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    Clinical Trial Results:
    A Phase 3 Double-blind Randomized Study to Assess the Efficacy and Safety of Intravenous ATB200 Co-administered With Oral AT2221 in Adult Subjects With Late-onset Pompe Disease Compared With Alglucosidase Alfa/Placebo

    Summary
    EudraCT number
    		 2018-000755-40
    Trial protocol
    		 DE   DK   GB   SE   HU   BE   SK   ES   NL   BG   SI   GR   AT   IT  
    Global end of trial date
    15 Dec 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Dec 2021
    First version publication date
    16 Dec 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ATB200-03
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03729362
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amicus Therapeutics, Inc.
    Sponsor organisation address
    3675 Market Street, Philadelphia, PA , United States, 19104
    Public contact
    Patient advocacy, Amicus Therapeutics, Inc., 001 6096622000, clinicaltrials@amicusrx.com
    Scientific contact
    Patient advocacy, Amicus Therapeutics, Inc., 001 6096622000, clinicaltrials@amicusrx.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
    10 May 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Dec 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Dec 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective is to assess the efficacy of ATB200 (also known as cipaglucosidase alfa)/AT2221 (also known as miglustat) co-administration on ambulatory function, as measured by the 6-Minute Walk Test (6MWT), compared with alglucosidase alfa/placebo co-administration. Following completion of Study ATB200-03, participants had the option to enroll in a long-term extension study (Study ATB200-07, EudraCT Number: 2019-000954-67) and receive cipaglucosidase alfa/ miglustat treatment until regulatory approval, marketing authorization, commercialization, or study termination.
    Protection of trial subjects
    This study was conducted in accordance with International Council on Harmonisation (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the countries in which the study was conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Nov 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 4 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Slovakia: 1
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Denmark: 6
    Country: Number of subjects enrolled
    France: 11
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Greece: 1
    Country: Number of subjects enrolled
    Hungary: 7
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 2
    Country: Number of subjects enrolled
    Argentina: 1
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    United States: 37
    Country: Number of subjects enrolled
    Australia: 18
    Country: Number of subjects enrolled
    Japan: 6
    Country: Number of subjects enrolled
    Taiwan: 2
    Country: Number of subjects enrolled
    Korea, Republic of: 1
    Worldwide total number of subjects
    123
    EEA total number of subjects
    44
    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)
    109
    From 65 to 84 years
    14
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 123 participants were enrolled in the study and dosed at 62 clinical sites across 24 countries. Two participants were randomly assigned to the alglucosidase alfa/placebo group but never dosed because genotyping did not confirm diagnosis of Pompe disease.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cipaglucosidase Alfa/Miglustat
    Arm description
    		 Cipaglucosidase alfa co-administered with miglustat every 2 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cipaglucosidase Alfa
    Investigational medicinal product code
    Other name
    ATB200
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    20 milligram (mg)/kilogram (kg) intravenous (IV) infusion over a 4-hour duration every 2 weeks.

    Investigational medicinal product name
    Miglustat
    Investigational medicinal product code
    Other name
    AT2221
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Weight-based doses of 195 or 260 mg 1 hour prior to cipaglucosidase alfa infusion every 2 weeks.

    Arm title
    		 Alglucosidase Alfa/Placebo
    Arm description
    		 Alglucosidase alfa co-administered with placebo every 2 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Alglucosidase Alfa
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    20 mg/kg IV infusion over a 4-hour duration every 2 weeks.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Miglustat matching placebo was administered 1 hour prior to alglucosidase alfa infusion every 2 weeks.

    Number of subjects in period 1
    		Cipaglucosidase Alfa/Miglustat Alglucosidase Alfa/Placebo
    Started
    85
    38
    Received at Least 1 Dose of Study Drug
    85
    38
    Completed
    80
    37
    Not completed
    5
    1
         COVID-19 pandemic
    1
    -
         Discontinued due to COVID-19-related pneumonia
    1
    -
         Consent withdrawn by subject
    2
    -
         Investigator's decision
    1
    -
         Adverse event, non-fatal
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cipaglucosidase Alfa/Miglustat
    Reporting group description
    		 Cipaglucosidase alfa co-administered with miglustat every 2 weeks.

    Reporting group title
    Alglucosidase Alfa/Placebo
    Reporting group description
    		 Alglucosidase alfa co-administered with placebo every 2 weeks.

    Reporting group values
    		 Cipaglucosidase Alfa/Miglustat Alglucosidase Alfa/Placebo Total
    Number of subjects
    		 85 38 123
    Age categorical
    Units: Subjects
        ≥ 18 to < 35 years
    		 17 10 27
        ≥ 35 to < 50 years
    		 27 13 40
        ≥ 50 to < 65 years
    		 30 12 42
        ≥ 65 years
    		 11 3 14
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 47.6 ± 13.25 45.1 ± 13.30 -
    Gender categorical
    Units: Subjects
        Female
    		 49 18 67
        Male
    		 36 20 56
    Race
    Units: Subjects
        Asian
    		 3 1 4
        Japanese
    		 2 4 6
        American Indian or Alaska Native
    		 0 1 1
        Black or African American
    		 0 1 1
        Native Hawaiian or other Pacific Islander
    		 1 0 1
        White
    		 74 30 104
        Other
    		 5 1 6

    End points

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    End points reporting groups
    Reporting group title
    Cipaglucosidase Alfa/Miglustat
    Reporting group description
    		 Cipaglucosidase alfa co-administered with miglustat every 2 weeks.

    Reporting group title
    Alglucosidase Alfa/Placebo
    Reporting group description
    		 Alglucosidase alfa co-administered with placebo every 2 weeks.

    Subject analysis set title
    Cipaglucosidase Alfa/Miglustat
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All participants who received at least 1 dose of study drug (cipaglucosidase alfa/miglustat).

    Subject analysis set title
    Alglucosidase Alfa/Placebo
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All participants who received at least 1 dose of study drug (alglucosidase alfa/placebo).

    Subject analysis set title
    Cipaglucosidase Alfa/Miglustat (ITT-OBS)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The Intent-to-Treat (ITT)-observed (OBS) population consisted of all randomized participants who received at least 1 dose of study drug. Analyses used all available, observed data without imputation for missing post-baseline data. That is, missing data at Week 52 and at other visits were not replaced. An outlier participant was identified in the alglucosidase alfa/placebo group. Analysis excluding this participant was considered the primary analysis. All efficacy results in the ITT Population are presented excluding the 1 outlier participant.

    Subject analysis set title
    Alglucosidase Alfa/Placebo (ITT-OBS)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT-OBS population consisted of all randomized participants who received at least 1 dose of study drug. Analyses used all available, observed data without imputation for missing post-baseline data. That is, missing data at Week 52 and at other visits were not replaced. An outlier participant was identified in the alglucosidase alfa/placebo group. Analysis excluding this participant was considered the primary analysis. All efficacy results in the ITT Population are presented excluding the 1 outlier participant.

    Subject analysis set title
    Cipaglucosidase Alfa/Miglustat (ITT-LOCF)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT–Last Observation Carried Forward (ITT-LOCF) population consisted of all randomized participants who received at least 1 dose of study drug. Analyses used the LOCF method to replace missing data. An outlier participant was identified in the alglucosidase alfa/placebo group. Analysis excluding this participant was considered the primary analysis. All efficacy results in the ITT Population are presented excluding the 1 outlier participant.

