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    Clinical Trial Results:
    An Exploratory Study of the Safety and Efficacy of Immune Tolerance Induction (ITI) in Subjects with Pompe Disease Who Have Previously Received Myozyme

    Summary
    EudraCT number
    2015-000583-34
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    18 Feb 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    08 Aug 2020
    First version publication date
    08 Aug 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AGLU03707_MSC12817
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00701701
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Genzyme, a Sanofi company
    Sponsor organisation address
    50 Binney St, Cambridge, MA, United States, 02142
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    22 Jan 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Feb 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the safety of ITI regimens, as assessed by the incidence of adverse events (AEs), serious adverse events (SAEs), and clinical laboratory abnormalities.
    Protection of trial subjects
    The study was conducted by investigators experienced in the treatment of pediatric 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 may have been used to minimise distress and discomfort.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    14 Dec 2008
    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 States: 3
    Country: Number of subjects enrolled
    Israel: 1
    Worldwide total number of subjects
    4
    EEA total number of subjects
    0
    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)
    2
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted in 2 countries. A total of 5 subjects were screened between 14 December 2008 and 17 August 2010 (dates when first subject and last subject signed informed consent), of which one subject died before enrollment.

    Pre-assignment
    Screening details
    A total of 4 subjects were included and treated in this study. Subjects were assigned to either Regimen A or Regimen B.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Regimen A: Alglucosidase alfa and Cyclophosphamide
    Arm description
    Subjects exhibiting clinical decline since starting alglucosidase alfa (Myozyme®) therapy and had inhibitory antibodies and/or a sustained high recombinant human acid alpha-glucosidase (rhGAA) antibody titer (defined as at least 2 titers greater than or equal to (>=) 25,600 obtained at least 1 month apart), regardless of their cross-reacting immunologic material (CRIM ) status, were assigned to Regimen A. Subjects received alglucosidase alfa (Myozyme®) Intravenous (IV) infusion of 20 milligram per kilogram (mg/kg) every other week (qow) for a minimum of 18 months or, until the subject reaches the age of 2 years (if the subject was less than (<6) months of age at the time of enrolment). In addition, cyclophosphamide 250 milligram per square meter (mg/m^2) IV infusion was administered every 4 weeks after Myozyme® infusion for 6 months.
    Arm type
    Experimental

    Investigational medicinal product name
    Alglucosidase alfa
    Investigational medicinal product code
    Other name
    Myozyme®
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Alglucosidase alfa (Myozyme®) 20 mg/kg IV infusion qow. Alglucosidase alfa (Myozyme®) was infused in a dedicated IV line. The length of infusion was approximately 3.5 to 4 hours for a dose of 20 mg/kg.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cyclophosphamide 250 mg/m^2 administered IV every 4 weeks.

    Arm title
    Regimen B: Alglucosidase alfa, Rituximab and Methotrexate
    Arm description
    CRIM-negative subjects were assigned to Regimen B if they either (1) exhibited clinical decline since starting alglucosidase alfa (Myozyme®)therapy and did not have inhibitory antibodies and/or a sustained rhGAA antibody titer (defined as at least 2 titers >=25,600 obtained at least 1 month apart),or (2) did not exhibit clinical decline since starting alglucosidase alfa (Myozyme®) therapy, regardless of their anti-rhGAA or inhibitory antibody status. Regimen B subjects with CRIM-negative status received alglucosidase alfa (Myozyme®) IV infusion of 20 mg/kg qow for a minimum of 18 months or, until subject reaches the age of 2 years (if subject was <6 months of age at time of enrolment). In addition, rituximab 375 mg/m^2 IV was administered weekly beginning the day after Myozyme® infusion for 4 weeks (an optional 2nd cycle might be administered at the discretion of the investigator) and biweekly methotrexate 15 mg/m^2 subcutaneous on the day after Myozyme® infusion for 6 months.
    Arm type
    Experimental

    Investigational medicinal product name
    Alglucosidase alfa
    Investigational medicinal product code
    Other name
    Myozyme®
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Alglucosidase alfa (Myozyme®) 20 mg/kg IV infusion qow. Alglucosidase alfa (Myozyme®) was infused in a dedicated IV line. The length of infusion was approximately 3.5 to 4 hours for a dose of 20 mg/kg.

