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    Clinical Trial Results:
    A Phase 3/4 Prospective Study to Characterize the Pharmacokinetics of Alglucosidase Alfa in Patients with Pompe Disease

    Summary
    EudraCT number
    		 2010-022231-11
    Trial protocol
    		 DE   GB  
    Global end of trial date
    20 Nov 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Jun 2021
    First version publication date
    02 Jun 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AGLU07710
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01410890
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Genzyme, a Sanofi Company
    Sponsor organisation address
    500 Kendall Street, Cambridge, United States, 02142
    Public contact
    Trial Transparency Team, Genzyme, a Sanofi Company, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Genzyme, a Sanofi Company, 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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    16 Dec 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Nov 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To characterise the pharmacokinetics (PK) of alglucosidase alfa manufactured at the 4000 L scale in subjects who had a confirmed diagnosis of Pompe disease.
    Protection of trial subjects
    The study was conducted by investigators experienced in the treatment of paediatric and adult subjects. 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
    		 -
    Actual start date of recruitment
    03 Nov 2014
    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
    United Kingdom: 6
    Country: Number of subjects enrolled
    Bulgaria: 1
    Country: Number of subjects enrolled
    India: 4
    Country: Number of subjects enrolled
    Russian Federation: 2
    Country: Number of subjects enrolled
    Ukraine: 2
    Country: Number of subjects enrolled
    United States: 6
    Worldwide total number of subjects
    21
    EEA total number of subjects
    1
    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)
    2
    Children (2-11 years)
    7
    Adolescents (12-17 years)
    1
    Adults (18-64 years)
    11
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 12 sites in 6 countries. A total of 27 subjects were screened between 03-Nov-2014 and 23-Sep-2020, of whom 6 subjects were screen failures and 21 subjects were enrolled in the study.

    Pre-assignment
    Screening details
    		 Out of 21 subjects, 1 subject signed the informed consent, but due to health status did not continue in the study to the treatment visit.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Alglucosidase Alfa: <18 Years
    Arm description
    		 Subjects with less than (<) 18 years of age received intravenous (IV) infusion of Alglucosidase alfa 20 milligrams per kilogram (mg/kg) body weight on Day 1. Infusion was administered at an initial rate of approximately 1 milligrams per kilogram per hour (mg/kg/hr) with allowed rate increased of 2 mg/kg/hr every 30 minutes, if there were no signs of infusion-associated reactions (IARs), until a maximum rate of approximately 7 mg/kg/hr was reached.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alglucosidase Alfa
    Investigational medicinal product code
    GZ419829
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single IV infusion of Alglucosidase alfa 20 mg/kg body weight on Day 1.

    Arm title
    		 Alglucosidase Alfa: >=18 Years
    Arm description
    		 Subjects with greater than or equal to (>=) 18 years of age received IV infusion of Alglucosidase alfa 20 mg/kg body weight on Day 1. Infusion was administered at an initial rate of approximately 1 mg/kg/hr with allowed rate increased of 2 mg/kg/hr every 30 minutes, if there were no signs of IARs, until a maximum rate of approximately 7 mg/kg/hr was reached.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alglucosidase Alfa
    Investigational medicinal product code
    GZ419829
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single IV infusion of Alglucosidase alfa 20 mg/kg body weight on Day 1.

    Number of subjects in period 1 [1]
    		Alglucosidase Alfa: <18 Years Alglucosidase Alfa: >=18 Years
    Started
    10
    10
    Treated
    10
    10
    Completed
    10
    10
    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 subject signed the informed consent, but due to health status did not continue in the study to the treatment visit.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Alglucosidase Alfa: <18 Years
    Reporting group description
    		 Subjects with less than (<) 18 years of age received intravenous (IV) infusion of Alglucosidase alfa 20 milligrams per kilogram (mg/kg) body weight on Day 1. Infusion was administered at an initial rate of approximately 1 milligrams per kilogram per hour (mg/kg/hr) with allowed rate increased of 2 mg/kg/hr every 30 minutes, if there were no signs of infusion-associated reactions (IARs), until a maximum rate of approximately 7 mg/kg/hr was reached.

    Reporting group title
    Alglucosidase Alfa: >=18 Years
    Reporting group description
    		 Subjects with greater than or equal to (>=) 18 years of age received IV infusion of Alglucosidase alfa 20 mg/kg body weight on Day 1. Infusion was administered at an initial rate of approximately 1 mg/kg/hr with allowed rate increased of 2 mg/kg/hr every 30 minutes, if there were no signs of IARs, until a maximum rate of approximately 7 mg/kg/hr was reached.

