.90 50.1 ± 5.37 -
    Gender categorical
    Units: Subjects
        Female
    		 0 2 6 8
        Male
    		 3 1 10 14

    End points

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    End points reporting groups
    Reporting group title
    5 mg/kg
    Reporting group description
    		 5 mg/kg

    Reporting group title
    10 mg/kg
    Reporting group description
    		 10 mg/kg

    Reporting group title
    20 mg/kg
    Reporting group description
    		 20 mg/kg

    Subject analysis set title
    intent to treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    It includes all enrolled subjects

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population includes all enrolled subjects treated with at least 1 dose of study drug.

    Primary: Adverse Events

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    End point title
    		 Adverse Events [1]
    End point description
    End point type
    Primary
    End point timeframe
    0-24 weeks
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Please see Adverse event section below for further details.
    End point values
    		 5 mg/kg 10 mg/kg 20 mg/kg Safety Population
    Number of subjects analysed
    3
    3
    16
    22
    Units: measureble
    3
    3
    15
    21
    No statistical analyses for this end point

    Secondary: Baseline Six Minutes Walk Test

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    End point title
    		 Baseline Six Minutes Walk Test
    End point description
    End point type
    Secondary
    End point timeframe
    baseline
    End point values
    		 5 mg/kg 10 mg/kg 20 mg/kg intent to treat
    Number of subjects analysed
    3
    3
    16
    22
    Units: meter
        arithmetic mean (standard deviation)
    334 ± 227.12
    360 ± 51.4
    354.5 ± 156.94
    352.5 ± 151.05
    No statistical analyses for this end point

    Secondary: Change from baseline at week 6 - Six Minutes Walk Test

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    End point title
    		 Change from baseline at week 6 - Six Minutes Walk Test
    End point description
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 5 mg/kg 10 mg/kg 20 mg/kg intent to treat
    Number of subjects analysed
    2
    3
    16
    21
    Units: meter
        arithmetic mean (standard deviation)
    -2.5 ± 23.33
    -30.3 ± 56.5
    19.8 ± 35.11
    10.5 ± 40.08
    No statistical analyses for this end point

    Secondary: Change from baseline at week 12 - Six Minutes Walk Test

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    End point title
    		 Change from baseline at week 12 - Six Minutes Walk Test
    End point description
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 5 mg/kg 10 mg/kg 20 mg/kg intent to treat
    Number of subjects analysed
    3
    3
    15
    21
    Units: meter
        arithmetic mean (standard deviation)
    31.2 ± 78.81
    -13.7 ± 8.04
    11.1 ± 42.67
    10.4 ± 45.32
    No statistical analyses for this end point

    Secondary: Change from baseline at week 18 - Six Minutes Walk Test

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    End point title
    		 Change from baseline at week 18 - Six Minutes Walk Test
    End point description
    End point type
    Secondary
    End point timeframe
    18 weeks
    End point values
    		 5 mg/kg 10 mg/kg 20 mg/kg intent to treat
    Number of subjects analysed
    3
    3
    15
    21
    Units: meter
        arithmetic mean (standard deviation)
    43.3 ± 89.44
    -79 ± 104.61
    16.4 ± 55.09
    6.6 ± 73.43
    No statistical analyses for this end point

    Secondary: Change from baseline at week 24 - Six Minutes Walk Test

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    End point title
    		 Change from baseline at week 24 - Six Minutes Walk Test
    End point description
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 5 mg/kg 10 mg/kg 20 mg/kg intent to treat
    Number of subjects analysed
    3
    3
    16
    22
    Units: meter
        arithmetic mean (standard deviation)
    36 ± 76.02
    -42.7 ± 12.57
    22.3 ± 54.23
    15.3 ± 56.97
    No statistical analyses for this end point

    Other pre-specified: Baseline Percent Predicted Upright Forced Vital Capacity

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    End point title
    		 Baseline Percent Predicted Upright Forced Vital Capacity
    End point description
    End point type
    Other pre-specified
    End point timeframe
    baseline
    End point values
    		 5 mg/kg 10 mg/kg 20 mg/kg intent to treat
    Number of subjects analysed
    3
    3
    16
    22
    Units: percent
        arithmetic mean (standard deviation)
    69.3 ± 19.73
    67.3 ± 26.58
    58.1 ± 18.42
    60.9 ± 19.21
    No statistical analyses for this end point

    Other pre-specified: Change from baseline at week 6 - Percent Predicted Upright Forced Vital Capacity