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab 375 mg/m^2 IV administered weekly.

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Methotrexate 15 mg/m^2 subcutaneous every other week.

    Number of subjects in period 1
    Regimen A: Alglucosidase alfa and Cyclophosphamide Regimen B: Alglucosidase alfa, Rituximab and Methotrexate
    Started
    1
    3
    Completed
    1
    1
    Not completed
    0
    2
         Consent withdrawn by subject
    -
    1
         Adverse Event
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Regimen A: Alglucosidase alfa and Cyclophosphamide
    Reporting group description
    Subjects exhibiting clinical decline since starting alglucosidase alfa (Myozyme®) therapy and had inhibitory antibodies and/or a sustained high recombinant human acid alpha-glucosidase (rhGAA) antibody titer (defined as at least 2 titers greater than or equal to (>=) 25,600 obtained at least 1 month apart), regardless of their cross-reacting immunologic material (CRIM ) status, were assigned to Regimen A. Subjects received alglucosidase alfa (Myozyme®) Intravenous (IV) infusion of 20 milligram per kilogram (mg/kg) every other week (qow) for a minimum of 18 months or, until the subject reaches the age of 2 years (if the subject was less than (<6) months of age at the time of enrolment). In addition, cyclophosphamide 250 milligram per square meter (mg/m^2) IV infusion was administered every 4 weeks after Myozyme® infusion for 6 months.

    Reporting group title
    Regimen B: Alglucosidase alfa, Rituximab and Methotrexate
    Reporting group description
    CRIM-negative subjects were assigned to Regimen B if they either (1) exhibited clinical decline since starting alglucosidase alfa (Myozyme®)therapy and did not have inhibitory antibodies and/or a sustained rhGAA antibody titer (defined as at least 2 titers >=25,600 obtained at least 1 month apart),or (2) did not exhibit clinical decline since starting alglucosidase alfa (Myozyme®) therapy, regardless of their anti-rhGAA or inhibitory antibody status. Regimen B subjects with CRIM-negative status received alglucosidase alfa (Myozyme®) IV infusion of 20 mg/kg qow for a minimum of 18 months or, until subject reaches the age of 2 years (if subject was <6 months of age at time of enrolment). In addition, rituximab 375 mg/m^2 IV was administered weekly beginning the day after Myozyme® infusion for 4 weeks (an optional 2nd cycle might be administered at the discretion of the investigator) and biweekly methotrexate 15 mg/m^2 subcutaneous on the day after Myozyme® infusion for 6 months.

    Reporting group values
    Regimen A: Alglucosidase alfa and Cyclophosphamide Regimen B: Alglucosidase alfa, Rituximab and Methotrexate Total
    Number of subjects
    1 3 4
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 2 2
        Children (2-11 years)
    1 1 2
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    0 0 0
        From 65-84 years
    0 0 0
        85 years and over
    0 0 0
    Gender categorical
    Units: Subjects
        Female
    0 2 2
        Male
    1 1 2

    End points

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    End points reporting groups
    Reporting group title
    Regimen A: Alglucosidase alfa and Cyclophosphamide
    Reporting group description
    Subjects exhibiting clinical decline since starting alglucosidase alfa (Myozyme®) therapy and had inhibitory antibodies and/or a sustained high recombinant human acid alpha-glucosidase (rhGAA) antibody titer (defined as at least 2 titers greater than or equal to (>=) 25,600 obtained at least 1 month apart), regardless of their cross-reacting immunologic material (CRIM ) status, were assigned to Regimen A. Subjects received alglucosidase alfa (Myozyme®) Intravenous (IV) infusion of 20 milligram per kilogram (mg/kg) every other week (qow) for a minimum of 18 months or, until the subject reaches the age of 2 years (if the subject was less than (<6) months of age at the time of enrolment). In addition, cyclophosphamide 250 milligram per square meter (mg/m^2) IV infusion was administered every 4 weeks after Myozyme® infusion for 6 months.

