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    Clinical Trial Results:
    A Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Pharmacodynamics of AT1001 in Patients with Fabry Disease and AT1001-Responsive GLA Mutations

    Summary
    EudraCT number
    		 2009-013459-31
    Trial protocol
    		 GB   FR   DE   NL   BE   ES   IT   DK  
    Global end of trial date
    29 Jan 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Aug 2016
    First version publication date
    12 Aug 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AT1001-011
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00925301
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amicus Therapeutics, Inc.
    Sponsor organisation address
    1 Cedarbrook Drive, Cranbury, United States, NJ 08512
    Public contact
    Medical Information, Amicus Therapeutics, Inc., MedInfo_Amicus@quintiles.com
    Scientific contact
    Medical Information, Amicus Therapeutics, Inc., MedInfo_Amicus@quintiles.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
    29 Jan 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Jan 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jan 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the effect of migalastat hydrochloride (migalastat HCl) versus placebo on kidney globotriaosylceramide (GL-3) as assessed by histological scoring of the number of inclusions in interstitial capillaries (ICs) in subjects with Fabry disease with a mutation in alpha galactosidase A gene (GLA) that was responsive to migalastat.
    Protection of trial subjects
    This study was designed and monitored in accordance with sponsor procedures, which comply with the ethical principles of Good Clinical Practice, as required by the major regulatory authorities and in accordance with the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Oct 2009
    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
    Argentina: 11
    Country: Number of subjects enrolled
    Australia: 23
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Brazil: 11
    Country: Number of subjects enrolled
    Canada: 11
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Denmark: 4
    Country: Number of subjects enrolled
    Egypt: 14
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Italy: 11
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Turkey: 9
    Country: Number of subjects enrolled
    United States: 53
    Worldwide total number of subjects
    180
    EEA total number of subjects
    48
    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)
    5
    Adults (18-64 years)
    168
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 180 subjects enrolled (signed informed consent) & attended 36 study centers in 16 countries. First subject randomized: 23 Oct 2009. Last subject completed: 29 Jan 2014. Period 1 was a 6-month double-blind randomized treatment period. Period 2 was a 6-month OL treatment period. There was an optional 12-month OLE for subjects completing both periods.

    Pre-assignment
    Screening details
    		 67 subjects with Fabry disease, naïve to enzyme replacement therapy (ERT) or had not received ERT for at least 6 months and met all eligibility criteria (including having a migalastat-responsive GLA mutation based on the Clinical Trial HEK assay) were randomized to treatment groups in Period 1, 34 Migalastat; 33 Placebo.

    Pre-assignment period milestones
    Number of subjects started
    		 180
    Number of subjects completed
    		 67

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Screen Failure: 113
    Period 1
    Period 1 title
    Period 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Migalastat - Migalastat ITT Population
    Arm description
    		 During Period 1 (6-month randomized treatment period), subjects received migalastat HCl 150 millgram (mg) orally every other day (QOD) at approximately the same time. During Period 2 (6-month open-label [OL] treatment period) all subjects received migalastat HCl 150 mg orally QOD. Subjects completing both Periods 1 and 2 were eligible to participate in a 12-month open-label extension (OLE) phase and continued to take migalastat HCl 150 mg QOD for up to 12 months. Subjects were required to fast 2 hours before and 2 hours after each dose. Inactive reminder capsules were taken on alternate days during each treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Migalastat HCl
    Investigational medicinal product code
    Migalastat
    Other name
    AT1001
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg of migalastat HCl was administered orally QOD at approximately the same time each day. Subjects were required to fast 2 hours before and 2 hours after taking each dose of migalastat.

    Arm title
    		 Placebo - Migalastat ITT Population
    Arm description
    		 During Period 1 (6-month randomized treatment period), subjects received a matching placebo orally QOD. During Period 2 (6-month OL treatment period) all subjects received migalastat HCl 150 mg orally QOD. Inactive reminder capsules were taken on alternate days. Subjects completing both Periods 1 and 2 were eligible to participate in a 12-month OLE phase and continued to take migalastat HCl 150 mg QOD for up to 12 months. Subjects were required to fast 2 hours before and 2 hours after each dose.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Placebo
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo capsules were identical in appearance to migalastat capsules and contained magnesium stearate and pregelatinized starch. Placebo was administered orally QOD at approximately the same time each day. Subjects were required to fast 2 hours before and 2 hours after taking each placebo capsule.

    Number of subjects in period 1 [1]
    		Migalastat - Migalastat ITT Population Placebo - Migalastat ITT Population
    Started
    34
    33
    Completed
    34
    30
    Not completed
    0
    3
         Consent withdrawn by subject
    -
    2
         Pregnancy
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of subjects starting the baseline period includes all subjects who met the eligibility criteria for the study and is equivalent to the number of subjects completing the pre-assignment period.
    Period 2
    Period 2 title
    Period 2
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Migalastat - Migalastat ITT Population
    Arm description
    		 During Period 1 (6-month randomized treatment period), subjects received migalastat HCl 150 millgram (mg) orally every other day (QOD) at approximately the same time. During Period 2 (6-month open-label [OL] treatment period) all subjects received migalastat HCl 150 mg orally QOD. Subjects completing both Periods 1 and 2 were eligible to participate in a 12-month open-label extension (OLE) phase and continued to take migalastat HCl 150 mg QOD for up to 12 months. Subjects were required to fast 2 hours before and 2 hours after each dose. Inactive reminder capsules were taken on alternate days during each treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Migalastat HCl
    Investigational medicinal product code
    Migalastat
    Other name
    AT1001
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg of migalastat HCl was administered orally QOD at approximately the same time each day. Subjects were required to fast 2 hours before and 2 hours after taking each dose of migalastat.