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    End point title
    		 Change from baseline at week 6 - Percent Predicted Upright Forced Vital Capacity
    End point description
    End point type
    Other pre-specified
    End point timeframe
    6 weeks
    End point values
    		 5 mg/kg 10 mg/kg 20 mg/kg intent to treat
    Number of subjects analysed
    2
    3
    16
    21
    Units: percent
        arithmetic mean (standard deviation)
    4 ± 4.24
    -2 ± 2.65
    0.4 ± 3.3
    0.4 ± 3.46
    No statistical analyses for this end point

    Other pre-specified: Change from baseline at week 12 - Percent Predicted Upright Forced Vital Capacity

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    End point title
    		 Change from baseline at week 12 - Percent Predicted Upright Forced Vital Capacity
    End point description
    End point type
    Other pre-specified
    End point timeframe
    12 weeks
    End point values
    		 5 mg/kg 10 mg/kg 20 mg/kg intent to treat
    Number of subjects analysed
    3
    3
    16
    22
    Units: percent
        arithmetic mean (standard deviation)
    -2.6 ± 9.5
    -3.7 ± 2.89
    1.6 ± 4.35
    0.3 ± 5.25
    No statistical analyses for this end point

    Other pre-specified: Change from baseline at week 18 - Percent Predicted Upright Forced Vital Capacity

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    End point title
    		 Change from baseline at week 18 - Percent Predicted Upright Forced Vital Capacity
    End point description
    End point type
    Other pre-specified
    End point timeframe
    18 weeks
    End point values
    		 5 mg/kg 10 mg/kg 20 mg/kg intent to treat
    Number of subjects analysed
    3
    3
    15
    21
    Units: percent
        arithmetic mean (standard deviation)
    1.5 ± 4.09
    0.3 ± 3.06
    1.2 ± 4.49
    1.1 ± 4.1
    No statistical analyses for this end point

    Other pre-specified: Change from baseline at week 24 - Percent Predicted Upright Forced Vital Capacity

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    End point title
    		 Change from baseline at week 24 - Percent Predicted Upright Forced Vital Capacity
    End point description
    End point type
    Other pre-specified
    End point timeframe
    24 weeks
    End point values
    		 5 mg/kg 10 mg/kg 20 mg/kg intent to treat
    Number of subjects analysed
    3
    3
    16
    22
    Units: percent
        arithmetic mean (standard deviation)
    1 ± 2.65
    -1.7 ± 3.06
    1.2 ± 3.89
    0.8 ± 3.65
    No statistical analyses for this end point

    Other pre-specified: Baseline Percent Predicted Supine Forced Vital Capacity

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    End point title
    		 Baseline Percent Predicted Supine Forced Vital Capacity
    End point description
    End point type
    Other pre-specified
    End point timeframe
    baseline
    End point values
    		 5 mg/kg 10 mg/kg 20 mg/kg intent to treat
    Number of subjects analysed
    3
    3
    13
    19
    Units: percent
        arithmetic mean (standard deviation)
    36.7 ± 17.95
    47.7 ± 32.58
    46.3 ± 21.93
    45 ± 22.1
    No statistical analyses for this end point

    Other pre-specified: Change from baseline at week 6 - Percent Predicted Supine Forced Vital Capacity

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    End point title
    		 Change from baseline at week 6 - Percent Predicted Supine Forced Vital Capacity
    End point description
    End point type
    Other pre-specified
    End point timeframe
    6 weeks
    End point values
    		 5 mg/kg 10 mg/kg 20 mg/kg intent to treat
    Number of subjects analysed
    2
    3
    13
    18
    Units: percent
        arithmetic mean (standard deviation)
    2.1 ± 1.2
    -1.3 ± 4.04
    -0.8 ± 4.86
    -0.6 ± 4.44
    No statistical analyses for this end point

    Other pre-specified: Change from baseline at week 12 - Percent Predicted Supine Forced Vital Capacity

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    End point title
    		 Change from baseline at week 12 - Percent Predicted Supine Forced Vital Capacity
    End point description
    End point type
    Other pre-specified
    End point timeframe
    12 weeks
    End point values
    		 5 mg/kg 10 mg/kg 20 mg/kg intent to treat
    Number of subjects analysed
    3
    3
    12
    18
    Units: percent
        arithmetic mean (standard deviation)
    0.3 ± 4.22
    -4.7 ± 2.89
    3.3 ± 3.87
    1.5 ± 4.7
    No statistical analyses for this end point