    Reporting group values
    		 Alglucosidase Alfa: <18 Years Alglucosidase Alfa: >=18 Years Total
    Number of subjects
    		 10 10 20
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 5.1 ( 3.95 ) 41.8 ( 12.44 ) -
    Gender categorical
    Units: Subjects
        Female
    		 5 2 7
        Male
    		 5 8 13
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 1 1 2
        Not Hispanic or Latino
    		 6 8 14
        Unknown or Not Reported
    		 3 1 4
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 3 1 4
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 5 9 14
        More than one race
    		 2 0 2
        Unknown or Not Reported
    		 0 0 0
    Anti-Recombinant Human Acid Alpha-Glucosidase (rhGAA) Immunoglobulin G (IgG) Antibody Status
    Positive antibody status indicated presence of anti-rhGAA IgG antibodies and negative antibody status indicated absence of anti-rhGAA IgG antibodies.
    Units: Subjects
        Positive
    		 3 4 7
        Negative
    		 6 6 12
        Missing
    		 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Alglucosidase Alfa: <18 Years
    Reporting group description
    		 Subjects with less than (<) 18 years of age received intravenous (IV) infusion of Alglucosidase alfa 20 milligrams per kilogram (mg/kg) body weight on Day 1. Infusion was administered at an initial rate of approximately 1 milligrams per kilogram per hour (mg/kg/hr) with allowed rate increased of 2 mg/kg/hr every 30 minutes, if there were no signs of infusion-associated reactions (IARs), until a maximum rate of approximately 7 mg/kg/hr was reached.

    Reporting group title
    Alglucosidase Alfa: >=18 Years
    Reporting group description
    		 Subjects with greater than or equal to (>=) 18 years of age received IV infusion of Alglucosidase alfa 20 mg/kg body weight on Day 1. Infusion was administered at an initial rate of approximately 1 mg/kg/hr with allowed rate increased of 2 mg/kg/hr every 30 minutes, if there were no signs of IARs, until a maximum rate of approximately 7 mg/kg/hr was reached.

    Subject analysis set title
    Anti-rhGAA Antibody Negative Subjects
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects with negative anti-rhGAA IgG antibody status at Baseline received IV infusion of Alglucosidase alfa 20 mg/kg body weight on Day 1. Infusion was administered at an initial rate of approximately 1 mg/kg/hr with allowed rate increased of 2 mg/kg/hr every 30 minutes, if there were no signs of IARs, until a maximum rate of approximately 7 mg/kg/hr was reached.

    Subject analysis set title
    Anti-rhGAA Antibody Positive Subjects
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects with positive anti-rhGAA IgG antibody status at Baseline received IV infusion of Alglucosidase alfa 20 mg/kg body weight on Day 1. Infusion was administered at an initial rate of approximately 1 mg/kg/hr with allowed rate increased of 2 mg/kg/hr every 30 minutes, if there were no signs of IARs, until a maximum rate of approximately 7 mg/kg/hr was reached.

    Primary: Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of Alglucosidase Alfa

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    End point title
    		 Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of Alglucosidase Alfa [1]
    End point description
    Cmax was defined as maximum observed plasma concentration. Analysis was performed on all subjects who received any amount of alglucosidase alfa.
    End point type
    Primary
    End point timeframe
    Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    		 Alglucosidase Alfa: <18 Years Alglucosidase Alfa: >=18 Years
    Number of subjects analysed
    10
    10
    Units: nanograms per millilitre (ng/mL)
        arithmetic mean (standard deviation)
    204000 ( 94600 )
    307000 ( 143000 )
    No statistical analyses for this end point

    Primary: Pharmacokinetics: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Alglucosidase Alfa

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    End point title
    		 Pharmacokinetics: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Alglucosidase Alfa [2]
    End point description
    Tmax was defined as time to reach maximum observed plasma concentration. Analysis was performed on all subjects who received any amount of alglucosidase alfa.
    End point type
    Primary
    End point timeframe
    Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    		 Alglucosidase Alfa: <18 Years Alglucosidase Alfa: >=18 Years
    Number of subjects analysed
    10
    10
    Units: hours
        median (full range (min-max))
    4.23 (1.92 to 6.42)
    3.85 (1.42 to 5.33)
    No statistical analyses for this end point

    Primary: Pharmacokinetics: Area Under the Plasma Concentration-Time Curve (AUC) of Alglucosidase Alfa