    Arm title
    		 Placebo - Migalastat ITT Population
    Arm description
    		 During Period 1 (6-month randomized treatment period), subjects received a matching placebo orally QOD. During Period 2 (6-month OL treatment period) all subjects received migalastat HCl 150 mg orally QOD. Inactive reminder capsules were taken on alternate days. Subjects completing both Periods 1 and 2 were eligible to participate in a 12-month OLE phase and continued to take migalastat HCl 150 mg QOD for up to 12 months. Subjects were required to fast 2 hours before and 2 hours after each dose.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Migalastat HCl
    Investigational medicinal product code
    Migalastat
    Other name
    AT1001
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg of migalastat HCl was administered orally QOD at approximately the same time each day. Subjects were required to fast 2 hours before and 2 hours after taking each dose of migalastat.

    Number of subjects in period 2 [2]
    		Migalastat - Migalastat ITT Population Placebo - Migalastat ITT Population
    Started
    33
    30
    Completed
    31
    29
    Not completed
    2
    1
         Consent withdrawn by subject
    1
    -
         Adverse event, non-fatal
    1
    1
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 1 subject who completed Period 1 in the Migalastat - Migalastat arm withdrew consent before starting Period 2. As such, in the Migalastat - Migalastat arm 34 subjects completed Period 1 and 33 subjects started Period 2.
    Period 3
    Period 3 title
    Open-Label Extension
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Migalastat - Migalastat ITT Population
    Arm description
    		 During Period 1 (6-month randomized treatment period), subjects received migalastat HCl 150 millgram (mg) orally every other day (QOD) at approximately the same time. During Period 2 (6-month open-label [OL] treatment period) all subjects received migalastat HCl 150 mg orally QOD. Subjects completing both Periods 1 and 2 were eligible to participate in a 12-month open-label extension (OLE) phase and continued to take migalastat HCl 150 mg QOD for up to 12 months. Subjects were required to fast 2 hours before and 2 hours after each dose. Inactive reminder capsules were taken on alternate days during each treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Migalastat HCl
    Investigational medicinal product code
    Migalastat
    Other name
    AT1001
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg of migalastat HCl was administered orally QOD at approximately the same time each day. Subjects were required to fast 2 hours before and 2 hours after taking each dose of migalastat.

    Arm title
    		 Placebo - Migalastat ITT Population
    Arm description
    		 During Period 1 (6-month randomized treatment period), subjects received a matching placebo orally QOD. During Period 2 (6-month OL treatment period) all subjects received migalastat HCl 150 mg orally QOD. Inactive reminder capsules were taken on alternate days. Subjects completing both Periods 1 and 2 were eligible to participate in a 12-month OLE phase and continued to take migalastat HCl 150 mg QOD for up to 12 months. Subjects were required to fast 2 hours before and 2 hours after each dose.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Migalastat HCl
    Investigational medicinal product code
    Migalastat
    Other name
    AT1001
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg of migalastat HCl was administered orally QOD at approximately the same time each day. Subjects were required to fast 2 hours before and 2 hours after taking each dose of migalastat.

    Number of subjects in period 3 [3]
    		Migalastat - Migalastat ITT Population Placebo - Migalastat ITT Population
    Started
    29
    28
    Completed
    27
    27
    Not completed
    2
    1
         Consent withdrawn by subject
    -
    1
         Pregnancy
    1
    -
         Lost to follow-up
    1
    -
    Notes
    [3] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Period 3 of the Study was an optional 12-month open-label extension. As such not all subjects who completed the preceding Period 2 entered the open-label extension.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Migalastat - Migalastat ITT Population
    Reporting group description
    		 During Period 1 (6-month randomized treatment period), subjects received migalastat HCl 150 millgram (mg) orally every other day (QOD) at approximately the same time. During Period 2 (6-month open-label [OL] treatment period) all subjects received migalastat HCl 150 mg orally QOD. Subjects completing both Periods 1 and 2 were eligible to participate in a 12-month open-label extension (OLE) phase and continued to take migalastat HCl 150 mg QOD for up to 12 months. Subjects were required to fast 2 hours before and 2 hours after each dose. Inactive reminder capsules were taken on alternate days during each treatment period.

    Reporting group title
    Placebo - Migalastat ITT Population
    Reporting group description
    		 During Period 1 (6-month randomized treatment period), subjects received a matching placebo orally QOD. During Period 2 (6-month OL treatment period) all subjects received migalastat HCl 150 mg orally QOD. Inactive reminder capsules were taken on alternate days. Subjects completing both Periods 1 and 2 were eligible to participate in a 12-month OLE phase and continued to take migalastat HCl 150 mg QOD for up to 12 months. Subjects were required to fast 2 hours before and 2 hours after each dose.