    Other pre-specified: Change from baseline at week 18 - Percent Predicted Supine Forced Vital Capacity

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    End point title
    		 Change from baseline at week 18 - Percent Predicted Supine Forced Vital Capacity
    End point description
    End point type
    Other pre-specified
    End point timeframe
    18 weeks
    End point values
    		 5 mg/kg 10 mg/kg 20 mg/kg intent to treat
    Number of subjects analysed
    3
    3
    12
    18
    Units: percent
        arithmetic mean (standard deviation)
    1.3 ± 1.53
    -1.3 ± 6.66
    2.3 ± 3.14
    1.5 ± 3.7
    No statistical analyses for this end point

    Other pre-specified: Change from baseline at week 24 - Percent Predicted Supine Forced Vital Capacity

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    End point title
    		 Change from baseline at week 24 - Percent Predicted Supine Forced Vital Capacity
    End point description
    End point type
    Other pre-specified
    End point timeframe
    24 weeks
    End point values
    		 5 mg/kg 10 mg/kg 20 mg/kg intent to treat
    Number of subjects analysed
    3
    3
    13
    19
    Units: percent
        arithmetic mean (standard deviation)
    2 ± 3
    -3.3 ± 5.51
    1.1 ± 4.42
    0.5 ± 4.53
    No statistical analyses for this end point

    Other pre-specified: Baseline Percent Predicted Upright Maximum Expiratory Pressure

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    End point title
    		 Baseline Percent Predicted Upright Maximum Expiratory Pressure
    End point description
    End point type
    Other pre-specified
    End point timeframe
    baseline
    End point values
    		 5 mg/kg 10 mg/kg 20 mg/kg intent to treat
    Number of subjects analysed
    0 [2]
    3
    16
    19
    Units: percent
        arithmetic mean (standard deviation)
    ±
    31.1 ± 6.64
    36.3 ± 15.46
    35.5 ± 14.42
    Notes
    [2] - no patient has data
    No statistical analyses for this end point

    Other pre-specified: Change from baseline at week 6 - Percent Predicted Upright Maximum Expiratory Pressure

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    End point title
    		 Change from baseline at week 6 - Percent Predicted Upright Maximum Expiratory Pressure
    End point description
    End point type
    Other pre-specified
    End point timeframe
    6 weeks
    End point values
    		 5 mg/kg 10 mg/kg 20 mg/kg intent to treat
    Number of subjects analysed
    0 [3]
    3
    16
    19
    Units: percent
        arithmetic mean (standard deviation)
    ±
    6.8 ± 4.06
    3.2 ± 5.38
    3.8 ± 5.27
    Notes
    [3] - None of patients has baseline data
    No statistical analyses for this end point

    Other pre-specified: Change from baseline at week 12 - Percent Predicted Upright Maximum Expiratory Pressure

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    End point title
    		 Change from baseline at week 12 - Percent Predicted Upright Maximum Expiratory Pressure
    End point description
    End point type
    Other pre-specified
    End point timeframe
    12 weeks
    End point values
    		 5 mg/kg 10 mg/kg 20 mg/kg intent to treat
    Number of subjects analysed
    0 [4]
    3
    16
    19
    Units: percent
        arithmetic mean (standard deviation)
    ±
    1.4 ± 4.53
    2.2 ± 8.68
    2 ± 8.07
    Notes
    [4] - None of patients has baseline data
    No statistical analyses for this end point

    Other pre-specified: Change from baseline at week 18 - Percent Predicted Upright Maximum Expiratory Pressure

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    End point title
    		 Change from baseline at week 18 - Percent Predicted Upright Maximum Expiratory Pressure
    End point description
    End point type
    Other pre-specified
    End point timeframe
    18 weeks
    End point values
    		 5 mg/kg 10 mg/kg 20 mg/kg intent to treat
    Number of subjects analysed
    0 [5]
    3
    15
    18
    Units: percent
        arithmetic mean (standard deviation)
    ±
    1.2 ± 2.06
    6.9 ± 7.21
    6 ± 6.94
    Notes
    [5] - None of patients has baseline data
    No statistical analyses for this end point

    Other pre-specified: Change from baseline at week 24 - Percent Predicted Upright Maximum Expiratory Pressure

