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    Clinical Trial Results:
    A Phase 3 Randomized, Multicenter, Multinational, Double-blinded Study Comparing the Efficacy and Safety of Repeated Biweekly Infusions of Avalglucosidase Alfa (neoGAA, GZ402666) and Alglucosidase Alfa in Treatment naïve Patients with Late-onset Pompe Disease

    Summary
    EudraCT number
    		 2016-000942-77
    Trial protocol
    		 GB   DK   SE   NL   ES   CZ   DE   BE   AT   PL   IT   PT   BG   HU   Outside EU/EEA  
    Global end of trial date
    31 May 2023

    Results information
    Results version number
    		 v2(current)
    This version publication date
    07 Dec 2023
    First version publication date
    12 Jun 2021
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    Final results that include data of secondary endpoints

    Trial information

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    Trial identification
    Sponsor protocol code
    EFC14028
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02782741
    WHO universal trial number (UTN)
    		 U1111-1178-4806
    Sponsors
    Sponsor organisation name
    Genzyme Corporation, A Sanofi company
    Sponsor organisation address
    500 Kendall Street, Cambridge, MA, United States, 02142
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.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
    31 May 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 May 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the effect of avalglucosidase alfa treatment on respiratory muscle strength measured by percent (%) predicted forced vital capacity (% FVC) in the upright position, as compared to alglucosidase alfa.
    Protection of trial subjects
    The study was conducted by investigators experienced in the treatment of paediatric and adult patients. The parent(s) or guardian(s) as well as the children were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time. In addition to the consent form for the parent(s)/guardian(s), an assent form in child-appropriate language was provided and explained to the child. Repeated invasive procedures were minimised. The number of blood samples as well as the amount of blood drawn were adjusted according to age and weight. A topical anesthesia might have been used to minimise distress and discomfort. Adult subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    		 -
    Evidence for comparator
    		 Alglucosidase alfa, a globally approved standard-of-care treatment, was used as a comparator in the blinded treatment period which was also known as primary analysis period (PAP).
    Actual start date of recruitment
    02 Nov 2016
    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
    Netherlands: 5
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Portugal: 1
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Czechia: 1
    Country: Number of subjects enrolled
    France: 12
    Country: Number of subjects enrolled
    Germany: 7
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Argentina: 2
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Brazil: 7
    Country: Number of subjects enrolled
    Japan: 1
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    Russian Federation: 6
    Country: Number of subjects enrolled
    United States: 33
    Country: Number of subjects enrolled
    Turkey: 3
    Worldwide total number of subjects
    101
    EEA total number of subjects
    41
    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)
    1
    Adolescents (12-17 years)
    1
    Adults (18-64 years)
    85
    From 65 to 84 years
    14
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study: Conducted at 69 centers. 149 subjects were screened between 02 November 2016 and 22 March 2019, of which 100 subjects were enrolled and randomized (1:1 ratio) to receive avalglucosidase alfa or alglucosidase alfa. 48 subjects: screening failures. 1 pediatric participant entered open-label treatment period directly.

    Pre-assignment
    Screening details
    		 Randomization was stratified by baseline % predicted FVC: less than (<) 55% or greater than or equal to (>=) 55%, gender, age (<18 years and >=18 years), and country (Japan or ex- Japan). Data reported based on study completion date, i.e. 31 May 2023.

    Period 1
    Period 1 title
    Blinded Treatment Period: up to Week 49
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Avalglucosidase Alfa-PAP
    Arm description
    		 Avalglucosidase alfa 20 milligrams per kilogram (mg/kg) intravenous (IV) infusion every 2 weeks (q2w) up to Week 49 in blinded treatment period (also known as primary analysis period [PAP]).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avalglucosidase alfa
    Investigational medicinal product code
    neoGAA, GZ402666
    Other name
    Nexviadyme
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    20 mg/kg, IV infusion q2w for a total of 25 doses.

    Arm title
    		 Alglucosidase Alfa-PAP
    Arm description
    		 Alglucosidase alfa 20 mg/kg IV infusion q2w up to Week 49 in blinded treatment period (also known as PAP).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Alglucosidase alfa
    Investigational medicinal product code
    Other name
    Myozyme® and Lumizyme®
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    20 mg/kg, IV infusion q2w for a total of 25 doses.

    Number of subjects in period 1 [1]
    		Avalglucosidase Alfa-PAP Alglucosidase Alfa-PAP
    Started
    51
    49
    Safety Population
    51
    49
    Completed
    51
    44
    Not completed
    0
    5
         Adverse event, non-fatal
    -
    4
         Unspecified
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 1 pediatric participant entered open-label treatment period directly.
    Period 2
    Period 2 title
    Open-label Long-term: Week 50-289
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Avalglucosidase Alfa-Open-label After Avalglucosidase Alfa-PAP
    Arm description
    		 Avalglucosidase alfa 20 mg/kg IV infusion q2w from Week 50 up to 289 based on product approval status in an open-label avalglucosidase alfa long-term follow-up phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avalglucosidase alfa
    Investigational medicinal product code
    neoGAA, GZ402666
    Other name
    Nexviadyme
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    20 mg/kg, IV infusion q2w for a total 48 doses.

    Arm title
    		 Avalglucosidase Alfa-Open-label After Alglucosidase Alfa-PAP
    Arm description
    		 Avalglucosidase alfa 20 mg/kg IV infusion q2w from Week 50 up to 289 based on product approval status in an open-label avalglucosidase alfa long-term follow-up phase.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Alglucosidase alfa
    Investigational medicinal product code
    Other name
    Myozyme® and Lumizyme®
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    20 mg/kg, IV infusion q2w for a total 48 doses.

    Number of subjects in period 2
    		Avalglucosidase Alfa-Open-label After Avalglucosidase Alfa-PAP Avalglucosidase Alfa-Open-label After Alglucosidase Alfa-PAP
    Started
    51
    44
    Safety Population
    51
    44
    Completed
    44
    36
    Not completed
    7
    8
         Adverse event, non-fatal
    2
    3
         Unspecified
    5
    4
         Poor compliance to protocol
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Avalglucosidase Alfa-PAP
    Reporting group description
    		 Avalglucosidase alfa 20 milligrams per kilogram (mg/kg) intravenous (IV) infusion every 2 weeks (q2w) up to Week 49 in blinded treatment period (also known as primary analysis period [PAP]).