    Reporting group title
    Regimen B: Alglucosidase alfa, Rituximab and Methotrexate
    Reporting group description
    CRIM-negative subjects were assigned to Regimen B if they either (1) exhibited clinical decline since starting alglucosidase alfa (Myozyme®)therapy and did not have inhibitory antibodies and/or a sustained rhGAA antibody titer (defined as at least 2 titers >=25,600 obtained at least 1 month apart),or (2) did not exhibit clinical decline since starting alglucosidase alfa (Myozyme®) therapy, regardless of their anti-rhGAA or inhibitory antibody status. Regimen B subjects with CRIM-negative status received alglucosidase alfa (Myozyme®) IV infusion of 20 mg/kg qow for a minimum of 18 months or, until subject reaches the age of 2 years (if subject was <6 months of age at time of enrolment). In addition, rituximab 375 mg/m^2 IV was administered weekly beginning the day after Myozyme® infusion for 4 weeks (an optional 2nd cycle might be administered at the discretion of the investigator) and biweekly methotrexate 15 mg/m^2 subcutaneous on the day after Myozyme® infusion for 6 months.

    Primary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) [1]
    End point description
    An AE was defined as any undesirable physical, psychological, or behavioral effect experienced by subject during his/her participation in an investigational study, in conjunction with the use of the drug or biologic, whether or not product-related. TEAEs were defined as AEs that occurred or worsened during the on-treatment period (time from the start of investigational medicinal product [IMP] administration up to 18 months). SAE was any AE that resulted in any of the following outcomes: death, was life-threatening, required or prolonged inpatient hospitalisation, persistent or significant disability/incapacity; congenital anomaly; or important medical events that may jeopardise the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed above; new invasive ventilator use. Analysis was performed on safety set that included subjects who received at least 1 dose of alglucosidase alfa in the study.
    End point type
    Primary
    End point timeframe
    From baseline up to 18 months
    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 was descriptive in nature, no statistical analysis was provided.
    End point values
    Regimen A: Alglucosidase alfa and Cyclophosphamide Regimen B: Alglucosidase alfa, Rituximab and Methotrexate
    Number of subjects analysed
    1
    3
    Units: subject
    number (not applicable)
        Any TEAE
    1
    3
        Any Treatment-emergent SAE
    1
    3
        Any TEAE leading to withdrawal
    0
    1
        Any TEAE leading to death
    0
    1
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Anti-Recombinant Human Acid Alpha-glucosidase (Anti-rhGAA) Immunoglobulin G (IgG) Antibodies at Month 18

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    End point title
    Number of Subjects With Anti-Recombinant Human Acid Alpha-glucosidase (Anti-rhGAA) Immunoglobulin G (IgG) Antibodies at Month 18
    End point description
    Serum samples from subjects were planned to be analysed for the presence of anti-rhGAA IgG antibodies. Analysis was performed on Full Analysis Set (FAS) which included subjects who signed informed consent, completed all baseline assessments, and received at least 1 dose of alglucosidase alfa. Here, "99999" was used as space fillers and signifies that data were not summarised for this exploratory end-point due to low number of enrollment of subjects.
    End point type
    Other pre-specified
    End point timeframe
    Month 18
    End point values
    Regimen A: Alglucosidase alfa and Cyclophosphamide Regimen B: Alglucosidase alfa, Rituximab and Methotrexate
    Number of subjects analysed
    1
    3
    Units: subjects
        number (not applicable)
    99999
    99999
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Recombinant Human Acid Alpha-glucosidase (rhGAA) Inhibitory Antibody at Month 18

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    End point title
    Number of Subjects With Recombinant Human Acid Alpha-glucosidase (rhGAA) Inhibitory Antibody at Month 18
    End point description
    Subjects with positive anti-rhGAA IgG antibody were assessed for the presence of inhibitory antibodies (inhibition of enzyme activity and inhibition of enzyme uptake). Enzyme-linked immunosorbent assay (ELISA) was used to measure inhibition of rhGAA enzymatic activity in vitro and a cell-based assay was used to measure the inhibition of the uptake of rhGAA in normal fibroblast cells by flow cytometry. Analysis was performed on FAS. Here, "99999" was used as space fillers and signifies that data were not summarised for this exploratory end-point due to low number of enrollment of subjects.
    End point type
    Other pre-specified
    End point timeframe
    Month 18
    End point values
    Regimen A: Alglucosidase alfa and Cyclophosphamide Regimen B: Alglucosidase alfa, Rituximab and Methotrexate
    Number of subjects analysed
    1
    3
    Units: subjects
    number (not applicable)
        Inhibition of enzyme activity
    99999
    99999
        Inhibition of enzyme uptake
    99999
    99999
    No statistical analyses for this end point