    Subject analysis set title
    Alglucosidase Alfa/Placebo (ITT-LOCF)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT–Last Observation Carried Forward (ITT-LOCF) population consisted of all randomized participants who received at least 1 dose of study drug. Analyses used the LOCF method to replace missing data. An outlier participant was identified in the alglucosidase alfa/placebo group. Analysis excluding this participant was considered the primary analysis. All efficacy results in the ITT Population are presented excluding the 1 outlier participant.

    Subject analysis set title
    Cipaglucosidase Alfa
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Pharmacokinetic (PK) Population: Participants who were exposed to at least 1 dose of cipaglucosidase alfa and had at least 1 PK assessment.

    Subject analysis set title
    Alglucosidase Alfa
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    PK Population: Participants who were exposed to at least 1 dose of alglucosidase alfa and had at least 1 PK assessment.

    Subject analysis set title
    Miglustat
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    PK Population: Participants who were exposed to at least 1 dose of miglustat and had at least 1 PK assessment.

    Subject analysis set title
    Cipaglucosidase Alfa
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Immunogenicity Population: All participants who received at least 1 dose of cipaglucosidase alfa.

    Subject analysis set title
    Alglucosidase Alfa
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Immunogenicity Population: All participants who received at least 1 dose of alglucosidase alfa.

    Primary: Change From Baseline To Week 52 In 6 Minute Walk Distance (6MWD)

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    End point title
    		 Change From Baseline To Week 52 In 6 Minute Walk Distance (6MWD)
    End point description
    The efficacy of cipaglucosidase alfa/miglustat co-administration on ambulatory function was measured by the 6MWT. The 6MWD, measured in meters, is the distance walked on the 6MWT. A greater distance indicated greater endurance. An increase from baseline indicated improvement.
    End point type
    Primary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Cipaglucosidase Alfa/Miglustat (ITT-OBS) Alglucosidase Alfa/Placebo (ITT-OBS)
    Number of subjects analysed
    81
    36
    Units: meter
        least squares mean (standard error)
    21.31 ± 11.56
    7.10 ± 7.043
    Statistical analysis title
    		 Change From Baseline (CFBL) To Week 52 In 6MWD
    Statistical analysis description
    The primary and key secondary endpoints were tested in a hierarchical order as follows: The test for the primary endpoint was conducted first at the 1-sided 0.025 significance level, and if significant, the ordered key secondary endpoints were similarly tested. If at any point the null hypothesis for superiority failed to be rejected, then that comparison and any other comparison below it could not be claimed as successful and would be considered nominal.
    Comparison groups
    Cipaglucosidase Alfa/Miglustat (ITT-OBS) v Alglucosidase Alfa/Placebo (ITT-OBS)
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.048 [2]
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    14.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.6
         upper limit
    		 31.02
    Variability estimate
    Standard error of the mean
    Dispersion value
    8.481
    Notes
    [1] - Analysis used mixed-effect model for repeated measures (MMRM). The model included terms for treatment, baseline 6MWD, age, height, weight (all as continuous covariates), enzyme replacement therapy (ERT) status (ERT-naïve versus ERT-experienced), gender, time, and treatment-by-time interaction. Time was used as a repeated measure, and an unstructured covariance approach was applied.
    [2] - 1-sided significance level of 0.025.

    Secondary: Change From Baseline To Week 52 In Sitting Forced Vital Capacity (FVC; % predicted)

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    End point title
    		 Change From Baseline To Week 52 In Sitting Forced Vital Capacity (FVC; % predicted)
    End point description
    The efficacy of cipaglucosidase alfa/miglustat co-administration on pulmonary function was measured by sitting FVC (% predicted). FVC is a standard pulmonary function test used to quantify respiratory muscle weakness.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Cipaglucosidase Alfa/Miglustat (ITT-LOCF) Alglucosidase Alfa/Placebo (ITT-LOCF)
    Number of subjects analysed
    84
    37
    Units: score
        least squares mean (standard error)
    -1.04 ± 0.624
    -3.70 ± 0.953
    Statistical analysis title
    		 CFBL To Week 52 In Sitting FVC (% predicted)
    Statistical analysis description
    Change from baseline to Week 52 in sitting FVC was the first of 6 key secondary efficacy endpoints, which were analyzed according to a hierarchical order.
    Comparison groups
    Cipaglucosidase Alfa/Miglustat (ITT-LOCF) v Alglucosidase Alfa/Placebo (ITT-LOCF)
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.012 [4]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    2.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.37
         upper limit
    		 4.95
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.156
    Notes
    [3] - The analysis used an ANCOVA model adjusted for the baseline value (as a continuous covariate) and ERT status (ERT-naïve versus ERT-experienced), as well as baseline age, gender, baseline height, and baseline weight.
    [4] - 1-sided significance level of 0.025.

    Secondary: Change From Baseline To Week 52 In The Manual Muscle Test (MMT) Score For The Lower Extremities

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    End point title
    		 Change From Baseline To Week 52 In The Manual Muscle Test (MMT) Score For The Lower Extremities
    End point description
    The total score for the MMT lower extremity strength included the following 8 body parts: right/left hip flexion, right/left hip abduction, right/left knee flexion, and right/left knee extension. The MMT lower extremity score ranged from 0 to 40, with lower scores indicating weaker muscle strength. An increase from baseline indicated increased muscle strength.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Cipaglucosidase Alfa/Miglustat (ITT-LOCF) Alglucosidase Alfa/Placebo (ITT-LOCF)
    Number of subjects analysed
    80
    34
    Units: score on a scale
        least squares mean (standard error)
    1.64 ± 0.388
    0.68 ± 0.603
    Statistical analysis title
    		 CFBL To Week 52 In MMT Lower Extremity
    Statistical analysis description
    Change from baseline to Week 52 in the MMT score for the lower extremities was the second of 6 key secondary efficacy endpoints, which were analyzed according to a hierarchical order.
    Comparison groups
    Cipaglucosidase Alfa/Miglustat (ITT-LOCF) v Alglucosidase Alfa/Placebo (ITT-LOCF)
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.095 [6]
    Method
    		 ANCOVA
    Parameter type
    		 LS Means Difference
    Point estimate
    0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.48
         upper limit
    		 2.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.727
    Notes
    [5] - The analysis used an ANCOVA model adjusted for the baseline value (as a continuous covariate) and ERT status (ERT-naïve versus ERT-experienced), as well as baseline age, gender, baseline height, and baseline weight.
    [6] - 1-sided significance level of 0.025.