    Reporting group title
    Alglucosidase Alfa-PAP
    Reporting group description
    		 Alglucosidase alfa 20 mg/kg IV infusion q2w up to Week 49 in blinded treatment period (also known as PAP).

    Reporting group values
    		 Avalglucosidase Alfa-PAP Alglucosidase Alfa-PAP Total
    Number of subjects
    		 51 49 100
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 46.0 ± 14.5 50.3 ± 13.7 -
    Gender categorical
    Units: Subjects
        Female
    		 24 24 48
        Male
    		 27 25 52
    Race
    Units: Subjects
        Asian
    		 3 0 3
        Black or African American
    		 1 2 3
        White
    		 47 47 94
    Percent Predicted FVC in Upright Position
    Measure Description: FVC is a standard pulmonary function test used to quantify respiratory muscle weakness. FVC is the volume of air (in litres) that can be forcibly blown out after full inspiration in the upright position.
    Units: percent predicted FVC
        arithmetic mean (standard deviation)
    		 62.5 ± 14.4 61.6 ± 12.4 -

    End points

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    End points reporting groups
    Reporting group title
    Avalglucosidase Alfa-PAP
    Reporting group description
    		 Avalglucosidase alfa 20 milligrams per kilogram (mg/kg) intravenous (IV) infusion every 2 weeks (q2w) up to Week 49 in blinded treatment period (also known as primary analysis period [PAP]).

    Reporting group title
    Alglucosidase Alfa-PAP
    Reporting group description
    		 Alglucosidase alfa 20 mg/kg IV infusion q2w up to Week 49 in blinded treatment period (also known as PAP).
    Reporting group title
    Avalglucosidase Alfa-Open-label After Avalglucosidase Alfa-PAP
    Reporting group description
    		 Avalglucosidase alfa 20 mg/kg IV infusion q2w from Week 50 up to 289 based on product approval status in an open-label avalglucosidase alfa long-term follow-up phase.

    Reporting group title
    Avalglucosidase Alfa-Open-label After Alglucosidase Alfa-PAP
    Reporting group description
    		 Avalglucosidase alfa 20 mg/kg IV infusion q2w from Week 50 up to 289 based on product approval status in an open-label avalglucosidase alfa long-term follow-up phase.

    Subject analysis set title
    PAP: Avalglucosidase Alfa
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Avalglucosidase alfa, 20 mg/kg IV infusion q2w up to Week 49 in blinded treatment period (also known as PAP).

    Subject analysis set title
    PAP: Alglucosidase Alfa
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Alglucosidase alfa, 20 mg/kg IV infusion q2w up to Week 49 in blinded treatment period (also known as PAP).

    Primary: PAP: Change From Baseline in Percent Predicted FVC in Upright Position at Week 49

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    End point title
    		 PAP: Change From Baseline in Percent Predicted FVC in Upright Position at Week 49
    End point description
    FVC is a standard pulmonary function test used to quantify respiratory muscle weakness. FVC is the volume of air (in litres) that can be forcibly blown out after full inspiration in the upright position. Least square (LS) mean and standard error (SE) were derived from mixed model for repeated measure (MMRM) model with Baseline FVC (% predicted, as continuous), sex, age (in years at Baseline), treatment group, visit, interaction term between treatment group and visit as fixed effects. Percent of predicted FVC = (actual FVC measurement)/(predicted value of FVC) * 100. After non-inferiority (NI) testing, a test for superiority of avalglucosidase alfa versus alglucosidase alfa was performed with an overall 2- sided 5% level of significance. Analysis was performed on modified intent-to-treat (mITT) population which included all randomised subjects who had received at least 1 infusion (partial or total) and were analysed according to the treatment arm allocated by randomisation.
    End point type
    Primary
    End point timeframe
    Baseline, Week 49
    End point values
    		 PAP: Avalglucosidase Alfa PAP: Alglucosidase Alfa
    Number of subjects analysed
    51
    49
    Units: percent predicted FVC
        least squares mean (standard error)
    2.89 ± 0.88
    0.46 ± 0.93
    Statistical analysis title
    		 Avalglucosidase Alfa versus Alglucosidase Alfa
    Statistical analysis description
    Analysis performed using MMRM model with Baseline FVC (% predicted, as continuous), sex, age (in years at Baseline), treatment group, visit, interaction term between treatment group and visit as fixed effects.
    Comparison groups
    PAP: Avalglucosidase Alfa v PAP: Alglucosidase Alfa
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 = 0.0074
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    2.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.13
         upper limit
    		 4.99
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.29
    Notes
    [1] - NI was demonstrated if the lower bound of the 2-sided 95% confidence interval (CI) for the difference of avalglucosidase alfa minus alglucosidase alfa was greater than (>) -1.1.
    Statistical analysis title
    		 Avalglucosidase Alfa versus Alglucosidase Alfa
    Statistical analysis description
    Analysis performed using MMRM model with Baseline FVC (% predicted, as continuous), sex, age (in years at Baseline), treatment group, visit, interaction term between treatment group and visit as fixed effects.
    Comparison groups
    PAP: Avalglucosidase Alfa v PAP: Alglucosidase Alfa
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.0626 [3]
    Method
    		 MMRM
    Confidence interval
    Notes
    [2] - A test for superiority of avalglucosidase alfa versus alglucosidase alfa was performed with an overall 5% level of significance.
    [3] - Threshold for significance at <0.05 level.

    Secondary: PAP: Change From Baseline in Total Distance Walked During Six-minute Walk Test (6MWT) at Week 49

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    End point title
    		 PAP: Change From Baseline in Total Distance Walked During Six-minute Walk Test (6MWT) at Week 49
    End point description
    6MWT was a standardised test that measured the distance (in metres) covered by the subject by walking on a flat, hard surface in a period of a 6-minute walk. Mean distance walked gives an indication of functional endurance. The greater the distance (that a subject could walk in 6 minutes), the greater the endurance. LS mean and SE were derived from MMRM model with Baseline FVC (% predicted) and Baseline 6MWT (distance walked in metre), age (in years, at Baseline), gender, treatment group, visit, and treatment-by-visit interaction as fixed effects. Analysis was performed on mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 49
    End point values
    		 PAP: Avalglucosidase Alfa PAP: Alglucosidase Alfa
    Number of subjects analysed
    51
    49
    Units: metres
        least squares mean (standard error)
    32.21 ± 9.93
    2.19 ± 10.40
    Statistical analysis title
    		 Avalglucosidase Alfa Versus Alglucosidase Alfa
    Statistical analysis description
    LS mean difference was derived from MMRM model with Baseline FVC (% predicted) and Baseline 6MWT (distance walked in metre), age (in years, at Baseline), gender, treatment group, visit, and treatment-by- visit interaction as fixed effects.
    Comparison groups
    PAP: Avalglucosidase Alfa v PAP: Alglucosidase Alfa
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.0405
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    30.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.33
         upper limit
    		 58.69
    Variability estimate
    Standard error of the mean
    Dispersion value
    14.43
    Notes
    [4] - Per the protocol-defined statistical test strategy for multiplicity adjustment, and since superiority was narrowly missed for FVC % predicted, superiority testing for the secondary endpoints couldn’t be performed.