    Reporting group values
    		 Migalastat - Migalastat ITT Population Placebo - Migalastat ITT Population Total
    Number of subjects
    		 34 33 67
    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 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 2 0 2
        Adults (18-64 years)
    		 31 33 64
        From 65-84 years
    		 1 0 1
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 40 ± 13.29 44.5 ± 10.18 -
    Gender categorical
    Units: Subjects
        Male
    		 12 12 24
        Female
    		 22 21 43

    End points

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    End points reporting groups
    Reporting group title
    Migalastat - Migalastat ITT Population
    Reporting group description
    		 During Period 1 (6-month randomized treatment period), subjects received migalastat HCl 150 millgram (mg) orally every other day (QOD) at approximately the same time. During Period 2 (6-month open-label [OL] treatment period) all subjects received migalastat HCl 150 mg orally QOD. Subjects completing both Periods 1 and 2 were eligible to participate in a 12-month open-label extension (OLE) phase and continued to take migalastat HCl 150 mg QOD for up to 12 months. Subjects were required to fast 2 hours before and 2 hours after each dose. Inactive reminder capsules were taken on alternate days during each treatment period.

    Reporting group title
    Placebo - Migalastat ITT Population
    Reporting group description
    		 During Period 1 (6-month randomized treatment period), subjects received a matching placebo orally QOD. During Period 2 (6-month OL treatment period) all subjects received migalastat HCl 150 mg orally QOD. Inactive reminder capsules were taken on alternate days. Subjects completing both Periods 1 and 2 were eligible to participate in a 12-month OLE phase and continued to take migalastat HCl 150 mg QOD for up to 12 months. Subjects were required to fast 2 hours before and 2 hours after each dose.
    Reporting group title
    Migalastat - Migalastat ITT Population
    Reporting group description
    		 During Period 1 (6-month randomized treatment period), subjects received migalastat HCl 150 millgram (mg) orally every other day (QOD) at approximately the same time. During Period 2 (6-month open-label [OL] treatment period) all subjects received migalastat HCl 150 mg orally QOD. Subjects completing both Periods 1 and 2 were eligible to participate in a 12-month open-label extension (OLE) phase and continued to take migalastat HCl 150 mg QOD for up to 12 months. Subjects were required to fast 2 hours before and 2 hours after each dose. Inactive reminder capsules were taken on alternate days during each treatment period.

    Reporting group title
    Placebo - Migalastat ITT Population
    Reporting group description
    		 During Period 1 (6-month randomized treatment period), subjects received a matching placebo orally QOD. During Period 2 (6-month OL treatment period) all subjects received migalastat HCl 150 mg orally QOD. Inactive reminder capsules were taken on alternate days. Subjects completing both Periods 1 and 2 were eligible to participate in a 12-month OLE phase and continued to take migalastat HCl 150 mg QOD for up to 12 months. Subjects were required to fast 2 hours before and 2 hours after each dose.
    Reporting group title
    Migalastat - Migalastat ITT Population
    Reporting group description
    		 During Period 1 (6-month randomized treatment period), subjects received migalastat HCl 150 millgram (mg) orally every other day (QOD) at approximately the same time. During Period 2 (6-month open-label [OL] treatment period) all subjects received migalastat HCl 150 mg orally QOD. Subjects completing both Periods 1 and 2 were eligible to participate in a 12-month open-label extension (OLE) phase and continued to take migalastat HCl 150 mg QOD for up to 12 months. Subjects were required to fast 2 hours before and 2 hours after each dose. Inactive reminder capsules were taken on alternate days during each treatment period.

    Reporting group title
    Placebo - Migalastat ITT Population
    Reporting group description
    		 During Period 1 (6-month randomized treatment period), subjects received a matching placebo orally QOD. During Period 2 (6-month OL treatment period) all subjects received migalastat HCl 150 mg orally QOD. Inactive reminder capsules were taken on alternate days. Subjects completing both Periods 1 and 2 were eligible to participate in a 12-month OLE phase and continued to take migalastat HCl 150 mg QOD for up to 12 months. Subjects were required to fast 2 hours before and 2 hours after each dose.

    Subject analysis set title
    Migalastat-Migalastat ITT Population (amenable GLA mutations)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The Migalastat - Migalastat ITT population with amenable GLA mutations includes subjects in the Intent-to-Treat (ITT) population who were randomized to receive migalastat in Period 1 and who had amenable mutations based on the Good Laboratory Practice (GLP) Human Embryonic Kidney (HEK) assay.

    Subject analysis set title
    Placebo-Migalastat ITT Population (amenable GLA mutations)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The Placebo - Migalastat ITT population with amenable GLA mutations includes subjects in the ITT population who were randomized to receive placebo in Period 1 and who had amenable mutations based on the GLP HEK assay.

    Subject analysis set title
    OLE Population with amenable GLA mutations
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The OLE population includes all randomized subjects included in the OLE population with amenable mutations based on the GLP HEK assay.

    Subject analysis set title
    Migalastat Safety Population (24-month analyses)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The migalastat safety population (24-month analyses) includes all subjects in the ITT population who received at least 1 dose of migalastat during Periods 1, 2 and 3.

    Subject analysis set title
    Placebo Safety Population (6-month analyses)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The placebo safety population (6-month analyses) includes all subjects in the ITT population who received at least 1 dose of placebo during Period 1.