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    End point title
    		 Pharmacokinetics: Area Under the Plasma Concentration-Time Curve (AUC) of Alglucosidase Alfa [3]
    End point description
    AUC was defined as area under the plasma concentration-time curve from time 0 to 24 hours post-dose. Analysis was performed on all subjects who received any amount of alglucosidase alfa.
    End point type
    Primary
    End point timeframe
    Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    		 Alglucosidase Alfa: <18 Years Alglucosidase Alfa: >=18 Years
    Number of subjects analysed
    10
    10
    Units: hours per nanograms per milliliter
        arithmetic mean (standard deviation)
    1110000 ( 753000 )
    1890000 ( 969000 )
    No statistical analyses for this end point

    Primary: Pharmacokinetics: Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) of Alglucosidase Alfa

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    End point title
    		 Pharmacokinetics: Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) of Alglucosidase Alfa [4]
    End point description
    AUC0-last was defined as area under the concentration-time curve from time 0 to the time of the last quantifiable concentration. Analysis was performed on all subjects who received any amount of alglucosidase alfa.
    End point type
    Primary
    End point timeframe
    Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    		 Alglucosidase Alfa: <18 Years Alglucosidase Alfa: >=18 Years
    Number of subjects analysed
    10
    10
    Units: hours per nanograms per milliliter
        arithmetic mean (standard deviation)
    1040000 ( 590000 )
    1840000 ( 901000 )
    No statistical analyses for this end point

    Primary: Pharmacokinetics: Terminal Elimination Half-life (T1/2) of Alglucosidase Alfa

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    End point title
    		 Pharmacokinetics: Terminal Elimination Half-life (T1/2) of Alglucosidase Alfa [5]
    End point description
    T1/2 was defined as the time taken by drug to reduce to half of its initial plasma concentration. Analysis was performed on all subjects who received any amount of alglucosidase alfa.
    End point type
    Primary
    End point timeframe
    Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    		 Alglucosidase Alfa: <18 Years Alglucosidase Alfa: >=18 Years
    Number of subjects analysed
    10
    10
    Units: hours
        arithmetic mean (standard deviation)
    5.43 ( 3.82 )
    3.84 ( 0.801 )
    No statistical analyses for this end point

    Primary: Pharmacokinetics: Total Systemic Clearance (CL) of Alglucosidase Alfa

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    End point title
    		 Pharmacokinetics: Total Systemic Clearance (CL) of Alglucosidase Alfa [6]
    End point description
    CL of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Analysis was performed on all subjects who received any amount of alglucosidase alfa.
    End point type
    Primary
    End point timeframe
    Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    		 Alglucosidase Alfa: <18 Years Alglucosidase Alfa: >=18 Years
    Number of subjects analysed
    10
    10
    Units: Litres per hour
        arithmetic mean (standard deviation)
    0.529 ( 0.613 )
    1.26 ( 1.24 )
    No statistical analyses for this end point

    Primary: Pharmacokinetics: Volume of Distribution at Steady State (Vss) of Alglucosidase Alfa

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    End point title
    		 Pharmacokinetics: Volume of Distribution at Steady State (Vss) of Alglucosidase Alfa [7]
    End point description
    Volume of distribution (Vd) is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss is the apparent volume of distribution at steady-state. Analysis was performed on all subjects who received any amount of alglucosidase alfa.
    End point type
    Primary
    End point timeframe
    Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    		 Alglucosidase Alfa: <18 Years Alglucosidase Alfa: >=18 Years
    Number of subjects analysed
    10
    10
    Units: Litres
        arithmetic mean (standard deviation)
    2.35 ( 2.02 )
    5.59 ( 3.72 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Maximum Observed Plasma Concentration of Alglucosidase Alfa in Anti-Recombinant Human Acid Alpha-Glucosidase Antibody Positive and Negative Subjects

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    End point title
    		 Pharmacokinetics: Maximum Observed Plasma Concentration of Alglucosidase Alfa in Anti-Recombinant Human Acid Alpha-Glucosidase Antibody Positive and Negative Subjects
    End point description
    Cmax was defined as maximum observed plasma concentration. Analysis was performed on full analysis set (FAS) that included subjects who received any amount of alglucosidase alfa. Here, number of subjects analysed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1
    End point values
    		 Anti-rhGAA Antibody Negative Subjects Anti-rhGAA Antibody Positive Subjects
    Number of subjects analysed
    12
    7
    Units: ng/mL
        arithmetic mean (standard deviation)
    256000 ( 121000 )
    262000 ( 160000 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Time to Reach Maximum Observed Plasma Concentration in Anti-rhGAA Antibody Positive and Negative Subjects