    Secondary: PAP: Change From Baseline in Percent Predicted Maximal Inspiratory Pressure (MIP) in Upright Position at Week 49

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    End point title
    		 PAP: Change From Baseline in Percent Predicted Maximal Inspiratory Pressure (MIP) in Upright Position at Week 49
    End point description
    MIP is a quick and non-invasive test to measure strength of inspiratory muscles, primarily diaphragm, and allows for assessment of ventilatory failure, restrictive lung disease and respiratory muscle strength. MIP refers to how much air pressure force an individual creates by inhaling through the mouth as hard as possible. LS mean and SE were derived from MMRM model for MIP % predicted adjusted for MIP % predicted at Baseline, age (in years, at Baseline), gender, treatment group, visit, and treatment-by-visit interaction as fixed effects. Analysis was performed on mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 49
    End point values
    		 PAP: Avalglucosidase Alfa PAP: Alglucosidase Alfa
    Number of subjects analysed
    51
    49
    Units: percent predicted MIP
        least squares mean (standard error)
    0.17 ± 3.60
    -2.96 ± 3.79
    Statistical analysis title
    		 Avalglucosidase Alfa versus Alglucosidase Alfa
    Statistical analysis description
    LS mean difference was derived from MMRM model for MIP % predicted adjusted for MIP % predicted at Baseline, age (in years, at Baseline), gender, treatment group, visit, and treatment-by-visit interaction as fixed effects.
    Comparison groups
    PAP: Avalglucosidase Alfa v PAP: Alglucosidase Alfa
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.5522
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    3.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.31
         upper limit
    		 13.57
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.24
    Notes
    [5] - Per the protocol-defined statistical test strategy for multiplicity adjustment, and since superiority was narrowly missed for FVC % predicted, superiority testing for the secondary endpoints couldn’t be performed.

    Secondary: PAP: Change From Baseline in Percent Predicted Maximal Expiratory Pressure (MEP) in Upright Position at Week 49

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    End point title
    		 PAP: Change From Baseline in Percent Predicted Maximal Expiratory Pressure (MEP) in Upright Position at Week 49
    End point description
    MEP is a quick and non-invasive test to measure strength of expiratory muscles, primarily diaphragm, and allows for assessment of ventilatory failure, restrictive lung disease and respiratory muscle strength. MEP is the greater pressure generated during maximal expiration. LS mean and SE was derived from MMRM model for MEP % predicted adjusted for MEP % predicted at Baseline, age (in years, at Baseline), gender, treatment group, visit, and treatment-by-visit interaction as fixed effects. Analysis was performed on mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 49
    End point values
    		 PAP: Avalglucosidase Alfa PAP: Alglucosidase Alfa
    Number of subjects analysed
    51
    49
    Units: percent predicted MEP
        least squares mean (standard error)
    3.02 ± 3.87
    4.95 ± 4.07
    Statistical analysis title
    		 Avalglucosidase Alfa versus Alglucosidase Alfa
    Statistical analysis description
    LS mean difference was derived from MMRM model for MEP % predicted adjusted for MEP % predicted at Baseline, age (in years, at Baseline), gender, treatment group, visit, and treatment-by-visit interaction as fixed effects.
    Comparison groups
    PAP: Avalglucosidase Alfa v PAP: Alglucosidase Alfa
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.7321
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -1.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.17
         upper limit
    		 9.29
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.64
    Notes
    [6] - Per the protocol-defined statistical test strategy for multiplicity adjustment, and since superiority was narrowly missed for FVC % predicted, superiority testing for the secondary endpoints couldn’t be performed.

    Secondary: PAP: Change From Baseline in Lower Extremity Muscle Strength at Week 49 as Assessed by Hand-Held Dynamometry (HHD)

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    End point title
    		 PAP: Change From Baseline in Lower Extremity Muscle Strength at Week 49 as Assessed by Hand-Held Dynamometry (HHD)
    End point description
    HHD: portable method for strength quantitation. To complete a make test, subject exerted maximal force against dynamometer with gradual increase in force and completed isometric hold for 4-5 seconds. Muscle strengths were collected in Newton. Every muscle group (hip: flexion, extension, abduction; knee: flexion, extension and ankle dorsiflexion) were measured 2 times and highest value was reported. Summary score: sum of 12 measurements (2 measurements per muscle group) from 6 muscle groups on each side (left and right). Increase from Baseline was reflective of increased muscle strength, whereas decrease from Baseline was reflective of decreased muscle strength. LS mean and SE were derived from MMRM model for HHD lower extremity muscle strength composite score adjusted for summary HHD lower extremity score at Baseline, Baseline FVC (% predicted), age (in years, at Baseline), gender, treatment group, visit and treatment-by-visit interaction as fixed effects. Analysed on mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 49
    End point values
    		 PAP: Avalglucosidase Alfa PAP: Alglucosidase Alfa
    Number of subjects analysed
    51
    49
    Units: newton
        least squares mean (standard error)
    260.69 ± 46.07
    153.72 ± 48.54
    Statistical analysis title
    		 Avalglucosidase Alfa versus Alglucosidase Alfa
    Statistical analysis description
    LS mean difference was derived from MMRM model for HHD lower extremity muscle strength composite score adjusted for summary HHD lower extremity score at Baseline, Baseline FVC (% predicted), age (in years, at Baseline), gender, treatment group, visit, and treatment-by-visit interaction as fixed effects.
    Comparison groups
    PAP: Avalglucosidase Alfa v PAP: Alglucosidase Alfa
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.115
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    106.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.56
         upper limit
    		 240.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    67.17
    Notes
    [7] - Per the protocol-defined statistical test strategy for multiplicity adjustment, and since superiority was narrowly missed for FVC % predicted, superiority testing for the secondary endpoints couldn’t be performed.