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    End point title
    		 Change from baseline at week 24 - Percent Predicted Upright Maximum Expiratory Pressure
    End point description
    End point type
    Other pre-specified
    End point timeframe
    24 weeks
    End point values
    		 5 mg/kg 10 mg/kg 20 mg/kg intent to treat
    Number of subjects analysed
    0 [6]
    3
    16
    19
    Units: percent
        arithmetic mean (standard deviation)
    ±
    2.5 ± 10.4
    5.2 ± 8.25
    4.8 ± 8.36
    Notes
    [6] - None of patients has baseline data
    No statistical analyses for this end point

    Other pre-specified: Baseline Percent Predicted Upright Maximum Inspiratory Pressure

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    End point title
    		 Baseline Percent Predicted Upright Maximum Inspiratory Pressure
    End point description
    End point type
    Other pre-specified
    End point timeframe
    baseline
    End point values
    		 5 mg/kg 10 mg/kg 20 mg/kg intent to treat
    Number of subjects analysed
    0 [7]
    3
    16 [8]
    19
    Units: percent
        arithmetic mean (standard deviation)
    ±
    39.5 ± 21.87
    40.5 ± 25.01
    40.3 ± 23.97
    Notes
    [7] - None of patients has baseline data
    [8] - None of patients has baseline data
    No statistical analyses for this end point

    Other pre-specified: Change from baseline at week 6 - Percent Predicted Upright Maximum Inspiratory Pressure

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    End point title
    		 Change from baseline at week 6 - Percent Predicted Upright Maximum Inspiratory Pressure
    End point description
    End point type
    Other pre-specified
    End point timeframe
    6 weeks
    End point values
    		 5 mg/kg 10 mg/kg 20 mg/kg intent to treat
    Number of subjects analysed
    0 [9]
    3
    16
    19
    Units: percent
        arithmetic mean (standard deviation)
    ±
    1.7 ± 1.46
    5.3 ± 9.8
    4.7 ± 9.06
    Notes
    [9] - None of patients has baseline data
    No statistical analyses for this end point

    Other pre-specified: Change from baseline at week 12 - Percent Predicted Upright Maximum Inspiratory Pressure

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    End point title
    		 Change from baseline at week 12 - Percent Predicted Upright Maximum Inspiratory Pressure
    End point description
    End point type
    Other pre-specified
    End point timeframe
    12 weeks
    End point values
    		 5 mg/kg 10 mg/kg 20 mg/kg intent to treat
    Number of subjects analysed
    0 [10]
    3
    16
    19
    Units: percent
        arithmetic mean (standard deviation)
    ±
    3.4 ± 6.74
    11.4 ± 10.92
    10.1 ± 10.65
    Notes
    [10] - None of patients has baseline data
    No statistical analyses for this end point

    Other pre-specified: Change from baseline at week 18 - Percent Predicted Upright Maximum Inspiratory Pressure

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    End point title
    		 Change from baseline at week 18 - Percent Predicted Upright Maximum Inspiratory Pressure
    End point description
    End point type
    Other pre-specified
    End point timeframe
    18 weeks
    End point values
    		 5 mg/kg 10 mg/kg 20 mg/kg intent to treat
    Number of subjects analysed
    0 [11]
    3
    15
    18
    Units: percent
        arithmetic mean (standard deviation)
    ±
    2.9 ± 11.77
    14.5 ± 14.48
    12.6 ± 14.45
    Notes
    [11] - None of patients has baseline data
    No statistical analyses for this end point

    Other pre-specified: Change from baseline at week 24 - Percent Predicted Upright Maximum Inspiratory Pressure

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    End point title
    		 Change from baseline at week 24 - Percent Predicted Upright Maximum Inspiratory Pressure
    End point description
    End point type
    Other pre-specified
    End point timeframe
    24 weeks
    End point values
    		 5 mg/kg 10 mg/kg 20 mg/kg intent to treat
    Number of subjects analysed
    0 [12]
    3
    16
    19
    Units: percent
        arithmetic mean (standard deviation)
    ±
    0.7 ± 6.69
    11.1 ± 8.31
    9.5 ± 8.81
    Notes
    [12] - None of patients has baseline data
    No statistical analyses for this end point

    Other pre-specified: Baseline Upright Maximum Ventilatory Volume

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    End point title
    		 Baseline Upright Maximum Ventilatory Volume
    End point description
    End point type
    Other pre-specified
    End point timeframe
    baseline
    End point values
    		 5 mg/kg 10 mg/kg 20 mg/kg intent to treat
    Number of subjects analysed
    0 [13]
    3
    16
    19
    Units: litre(s)
        arithmetic mean (standard deviation)
    ±
    76 ± 41.04
    67.6 ± 25.9
    68.9 ± 27.5
    Notes
    [13] - None of patients has baseline data
    No statistical analyses for this end point