    Other pre-specified: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    Overall Survival was defined as the time interval from the date of first study drug administration to the date of death due to any cause. Analysis was performed on FAS. Here, "99999" was used as space fillers and signifies that data were not summarised for this exploratory end-point due to low number of enrollment of subjects.
    End point type
    Other pre-specified
    End point timeframe
    From randomisation until death or study cut-off whichever comes earlier (up to 18 months)
    End point values
    Regimen A: Alglucosidase alfa and Cyclophosphamide Regimen B: Alglucosidase alfa, Rituximab and Methotrexate
    Number of subjects analysed
    1
    3
    Units: month
        median (full range (min-max))
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Ventilator Use

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    End point title
    Number of Subjects With Ventilator Use
    End point description
    Number of subjects requiring ventilator support were planned to be reported. Analysis was performed on FAS. Here,"99999" was used as space fillers and signifies that data were not summarised for this exploratory end-point and only individual subject listings were generated due to low number of enrollment of subjects.
    End point type
    Other pre-specified
    End point timeframe
    From baseline up to 18 months
    End point values
    Regimen A: Alglucosidase alfa and Cyclophosphamide Regimen B: Alglucosidase alfa, Rituximab and Methotrexate
    Number of subjects analysed
    1
    3
    Units: subjects
        number (not applicable)
    99999
    99999
    No statistical analyses for this end point

    Other pre-specified: Left Ventricular Mass (LVM) Z-Score and LVM Index

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    End point title
    Left Ventricular Mass (LVM) Z-Score and LVM Index
    End point description
    LVM Z-score and LVM index were assessed by echocardiograms (ECHOs). LVM Z-Score is an indicator of degree of standard deviations from the mean in a normal distribution. The normal range for LVM Z-Score is -2 to 2. Values <-2 or >2 indicate abnormal LVM Z-Score. Values less than 0 (negative values) indicated a smaller LVM than mean and values higher than 0 indicate a larger LVM than the mean. LVM index is an index value derived by normalising LVM by body surface area. LVM index provides evidence of cardiomyopathy. LVM index values <65 gram per meter^2 (g/m^2) were considered as normal and LVM index values >=65 g/m^2 were considered as abnormal. Analysis was performed on FAS. Here, "99999" was used as space fillers and signifies that data were not summarised for this exploratory end-point due to low number of enrollment of subjects.
    End point type
    Other pre-specified
    End point timeframe
    From baseline up to 18 months
    End point values
    Regimen A: Alglucosidase alfa and Cyclophosphamide Regimen B: Alglucosidase alfa, Rituximab and Methotrexate
    Number of subjects analysed
    1
    3
    Units: subjects
    number (not applicable)
        LVM Z-score
    99999
    99999
        LVM index
    99999
    99999
    No statistical analyses for this end point

    Other pre-specified: Gross Motor Disability Assessed by Gross Motor Function Measure-88 (GMFM-88) Score

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    End point title
    Gross Motor Disability Assessed by Gross Motor Function Measure-88 (GMFM-88) Score
    End point description
    GMFM-88 is an 88-item measure to detect gross motor function. It consists of 5 categories: lying and rolling; sitting; crawling and kneeling; standing; and walking, running and jumping. Each item is scored on a 4-point Likert scale (0=cannot do;1=initiates [<10% of the task];2=partially completes [10% to <100% of the task];3=task completion). The score for each dimension is expressed as a percentage of the maximum score for that dimension. Total score is obtained by adding the percentage scores for each dimension and dividing the sum by the total number of dimensions. Total score ranges from 0% to 100%, where higher scores indicate better motor functions. A total score of <7.5% demonstrates gross motor disability. Analysis was performed on FAS. Here, "99999" was used as space fillers and signifies that data were not summarised for this exploratory end-point due to low number of enrollment of subjects.
    End point type
    Other pre-specified
    End point timeframe
    From baseline up to 18 months
    End point values
    Regimen A: Alglucosidase alfa and Cyclophosphamide Regimen B: Alglucosidase alfa, Rituximab and Methotrexate
    Number of subjects analysed
    1
    3
    Units: percentage of total score
        number (not applicable)
    99999
    99999
    No statistical analyses for this end point