    Secondary: PAP: Change From Baseline in Quick Motor Function Test (QMFT) Total Scores at Week 49

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    End point title
    		 PAP: Change From Baseline in Quick Motor Function Test (QMFT) Total Scores at Week 49
    End point description
    The QMFT was an observer administered test to evaluate changes in motor function. QMFT comprised of 16 items specifically difficult for subjects with Pompe disease. Each item was scored separately on a 5-point ordinal scale (ranged from 0 to 4, higher score indicated better outcome). Total QMFT score was obtained by adding the scores of all items and ranged from 0 (unable to perform motor function tests) to 64 (normal muscle function), higher score represented better outcome. LS mean and SE were derived from MMRM models adjusted for total QMFT score at Baseline, Baseline FVC (% predicted), age (in years, at Baseline), gender, treatment group, visit, and treatment-by-visit interaction as fixed effects. Analysis was performed on mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 49
    End point values
    		 PAP: Avalglucosidase Alfa PAP: Alglucosidase Alfa
    Number of subjects analysed
    51
    49
    Units: scores on a scale
        least squares mean (standard error)
    3.98 ± 0.63
    1.89 ± 0.69
    Statistical analysis title
    		 Avalglucosidase Alfa versus Alglucosidase Alfa
    Statistical analysis description
    LS mean difference was derived from MMRM models adjust for total QMFT score at baseline, baseline FVC (% predicted), age (in years, at baseline), gender, treatment group, visit, and treatment-by-visit interaction as fixed effects.
    Comparison groups
    PAP: Avalglucosidase Alfa v PAP: Alglucosidase Alfa
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0288
    Method
    		 mixed model for repeated measures
    Parameter type
    		 LS mean difference
    Point estimate
    2.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.22
         upper limit
    		 3.95
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.94

    Secondary: PAP: Change From Baseline in 12-Item Short-Form Health Survey (SF-12): Physical Component Summary (PCS) and Mental Component Summary (MCS) Scores at Week 49

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    End point title
    		 PAP: Change From Baseline in 12-Item Short-Form Health Survey (SF-12): Physical Component Summary (PCS) and Mental Component Summary (MCS) Scores at Week 49
    End point description
    SF-12: 12 item-questionnaire, assessed health-related quality of life in subjects aged >=18 years at screening/Baseline. 12 items were categorised into 8 domains (subscales) of functioning and well-being: physical functioning, role-physical, role emotional, mental health, bodily pain, general health, vitality and social functioning, with each domain score range: 0 (poor health) to 100 (better health), higher scores=good health condition. These 8 domains were further summarised into 2 summary scores, PCS and MCS. Score range for each of these 2 summary scores was from 0 (poor health) to 100 (better health), higher scores=better health-related quality of life. LS mean and SE were derived from MMRM models adjust for Baseline score (PCS or MCS), Baseline FVC (% predicted), age (in years, at Baseline), gender, treatment group, visit, and treatment-by-visit interaction as fixed effects. Analysed on mITT population. Here, 'number of subjects analysed'=subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 49
    End point values
    		 PAP: Avalglucosidase Alfa PAP: Alglucosidase Alfa
    Number of subjects analysed
    50
    49
    Units: scores on a scale
    least squares mean (standard error)
        PCS score
    2.37 ± 0.99
    1.60 ± 1.07
        MCS score
    2.88 ± 1.22
    0.76 ± 1.32
    Statistical analysis title
    		 Avalglucosidase Alfa versus Alglucosidase Alfa
    Statistical analysis description
    The MMRM models adjust for baseline score (PCS), baseline FVC (% predicted), age (in years, at baseline), gender, treatment group, visit, and treatment-by-visit interaction as fixed effects.
    Comparison groups
    PAP: Avalglucosidase Alfa v PAP: Alglucosidase Alfa
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5996
    Method
    		 mixed model for repeated measures
    Parameter type
    		 Score difference
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.13
         upper limit
    		 3.67
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.46
    Statistical analysis title
    		 Avalglucosidase Alfa versus Alglucosidase Alfa
    Statistical analysis description
    The MMRM models adjust for baseline score (MCS), baseline FVC (% predicted), age (in years, at baseline), gender, treatment group, visit, and treatment-by-visit interaction as fixed effects.
    Comparison groups
    PAP: Avalglucosidase Alfa v PAP: Alglucosidase Alfa
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2427
    Method
    		 mixed model for repeated measures
    Parameter type
    		 Score difference
    Point estimate
    2.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.46
         upper limit
    		 5.69
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.8

    Secondary: PAP: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Infusion-Associated Reactions (IARs)

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    End point title
    		 PAP: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Infusion-Associated Reactions (IARs)
    End point description
    AE: any untoward medical occurrence in subject who had drug and not necessarily had causal relationship with treatment. TEAEs:AEs-developed/worsened in grade/became serious during TEAE period in PAP (from time of 1st treatment date to last treatment date+4 weeks for subjects who didn't take any treatment in open-label or to time just prior to 1st treatment in open-label for subjects who had treatment in open-label). Protocol-defined IARs:AE of special interest (AESIs)-occurred during either infusion/observation period after infusion; deemed to be related/possibly related to drug. Algorithm-defined IARs: any TEAE meeting either criteria 1) event occurred from start to end of infusion+24 hours, considered related to drug or 2) If AE time component missed, compare AE start date with infusion start and end date. If AE start date was between infusion start and end date+1 day and related to drug. safety population:subjects who had at least 1 infusion (partial/total); analysed per treatment.
    End point type
    Secondary
    End point timeframe
    From Baseline up to Week 49
    End point values
    		 PAP: Avalglucosidase Alfa PAP: Alglucosidase Alfa
    Number of subjects analysed
    51
    49
    Units: subjects
        Any TEAE
    44
    45
        Any Protocol-defined IARs
    13
    16
        Any Algorithm-defined IARs
    15
    20
    No statistical analyses for this end point