    Other pre-specified: Change from baseline at week 6 - Upright Maximum Ventilatory Volume

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    End point title
    		 Change from baseline at week 6 - Upright Maximum Ventilatory Volume
    End point description
    End point type
    Other pre-specified
    End point timeframe
    6 weeks
    End point values
    		 5 mg/kg 10 mg/kg 20 mg/kg intent to treat
    Number of subjects analysed
    0 [14]
    3
    16
    19
    Units: litre(s)
        arithmetic mean (standard deviation)
    ±
    -1 ± 0.35
    1.5 ± 11.1
    1.1 ± 10.18
    Notes
    [14] - None of patients has baseline data
    No statistical analyses for this end point

    Other pre-specified: Change from baseline at week 12 - Upright Maximum Ventilatory Volume

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    End point title
    		 Change from baseline at week 12 - Upright Maximum Ventilatory Volume
    End point description
    End point type
    Other pre-specified
    End point timeframe
    12 weeks
    End point values
    		 5 mg/kg 10 mg/kg 20 mg/kg intent to treat
    Number of subjects analysed
    0 [15]
    3
    16
    19
    Units: litre(s)
        arithmetic mean (standard deviation)
    ±
    -1.1 ± 2.73
    3.8 ± 11.64
    3 ± 10.82
    Notes
    [15] - None of patients has baseline data
    No statistical analyses for this end point

    Other pre-specified: Change from baseline at week 18 - Upright Maximum Ventilatory Volume

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    End point title
    		 Change from baseline at week 18 - Upright Maximum Ventilatory Volume
    End point description
    End point type
    Other pre-specified
    End point timeframe
    18 weeks
    End point values
    		 5 mg/kg 10 mg/kg 20 mg/kg intent to treat
    Number of subjects analysed
    0 [16]
    3
    15
    18
    Units: litre(s)
        arithmetic mean (standard deviation)
    ±
    -3.9 ± 2.86
    4.7 ± 10.89
    3.3 ± 10.46
    Notes
    [16] - None of patients has baseline data
    No statistical analyses for this end point

    Other pre-specified: Change from baseline at week 24 - Upright Maximum Ventilatory Volume

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    End point title
    		 Change from baseline at week 24 - Upright Maximum Ventilatory Volume
    End point description
    End point type
    Other pre-specified
    End point timeframe
    24 weeks
    End point values
    		 5 mg/kg 10 mg/kg 20 mg/kg intent to treat
    Number of subjects analysed
    0 [17]
    3
    15
    18
    Units: litre(s)
        arithmetic mean (standard deviation)
    ±
    -0.7 ± 9.1
    2.3 ± 10.71
    1.8 ± 10.28
    Notes
    [17] - None of patients has baseline data
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    32 weeks (27 days of screening and baseline measurements + 24 weeks of treatment + 20 days of follow-up)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    5 mg/kg
    Reporting group description
    		 -