    Other pre-specified: Motor Development Status Assessed by Alberta Infantile Motor Scale (AIMS) Score

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    End point title
    Motor Development Status Assessed by Alberta Infantile Motor Scale (AIMS) Score
    End point description
    AIMS is a 58-item reliable and valid measure of motor development for infants at risk for motor delay. It assesses infant movement in 4 positions(subscales): prone(reciprocal crawling); supine(moving hands to feet); sitting(sitting with arm support); and standing (pulls to stand).For each subscale, items are scored as "observed" or "not observed". Item in observed range create a motor window. When scoring, subscale scores are calculated by giving child credit (1 point) for observed items within motor window in addition to being given credit (1 point) for all of the less mature items before motor window. AIMS total score is calculated by summing scores for 58 items and ranges from 0-58, with higher score indicating more mature motor development. Analysis was performed on FAS. Here, "99999" was used as space fillers and signifies that data were not summarised for this exploratory end-point due to low number of enrollment of subjects.
    End point type
    Other pre-specified
    End point timeframe
    From baseline up to 18 months
    End point values
    Regimen A: Alglucosidase alfa and Cyclophosphamide Regimen B: Alglucosidase alfa, Rituximab and Methotrexate
    Number of subjects analysed
    1
    3
    Units: score on a scale
        number (not applicable)
    99999
    99999
    No statistical analyses for this end point

    Other pre-specified: Disability Index Assessed by the Pompe Pediatric Evaluation of Disability Inventory (Pompe PEDI) Score

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    End point title
    Disability Index Assessed by the Pompe Pediatric Evaluation of Disability Inventory (Pompe PEDI) Score
    End point description
    Pompe PEDI: assesses functional capabilities and performance in children with Pompe disease from 2 months through adolescence. It consists of all items of original PEDI (197 functional skill items in 3 domains:self-care; mobility; and social function) and additional items in functional skills, mobility, and self-care domains to reflect clinically relevant functional skills. Each domain consisted of 2 subdomains: functional skill performance and caregiver assistance scale. Norm-based scoring was developed for these additional items, and scoring algorithms for PEDI have been adjusted to reflect additional normative data collected for Pompe PEDI. Total score range for each domain (mean of subdomains) and subdomains ranges from 0-100, higher score indicated higher capability. Analysis was performed on FAS. Here, "99999" was used as space fillers and signifies that data were not summarised for this exploratory end-point due to low number of enrollment of subjects.
    End point type
    Other pre-specified
    End point timeframe
    From baseline up to 18 months
    End point values
    Regimen A: Alglucosidase alfa and Cyclophosphamide Regimen B: Alglucosidase alfa, Rituximab and Methotrexate
    Number of subjects analysed
    1
    3
    Units: score on a scale
        number (not applicable)
    99999
    99999
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs were collected from first IMP administration up to 18 months.
    Adverse event reporting additional description
    Reported AEs and deaths are treatment-emergent adverse events that are AEs that developed/worsened and deaths that occurred during the ‘on treatment period’ (time from first IMP administration until 18 months). Analysis was performed on safety population.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Regimen A: Alglucosidase alfa and Cyclophosphamide
    Reporting group description
    Subjects exhibiting clinical decline since starting alglucosidase alfa (Myozyme®) therapy and had inhibitory antibodies and/or a sustained high rhGAA antibody titer (defined as at least 2 titers >=25,600 obtained at least 1 month apart), regardless of their CRIM status, were assigned to Regimen A. Subjects received alglucosidase alfa (Myozyme®) IV infusion of 20 mg/kg qow for a minimum of 18 months or, until the subject reaches the age of 2 years (if the subject was less than (<6) months of age at the time of enrolment). In addition, cyclophosphamide 250 mg/m^2 IV infusion was administered every 4 weeks after Myozyme® infusion for 6 months.