    Secondary: Open-label Period: Number of Subjects With TEAEs and IARs

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    End point title
    		 Open-label Period: Number of Subjects With TEAEs and IARs
    End point description
    AE: any untoward medical occurrence in a subject who received study drug and did not necessarily have to had a causal relationship with treatment. TEAEs in open-label: AEs that developed/worsened in grade/became serious during TEAE period in open-label (from time of 1st open-label treatment to last treatment date + 4 weeks). Protocol-defined IARs: defined as AESIs that occurred during either infusion/observation period following infusion which were deemed to be related/possibly related to study drug. Algorithm-defined IARs: any TEAE meeting either 1 of 2 criteria: 1) event occurred from start to end of infusion plus 24 hours, considered related to study drug, 2) If AE time component missed, compare AE start date with infusion start and end date. If AE start date was between infusion start and end date plus 1 day and it was related to study drug. Analysis was performed on safety population.
    End point type
    Secondary
    End point timeframe
    Week 50 to 289 in open-label long-term period
    End point values
    		 Avalglucosidase Alfa-PAP Alglucosidase Alfa-PAP
    Number of subjects analysed
    51
    44
    Units: subjects
        Any TEAE
    51
    43
        Any Protocol-defined IARs
    12
    22
        Any Algorithm-defined IARs
    16
    24
    No statistical analyses for this end point

    Secondary: PAP: Percentage of Subjects With Treatment-Emergent Antidrug Antibodies (ADA) Response

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    End point title
    		 PAP: Percentage of Subjects With Treatment-Emergent Antidrug Antibodies (ADA) Response
    End point description
    ADA response categories: 1) Treatment-induced: ADAs developed following administration of the study drug. If the Baseline ADA sample was missing or non-reportable and at least one reportable on-treatment ADA sample was available, the Baseline sample was considered as "negative". 2) Treatment boosted: Pre-existing ADAs that were boosted at least two titer steps from Baseline (i.e., 4-fold increase in titers) following administration of the study drug (any time after the first drug administration). 3) Treatment emergent: combination of treatment induced and treatment boosted. Analysis was performed on ADA evaluable population which consisted of subjects who had received at least 1 infusion (partial or total) and had at least one ADA sample taken post-baseline after drug administration that was appropriate for ADA testing with a reportable result.
    End point type
    Secondary
    End point timeframe
    From Baseline up to Week 49
    End point values
    		 PAP: Avalglucosidase Alfa PAP: Alglucosidase Alfa
    Number of subjects analysed
    51
    48
    Units: percentage of subjects
    number (not applicable)
        Treatment Induced
    95.9
    95.7
        Treatment-boosted ADA
    100
    100
        Treatment-emergent ADA
    96.1
    95.8
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Week 49 in PAP and from Week 50 to 289 in open-label long-term period
    Adverse event reporting additional description
    AEs and deaths:TEAEs that developed/worsened in grade/became serious during ‘TEAE period’ (PAP:from 1st treatment date to last treatment date+4 weeks for subjects not exposed to treatment in open-label or to time just prior to 1st dose in open-label for those exposed to open-label [time from 1st study drug to last dose+4 weeks]). Safety population.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    PAP: Avalglucosidase Alfa
    Reporting group description
    		 Avalglucosidase alfa, 20 mg/kg IV infusion q2w up to Week 49 in blinded treatment period (also known as PAP).

    Reporting group title
    Open-label: Alglucosidase Alfa-PAP Then Avalglucosidase Alfa
    Reporting group description
    		 Included all subjects who received avalglucosidase alfa 20 mg/kg IV infusion q2w treatment from Week 50 up to 289 based on product approval status in an open-label avalglucosidase alfa long-term follow-up phase.

    Reporting group title
    Open-label: Avalglucosidase Alfa
    Reporting group description
    		 Included all subjects who received avalglucosidase alfa, 20 mg/kg IV infusion q2w from Week 50 up to 289 based on product approval status in an open-label avalglucosidase alfa long-term follow-up phase.

    Reporting group title
    PAP: Alglucosidase Alfa
    Reporting group description
    		 Alglucosidase alfa, 20 mg/kg IV infusion q2w up to Week 49 in blinded treatment period (also known as PAP).