    Reporting group title
    10 mg/kg
    Reporting group description
    		 -

    Reporting group title
    20 mg/kg
    Reporting group description
    		 -

    Serious adverse events
    		 5 mg/kg 10 mg/kg 20 mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    4 / 16 (25.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 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
    		 5 mg/kg 10 mg/kg 20 mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    15 / 16 (93.75%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    5
    0
    1
    Haematoma
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    Hot flush
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Hypertension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    3 / 16 (18.75%)
         occurrences all number
    0
    0
    5
    Hypotension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Pallor
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    2
    Poor venous access
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    Systolic hypertension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Venous thrombosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Application site erythema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Asthenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Chest discomfort
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    5 / 16 (31.25%)
         occurrences all number
    6
    2
    6
    Chills
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    3 / 16 (18.75%)
         occurrences all number
    0
    1
    3
    Fatigue
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 16 (0.00%)
         occurrences all number
    1
    1
    0
    Feeling cold
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    1
    Feeling hot
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    3 / 16 (18.75%)
         occurrences all number
    0
    0
    3
    Infusion site discomfort
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Local swelling
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    2
    Malaise
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    3
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Oedema peripheral
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    3 / 16 (18.75%)
         occurrences all number
    0
    0
    3
    Pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    1
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    Tenderness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Thirst
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Vaccination site inflammation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Vessel puncture site bruise
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    2 / 16 (12.50%)
         occurrences all number
    1
    1
    2
    Dyspnoea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    5 / 16 (31.25%)
         occurrences all number
    0
    2
    10
    Dyspnoea exertional
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    Hypopnoea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Laryngeal oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Nasal congestion
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    1
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    3 / 16 (18.75%)
         occurrences all number
    1
    0
    3
    Pharyngeal oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Respiratory distress
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Throat irritation
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    Confusional state
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Depression
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Depressive symptom
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Nervousness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    2
    Investigations
    Blood glucose decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Body temperature increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac murmur
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Complement factor decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Respiratory rate increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    5
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Arthropod bite
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Contusion
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    3 / 16 (18.75%)
         occurrences all number
    1
    1
    4
    Fall
         subjects affected / exposed
    1 / 3 (33.33%)
    3 / 3 (100.00%)
    3 / 16 (18.75%)
         occurrences all number
    2
    5
    4
    Infusion related reaction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    2
    Laceration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Procedural pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Bundle branch block right
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Palpitations
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    3 / 16 (18.75%)
         occurrences all number
    0
    1
    4
    Sinus tachycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Tachycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    4 / 16 (25.00%)
         occurrences all number
    0
    2
    16
    Nervous system disorders
    Disturbance in attention
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Dizziness
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    6 / 16 (37.50%)
         occurrences all number
    0
    1
    9
    Headache
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    6 / 16 (37.50%)
         occurrences all number
    2
    8
    27
    Hypoaesthesia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    Lethargy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Paraesthesia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    1
    0
    1
    Tremor
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    3 / 16 (18.75%)
         occurrences all number
    0
    0
    4
    Eye disorders
    Diplopia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Vision blurred
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    2
    Abdominal distension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Abdominal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    2
    Abdominal pain upper
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    2
    Abdominal tenderness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Constipation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    2
    Diarrhoea
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    4 / 16 (25.00%)
         occurrences all number
    1
    0
    5
    Dry mouth
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Dyspepsia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Dysphagia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Epigastric discomfort
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Gastritis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Haemorrhoids
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Nausea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    8 / 16 (50.00%)
         occurrences all number
    0
    0
    15
    Rectal haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Retching
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    Tongue discolouration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Vomiting
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    5 / 16 (31.25%)
         occurrences all number
    1
    1
    9
    Skin and subcutaneous tissue disorders
    Cold sweat
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    2
    Dermatitis allergic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Eczema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    2
    Hyperhidrosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    2
    Pruritus
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    4