    Reporting group title
    Regimen B: Alglucosidase alfa, Rituximab and Methotrexate
    Reporting group description
    CRIM-negative subjects were assigned to Regimen B if they either (1) exhibited clinical decline since starting alglucosidase alfa (Myozyme®)therapy and did not have inhibitory antibodies and/or a sustained rhGAA antibody titer (defined as at least 2 titers >=25,600 obtained at least 1 month apart),or (2) did not exhibit clinical decline since starting alglucosidase alfa (Myozyme®) therapy, regardless of their anti-rhGAA or inhibitory antibody status. Regimen B subjects with CRIM-negative status received alglucosidase alfa (Myozyme®) IV infusion of 20 mg/kg qow for a minimum of 18 months or, until subject reaches the age of 2 years (if subject was <6 months of age at time of enrolment). In addition, rituximab 375 mg/m^2 IV was administered weekly beginning the day after Myozyme® infusion for 4 weeks (an optional 2nd cycle might be administered at the discretion of the investigator) and biweekly methotrexate 15 mg/m^2 subcutaneous on the day after Myozyme® infusion for 6 months.

    Serious adverse events
    Regimen A: Alglucosidase alfa and Cyclophosphamide Regimen B: Alglucosidase alfa, Rituximab and Methotrexate
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 1 (100.00%)
    3 / 3 (100.00%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    Vascular disorders
    Pallor
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood Pressure Decreased
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oxygen Saturation Decreased
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcus Test Positive
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial Thrombosis
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Hypertrophy
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cyanosis
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertrophic Cardiomyopathy
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    1 / 1 (100.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercapnia
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Increased Upper Airway Secretion
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Distress
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Failure
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 3 (66.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General Physical Health Deterioration
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 1 (100.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Cold Sweat
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Influenza
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia
         subjects affected / exposed
    1 / 1 (100.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Streptococcal
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Viral
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    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
    Regimen A: Alglucosidase alfa and Cyclophosphamide Regimen B: Alglucosidase alfa, Rituximab and Methotrexate
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 1 (100.00%)
    3 / 3 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Hypotension
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Phlebitis
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    General disorders and administration site conditions
    Catheter Site Phlebitis
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    Medical Device Complication
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    Oedema Peripheral
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Pyrexia
         subjects affected / exposed
    1 / 1 (100.00%)
    2 / 3 (66.67%)
         occurrences all number
    10
    10
    Pain
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Thrombosis In Device
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Insomnia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Restlessness
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Arthropod Bite
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    2
    Excoriation
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Feeding Tube Complication
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Thermal Burn
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Tracheal Haemorrhage
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    3
    Blood Creatine Phosphokinase Mb Increased
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    3
    Blood Creatine Phosphokinase Increased
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    2
    Blood Immunoglobulin M Increased
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Blood Magnesium Decreased
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Blood Potassium Decreased
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    2
    Body Temperature Increased
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 3 (100.00%)
         occurrences all number
    0
    10
    Heart Rate Increased
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    4
    Lymphocyte Count Decreased
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Lymphocyte Percentage Decreased
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Muscle Enzyme Increased
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Neutrophil Count Decreased
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Neutrophil Percentage Increased
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Oxygen Saturation Decreased
         subjects affected / exposed
    1 / 1 (100.00%)
    1 / 3 (33.33%)
         occurrences all number
    3
    1
    Urine Output Decreased
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    2
    White Blood Cell Count Decreased
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 3 (66.67%)
         occurrences all number
    0
    2
    White Blood Cells Urine Positive
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    5
    0
    Tachycardia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    3
    Ventricular Hypertrophy
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Atelectasis
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Dyspnoea
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Cough
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    2
    Haemoptysis
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Hypoxia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    3
    Increased Bronchial Secretion
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    3
    0
    Increased Upper Airway Secretion
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Pleural Effusion