    Primary: IC GL-3 Responder Analysis

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    End point title
    		 IC GL-3 Responder Analysis
    End point description
    A subject was described as a responder if the average number of IC GL-3 inclusions at Month 6 (Visit 4) had been reduced by at least 50% from the average number of inclusions at Baseline (Visit 1). The percentage of subjects meeting this definition is presented. The full ITT Population was used for this analysis and included all randomized subjects regardless of mutation status in the GLP HEK assay.
    End point type
    Primary
    End point timeframe
    Baseline (Visit 1) to Month 6 (Visit 4)
    End point values
    		 Migalastat - Migalastat ITT Population Placebo - Migalastat ITT Population
    Number of subjects analysed
    34
    33
    Units: Responder rate (percentage responders)
    number (not applicable)
        IC GL-3 Responder Analysis
    40.6
    28.1
    Statistical analysis title
    		 Rate Difference (Migalastat minus Placebo)
    Statistical analysis description
    The proportion of successes (i.e. ≥50% reduction from Baseline to Month 6 in the average number of IC GL-3 inclusions) in each treatment group was compared using the exact Cochran-Mantel-Haenszel test stratified by sex. The difference of the proportion of successes between the 2 groups and its exact 95% confidence interval was calculated.
    Comparison groups
    Migalastat - Migalastat ITT Population v Placebo - Migalastat ITT Population
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.2996
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Responder Rate Difference
    Point estimate
    12.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.4
         upper limit
    		 37.3

    Secondary: IC GL-3 lnclusions Percent Change from Baseline (Visit 1)

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    End point title
    		 IC GL-3 lnclusions Percent Change from Baseline (Visit 1)
    End point description
    Percent changes from Baseline (Visit 1) were based on a summary of individual percent change from Baseline (Visit 1) in GL-3 inclusions. The full ITT Population was used for this analysis and included all randomized subjects regardless of mutation status in the GLP HEK assay.
    End point type
    Secondary
    End point timeframe
    Baseline (Visit 1) to Month 6 (Visit 4)
    End point values
    		 Migalastat - Migalastat ITT Population Placebo - Migalastat ITT Population
    Number of subjects analysed
    30
    30
    Units: Percentage responders
    arithmetic mean (standard deviation)
        IC GL-3 lnclusions Percent Change from Baseline
    -7.948 ± 105.2736
    12.985 ± 90.5131
    Statistical analysis title
    		 Treatment Difference (Migalastat minus Placebo)
    Statistical analysis description
    The percent change from Baseline (Visit 1) in the average number of IC GL-3 inclusions was analyzed using an analysis of covariance (ANCOVA) model based on ranked observations with covariate adjustment for the baseline value and factors for treatment group and the treatment by baseline interaction. The p-value corresponds to the least-square (LS) mean difference between migalastat-migalastat and placebo-migalastat.
    Comparison groups
    Migalastat - Migalastat ITT Population v Placebo - Migalastat ITT Population
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.0974
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [1] - Non-parametric analysis

    Other pre-specified: Change in Percent ICs with Zero GL-3 Inclusions

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    End point title
    		 Change in Percent ICs with Zero GL-3 Inclusions
    End point description
    The change from Baseline (Visit 1) to Month 6 (Visit 4) in the percent of ICs with zero GL-3 inclusions was a tertiary efficacy endpoint. The full ITT Population was used for this analysis and included all randomized subjects regardless of mutation status in the GLP HEK assay.
    End point type
    Other pre-specified
    End point timeframe
    Baseline (Visit 1) to Month 6 (Visit 4)
    End point values
    		 Migalastat - Migalastat ITT Population Placebo - Migalastat ITT Population
    Number of subjects analysed
    30
    30
    Units: Percent ICs
    least squares mean (standard deviation)
        Change in Percent ICs with Zero GL-3 Inclusions
    7.304 ± 9.7206
    1.317 ± 11.7467
    Statistical analysis title
    		 Treatment Difference (Migalastat minus Placebo)
    Statistical analysis description
    The change from Baseline in percent of capillaries with zero GL-3 inclusions was analyzed using an ANCOVA model with covariate adjustment for the Baseline value and factors for treatment group, sex, and the treatment by Baseline interaction, sex by treatment interaction and sex by Baseline interaction. The p-value corresponds to the LS mean difference between migalastat-migalastat and placebo-migalastat.
    Comparison groups
    Migalastat - Migalastat ITT Population v Placebo - Migalastat ITT Population
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.0418
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 11.7
    Notes
    [2] - Non-parametric analysis

    Other pre-specified: Change in Plasma globotriaosylsphingosine (Lyso-Gb3)

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    End point title
    		 Change in Plasma globotriaosylsphingosine (Lyso-Gb3)
    End point description
    The change from Baseline (Visit 1) to Month 6 (Visit 4) in Plasma Lyso-Gb3 was a pre-specified exploratory endpoint. The ITT Population with amenable mutations was used for this analysis and included all randomized subjects with amenable mutations based on the GLP HEK assay.
    End point type
    Other pre-specified
    End point timeframe
    Baseline (Visit 1) to Month 6 (Visit 4)
    End point values
    		 Migalastat-Migalastat ITT Population (amenable GLA mutations) Placebo-Migalastat ITT Population (amenable GLA mutations)
    Number of subjects analysed
    18
    13
    Units: nmol/L
    least squares mean (standard deviation)
        Change in Plasma Lyso-Gb3
    -10.58 ± 20.196
    0.83 ± 8.548
    Statistical analysis title
    		 Treatment Difference (Migalastat minus Placebo)
    Statistical analysis description
    Data were analyzed using an ANCOVA model that included treatment as a factor with the Baseline value as a covariate and the treatment by Baseline interaction. The treatment effect was estimated as the difference between migalastat and placebo in the LS mean estimates for treatment.
    Comparison groups
    Migalastat-Migalastat ITT Population (amenable GLA mutations) v Placebo-Migalastat ITT Population (amenable GLA mutations)
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.0033
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -11.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -18.7
         upper limit
    		 -4.1
    Notes
    [3] - Non-parametric analysis