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    End point title
    		 Pharmacokinetics: Time to Reach Maximum Observed Plasma Concentration in Anti-rhGAA Antibody Positive and Negative Subjects
    End point description
    Tmax was defined as time to reach maximum observed plasma concentration. Analysis was performed on FAS that included all subjects who received any amount of alglucosidase alfa. Here, number of subjects analysed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1
    End point values
    		 Anti-rhGAA Antibody Negative Subjects Anti-rhGAA Antibody Positive Subjects
    Number of subjects analysed
    12
    7
    Units: hours
        median (full range (min-max))
    3.94 (1.92 to 5.27)
    4.33 (1.42 to 6.42)
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Terminal Elimination Half-life of Alglucosidase Alfa in Anti-rhGAA Antibody Positive and Negative Subjects

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    End point title
    		 Pharmacokinetics: Terminal Elimination Half-life of Alglucosidase Alfa in Anti-rhGAA Antibody Positive and Negative Subjects
    End point description
    T1/2 was defined as the time taken by drug to reduce to half of its initial plasma concentration. Analysis was performed on FAS that included subjects who received any amount of alglucosidase alfa. Here, number of subjects analysed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1
    End point values
    		 Anti-rhGAA Antibody Negative Subjects Anti-rhGAA Antibody Positive Subjects
    Number of subjects analysed
    12
    7
    Units: hours
        arithmetic mean (standard deviation)
    4.68 ( 2.95 )
    4.79 ( 2.93 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration of Alglucosidase Alfa in Anti-rhGAA Antibody Positive and Negative Subjects

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    End point title
    		 Pharmacokinetics: Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration of Alglucosidase Alfa in Anti-rhGAA Antibody Positive and Negative Subjects
    End point description
    AUC0-last was defined as area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration. Analysis was performed on FAS that included subjects who received any amount of alglucosidase alfa. Here, number of subjects analysed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1
    End point values
    		 Anti-rhGAA Antibody Negative Subjects Anti-rhGAA Antibody Positive Subjects
    Number of subjects analysed
    12
    7
    Units: hours per nanograms per milliliter
        arithmetic mean (standard deviation)
    1410000 ( 865000 )
    1610000 ( 86800 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Area Under the Concentration-time Curve From Time 0 and Extrapolated to Infinite Time (AUC0-inf) in Anti-rhGAA Antibody Positive and Negative Subjects

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    End point title
    		 Pharmacokinetics: Area Under the Concentration-time Curve From Time 0 and Extrapolated to Infinite Time (AUC0-inf) in Anti-rhGAA Antibody Positive and Negative Subjects
    End point description
    AUC0-inf was defined as area under the concentration-time curve from time 0 extrapolated to infinite time. Analysis was performed on FAS that included subjects who received any amount of alglucosidase alfa. Here, number of subjects analysed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1
    End point values
    		 Anti-rhGAA Antibody Negative Subjects Anti-rhGAA Antibody Positive Subjects
    Number of subjects analysed
    12
    7
    Units: hours per nanograms per milliliter
        arithmetic mean (standard deviation)
    1450000 ( 941000 )
    1700000 ( 985000 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Total Systemic Clearance in Anti-rhGAA Antibody Positive and Negative Subjects

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    End point title
    		 Pharmacokinetics: Total Systemic Clearance in Anti-rhGAA Antibody Positive and Negative Subjects
    End point description
    CL of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Analysis was performed on FAS that included subjects who received any amount of alglucosidase alfa. Here, number of subjects analysed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1
    End point values
    		 Anti-rhGAA Antibody Negative Subjects Anti-rhGAA Antibody Positive Subjects
    Number of subjects analysed
    12
    7
    Units: Litres per hour
        arithmetic mean (standard deviation)
    0.765 ( 0.518 )
    1.21 ( 1.60 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Volume of Distribution in Anti-rhGAA Antibody Positive and Negative Subjects