    Rash
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    4 / 16 (25.00%)
         occurrences all number
    0
    0
    5
    Rash erythematous
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Rash maculo-papular
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Rash pruritic
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    4
    Skin discolouration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Urticaria
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    13
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    1
    Back pain
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    2 / 16 (12.50%)
         occurrences all number
    4
    0
    3
    Joint swelling
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Muscle spasms
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Neck pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    2
    0
    1
    Pain in extremity
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    3 / 16 (18.75%)
         occurrences all number
    0
    0
    4
    Infections and infestations
    Candida infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Laryngitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    Localised infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    2
    Nasopharyngitis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    2 / 16 (12.50%)
         occurrences all number
    2
    0
    3
    Sinusitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    Tooth abscess
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    2
    Urinary tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Hyperglycaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Hyperphagia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Hypoglycaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    14 / 16 (87.50%)
         occurrences all number
    0
    0
    41
    Lactic acidosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Aug 2009
    The purposes of Amendment 1 were to: • Add a final study visit (end of study assessment) at approximately 30 days after the last infusion. • Modify enrollment of dose-escalation cohorts such that: o The first patient of each dose level would complete Visit 2 (Day 14) safety assessments before enrolling the second patient, and the second patient would complete Visit 2 (Day 14) safety assessments prior to enrolling the third patient. o Dose escalation to the next dose level would occur after completion of the Week 12 Visit of the third subject in the lower dose cohort. • Specify enrollment of patients under 18 years of age would be deferred until at least two adult patients had completed the Visit 2 (Day 14) assessments. • Clarify that up to 3 subjects who are withdrawn for any reason prior to completion of all scheduled infusions could be replaced if enrollment into the study was ongoing. • Add a height assessment at Week 12 for patients less than 18 years of age.
    19 Jan 2011
    The purposes of Amendment 2 were to: • Convert the protocol from the ZyStor style, including the following: changed from the ZyStor protocol template to the BioMarin clinical protocol template; changed the protocol number from "ZS0l-Al-09-00l" to "POM-00l"; changed the study drug name from "ZC-70l" to "BMN 701". • Change from a Phase 1 to Phase 1/2. • Increase the number of sites from "1-2" to "approximately 15". • Change the number of subjects to be enrolled from "10" to "approximately 30" and extended the study period from 12 weeks to 24 weeks • Eliminate the following assessment tools: the 10-meter walk test; the home diary for collection of safety data; the LifeShirt diary system for collection of 24-hour plethysmography data. • Expand the age range of eligible subjects from 13 to 50 years to 13 years of age or older. • Add the option of a whole blood assay option for diagnosis of Pompe Disease before or during the Screening Period for endogenous GAA activity < 75% of the lower limit of the normal adult range reported by the testing laboratory. • Restrict enrollment to subjects who were naïve to ERT with rhGAA; previous version had provided eligibility for subjects who had not received ERT with GAA within 30 days prior to Screening initiation. • Clarify and reorder several exclusion criteria, eg, those involving childbearing potential and other sexual considerations. • Remove the exclusion of subjects with a major congenital anomaly other than Pompe disease from entering the study. • Add an exclusion criterion dealing with diabetes or diseases known to cause hypoglycemia. • Delete condition-specific exclusion criteria 4, 6, 7, and 8 and replaced them with the last 2 exclusion criteria in the current protocol. • Add MEP, MIP, and MVV at the time points where FVC was measured (except at Screening) • Add QMT of the arm and leg. • Add measurement of urinary tetrasaccharide. • Add lipase and thyroid screening to clinical laboratory tests performed.
    29 Mar 2011
    The purposes of Amendment 3 were to: • Change from completion of 12 weeks of treatment to 8 weeks between cohorts • Change the period of time required between dosing 2 subjects within the same cohort from 2 weeks to 1 week • Change the following inclusion criterion from "Subject has ≥ 40% and < 80% predicted upright FVC during the Screening Period" to "Subject has ≥ 30% predicted upright FVC and either < 80% predicted upright FVC or > 10% reduction in supine FVC compared to upright FVC during the Screening Period"
    10 May 2011
    The purposes of Amendment 4 were to: • Change the inclusion criteria guidance on period of contraceptive use from ‘at least 30 days’, to ‘at least 4 months following last dose of BMN 701’. This change was made in response to the UK Regulatory Authority (MHRA) recommendation that, in the absence of reproductive toxicology data and given the long half-life of BMN 701, a duration covering a whole spermatogenic cycle and five half-lives was appropriate. • Creatine kinase was restored to the blood chemistry analytes listed, having been inadvertently deleted in Protocol Amendments 2 and 3.
    09 Mar 2012
    The purposes of Amendment 5 were to: • Add information for a second clinical drug lot of BMN 701. • Clarify in the schedule of events table that a subject's weight from the previous clinic visit could be used to calculate BMN 701 infusion dosage on the day before or on the day of infusion. • Add testing of C3, C4, and CH50 at the time of a hypersensitivity reaction. In addition, plasma was obtained every 4 weeks for storage for testing of C3, C4, and CH50 and other possible immunologic and inflammatory markers in the event a subject experienced a hypersensitivity reaction. • Add assays of IGF analytes (IGF-I, IGF-II, and IGFBP3) in serum samples being collected at study visits. • Remove the Week 12 chest X-ray requirement. • Remove the Week 12 ECG requirement. • Remove the requirement for dosing of 2 adults prior to dosing of children. • Broaden language regarding requirement to use FDA approved medications to allow for use of medications approved by the local competent health authority. • Add option to increase BMN 701 infusion time as required. • Add option to use anti-inflammatory medications (eg, ibuprofen) as an infusion pretreatment at the Investigator's discretion. • Revise administration of 6MWT to note that portions of the 6MWT could be videotaped to assess gait abnormalities. Subject identities would be protected by obscuring the facial area in the videos. • Add language clarifying that, along with antibody testing, immune and cytokine testing was performed every 4 weeks. • Change the population of subjects who would undergo PK sampling from all subjects to all subjects in the 5 and 10 mg/kg cohorts and up to approximately 8 subjects in the 20 mg/kg cohort.

    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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