    Secondary: Change From Baseline To Week 26 In 6MWD

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    End point title
    		 Change From Baseline To Week 26 In 6MWD
    End point description
    The 6MWD, measured in meters, is the distance walked on the 6MWT.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    		 Cipaglucosidase Alfa/Miglustat (ITT-LOCF) Alglucosidase Alfa/Placebo (ITT-LOCF)
    Number of subjects analysed
    85
    37
    Units: meter
        least squares mean (standard error)
    16.45 ± 3.360
    8.28 ± 5.168
    Statistical analysis title
    		 CFBL To Week 26 In 6MWD
    Statistical analysis description
    Change from baseline to Week 26 in 6MWD was the third of 6 key secondary efficacy endpoints, which were analyzed according to a hierarchical order.
    Comparison groups
    Cipaglucosidase Alfa/Miglustat (ITT-LOCF) v Alglucosidase Alfa/Placebo (ITT-LOCF)
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.097 [8]
    Method
    		 ANCOVA
    Parameter type
    		 LS Means Difference
    Point estimate
    8.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.24
         upper limit
    		 20.57
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.261
    Notes
    [7] - The analysis used an ANCOVA model adjusted for the baseline value (as a continuous covariate) and ERT status (ERT-naïve versus ERT-experienced), as well as baseline age, gender, baseline height, and baseline weight.
    [8] - 1-sided significance level of 0.025.

    Secondary: Change From Baseline To Week 52 In The Total Score For The Patient-Reported Outcomes Measurement Information System (PROMIS®) – Physical Function

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    End point title
    		 Change From Baseline To Week 52 In The Total Score For The Patient-Reported Outcomes Measurement Information System (PROMIS®) – Physical Function
    End point description
    Physical Function Short Form 20a (v2.0) consisted of 20 questions. The first 14 questions were each scored on a scale from 1 to 5 as follows: 1 = unable to do; 2 = with much difficulty; 3 = with some difficulty; 4 = with a little difficulty; 5 = without any difficulty; the next 6 questions were each scored on a scale from 1 to 5 as follows: 1 = cannot do; 2 = quite a lot; 3 = somewhat; 4 = very little; 5 = not at all. The total score was calculated by summing up scores (1 to 5) across all items. A higher score represented better outcome.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Cipaglucosidase Alfa/Miglustat (ITT-LOCF) Alglucosidase Alfa/Placebo (ITT-LOCF)
    Number of subjects analysed
    84
    37
    Units: score on a scale
        least squares mean (standard error)
    1.98 ± 0.921
    0.11 ± 1.406
    Statistical analysis title
    		 CFBL To Week 52 In PROMIS® – Physical Function
    Statistical analysis description
    Change from baseline to Week 52 in the total score for the PROMIS® – Physical Function was the fourth of 6 key secondary efficacy endpoints, which were analyzed according to a hierarchical order.
    Comparison groups
    Cipaglucosidase Alfa/Miglustat (ITT-LOCF) v Alglucosidase Alfa/Placebo (ITT-LOCF)
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.138 [10]
    Method
    		 ANCOVA
    Parameter type
    		 LS Means Difference
    Point estimate
    1.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.51
         upper limit
    		 5.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.706
    Notes
    [9] - The analysis used an ANCOVA model adjusted for the baseline value (as a continuous covariate) and ERT status (ERT-naïve versus ERT-experienced), as well as baseline age, gender, baseline height, and baseline weight.
    [10] - 1-sided significance level of 0.025

    Secondary: Change From Baseline To Week 52 In The Total Score For The PROMIS® – Fatigue

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    End point title
    		 Change From Baseline To Week 52 In The Total Score For The PROMIS® – Fatigue
    End point description
    Fatigue Short Form 8a consisted of 6 questions, each scored on a scale from 1 to 5 as follows: 1 = not at all; 2 = a little bit; 3 = somewhat; 4 = quite a bit; 5 = very much; and 2 questions, each scored on a scale from 1 to 5 as follows: 1 = never; 2 = rarely; 3 = sometimes; 4 = often; 5 = always. The total score was calculated by summing up scores (1 to 5) across all items. A lower score represented lower fatigue symptoms.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Cipaglucosidase Alfa/Miglustat (ITT-LOCF) Alglucosidase Alfa/Placebo (ITT-LOCF)
    Number of subjects analysed
    85
    37
    Units: score on a scale
        least squares mean (standard error)
    -1.90 ± 0.585
    -1.94 ± 0.901
    Statistical analysis title
    		 CFBL To Week 52 In PROMIS® – Fatigue
    Statistical analysis description
    Change from baseline to Week 52 in the total score for the PROMIS® – Fatigue was the fifth of 6 key secondary efficacy endpoints, which were analyzed according to a hierarchical order.
    Comparison groups
    Cipaglucosidase Alfa/Miglustat (ITT-LOCF) v Alglucosidase Alfa/Placebo (ITT-LOCF)
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.515 [12]
    Method
    		 ANCOVA
    Parameter type
    		 LS Means Difference
    Point estimate
    0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.12
         upper limit
    		 2.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.092
    Notes
    [11] - The analysis used an ANCOVA model adjusted for the baseline value (as a continuous covariate) and ERT status (ERT-naïve versus ERT-experienced), as well as baseline age, gender, baseline height, and baseline weight.
    [12] - 1-sided significance level of 0.025.

    Secondary: Change From Baseline To Week 52 In The Total Score For The Gait, Stairs, Gowers’ Maneuver, And Chair (GSGC)

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    End point title
    		 Change From Baseline To Week 52 In The Total Score For The Gait, Stairs, Gowers’ Maneuver, And Chair (GSGC)
    End point description
    The GSGC consisted of a 10-meter walk for evaluation of gait, a 4-stair climb, Gowers' maneuver, and arising from a chair. Results of the GSGC included the time required to complete the individual tests, individual scores for each of the tests (1 to 7 points for each of gait, 4-stair climb, and Gowers' maneuver and 1 to 6 points for arising from a chair), and a total score. GSGC total score was the sum of the component scores from the 4 functional tests. The total score ranged from a minimum of 4 points (normal performance) to a maximum of 27 points (worst performance).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Cipaglucosidase Alfa/Miglustat (ITT-LOCF) Alglucosidase Alfa/Placebo (ITT-LOCF)
    Number of subjects analysed
    72
    30
    Units: score on a scale
        least squares mean (standard error)
    -0.567 ± 0.280
    0.847 ± 0.440
    Statistical analysis title
    		 CFBL To Week 52 In GSGC Total Score
    Statistical analysis description
    Change from baseline to Week 52 in the total score for the GSGC was the sixth of 6 key secondary efficacy endpoints, which were analyzed according to a hierarchical order.
    Comparison groups
    Cipaglucosidase Alfa/Miglustat (ITT-LOCF) v Alglucosidase Alfa/Placebo (ITT-LOCF)
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.004 [14]
    Method
    		 ANCOVA
    Parameter type
    		 LS Means Difference
    Point estimate
    -1.414
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.463
         upper limit
    		 -0.364
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.528
    Notes
    [13] - The analysis used an ANCOVA model adjusted for the baseline value (as a continuous covariate) and ERT status (ERT-naïve versus ERT-experienced), as well as baseline age, gender, baseline height, and baseline weight.
    [14] - 1-sided significance level of 0.025.