    Serious adverse events
    		 PAP: Avalglucosidase Alfa Open-label: Alglucosidase Alfa-PAP Then Avalglucosidase Alfa Open-label: Avalglucosidase Alfa PAP: Alglucosidase Alfa
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 51 (15.69%)
    14 / 44 (31.82%)
    14 / 52 (26.92%)
    12 / 49 (24.49%)
         number of deaths (all causes)
    0
    2
    0
    1
         number of deaths resulting from adverse events
    0
    1
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma Pancreas
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 44 (2.27%)
    0 / 52 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Renal Oncocytoma
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    1 / 52 (1.92%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 44 (2.27%)
    0 / 52 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive Crisis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    2 / 52 (3.85%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    1 / 52 (1.92%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Breast Cyst
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 44 (0.00%)
    0 / 52 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute Respiratory Distress Syndrome
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 44 (2.27%)
    0 / 52 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 44 (2.27%)
    0 / 52 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Diaphragmatic Paralysis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    0 / 52 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 51 (1.96%)
    2 / 44 (4.55%)
    0 / 52 (0.00%)
    2 / 49 (4.08%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoventilation
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 44 (0.00%)
    0 / 52 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory Failure
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 44 (0.00%)
    2 / 52 (3.85%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory Distress
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 44 (2.27%)
    0 / 52 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory Acidosis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    1 / 52 (1.92%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 44 (2.27%)
    0 / 52 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Bipolar Disorder
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 44 (2.27%)
    0 / 52 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Oxygen Saturation Decreased
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 44 (2.27%)
    1 / 52 (1.92%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood Pressure Increased
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    1 / 52 (1.92%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Body Temperature Increased
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    1 / 52 (1.92%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoglobin Decreased
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    0 / 52 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Heart Rate Increased
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    1 / 52 (1.92%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Hip Fracture
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 44 (2.27%)
    0 / 52 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viiith Nerve Injury
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    1 / 52 (1.92%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound Dehiscence
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    1 / 52 (1.92%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Glycogen Storage Disease Type Ii
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    1 / 52 (1.92%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina Pectoris
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 44 (2.27%)
    0 / 52 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute Myocardial Infarction
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    1 / 52 (1.92%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Supraventricular Tachycardia
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    0 / 52 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 44 (0.00%)
    0 / 52 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid Haemorrhage
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    1 / 52 (1.92%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Moyamoya Disease
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    1 / 52 (1.92%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    1 / 52 (1.92%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    0 / 52 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depressed Level Of Consciousness
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 44 (2.27%)
    0 / 52 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebellar Ischaemia
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    0 / 52 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain Stem Stroke
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    0 / 52 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 44 (2.27%)
    0 / 52 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Visual Impairment
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    0 / 52 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Tongue Oedema
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 44 (2.27%)
    0 / 52 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    1 / 52 (1.92%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal Haemorrhage
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    0 / 52 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal Pain Upper
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    0 / 52 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    2 / 52 (3.85%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    2 / 52 (3.85%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Cold Sweat
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    0 / 52 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin Discolouration
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    1 / 52 (1.92%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pruritus
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    1 / 52 (1.92%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 44 (2.27%)
    0 / 52 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal Colic
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 44 (0.00%)
    0 / 52 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvi-Ureteric Obstruction
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    1 / 52 (1.92%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    0 / 52 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 44 (0.00%)
    0 / 52 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Calculus Urinary
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 44 (0.00%)
    0 / 52 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Inappropriate Antidiuretic Hormone Secretion
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    0 / 52 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    1 / 52 (1.92%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    1 / 52 (1.92%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Covid-19
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 44 (2.27%)
    0 / 52 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device Related Infection
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    1 / 52 (1.92%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 44 (2.27%)
    1 / 52 (1.92%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    0 / 52 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 44 (2.27%)
    0 / 52 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Covid-19 Pneumonia
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 44 (2.27%)
    1 / 52 (1.92%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    1 / 52 (1.92%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 PAP: Avalglucosidase Alfa Open-label: Alglucosidase Alfa-PAP Then Avalglucosidase Alfa Open-label: Avalglucosidase Alfa PAP: Alglucosidase Alfa
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    40 / 51 (78.43%)
    40 / 44 (90.91%)
    50 / 52 (96.15%)
    44 / 49 (89.80%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 51 (1.96%)
    4 / 44 (9.09%)
    7 / 52 (13.46%)
    3 / 49 (6.12%)
         occurrences all number
    2
    4
    21
    5
    Flushing
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 44 (4.55%)
    1 / 52 (1.92%)
    3 / 49 (6.12%)
         occurrences all number
    0