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Pneumonia Aspiration
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Pneumonitis
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Pneumothorax
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Pulmonary Oedema
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Respiratory Distress
         subjects affected / exposed
    1 / 1 (100.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    1
    Rhinorrhoea
         subjects affected / exposed
    1 / 1 (100.00%)
    1 / 3 (33.33%)
         occurrences all number
    2
    1
    Blood and lymphatic system disorders
    Leukocytosis
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Nervous system disorders
    Clonus
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Hypokinesia
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 3 (66.67%)
         occurrences all number
    0
    2
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    2
    Ear and labyrinth disorders
    Conductive Deafness
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    2
    Deafness Bilateral
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Mixed Deafness
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal Distension
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Constipation
         subjects affected / exposed
    1 / 1 (100.00%)
    1 / 3 (33.33%)
         occurrences all number
    5
    1
    Diarrhoea
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    2
    Faecaloma
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    Faeces Hard
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    3
    0
    Nausea
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Retching
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    1 / 1 (100.00%)
    1 / 3 (33.33%)
         occurrences all number
    4
    1
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Oliguria
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    Urinary Retention
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    5
    0
    Skin and subcutaneous tissue disorders
    Decubitus Ulcer
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Dermatitis Diaper
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Erythema
         subjects affected / exposed
    1 / 1 (100.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    1
    Papule
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Pruritus
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Rash
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    2
    Red Man Syndrome
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Skin Discolouration
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Skin Exfoliation
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Skin Irritation
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Skin Swelling
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    3
    Urticaria
         subjects affected / exposed
    1 / 1 (100.00%)
    2 / 3 (66.67%)
         occurrences all number
    2
    6
    Musculoskeletal and connective tissue disorders
    Joint Contracture
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Infections and infestations
    Bacterial Tracheitis
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Otitis Media
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 3 (100.00%)
         occurrences all number
    0
    3
    Otitis Media Acute
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 3 (66.67%)
         occurrences all number
    0
    2
    Pharyngitis
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Pneumonia
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Staphylococcal Bacteraemia
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Tracheitis
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 3 (66.67%)
         occurrences all number
    0
    7
    Urinary Tract Infection
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Aug 2008
    Following changes were made: Allowed enrollment at non-US sites; clarified that a second cycle of immunomodulatory therapy can only be administered within the first 6 months of study participation; clarified that infusion-associated reactions are related only to alglucosidase alfa for the purposes of the study.
    19 Mar 2009
    Following changes were made: Allowed subjects to be assigned to either ITI regimen based on their qualifications for a given regimen, and thereby address the greater number of cross-reacting immunologic material (CRIM)-negative subjects being identified by sites; allowed for CRIM testing, thereby minimising testing procedures for subjects while still ensuring consistency in testing standards, and ensured that sites receive the results; clarified the subjects who should receive intravenous immunoglobulin (IVIG) and the risks associated with IVIG therapy; clarified that subjects must have received at least 1 dose of alglucosidase alfa prior to enrollment, in place of a 6-month alglucosidase alfa treatment period.
    01 Oct 2009
    Following changes were made: Clarified that a central cardiologist reviews the electrocardiogram and echocardiogram data for consistency, while a local cardiologist reviews the ECG and ECHO data for safety and clinical management of the subject; removed plasmapheresis globally from the protocol as it had been determined that the frequency of administration allowed by the protocol would not be clinically meaningful for the subject population; added National Cancer Institute Common Terminology Criteria for Adverse Events grading to the associated severity category throughout the protocol; added details on the indication for IVIG administration; expanded criteria for removing a subject from the study to include receipt of interventions or procedures that may impact the efficacy or safety of the required study assessments and treatments; added new information on delayed onset of AEs related to rituximab administration; clarified that subjects are fully evaluated for clinical stability and lack of acute illness prior to dosing.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    26 Aug 2013
    Since Food and Drug Administration (FDA) feedback on post-marketing commitment (PMC) was pending, with FDA’s acknowledgement further enrollment of subjects were stopped; and the Study was deemed terminated after receiving FDA acknowledgment of PMC fulfillment on 18 Feb 2020.
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to low number of enrolment and exploratory nature of endpoints, only safety data were summarised and reported.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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