    Secondary: Change From Baseline To Week 52 In % Predicted 6MWD

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    End point title
    		 Change From Baseline To Week 52 In % Predicted 6MWD
    End point description
    The % predicted 6MWD = (actual 6MWD / predicted 6MWD) * 100. The predicted values were calculated using Enright And Sherrill 1998 Reference Equations.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Cipaglucosidase Alfa/Miglustat (ITT-LOCF) Alglucosidase Alfa/Placebo (ITT-LOCF)
    Number of subjects analysed
    85
    37
    Units: percentage
        least squares mean (standard error)
    4.039 ± 0.716
    1.655 ± 1.102
    No statistical analyses for this end point

    Secondary: Number Of Participants Improving On Both 6MWD And % Predicted FVC

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    End point title
    		 Number Of Participants Improving On Both 6MWD And % Predicted FVC
    End point description
    A composite subject-level response of the 2 relevant clinical outcomes, 6MWD and FVC (% predicted), was assessed. Prespecified thresholds were used for assessment of improvement consistent with published minimal clinically important difference values for comparable instruments in similar disease.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 Cipaglucosidase Alfa/Miglustat (ITT-OBS) Alglucosidase Alfa/Placebo (ITT-OBS)
    Number of subjects analysed
    85
    37
    Units: participants
    14
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline In the Time to Complete Individual GSGC Component Tests And Timed Up And Go (TUG) Test At Week 52

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    End point title
    		 Change From Baseline In the Time to Complete Individual GSGC Component Tests And Timed Up And Go (TUG) Test At Week 52
    End point description
    Motor function test assessed the time to complete individual GSGC component tests (10-meter walk, 4-stair climb, Gowers' maneuver, and arise from a chair) and the TUG test. The TUG test assessed the time a subject needed to rise from a chair, walk 3 meters, turn around, walk back to the chair, and sit down.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Cipaglucosidase Alfa/Miglustat (ITT-LOCF) Alglucosidase Alfa/Placebo (ITT-LOCF)
    Number of subjects analysed
    85
    37
    Units: seconds
    least squares mean (standard error)
        Time to complete the 10-meter walk
    -0.60 ± 0.631
    2.06 ± 0.967
        Time to complete the 4-stair climb
    -6.75 ± 0.851
    -3.61 ± 1.308
        Time to complete the Gowers' maneuver
    -0.36 ± 0.799
    -1.95 ± 1.281
        Time to arise from a chair
    -7.57 ± 0.409
    -6.75 ± 0.643
        Time to complete the timed up and go test
    -0.39 ± 0.768
    0.09 ± 1.217
    No statistical analyses for this end point

    Secondary: Change From Baseline To Week 52 In The Quantitative Muscle Test (QMT) Values (Kg)

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    End point title
    		 Change From Baseline To Week 52 In The Quantitative Muscle Test (QMT) Values (Kg)
    End point description
    QMT was measured using the hand-held dynamometer. Larger values (in kg) indicated greater muscle strength.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Cipaglucosidase Alfa/Miglustat (ITT-LOCF) Alglucosidase Alfa/Placebo (ITT-LOCF)
    Number of subjects analysed
    85
    37
    Units: kilogram
    least squares mean (standard error)
        QMT Value for the Upper Extremities
    1.839 ± 2.098
    -0.553 ± 3.195
        QMT Value for the Lower Extremities
    6.496 ± 3.185
    5.265 ± 4.854
        QMT Total Value
    8.195 ± 5.079
    5.198 ± 7.746
        QMT Value for the Proximal Muscle Group
    3.401 ± 2.920
    0.945 ± 4.477
    No statistical analyses for this end point

    Secondary: Change From Baseline To Week 52 In Other MMT Scores

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    End point title
    		 Change From Baseline To Week 52 In Other MMT Scores
    End point description
    Each manual muscle test was evaluated on a scoring scale from 0 to 5, as follows: 0 = no muscle movement; 1 = visible muscle movement, but no movement at the joint; 2 = movement at the joint, but not against gravity; 3 = movement against gravity, but not against added resistance; 4 = movement against resistance, but less than normal; 5 = normal strength. Upper extremity score was the sum of scores for right/left shoulder abduction, right/left shoulder adduction, right/left elbow extension, and right/left elbow flexion, with the total score ranging from 0 to 40. Proximal muscle group score was the sum of scores for right/left hip flexion, right/left hip abduction, right/left shoulder abduction, and right/left shoulder adduction, with the total score ranging from 0 to 40. MMT total score was the sum of the lower and upper extremity scores, and ranged from 0 to 80. Lower scores indicated lower overall muscle strength. An increase from baseline indicated improvement in muscle strength.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Cipaglucosidase Alfa/Miglustat (ITT-LOCF) Alglucosidase Alfa/Placebo (ITT-LOCF)
    Number of subjects analysed
    85
    37
    Units: Score on a scale
    least squares mean (standard error)
        MMT Upper Extremity Score
    1.54 ± 0.323
    0.60 ± 0.491
        MMT Total Score
    3.24 ± 0.622
    1.02 ± 0.966
        MMT Proximal Muscle Group Score
    1.82 ± 0.393
    0.70 ± 0.599
    No statistical analyses for this end point

    Secondary: Change From Baseline To Week 52 In Sitting Slow Vital Capacity (SVC) % Predicted

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    End point title
    		 Change From Baseline To Week 52 In Sitting Slow Vital Capacity (SVC) % Predicted
    End point description
    SVC is a standard pulmonary function test used to quantify respiratory muscle weakness.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Cipaglucosidase Alfa/Miglustat (ITT-LOCF) Alglucosidase Alfa/Placebo (ITT-LOCF)
    Number of subjects analysed
    83
    35
    Units: percentage
    least squares mean (standard error)
        Sitting % predicted SVC
    -2.527 ± 0.977
    -5.368 ± 1.527
    No statistical analyses for this end point

    Secondary: Change From Baseline To Week 52 In Maximum Vital Capacity (Maximum VC) % Predicted

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    End point title
    		 Change From Baseline To Week 52 In Maximum Vital Capacity (Maximum VC) % Predicted
    End point description
    Maximum VC is the greater of the two VC values (FVC or SVC).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Cipaglucosidase Alfa/Miglustat (ITT-LOCF) Alglucosidase Alfa/Placebo (ITT-LOCF)
    Number of subjects analysed
    84
    37
    Units: percentage
    least squares mean (standard error)
        % predicted maximum VC
    -1.286 ± 0.613
    -3.695 ± 0.936
    No statistical analyses for this end point

    Secondary: Change From Baseline To Week 52 In Maximal Inspiratory Pressure (MIP) % Predicted

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    End point title
    		 Change From Baseline To Week 52 In Maximal Inspiratory Pressure (MIP) % Predicted
    End point description
    The percent predicted values of MIP were calculated as: % predicted = (actual result / predicted result) * 100, where the predicted results were obtained using the reference equations from Uldry and Fitting (1995).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Cipaglucosidase Alfa/Miglustat (ITT-LOCF) Alglucosidase Alfa/Placebo (ITT-LOCF)
    Number of subjects analysed
    84
    37
    Units: percentage
    least squares mean (standard error)
        % predicted MIP
    1.89 ± 2.079
    -2.31 ± 3.178
    No statistical analyses for this end point

    Secondary: Change From Baseline To Week 52 In Maximal Expiratory Pressure (MEP) % Predicted