    Other pre-specified: Annualized Change in Estimated Glomerular Filtration Rate assessed by the Chronic Kidney Disease Epidemiology Collaboration equation (eGFR CKD-EPI)

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    End point title
    		 Annualized Change in Estimated Glomerular Filtration Rate assessed by the Chronic Kidney Disease Epidemiology Collaboration equation (eGFR CKD-EPI)
    End point description
    The eGFR CKD-EPI is calculated as GFR=141 x min(Scr/κ,1)α x max(Scr/κ,1)-1.209 x 0.993Age x 1.018 [if female] x 1.159 [if black], where Scr is serum creatinine, κ is 0.7 for females and 0.9 for males, α is -0.329 for females and -0.411 for males, min indicates the minimum of Scr/κ or 1, and max indicates the maximum of Scr/κ or 1. The OLE Population with amenable mutations was used for this analysis and included all randomized subjects included in the OLE with amenable mutations based on the GLP HEK assay.
    End point type
    Other pre-specified
    End point timeframe
    Baseline (Visit 1) to Month 24 (Visit 10)
    End point values
    		 OLE Population with amenable GLA mutations
    Number of subjects analysed
    41
    Units: mL/min/1.73m2
    arithmetic mean (standard error)
        Annualized Change in eGFR CKD-EPI
    -0.3 ± 0.663
    No statistical analyses for this end point

    Post-hoc: Change in Average Number of IC GL-3 Inclusions

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    End point title
    		 Change in Average Number of IC GL-3 Inclusions
    End point description
    The change from Baseline (Visit 1) to Month 6 (Visit 4) in average number of IC GL-3 inclusions was a Post-Hoc endpoint. The ITT Population with amenable mutations was used for this analysis and included all randomized subjects with amenable mutations based on the GLP HEK assay.
    End point type
    Post-hoc
    End point timeframe
    Baseline (Visit 1) to Month 6 (Visit 4)
    End point values
    		 Migalastat-Migalastat ITT Population (amenable GLA mutations) Placebo-Migalastat ITT Population (amenable GLA mutations)
    Number of subjects analysed
    25
    20
    Units: number
    least squares mean (standard deviation)
        Change in Average Number of IC GL-3 Inclusions
    -0.224 ± 0.5126
    0.106 ± 0.5627
    Statistical analysis title
    		 Treatment Difference (Migalastat minus Placebo)
    Statistical analysis description
    The change from Baseline (Visit 1) to Month 6 (Visit 4) in the average number of inclusions per capillary was analyzed using an ANCOVA model with covariate adjustment for the Baseline value and factors for treatment group and the treatment by Baseline interaction. The p-value corresponds to the LS mean difference between migalastat-migalastat and placebo-migalastat.
    Comparison groups
    Migalastat-Migalastat ITT Population (amenable GLA mutations) v Placebo-Migalastat ITT Population (amenable GLA mutations)
    Number of subjects included in analysis
    45
    Analysis specification
    Post-hoc
    Analysis type
    		 other [4]
    P-value
    		 = 0.0078
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.6
         upper limit
    		 -0.1
    Notes
    [4] - Non-parametric analysis

    Post-hoc: Change from Baseline (Visit 1) in the Gastrointestinal Symptom Rating Scale (GSRS) Diarrhea Subscale

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    End point title
    		 Change from Baseline (Visit 1) in the Gastrointestinal Symptom Rating Scale (GSRS) Diarrhea Subscale
    End point description
    The change from Baseline (Visit 1) to Month 6 (Visit 4) in the Diarrhea Subscale of the GSRS was a Post-Hoc endpoint. The ITT Population with amenable mutations was used for this analysis and included all randomized subjects with amenable mutations based on the GLP HEK assay.
    End point type
    Post-hoc
    End point timeframe
    Baseline (Visit 1) to Month 6 (Visit 4)
    End point values
    		 Migalastat-Migalastat ITT Population (amenable GLA mutations) Placebo-Migalastat ITT Population (amenable GLA mutations)
    Number of subjects analysed
    28
    19
    Units: units on a scale
    least squares mean (standard deviation)
        Change from Baseline in the GSRS Diarrhea Subscale
    -0.3 ± 0.86
    0.2 ± 0.75
    Statistical analysis title
    		 Treatment Difference (Migalastat minus Placebo)
    Statistical analysis description
    Data were analyzed using an ANCOVA model that included treatment, Baseline and treatment by Baseline interaction. The treatment effect was estimated as the difference between migalastat and placebo in the LS mean estimates for treatment.
    Comparison groups
    Migalastat-Migalastat ITT Population (amenable GLA mutations) v Placebo-Migalastat ITT Population (amenable GLA mutations)
    Number of subjects included in analysis
    47
    Analysis specification
    Post-hoc
    Analysis type
    		 other [5]
    P-value
    		 = 0.0264
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 -0.1
    Notes
    [5] - Non-parametric analysis