    3
    1
    3
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    1 / 51 (1.96%)
    5 / 44 (11.36%)
    4 / 52 (7.69%)
    2 / 49 (4.08%)
         occurrences all number
    1
    13
    13
    6
    Chest Discomfort
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 44 (6.82%)
    1 / 52 (1.92%)
    0 / 49 (0.00%)
         occurrences all number
    0
    5
    1
    0
    Pyrexia
         subjects affected / exposed
    2 / 51 (3.92%)
    6 / 44 (13.64%)
    8 / 52 (15.38%)
    4 / 49 (8.16%)
         occurrences all number
    2
    11
    10
    4
    Pain
         subjects affected / exposed
    2 / 51 (3.92%)
    6 / 44 (13.64%)
    3 / 52 (5.77%)
    5 / 49 (10.20%)
         occurrences all number
    3
    14
    5
    13
    Oedema Peripheral
         subjects affected / exposed
    3 / 51 (5.88%)
    4 / 44 (9.09%)
    5 / 52 (9.62%)
    3 / 49 (6.12%)
         occurrences all number
    4
    4
    7
    3
    Infusion Site Extravasation
         subjects affected / exposed
    0 / 51 (0.00%)
    5 / 44 (11.36%)
    2 / 52 (3.85%)
    3 / 49 (6.12%)
         occurrences all number
    0
    8
    2
    3
    Influenza Like Illness
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 44 (2.27%)
    3 / 52 (5.77%)
    0 / 49 (0.00%)
         occurrences all number
    4
    1
    8
    0
    Fatigue
         subjects affected / exposed
    9 / 51 (17.65%)
    9 / 44 (20.45%)
    4 / 52 (7.69%)
    7 / 49 (14.29%)
         occurrences all number
    11
    75
    8
    27
    Peripheral Swelling
         subjects affected / exposed
    1 / 51 (1.96%)
    5 / 44 (11.36%)
    1 / 52 (1.92%)
    3 / 49 (6.12%)
         occurrences all number
    3
    6
    1
    3
    Immune system disorders
    Seasonal Allergy
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    3 / 52 (5.77%)
    0 / 49 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Respiratory, thoracic and mediastinal disorders
    Nasal Congestion
         subjects affected / exposed
    1 / 51 (1.96%)
    2 / 44 (4.55%)
    2 / 52 (3.85%)
    5 / 49 (10.20%)
         occurrences all number
    1
    2
    2
    5
    Dyspnoea
         subjects affected / exposed
    2 / 51 (3.92%)
    3 / 44 (6.82%)
    2 / 52 (3.85%)
    2 / 49 (4.08%)
         occurrences all number
    2
    5
    3
    2
    Cough
         subjects affected / exposed
    2 / 51 (3.92%)
    5 / 44 (11.36%)
    4 / 52 (7.69%)
    4 / 49 (8.16%)
         occurrences all number
    2
    7
    7
    4
    Rhinorrhoea
         subjects affected / exposed
    0 / 51 (0.00%)
    5 / 44 (11.36%)
    0 / 52 (0.00%)
    2 / 49 (4.08%)
         occurrences all number
    0
    6
    0
    2
    Oropharyngeal Pain
         subjects affected / exposed
    2 / 51 (3.92%)
    4 / 44 (9.09%)
    2 / 52 (3.85%)
    5 / 49 (10.20%)
         occurrences all number
    2
    7
    6
    8
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 44 (2.27%)
    3 / 52 (5.77%)
    1 / 49 (2.04%)
         occurrences all number
    1
    1
    3
    1
    Depression
         subjects affected / exposed
    1 / 51 (1.96%)
    2 / 44 (4.55%)
    0 / 52 (0.00%)
    3 / 49 (6.12%)
         occurrences all number
    1
    2
    0
    3
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    2 / 51 (3.92%)
    2 / 44 (4.55%)
    1 / 52 (1.92%)
    3 / 49 (6.12%)
         occurrences all number
    2
    2
    1
    3
    Blood Pressure Increased
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 44 (6.82%)
    1 / 52 (1.92%)
    0 / 49 (0.00%)
         occurrences all number
    0
    3
    1
    0
    Injury, poisoning and procedural complications
    Arthropod Bite
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 44 (6.82%)
    1 / 52 (1.92%)
    1 / 49 (2.04%)
         occurrences all number
    0
    4
    1
    1
    Post-Traumatic Pain
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 44 (6.82%)
    0 / 52 (0.00%)
    1 / 49 (2.04%)
         occurrences all number
    0
    3
    0
    1
    Joint Injury
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    3 / 52 (5.77%)
    0 / 49 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Fall
         subjects affected / exposed
    7 / 51 (13.73%)
    8 / 44 (18.18%)
    10 / 52 (19.23%)
    10 / 49 (20.41%)
         occurrences all number
    12
    21
    28
    13
    Contusion
         subjects affected / exposed
    5 / 51 (9.80%)
    3 / 44 (6.82%)
    5 / 52 (9.62%)
    4 / 49 (8.16%)
         occurrences all number
    5
    4
    7
    4
    Nervous system disorders
    Tremor
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 44 (2.27%)
    3 / 52 (5.77%)
    0 / 49 (0.00%)
         occurrences all number
    1
    1
    12
    0
    Syncope
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 44 (0.00%)
    3 / 52 (5.77%)
    0 / 49 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Paraesthesia
         subjects affected / exposed
    3 / 51 (5.88%)
    2 / 44 (4.55%)
    0 / 52 (0.00%)
    2 / 49 (4.08%)
         occurrences all number
    3
    2
    0
    2
    Dizziness
         subjects affected / exposed
    5 / 51 (9.80%)
    3 / 44 (6.82%)
    6 / 52 (11.54%)
    3 / 49 (6.12%)
         occurrences all number
    6
    4
    8
    14
    Headache
         subjects affected / exposed
    11 / 51 (21.57%)
    17 / 44 (38.64%)
    12 / 52 (23.08%)
    16 / 49 (32.65%)
         occurrences all number
    32
    220
    42
    102
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 44 (6.82%)
    3 / 52 (5.77%)
    1 / 49 (2.04%)
         occurrences all number
    0
    3
    3
    1
    Eye disorders
    Conjunctival Haemorrhage
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 44 (6.82%)
    0 / 52 (0.00%)
    0 / 49 (0.00%)
         occurrences all number
    0
    4
    0
    0
    Ocular Hyperaemia
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 44 (0.00%)
    3 / 52 (5.77%)
    1 / 49 (2.04%)
         occurrences all number
    3
    0
    4
    1
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    1 / 51 (1.96%)
    4 / 44 (9.09%)
    5 / 52 (9.62%)
    1 / 49 (2.04%)
         occurrences all number
    1
    6
    8
    1
    Abdominal Pain Upper
         subjects affected / exposed
    2 / 51 (3.92%)
    3 / 44 (6.82%)
    3 / 52 (5.77%)
    2 / 49 (4.08%)
         occurrences all number
    4
    4
    6
    2
    Diarrhoea
         subjects affected / exposed
    6 / 51 (11.76%)
    14 / 44 (31.82%)
    7 / 52 (13.46%)
    8 / 49 (16.33%)
         occurrences all number
    9
    19
    15
    9
    Dyspepsia
         subjects affected / exposed
    3 / 51 (5.88%)
    3 / 44 (6.82%)
    2 / 52 (3.85%)
    3 / 49 (6.12%)
         occurrences all number
    9
    9
    2
    5
    Nausea
         subjects affected / exposed
    6 / 51 (11.76%)
    7 / 44 (15.91%)
    12 / 52 (23.08%)
    7 / 49 (14.29%)
         occurrences all number
    8
    22
    16
    15
    Toothache
         subjects affected / exposed
    1 / 51 (1.96%)
    4 / 44 (9.09%)
    2 / 52 (3.85%)
    0 / 49 (0.00%)
         occurrences all number
    2
    5
    3
    0
    Vomiting
         subjects affected / exposed
    4 / 51 (7.84%)
    6 / 44 (13.64%)
    3 / 52 (5.77%)
    3 / 49 (6.12%)
         occurrences all number
    5
    7
    4
    3
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    3 / 51 (5.88%)
    5 / 44 (11.36%)
    3 / 52 (5.77%)
    3 / 49 (6.12%)
         occurrences all number
    4
    7
    4
    7
    Pruritus
         subjects affected / exposed
    4 / 51 (7.84%)
    11 / 44 (25.00%)
    3 / 52 (5.77%)
    4 / 49 (8.16%)
         occurrences all number
    5
    51
    3
    11
    Rash
         subjects affected / exposed
    2 / 51 (3.92%)
    8 / 44 (18.18%)
    4 / 52 (7.69%)
    4 / 49 (8.16%)
         occurrences all number
    11
    16
    8
    4
    Urticaria
         subjects affected / exposed
    3 / 51 (5.88%)
    4 / 44 (9.09%)
    5 / 52 (9.62%)
    1 / 49 (2.04%)
         occurrences all number
    4
    9
    12
    5
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    2 / 51 (3.92%)
    3 / 44 (6.82%)
    0 / 52 (0.00%)
    0 / 49 (0.00%)
         occurrences all number
    4
    3
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 51 (11.76%)
    13 / 44 (29.55%)
    13 / 52 (25.00%)
    8 / 49 (16.33%)
         occurrences all number
    7
    29
    27
    11
    Back Pain
         subjects affected / exposed
    12 / 51 (23.53%)
    10 / 44 (22.73%)
    11 / 52 (21.15%)
    5 / 49 (10.20%)
         occurrences all number
    15
    20
    13
    7
    Muscle Spasms
         subjects affected / exposed
    3 / 51 (5.88%)