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    End point title
    		 Change From Baseline To Week 52 In Maximal Expiratory Pressure (MEP) % Predicted
    End point description
    The percent predicted values of MEP were calculated as: % predicted = (actual result / predicted result) * 100, where the predicted results were obtained using the reference equations from Uldry and Fitting (1995).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Cipaglucosidase Alfa/Miglustat (ITT-LOCF) Alglucosidase Alfa/Placebo (ITT-LOCF)
    Number of subjects analysed
    84
    37
    Units: percentage
    least squares mean (standard error)
        % predicted MEP
    0.51 ± 1.996
    -1.35 ± 3.052
    No statistical analyses for this end point

    Secondary: Change From Baseline To Week 52 In Sniff Nasal Inspiratory Pressure (SNIP) % Predicted

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    End point title
    		 Change From Baseline To Week 52 In Sniff Nasal Inspiratory Pressure (SNIP) % Predicted
    End point description
    The percent predicted values of SNIP were calculated as: % predicted = (actual result / predicted result) * 100, where the predicted results were obtained using the reference equations from Evans and Whitelaw (2009).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Cipaglucosidase Alfa/Miglustat (ITT-LOCF) Alglucosidase Alfa/Placebo (ITT-LOCF)
    Number of subjects analysed
    84
    37
    Units: percentage
    least squares mean (standard error)
        % predicted SNIP
    1.40 ± 1.918
    4.53 ± 2.929
    No statistical analyses for this end point

    Secondary: Change From Baseline To Week 52 In PROMIS-Dyspnea And Upper Extremities Total Scores

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    End point title
    		 Change From Baseline To Week 52 In PROMIS-Dyspnea And Upper Extremities Total Scores
    End point description
    The Upper Extremities Short Form 7a consisted of 7 items each scored on a decreasing scale from 1 to 5 as follows: 1 = unable to do; 2 = with much difficulty; 3 = with some difficulty; 4 = with a little difficulty; 5 = without any difficulty. Dyspnea Severity Short Form 10a consisted of 10 items each scored on a scale from 0 to 3 as follows: 0 = no shortness of breath; 1 = mildly short of breath; 2 = moderately short of breath; 3 = severely short of breath. A total score was generated for each instrument by adding up each item. A higher score for upper extremities represented improvement in symptoms. A lower score for dyspnea severity represented improvement in symptoms.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Cipaglucosidase Alfa/Miglustat (ITT-LOCF) Alglucosidase Alfa/Placebo (ITT-LOCF)
    Number of subjects analysed
    85
    37
    Units: Score on a scale
    least squares mean (standard error)
        PROMIS-Dyspnea Total Score
    -0.41 ± 0.426
    -1.50 ± 0.652
        PROMIS-Upper Extremities Total Score
    0.97 ± 0.545
    0.87 ± 0.833
    No statistical analyses for this end point

    Secondary: Change from Baseline To Week 52 In Rasch-Built Pompe-Specific Activity (R-PAct) Total Score

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    End point title
    		 Change from Baseline To Week 52 In Rasch-Built Pompe-Specific Activity (R-PAct) Total Score
    End point description
    The R-PAct scale was an 18-item questionnaire to measure limitations in activities and restriction in social participation. Possible responses to questions were as follows: unable to perform, able to perform, but with difficulty, and able to perform without difficulty. The total score was calculated by summing up the observed scores across the 18 items and it ranged from 0 to 36, with higher values representing lower level of disease impact on the muscles.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Cipaglucosidase Alfa/Miglustat (ITT-LOCF) Alglucosidase Alfa/Placebo (ITT-LOCF)
    Number of subjects analysed
    69
    33
    Units: Score on a scale
        least squares mean (standard error)
    0.04 ± 0.387
    0.51 ± 0.567
    No statistical analyses for this end point

    Secondary: Change From Baseline To Week 52 In European Quality Of Life-5 Dimensions 5 Response Levels (EQ-5D-5L) Based On The EuroQol Visual Analogue Scale (EQ VAS) Quantitative Score

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    End point title
    		 Change From Baseline To Week 52 In European Quality Of Life-5 Dimensions 5 Response Levels (EQ-5D-5L) Based On The EuroQol Visual Analogue Scale (EQ VAS) Quantitative Score
    End point description
    The EQ-5D-5L consisted of the EQ-5D descriptive system and the EQ VAS. Each of the 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) had 5 categorical responses/levels of perceived problems coded as follows: Level 1 = indicating no problem; Level 2 = indicating slight problems; Level 3 = indicating moderate problems; Level 4 = indicating severe problems; Level 5 = indicating extreme problems (for pain and anxiety) or indicating unable to (for mobility, self- care, and activity). The EQ VAS was a quantitative measure of health outcome that reflected the participants' own judgement. A lower score represented lower levels of perceived problems.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Cipaglucosidase Alfa/Miglustat (ITT-LOCF) Alglucosidase Alfa/Placebo (ITT-LOCF)
    Number of subjects analysed
    84
    36
    Units: Score on a scale
        least squares mean (standard error)
    0.03 ± 1.542
    3.61 ± 2.400
    No statistical analyses for this end point

    Secondary: Physician’s Global Impression Of Change (PGIC) Overall Status

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    End point title
    		 Physician’s Global Impression Of Change (PGIC) Overall Status
    End point description
    Physician’s Global Impression of Change is based on a single item that is scored on a 7-point rating scale ranging from 1 "very much worse" to 7 "very much improved". A tertiary response variable (improving, declining, stable) was defined as follows: “Improving”, which consisted of improved, moderately improved, and very much improved; “Declining”, which consisted of worse, moderately worse, and very much worse; and “Stable”, which equaled to no change.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 Cipaglucosidase Alfa/Miglustat (ITT-LOCF) Alglucosidase Alfa/Placebo (ITT-LOCF)
    Number of subjects analysed
    80
    36
    Units: participants
    number (not applicable)
        Improving
    31
    10
        Stable
    38
    16
        Declining
    11
    10
    No statistical analyses for this end point

    Secondary: Subject’s Global Impression Of Change (SGIC)

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    End point title
    		 Subject’s Global Impression Of Change (SGIC)
    End point description
    The SGIC is designed to record the participants' impression of their functional status since starting study drug using a 7-point scale ranging from 1 "very much worse" to 7 "very much improved". A tertiary response variable (improving, declining, stable) was defined as follows: “Improving”, which consisted of improved, moderately improved, and very much improved; “Declining”, which consisted of worse, moderately worse, and very much worse; and “Stable”, which equaled to no change.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 Cipaglucosidase Alfa/Miglustat (ITT-LOCF) Alglucosidase Alfa/Placebo (ITT-LOCF)
    Number of subjects analysed
    81
    36
    Units: participants
    number (not applicable)
        Improving
    36
    13
        Stable
    33
    12
        Declining
    12
    11
    No statistical analyses for this end point

    Secondary: Change From Baseline To Week 52 In Serum Creatine Kinase (CK) Level

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    End point title
    		 Change From Baseline To Week 52 In Serum Creatine Kinase (CK) Level
    End point description
    CK levels were measured as part of the serum chemistry panel.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Cipaglucosidase Alfa/Miglustat (ITT-LOCF) Alglucosidase Alfa/Placebo (ITT-LOCF)
    Number of subjects analysed
    85
    37
    Units: U/L
        arithmetic mean (standard deviation)
    -130.5 ± 231.18
    60.2 ± 159.49
    No statistical analyses for this end point