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) were reported from the first dose of study medication in Period 1 through to 1 month (±7 days) after the date of last study visit whether in Period 1, 2 or 3.
    Adverse event reporting additional description
    AE data is reported as treatment-emergent AEs. AEs are presented for the safety population for all study periods, i.e. 24 months. Reporting groups: Migalastat Safety Population (24-month analyses) (subjects received migalastat in Periods 1, 2 and 3); and Placebo Safety Population (6-month analyses) (subjects received placebo in Period 1).
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Migalastat Safety Population (24-month analyses)
    Reporting group description
    		 The migalastat safety population (24-month analyses) includes all subjects in the Intent-to Treat (ITT) population who received at least 1 dose of migalastat during Periods 1, 2 and 3.

    Reporting group title
    Placebo Safety Population (6-month analyses)
    Reporting group description
    		 The placebo safety population (6-month analyses) includes all subjects in the ITT population who received at least 1 dose of placebo during Period 1.

    Serious adverse events
    		 Migalastat Safety Population (24-month analyses) Placebo Safety Population (6-month analyses)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 64 (23.44%)
    4 / 33 (12.12%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    ANAPLASTIC LARGE CELL LYMPHOMA T- AND NULL-CELL TYPES
    Additional description: Reporting groups: Migalastat Safety Population (24-month analyses) (subjects received migalastat in Periods 1, 2 and 3); and Placebo Safety Population (6-month analyses) (subjects received placebo in Period 1).
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    MULTIPLE FRACTURES
    Additional description: Reporting groups: Migalastat Safety Population (24-month analyses) (subjects received migalastat in Periods 1, 2 and 3); and Placebo Safety Population (6-month analyses) (subjects received placebo in Period 1).
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    POST PROCEDURAL HAEMATOMA
    Additional description: Reporting groups: Migalastat Safety Population (24-month analyses) (subjects received migalastat in Periods 1, 2 and 3); and Placebo Safety Population (6-month analyses) (subjects received placebo in Period 1).
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    POST PROCEDURAL HAEMORRHAGE
    Additional description: Reporting groups: Migalastat Safety Population (24-month analyses) (subjects received migalastat in Periods 1, 2 and 3); and Placebo Safety Population (6-month analyses) (subjects received placebo in Period 1).
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    DEEP VEIN THROMBOSIS
    Additional description: Reporting groups: Migalastat Safety Population (24-month analyses) (subjects received migalastat in Periods 1, 2 and 3); and Placebo Safety Population (6-month analyses) (subjects received placebo in Period 1).
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    PALPITATIONS
    Additional description: Reporting groups: Migalastat Safety Population (24-month analyses) (subjects received migalastat in Periods 1, 2 and 3); and Placebo Safety Population (6-month analyses) (subjects received placebo in Period 1).
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VENTRICULAR TACHYCARDIA
    Additional description: Reporting groups: Migalastat Safety Population (24-month analyses) (subjects received migalastat in Periods 1, 2 and 3); and Placebo Safety Population (6-month analyses) (subjects received placebo in Period 1).
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    AMYOTROPHIC LATERAL SCLEROSIS
    Additional description: Reporting groups: Migalastat Safety Population (24-month analyses) (subjects received migalastat in Periods 1, 2 and 3); and Placebo Safety Population (6-month analyses) (subjects received placebo in Period 1).
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CEREBRAL HAEMORRHAGE
    Additional description: Reporting groups: Migalastat Safety Population (24-month analyses) (subjects received migalastat in Periods 1, 2 and 3); and Placebo Safety Population (6-month analyses) (subjects received placebo in Period 1).
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PARAESTHESIA
    Additional description: Reporting groups: Migalastat Safety Population (24-month analyses) (subjects received migalastat in Periods 1, 2 and 3); and Placebo Safety Population (6-month analyses) (subjects received placebo in Period 1).
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SYNCOPE
    Additional description: Reporting groups: Migalastat Safety Population (24-month analyses) (subjects received migalastat in Periods 1, 2 and 3); and Placebo Safety Population (6-month analyses) (subjects received placebo in Period 1).
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TRANSIENT ISCHAEMIC ATTACK
    Additional description: Reporting groups: Migalastat Safety Population (24-month analyses) (subjects received migalastat in Periods 1, 2 and 3); and Placebo Safety Population (6-month analyses) (subjects received placebo in Period 1).
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    FATIGUE
    Additional description: Reporting groups: Migalastat Safety Population (24-month analyses) (subjects received migalastat in Periods 1, 2 and 3); and Placebo Safety Population (6-month analyses) (subjects received placebo in Period 1).
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MALAISE
    Additional description: Reporting groups: Migalastat Safety Population (24-month analyses) (subjects received migalastat in Periods 1, 2 and 3); and Placebo Safety Population (6-month analyses) (subjects received placebo in Period 1).
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NON-CARDIAC CHEST PAIN