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    End point title
    		 Pharmacokinetics: Volume of Distribution in Anti-rhGAA Antibody Positive and Negative Subjects
    End point description
    Vd is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss is the apparent volume of distribution at steady-state. Analysis was performed on FAS that included subjects who received any amount of alglucosidase alfa. Here, number of subjects analysed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Pre-dose and at 1, 2, 4, 8, 12, and 24 hours Post-dose on Day 1
    End point values
    		 Anti-rhGAA Antibody Negative Subjects Anti-rhGAA Antibody Positive Subjects
    Number of subjects analysed
    12
    7
    Units: Litres
        arithmetic mean (standard deviation)
    5.82 ( 6.49 )
    7.26 ( 9.16 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AEs) were collected from signature of the informed consent form up to Week 4.
    Adverse event reporting additional description
    Reported AEs and deaths were treatment-emergent (TEAEs) that developed/worsened in grade/became serious during 'TEAE period' (i.e., from signature of the informed consent form up to Week 4. Analysis was performed on FAS that included all subjects who received any amount of alglucosidase alfa.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Alglucosidase Alfa: <18 Years
    Reporting group description
    		 Subjects with <18 years of age received IV infusion of Alglucosidase alfa 20 mg/kg body weight on Day 1. Infusion was administered at an initial rate of approximately 1 mg/kg/hr with allowed rate increased of 2 mg/kg/hr every 30 minutes, if there were no signs of IARs, until a maximum rate of approximately 7 mg/kg/hr was reached.

    Reporting group title
    Alglucosidase Alfa: >=18 Years
    Reporting group description
    		 Subjects with >=18 years of age received IV infusion of Alglucosidase alfa 20 mg/kg body weight on Day 1. Infusion was administered at an initial rate of approximately 1 mg/kg/hr with allowed rate increased of 2 mg/kg/hr every 30 minutes, if there were no signs of IARs, until a maximum rate of approximately 7 mg/kg/hr was reached.

    Serious adverse events
    		 Alglucosidase Alfa: <18 Years Alglucosidase Alfa: >=18 Years
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Respiratory Distress
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    		 Alglucosidase Alfa: <18 Years Alglucosidase Alfa: >=18 Years
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 10 (40.00%)
    3 / 10 (30.00%)
    Investigations
    Blood Pressure Increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Body Temperature Increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Pyrexia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Papule
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Urticaria
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    Musculoskeletal and connective tissue disorders
    Osteoporosis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Pain In Extremity
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Infections and infestations
    Fungal Skin Infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    Rhinitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 May 2011
    Following changes were made: Updated study personnel information; clarified the timing of the 30-day follow-up visit, which was the subjects last study visit; updated language for contraception requirements and pregnancy testing for consistency within the protocol and added urine pregnancy tests and use of contraception; reevaluated sample assay requirements to minimise burden on subjects. The PK sampling timepoints were extended out to 48 hours after the end of infusion to increase assurance of characterising the half-life of the second phase of the alglucosidase alfa concentration-time curve. Adjusted PK sampling timepoints to include samples immediately before each scheduled infusion rate change to make sure the true Cmax was not missed; unified text with language of approved label, where applicable; added text that dose increase and dose reduction was not permitted unless it was due to an AE; standardised collection of complete medical history and surgical procedure information; clarified that additional testing was needed only for IARs suggestive of hypersensitivity reactions. Window for testing was expanded based on experience across the program; revised the schedule of assessments to allow sufficient time between the last study infusion and last study IgG assessment to see if there was a change in IgG titer. Required that the follow-up visit be an office visit to allow collection of an IgG sample.
    17 Dec 2015
    Following changes were made: Modified inclusion criteria to remove the upper age limit of 18 years as a means to remedy the unsatisfactory number of subjects enrolled to date. Approximately 10 subjects <18 years old and 10 subjects >=18 years old was the target for enrollment; inclusion criteria was added and exclusion criteria was deleted to allow inclusion of subjects previously treated with alglucosidase alfa for at least 6 months; reduced number of infusions from 14 to 1, reducing study duration from approximately 30 weeks to approximately 4 to 9 weeks to enhance subjects recruitment into the study; limited collection of blood samples for PK assessment to infusion Day 1 and samples at 30, 36, 42, and 48 hours after the end of infusion were eliminated to enhance subjects recruitment into the study; eliminated determination of the exploratory biomarker urine hex4 level as a consequence of the reduced study duration; eliminated exploratory assessment of GAA activity in dried blood spot with the more focused emphasis on PK and immunology assessment.
    18 Jul 2016
    Following changes were made: modified Inclusion criteria to remove the lower age limit of 8 years of age to add the possibility to characterise PK in subjects <8 years old. Approximately 10 subjects <18 years old and 10 subjects >=18 years old remained the target for enrollment.

    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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