    Secondary: Change From Baseline To Week 52 In Urinary Hexose Tetrasaccharide (Hex4) Level

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    End point title
    		 Change From Baseline To Week 52 In Urinary Hexose Tetrasaccharide (Hex4) Level
    End point description
    Levels of urinary Hex4, a biomarker of disease substrate, were measured. The assay specifically targeted Hex4, the glucose tetrasaccharide Glc4, which was a biomarker of glycogen storage.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Cipaglucosidase Alfa/Miglustat (ITT-LOCF) Alglucosidase Alfa/Placebo (ITT-LOCF)
    Number of subjects analysed
    85
    37
    Units: mmol/mol creatinine
        arithmetic mean (standard deviation)
    -1.88 ± 2.380
    1.22 ± 4.432
    No statistical analyses for this end point

    Secondary: Population Pharmacokinetics (PK): Maximum Observed Concentration (Cmax) Of Cipaglucosidase Alfa And Alglucosidase Alfa In ERT-Experienced Participants Using Plasma Total GAA Protein Level By Signature Peptide Assay And Plasma Miglustat Concentration

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    End point title
    		 Population Pharmacokinetics (PK): Maximum Observed Concentration (Cmax) Of Cipaglucosidase Alfa And Alglucosidase Alfa In ERT-Experienced Participants Using Plasma Total GAA Protein Level By Signature Peptide Assay And Plasma Miglustat Concentration
    End point description
    On Days 1 and 364 (Week 52), sparse blood samples were collected for PK analysis in ERT-experienced participants at 0, 1, 4, 6, 12, and 24 hours post-dose. Collection of the 12-hour sample was optional.
    End point type
    Secondary
    End point timeframe
    Days 1 and 364 (Week 52)
    End point values
    		 Cipaglucosidase Alfa Alglucosidase Alfa
    Number of subjects analysed
    56 [15]
    26 [16]
    Units: μg/mL
    geometric mean (geometric coefficient of variation)
        Day 1
    280 ± 18.5
    289 ± 13.2
        Day 364
    293 ± 19.9
    283 ± 17.6
    Notes
    [15] - Day 1: n=56 Day 364: n=44
    [16] - Day 1: n=26 Day 364: n=21
    No statistical analyses for this end point

    Secondary: Population PK: Area Under The Concentration-Time Curve (AUC) Of Cipaglucosidase Alfa And Alglucosidase Alfa In ERT-Experienced Participants Using Plasma Total GAA Protein Level By Signature Peptide Assay And Plasma Miglustat Concentration

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    End point title
    		 Population PK: Area Under The Concentration-Time Curve (AUC) Of Cipaglucosidase Alfa And Alglucosidase Alfa In ERT-Experienced Participants Using Plasma Total GAA Protein Level By Signature Peptide Assay And Plasma Miglustat Concentration
    End point description
    On Days 1 and 364 (Week 52), sparse blood samples were collected for PK analysis in ERT-experienced participants at 0, 1, 4, 6, 12, and 24 hours post-dose. Collection of the 12-hour sample was optional.
    End point type
    Secondary
    End point timeframe
    Days 1 and 364 (Week 52)
    End point values
    		 Cipaglucosidase Alfa Alglucosidase Alfa
    Number of subjects analysed
    56 [17]
    26 [18]
    Units: μg·h/mL
    geometric mean (geometric coefficient of variation)
        Day 1
    1395 ± 21.5
    1700 ± 17.6
        Day 364
    1476 ± 21.8
    1688 ± 23.9
    Notes
    [17] - Day 1: n=56 Day 364: n=26
    [18] - Day 1: n=26 Day 364: n=21
    No statistical analyses for this end point

    Secondary: Population PK: Cmax Of Cipaglucosidase Alfa And Alglucosidase Alfa In ERT-Naïve Subjects

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    End point title
    		 Population PK: Cmax Of Cipaglucosidase Alfa And Alglucosidase Alfa In ERT-Naïve Subjects
    End point description
    On Days 1 and 364 (Week 52), sparse blood samples were collected for PK analysis in ERT-naïve participants at 0, 1, 4, 6, 12, and 24 hours post-dose. Collection of the 12-hour sample was optional.
    End point type
    Secondary
    End point timeframe
    Days 1 and 364 (Week 52)
    End point values
    		 Cipaglucosidase Alfa Alglucosidase Alfa
    Number of subjects analysed
    18 [19]
    7 [20]
    Units: μg/mL
    geometric mean (geometric coefficient of variation)
        Day 1
    273 ± 18.1
    342 ± 31.0
        Day 364
    290 ± 17.4
    359 ± 28.1
    Notes
    [19] - Day 1: n=18 Day 364: n=16
    [20] - Day 1: n=7 Day 364 n=7
    No statistical analyses for this end point

    Secondary: Population PK: AUC Of Cipaglucosidase Alfa And Alglucosidase Alfa In ERT-Naïve Subjects

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    End point title
    		 Population PK: AUC Of Cipaglucosidase Alfa And Alglucosidase Alfa In ERT-Naïve Subjects
    End point description
    On Days 1 and 364 (Week 52), sparse blood samples were collected for PK analysis in ERT-naïve participants at 0, 1, 4, 6, 12, and 24 hours post-dose. Collection of the 12-hour sample was optional.
    End point type
    Secondary
    End point timeframe
    Days 1 and 364 (Week 52)
    End point values
    		 Cipaglucosidase Alfa Alglucosidase Alfa
    Number of subjects analysed
    18 [21]
    7 [22]
    Units: μg·h/mL
    geometric mean (geometric coefficient of variation)
        Day 1
    1343 ± 25.7
    1859 ± 22.4
        Day 364
    1457 ± 19.2
    1964 ± 26.8
    Notes
    [21] - Day 1: n=18 Day 364: n=16
    [22] - Day 1: n=7 Day 364: n=7
    No statistical analyses for this end point

    Secondary: Noncompartmental Analysis: Cmax Of Plasma Total GAA Protein By Signature Peptide T09 in ERT-Naïve Subjects

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    End point title
    		 Noncompartmental Analysis: Cmax Of Plasma Total GAA Protein By Signature Peptide T09 in ERT-Naïve Subjects
    End point description
    A noncompartmental analysis was performed on ERT-naïve subjects, who underwent serial PK sampling during the study. On Day 1, serial blood samples were collected for ERT-naïve participants just prior to initiation of cipaglucosidase alfa/alglucosidase alfa infusion (time 0) and at 1, 2, 3, 3.5, 4, 4.5, 6, 8, 10, and 24 hours after the start of cipaglucosidase alfa/alglucosidase alfa infusion for plasma total human acid α-glucosidase (GAA) protein signature peptide T09 and plasma miglustat determinations.
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 Cipaglucosidase Alfa Alglucosidase Alfa Miglustat
    Number of subjects analysed
    12
    4
    12
    Units: μg/mL
        geometric mean (geometric coefficient of variation)
    260 ± 18.4
    364 ± 66.7
    2768 ± 30.8
    No statistical analyses for this end point