    Additional description: Reporting groups: Migalastat Safety Population (24-month analyses) (subjects received migalastat in Periods 1, 2 and 3); and Placebo Safety Population (6-month analyses) (subjects received placebo in Period 1).
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN LOWER
    Additional description: Reporting groups: Migalastat Safety Population (24-month analyses) (subjects received migalastat in Periods 1, 2 and 3); and Placebo Safety Population (6-month analyses) (subjects received placebo in Period 1).
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CONSTIPATION
    Additional description: Reporting groups: Migalastat Safety Population (24-month analyses) (subjects received migalastat in Periods 1, 2 and 3); and Placebo Safety Population (6-month analyses) (subjects received placebo in Period 1).
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    PNEUMOTHORAX
    Additional description: Reporting groups: Migalastat Safety Population (24-month analyses) (subjects received migalastat in Periods 1, 2 and 3); and Placebo Safety Population (6-month analyses) (subjects received placebo in Period 1).
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
    Additional description: Reporting groups: Migalastat Safety Population (24-month analyses) (subjects received migalastat in Periods 1, 2 and 3); and Placebo Safety Population (6-month analyses) (subjects received placebo in Period 1).
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    BULIMIA NERVOSA
    Additional description: Reporting groups: Migalastat Safety Population (24-month analyses) (subjects received migalastat in Periods 1, 2 and 3); and Placebo Safety Population (6-month analyses) (subjects received placebo in Period 1).
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    HYDRONEPHROSIS
    Additional description: Reporting groups: Migalastat Safety Population (24-month analyses) (subjects received migalastat in Periods 1, 2 and 3); and Placebo Safety Population (6-month analyses) (subjects received placebo in Period 1).
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    BONE CYST
    Additional description: Reporting groups: Migalastat Safety Population (24-month analyses) (subjects received migalastat in Periods 1, 2 and 3); and Placebo Safety Population (6-month analyses) (subjects received placebo in Period 1).
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    BACTERIAL INFECTION
    Additional description: Reporting groups: Migalastat Safety Population (24-month analyses) (subjects received migalastat in Periods 1, 2 and 3); and Placebo Safety Population (6-month analyses) (subjects received placebo in Period 1).
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HELICOBACTER GASTRITIS
    Additional description: Reporting groups: Migalastat Safety Population (24-month analyses) (subjects received migalastat in Periods 1, 2 and 3); and Placebo Safety Population (6-month analyses) (subjects received placebo in Period 1).
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MENINGITIS VIRAL
    Additional description: Reporting groups: Migalastat Safety Population (24-month analyses) (subjects received migalastat in Periods 1, 2 and 3); and Placebo Safety Population (6-month analyses) (subjects received placebo in Period 1).
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Migalastat Safety Population (24-month analyses) Placebo Safety Population (6-month analyses)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    56 / 64 (87.50%)
    23 / 33 (69.70%)
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    4 / 64 (6.25%)
    0 / 33 (0.00%)
         occurrences all number
    4
    0
    General disorders and administration site conditions
    FATIGUE
         subjects affected / exposed
    7 / 64 (10.94%)
    4 / 33 (12.12%)
         occurrences all number
    9
    4
    PYREXIA
         subjects affected / exposed
    4 / 64 (6.25%)
    1 / 33 (3.03%)
         occurrences all number
    9
    1
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    5 / 64 (7.81%)
    0 / 33 (0.00%)
         occurrences all number
    6
    0
    EPISTAXIS
         subjects affected / exposed
    4 / 64 (6.25%)
    1 / 33 (3.03%)
         occurrences all number
    4
    1
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    8 / 64 (12.50%)
    2 / 33 (6.06%)
         occurrences all number
    8
    2
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    4 / 64 (6.25%)
    1 / 33 (3.03%)
         occurrences all number
    4
    1
    DEPRESSION
         subjects affected / exposed
    7 / 64 (10.94%)
    0 / 33 (0.00%)
         occurrences all number
    8
    0
    INSOMNIA
         subjects affected / exposed
    3 / 64 (4.69%)
    2 / 33 (6.06%)
         occurrences all number
    3
    2
    Injury, poisoning and procedural complications
    INCORRECT DOSE ADMINISTERED
         subjects affected / exposed
    4 / 64 (6.25%)
    1 / 33 (3.03%)
         occurrences all number
    4
    1
    PROCEDURAL PAIN
         subjects affected / exposed
    8 / 64 (12.50%)
    1 / 33 (3.03%)
         occurrences all number
    10
    1
    Cardiac disorders
    TACHYCARDIA
         subjects affected / exposed
    4 / 64 (6.25%)
    1 / 33 (3.03%)
         occurrences all number
    4
    1
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    5 / 64 (7.81%)
    1 / 33 (3.03%)
         occurrences all number
    6
    1
    HEADACHE
         subjects affected / exposed
    22 / 64 (34.38%)
    7 / 33 (21.21%)
         occurrences all number
    60
    8
    PARAESTHESIA
         subjects affected / exposed
    10 / 64 (15.63%)
    4 / 33 (12.12%)
         occurrences all number
    13
    4
    Ear and labyrinth disorders
    VERTIGO
         subjects affected / exposed
    5 / 64 (7.81%)
    3 / 33 (9.09%)
         occurrences all number
    5
    3
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    5 / 64 (7.81%)