    5 / 44 (11.36%)
    4 / 52 (7.69%)
    4 / 49 (8.16%)
         occurrences all number
    3
    8
    7
    4
    Muscular Weakness
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 44 (6.82%)
    1 / 52 (1.92%)
    3 / 49 (6.12%)
         occurrences all number
    0
    5
    1
    6
    Musculoskeletal Pain
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 44 (6.82%)
    3 / 52 (5.77%)
    0 / 49 (0.00%)
         occurrences all number
    0
    117
    3
    0
    Musculoskeletal Stiffness
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 44 (6.82%)
    1 / 52 (1.92%)
    0 / 49 (0.00%)
         occurrences all number
    0
    4
    1
    0
    Myalgia
         subjects affected / exposed
    5 / 51 (9.80%)
    10 / 44 (22.73%)
    6 / 52 (11.54%)
    7 / 49 (14.29%)
         occurrences all number
    15
    22
    12
    12
    Neck Pain
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 44 (6.82%)
    3 / 52 (5.77%)
    2 / 49 (4.08%)
         occurrences all number
    0
    3
    4
    5
    Pain In Extremity
         subjects affected / exposed
    8 / 51 (15.69%)
    9 / 44 (20.45%)
    10 / 52 (19.23%)
    8 / 49 (16.33%)
         occurrences all number
    9
    19
    29
    15
    Infections and infestations
    Urinary Tract Infection
         subjects affected / exposed
    2 / 51 (3.92%)
    3 / 44 (6.82%)
    8 / 52 (15.38%)
    1 / 49 (2.04%)
         occurrences all number
    3
    9
    10
    4
    Upper Respiratory Tract Infection
         subjects affected / exposed
    4 / 51 (7.84%)
    8 / 44 (18.18%)
    3 / 52 (5.77%)
    2 / 49 (4.08%)
         occurrences all number
    5
    10
    4
    2
    Sinusitis
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 44 (2.27%)
    3 / 52 (5.77%)
    1 / 49 (2.04%)
         occurrences all number
    0
    1
    5
    1
    Pneumonia
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 44 (6.82%)
    1 / 52 (1.92%)
    1 / 49 (2.04%)
         occurrences all number
    0
    4
    1
    1
    Nasopharyngitis
         subjects affected / exposed
    12 / 51 (23.53%)
    13 / 44 (29.55%)
    15 / 52 (28.85%)
    12 / 49 (24.49%)
         occurrences all number
    15
    27
    23
    17
    Influenza
         subjects affected / exposed
    10 / 51 (19.61%)
    4 / 44 (9.09%)
    4 / 52 (7.69%)
    3 / 49 (6.12%)
         occurrences all number
    11
    5
    4
    4
    Cystitis
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 44 (0.00%)
    2 / 52 (3.85%)
    0 / 49 (0.00%)
         occurrences all number
    4
    0
    2
    0
    Covid-19
         subjects affected / exposed
    0 / 51 (0.00%)
    9 / 44 (20.45%)
    16 / 52 (30.77%)
    0 / 49 (0.00%)
         occurrences all number
    0
    9
    17
    0
    Bronchitis
         subjects affected / exposed
    0 / 51 (0.00%)
    4 / 44 (9.09%)
    3 / 52 (5.77%)
    2 / 49 (4.08%)
         occurrences all number
    0
    4
    3
    2
    Metabolism and nutrition disorders
    Gout
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 44 (6.82%)
    1 / 52 (1.92%)
    0 / 49 (0.00%)
         occurrences all number
    0
    4
    2
    0
    Vitamin D Deficiency
         subjects affected / exposed
    2 / 51 (3.92%)
    2 / 44 (4.55%)
    5 / 52 (9.62%)
    0 / 49 (0.00%)
         occurrences all number
    2
    2
    5
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Aug 2016
    Following changes were made: • Change to the inclusion/exclusion criteria. Inclusion criterion 1 and exclusion criterion 8 were reworded in order to comply with local requirements regarding age of minors and adults. Exclusion criterion 6 was modified to allow more severely compromised subjects into the study by reducing the lower cut-off for % predicted FVC from 40% to 30%. • Change to the sample size. Sample size was increased from approximately 86 to approximately 96 as a result of modification to the exclusion criteria for % predicted FVC (the primary endpoint) and using a more conservative 10% estimate for missing data.
    18 Jul 2017
    Following changes were made: • Minor editorial: spelling, punctuation, grammar and syntax. • Updated: abbreviations, table of contents, table footnotes and references. • Updated flow charts to reflect study procedures and to clarify that AEs and concomitant medication use information were to be collected at each visit to assure that information was kept up to date. • Renumbered: sections, table footnotes and citations and references. • Reformatted tables. • Extended screening period: screening phase (time from signing of informed consent form [ICF] to start of study treatment) should not exceed 14 days, but could be extended to a maximum of 8 weeks in pre-specified situations. • Added re-screening details: Subjects re-screened once when clinical condition changed. Subjects who were screen failed because FVC% predicted was >85% might be re-screened only if clinically relevant worsening respiratory condition related to Pompe Disease and not related to intercurrent illness as assessed by Investigator occurs. In rescreening, subject would be first screened failed in interactive voice/web response system, would sign new written ICF and new subject number would be provided. All screening assessments/procedures would had to be performed again, except GAA genotyping. • PFT details updated: Subjects might repeat assessment once up to 3 times within Screening Visit time window in case of failed quality as determined by central laboratory. • Clarified ADA tests: Subjects in neoGAA treatment arm would be tested for anti-neoGAA antibodies and subjects in glucosidase alfa treatment arm would be tested for anti-alglucosidase alfa antibodies. In open label follow-up phase, subjects from alglucosidase alfa treatment arm who had switched to neoGAA would be tested for both anti-alglucosidase alfa antibodies and anti-neoGAA antibodies. Subjects who were +ve for anti-neoGAA antibodies would be tested to determine if antibodies cross-react with alglucosidase alfa.
    10 Apr 2019
    Following changes were done: • In order to allow study subjects to continue to receive study drug after Week 145, study was extended to an additional period of up to 144 weeks (or until avalglucosidase alfa was approved in subject's country, whichever came first). • Enrollment of subjects aged 3 to <18 years had been challenging, mainly due to exclusion criterion related to respiratory function (requirements that FVC% predicted less than or equal to 85%). At end of recruitment, if <4 subjects 3 to <18 years were enrolled, in order to comply with Health Authority requirements to enroll a certain number of paediatric subjects, up to 2 additional paediatric subjects were to be enrolled directly in open-label avalglucosidase alfa long-term follow-up phase where they received avalglucosidase alfa. • In permitted countries, home infusion of avalglucosidase alfa in extension period was allowed. • Language was added in 'randomisation code-breaking during study' section, to document that an unblinded programmer prepared dataset for population pharmacokinetic analysis. • Updated statistical section: removed noninferiority test of 6MWT from testing order and used superiority instead for secondary endpoint of 6MWT in accordance with feedback from regulatory agency. Added superiority test of MEP to hierarchical testing and updated safety population definition. • Removed messenger ribonucleic acid test since it test was not performed. • Clarified conditions for temporary study drug discontinuation with Data Monitoring Committee consultation (eg, in case of abnormal liver function test). • HHD not required in Canadian sites. • Home infusion did not apply in France. • In the UK: updated extended open-label avalglucosidase alfa long-term follow-up period as ‘up to 144 weeks after last subject had been enrolled in study'.
    21 Dec 2020
    Following changes were done: • To include the recommendations that were developed for the coronavirus disease 2019 pandemic period and shared with the sites/Investigators. These recommendations will remain applicable after the end of the pandemic, especially the information regarding the post-infusion surveillance period. • To revise the text as per the current Sanofi protocol template to use the most updated wordings that are compliant with general guidance, including monitoring techniques. • To update the details regarding home infusion, to harmonize this text across the different studies included in the avalglucosidase alfa development program.

    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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