    Secondary: Noncompartmental Analysis: AUC From Time 0 (Predose) To The Time Of Last Quantifiable Concentration Of Plasma Total GAA Protein By Signature Peptide T09 In ERT-Naïve Subjects

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    End point title
    		 Noncompartmental Analysis: AUC From Time 0 (Predose) To The Time Of Last Quantifiable Concentration Of Plasma Total GAA Protein By Signature Peptide T09 In ERT-Naïve Subjects
    End point description
    A noncompartmental analysis was performed on ERT-naïve subjects, who underwent serial PK sampling during the study. On Day 1, serial blood samples were collected for ERT-naïve participants just prior to initiation of cipaglucosidase alfa/alglucosidase alfa infusion (time 0) and at 1, 2, 3, 3.5, 4, 4.5, 6, 8, 10, and 24 hours after the start of cipaglucosidase alfa/alglucosidase alfa infusion for plasma total GAA protein signature peptide T09 and plasma miglustat determinations.
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 Cipaglucosidase Alfa Alglucosidase Alfa Miglustat
    Number of subjects analysed
    12
    4
    12
    Units: μg·h/mL
        geometric mean (geometric coefficient of variation)
    1264 ± 28.9
    1656 ± 28.9
    20588 ± 36.8
    No statistical analyses for this end point

    Secondary: Comparison Of Cmax Of Cipaglucosidase Alfa In ERT-Experienced And ERT-Naïve Populations

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    End point title
    		 Comparison Of Cmax Of Cipaglucosidase Alfa In ERT-Experienced And ERT-Naïve Populations
    End point description
    On Days 1 and 364 (Week 52), sparse blood samples were collected for PK analysis at 0, 1, 4, 6, 12, and 24 hours post-dose. Collection of the 12-hour sample was optional. Data were combined for Days 1 and 364 (Week 52) and analyzed using ANOVA. Ratio of geometric LS mean (%) of the test (ERT-naïve) to the reference (ERT-experienced) and 90% confidence interval (CI) were calculated to assess bioequivalence. Bioequivalence criteria was met if the upper- and lower-bound 90% CIs were within 80% and 125%.
    End point type
    Secondary
    End point timeframe
    Days 1 and 364 (Week 52)
    End point values
    		 Cipaglucosidase Alfa
    Number of subjects analysed
    74
    Units: Ratio of geometric LS mean
        number (confidence interval 90%)
    98.0 (90.5 to 106.2)
    No statistical analyses for this end point

    Secondary: Comparison Of AUC Of Cipaglucosidase Alfa In ERT- Experienced And ERT-Naïve Populations

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    End point title
    		 Comparison Of AUC Of Cipaglucosidase Alfa In ERT- Experienced And ERT-Naïve Populations
    End point description
    On Days 1 and 364 (Week 52), sparse blood samples were collected for PK analysis at 0, 1, 4, 6, 12, and 24 hours post-dose. Collection of the 12-hour sample was optional. Data were combined for Days 1 and 364 (Week 52) and analyzed using ANOVA. Ratio of geometric LS mean (%) of the test (ERT-naïve) to the reference (ERT-experienced) and 90% CI were calculated to assess bioequivalence. Bioequivalence criteria was met if the upper- and lower-bound 90% CIs were within 80% and 125%.
    End point type
    Secondary
    End point timeframe
    Days 1 and 364 (Week 52)
    End point values
    		 Cipaglucosidase Alfa
    Number of subjects analysed
    74
    Units: Ratio of geometric LS mean
        number (confidence interval 90%)
    97.3 (88.1 to 106.2)
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment-Emergent Anti-Drug Antibodies (ADAs)

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    End point title
    		 Number of Participants With Treatment-Emergent Anti-Drug Antibodies (ADAs)
    End point description
    Treatment-emergent ADAs were defined as participants who had seroconverted or boosted their preexisting ADA during the study period.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    		 Cipaglucosidase Alfa Alglucosidase Alfa
    Number of subjects analysed
    65 [23]
    38 [24]
    Units: participants
    number (not applicable)
        ERT-experienced: Treatment-emergent ADAs
    31
    5
        ERT-naïve: Treatment-emergent ADAs
    19
    8
    Notes
    [23] - ERT-experienced: n=65 ERT-naïve: n=20
    [24] - ERT-experienced: n=30 ERT-naïve: n=8
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 (after dosing) through Week 52 and follow-up (30 days after last dose).
    Adverse event reporting additional description
    All participants who received at least 1 dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Cipaglucosidase Alfa/Miglustat
    Reporting group description
    		 -

    Reporting group title
    Alglucosidase Alfa/Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Cipaglucosidase Alfa/Miglustat Alglucosidase Alfa/Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 85 (9.41%)
    1 / 38 (2.63%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ilium fracture
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin laceration
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Removal of internal fixation
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactoid reaction
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Viral myositis
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cipaglucosidase Alfa/Miglustat Alglucosidase Alfa/Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    69 / 85 (81.18%)
    32 / 38 (84.21%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    5 / 85 (5.88%)
    3 / 38 (7.89%)
         occurrences all number
    10
    6
    Fall
         subjects affected / exposed
    25 / 85 (29.41%)
    15 / 38 (39.47%)
         occurrences all number
    70
    31
    Limb injury
         subjects affected / exposed
    3 / 85 (3.53%)
    2 / 38 (5.26%)
         occurrences all number
    4
    2
    Vascular disorders
    Hypertension
         subjects affected / exposed
    5 / 85 (5.88%)
    3 / 38 (7.89%)
         occurrences all number
    7
    3
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    1 / 85 (1.18%)
    2 / 38 (5.26%)
         occurrences all number
    1
    3
    Dizziness
         subjects affected / exposed
    8 / 85 (9.41%)
    3 / 38 (7.89%)
         occurrences all number
    10
    4
    Headache
         subjects affected / exposed
    20 / 85 (23.53%)
    9 / 38 (23.68%)
         occurrences all number
    49
    15
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 85 (1.18%)
    4 / 38 (10.53%)
         occurrences all number
    2
    4
    Fatigue
         subjects affected / exposed
    8 / 85 (9.41%)
    5 / 38 (13.16%)
         occurrences all number
    10
    7
    Infusion site bruising
         subjects affected / exposed
    1 / 85 (1.18%)
    2 / 38 (5.26%)
         occurrences all number
    1
    2
    Infusion site erythema
         subjects affected / exposed
    0 / 85 (0.00%)
    2 / 38 (5.26%)
         occurrences all number
    0
    2
    Pain
         subjects affected / exposed
    6 / 85 (7.06%)
    1 / 38 (2.63%)
         occurrences all number
    7
    1
    Pyrexia
         subjects affected / exposed
    6 / 85 (7.06%)
    1 / 38 (2.63%)
         occurrences all number
    9
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    5 / 85 (5.88%)
    2 / 38 (5.26%)
         occurrences all number
    7
    2
    Abdominal pain
         subjects affected / exposed
    2 / 85 (2.35%)
    3 / 38 (7.89%)
         occurrences all number
    2
    3
    Abdominal pain upper
         subjects affected / exposed
    4 / 85 (4.71%)
    3 / 38 (7.89%)
         occurrences all number
    11
    4
    Constipation
         subjects affected / exposed
    2 / 85 (2.35%)
    3 / 38 (7.89%)
         occurrences all number
    3
    3
    Diarrhoea
         subjects affected / exposed
    11 / 85 (12.94%)
    4 / 38 (10.53%)
         occurrences all number
    18
    4
    Dyspepsia
         subjects affected / exposed
    2 / 85 (2.35%)
    2 / 38 (5.26%)
         occurrences all number
    2
    2
    Flatulence
         subjects affected / exposed
    3 / 85 (3.53%)
    2 / 38 (5.26%)
         occurrences all number
    3
    2
    Nausea
         subjects affected / exposed
    10 / 85 (11.76%)
    8 / 38 (21.05%)
         occurrences all number
    14
    9
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    6 / 85 (7.06%)
    1 / 38 (2.63%)
         occurrences all number
    9
    1
    Nasal congestion
         subjects affected / exposed
    5 / 85 (5.88%)
    2 / 38 (5.26%)
         occurrences all number
    6
    2
    Oropharyngeal pain
         subjects affected / exposed
    10 / 85 (11.76%)
    2 / 38 (5.26%)
         occurrences all number
    13
    2
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    2 / 85 (2.35%)
    3 / 38 (7.89%)
         occurrences all number
    6
    3
    Rash
         subjects affected / exposed
    2 / 85 (2.35%)
    3 / 38 (7.89%)
         occurrences all number
    4
    3
    Skin lesion
         subjects affected / exposed
    0 / 85 (0.00%)
    2 / 38 (5.26%)
         occurrences all number
    0
    2
    Psychiatric disorders
    Panic attack
         subjects affected / exposed
    2 / 85 (2.35%)
    2 / 38 (5.26%)
         occurrences all number
    2
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    13 / 85 (15.29%)
    5 / 38 (13.16%)
         occurrences all number
    17
    6
    Back pain
         subjects affected / exposed
    9 / 85 (10.59%)
    7 / 38 (18.42%)
         occurrences all number
    13
    8
    Groin pain
         subjects affected / exposed
    1 / 85 (1.18%)
    2 / 38 (5.26%)
         occurrences all number
    1
    2
    Muscle spasms
         subjects affected / exposed
    8 / 85 (9.41%)
    1 / 38 (2.63%)
         occurrences all number
    10
    1
    Muscular weakness
         subjects affected / exposed
    3 / 85 (3.53%)
    5 / 38 (13.16%)
         occurrences all number
    4
    5
    Musculoskeletal pain
         subjects affected / exposed
    10 / 85 (11.76%)
    2 / 38 (5.26%)
         occurrences all number
    10
    2
    Myalgia
         subjects affected / exposed
    14 / 85 (16.47%)
    5 / 38 (13.16%)
         occurrences all number
    14
    9
    Pain in extremity
         subjects affected / exposed
    11 / 85 (12.94%)
    2 / 38 (5.26%)
         occurrences all number
    11
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    19 / 85 (22.35%)
    3 / 38 (7.89%)
         occurrences all number
    28
    3
    Pharyngitis
         subjects affected / exposed
    1 / 85 (1.18%)
    2 / 38 (5.26%)
         occurrences all number
    1
    2
    Rhinitis
         subjects affected / exposed
    6 / 85 (7.06%)
    2 / 38 (5.26%)
         occurrences all number
    8
    3
    Sinusitis
         subjects affected / exposed
    4 / 85 (4.71%)
    3 / 38 (7.89%)
         occurrences all number
    4
    3
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 85 (3.53%)
    6 / 38 (15.79%)
         occurrences all number
    3
    6
    Urinary tract infection
         subjects affected / exposed
    12 / 85 (14.12%)
    2 / 38 (5.26%)
         occurrences all number
    15
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Sep 2018
    • added sites and ERT-naïve participants to increase sample size and support an indication in all patients with LOPD • clarified the strength and number of capsules of miglustat and amount of cipaglucosidase alfa per vial • increased the duration of treatment • added the number of placebo capsules and amount of alglucosidase alfa per vial • updated interim statistical analyses to reflect changes in study design • changed the primary analysis from an intrasubject comparison to a between-group comparison per advice of the Food and Drug Administration (FDA) • identified key secondary objectives for hierarchical testing • updated results from Study ATB200-02 • revised primary objective to reflect change in study design • clarified definition of the final analysis • removed upper limit of the age restriction • broadened the FVC inclusion criterion • modified the screening criterion for 6MWD to be broader and less restrictive • updated other exclusion criteria, including the exclusion of previous gene therapy • clarified contraception guidance with respect to participants in the UK • clarified study drug storage criteria for global studies • removed restriction for registered pharmacist • allowed for an additional day to complete assessments • clarified assessments at infusions visits • separated ET visit from follow-up visit • clarified assessments during the follow-up period • specified collection of historical results for 6MWT, MMT, and FVC as available during the 5 years before the study • added body temperature assessment • replaced the FSS with EQ-5D-5L and added the PROMIS instrument for upper extremity • added MEP assessment • clarified that videotaping is optional • provided details about analysis of key secondary endpoints • updated study conduct considerations
    25 Jan 2019
    • changed the order of endpoints at the request of the FDA • added a PK substudy in ERT-naïve participants • increased the minimum number of ERT-naïve participants at the request of the FDA • reduced the minimum weight for inclusion • introduced new miglustat dosing guidelines based on participant weight • excluded participants with hypersensitivity to any of the excipients in cipaglucosidase alfa, alglucosidase alfa, or miglustat excluded participants without documentation of Pompe disease and who refused to undergo genetic testing • removed early study stopping and sample size re-estimation provisions in response to comments from the FDA • added the option for home infusions for participants meeting additional criteria • extended the follow-up period for immunogenicity at the request of the FDA • added criteria for the termination of the study at the request of the National Agency for the Safety of Medicines and Health Products (ANSM) • added monitoring of participants during and after the first 3 infusions at the request of the Danish Medicines Agency (DMA) • added sections on randomization, blinding, and unblinding at the request of the DMA and other European agencies • adjusted the collection of immunogenicity samples at the request of the FDA • adjusted scheduling of the Day -15 Screening Visit • revised the contraceptive requirements to align with Clinical Trial Facilitating Group recommendations • updated the severity ratings for AEs • revised which analyses will use the ITT and mITT Populations in response to comments from the FDA • updated the document to reflect additional data
    17 Aug 2020
    • updated the schedule of Screening Visits • added text due to COVID-19 • updated an exclusion criterion • revised acceptable contraception wording • revised study drug storage temperatures • removed incorrect text regarding ATB200 excipients • added footnote to the Schedule of Assessments to expand upon Week 52/ET visit details • updated schedule of screening visits • revised weeks for collection of blood samples for presence of rhGAA antibodies • revised text for doses based on body weight • defined fasting • revised the collection schedule for blood samples to test for presence of rhGAA Abs • updated the text on rescreening • modified the home infusion criteria to add eligibility for participants whose mild IAR could be controlled with medication • added windows for PK sample collection • revised and updated information regarding blood samples for genotyping for participant randomization • revised informed consent text

    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
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