    1 / 33 (3.03%)
         occurrences all number
    6
    1
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    6 / 64 (9.38%)
    0 / 33 (0.00%)
         occurrences all number
    6
    0
    CONSTIPATION
         subjects affected / exposed
    5 / 64 (7.81%)
    2 / 33 (6.06%)
         occurrences all number
    6
    2
    DIARRHEA
         subjects affected / exposed
    10 / 64 (15.63%)
    1 / 33 (3.03%)
         occurrences all number
    13
    1
    DRY MOUTH
         subjects affected / exposed
    2 / 64 (3.13%)
    2 / 33 (6.06%)
         occurrences all number
    2
    2
    NAUSEA
         subjects affected / exposed
    9 / 64 (14.06%)
    2 / 33 (6.06%)
         occurrences all number
    12
    2
    VOMITING
         subjects affected / exposed
    5 / 64 (7.81%)
    2 / 33 (6.06%)
         occurrences all number
    5
    2
    Renal and urinary disorders
    HAEMATURIA
         subjects affected / exposed
    4 / 64 (6.25%)
    0 / 33 (0.00%)
         occurrences all number
    4
    0
    PROTEINURIA
         subjects affected / exposed
    9 / 64 (14.06%)
    0 / 33 (0.00%)
         occurrences all number
    10
    0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    8 / 64 (12.50%)
    2 / 33 (6.06%)
         occurrences all number
    10
    2
    BACK PAIN
         subjects affected / exposed
    8 / 64 (12.50%)
    0 / 33 (0.00%)
         occurrences all number
    9
    0
    MUSCLE SPASMS
         subjects affected / exposed
    4 / 64 (6.25%)
    3 / 33 (9.09%)
         occurrences all number
    6
    4
    MYALGIA
         subjects affected / exposed
    5 / 64 (7.81%)
    1 / 33 (3.03%)
         occurrences all number
    6
    2
    NECK PAIN
         subjects affected / exposed
    4 / 64 (6.25%)
    1 / 33 (3.03%)
         occurrences all number
    11
    1
    PAIN IN EXTREMITY
         subjects affected / exposed
    3 / 64 (4.69%)
    4 / 33 (12.12%)
         occurrences all number
    5
    6
    Infections and infestations
    BRONCHITIS
         subjects affected / exposed
    8 / 64 (12.50%)
    0 / 33 (0.00%)
         occurrences all number
    10
    0
    INFLUENZA
         subjects affected / exposed
    2 / 64 (3.13%)
    3 / 33 (9.09%)
         occurrences all number
    2
    3
    NASOPHARYNGITIS
         subjects affected / exposed
    12 / 64 (18.75%)
    2 / 33 (6.06%)
         occurrences all number
    15
    2
    SINUSITIS
         subjects affected / exposed
    4 / 64 (6.25%)
    0 / 33 (0.00%)
         occurrences all number
    6
    0
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    8 / 64 (12.50%)
    3 / 33 (9.09%)
         occurrences all number
    13
    4
    URINARY TRACT INFECTION
         subjects affected / exposed
    9 / 64 (14.06%)
    0 / 33 (0.00%)
         occurrences all number
    11
    0
    Metabolism and nutrition disorders
    VITAMIN D DEFICIENCY
         subjects affected / exposed
    5 / 64 (7.81%)
    1 / 33 (3.03%)
         occurrences all number
    5
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Dec 2009
    • Changed the stopping criterion regarding serum creatinine from a 50% increase to a 30% increase. • Removed surgical sterilization as an acceptable method of contraception for male subjects. • Clarified methods of surgical sterilization allowed as contraception for female subjects to include hysterectomy or bilateral tubal ligation, oophorectomy or salpingectomy. • Changed to not require female subjects using a diaphragm as contraception to use the diaphragm in combination with male condoms. Eliminated monthly at home pregnancy tests. • Added Levaquin and amiodarone as prohibited medications.
    10 Aug 2010
    This description includes the cummulative changes from Amendment 2 (dated 27 July 2010) and Amendment 2.1 (dated 10 August 2010): • Added details of the open-label extension • Corrected inclusion criterion #4 “from urine GL-3 greater than 4 times…” to “urine GL-3 greater than or equal to 4 times…” • Removed exclusion criterion #3, which was related to QTc at Screening • Removed Levaquin and amiodarone from the list of prohibited medications • Permitted repeat assessments at Screening and rescreening of subjects who screen failed • No longer required repeat testing of persistent clinically significant results • Added blister packaged study drug. Corrected description of the color of study drug capsules • Prior versions of the protocol stipulated that the iohexol dose was to be administered over 1 to 2 minutes; the laboratory manual specified that the iohexol dose was to be administered over 30 seconds to 1 minute. The protocol was modified to align with the laboratory manual. • Provided guidance for cases in which a subject discontinued within a short time from Baseline (Visit 1), Month 6 (Visit 4), or Month 12 (Visit 6).
    20 Sep 2011
    • Added opportunity for subjects to transition into a separate open-label extension protocol • Revised so that the Follow-Up Visit occurred after the last study treatment visit • No longer required subjects to have a Follow-Up Visit if they entered the open-label extension • Clarified method of assessing study drug compliance • Clarified which female subjects were required to undergo pregnancy testing • Clarified visit windows and standardized definition of a study month • Clarified that it may not be possible to perform all assessments at certain visits within 1 day • Allowed an Unscheduled Visit to occur at the discretion of the investigator • Described procedures to occur for subjects taking study drug after 24 months of treatment • Clarified when serum and urine pregnancy tests would be taken • Added request to repeat urinalysis if visits involving a kidney biopsy spanned a long period of time • Clarified timing of blood draws and removed requirements for visit windows for pharmacokinetic assessments • Provided guidance for evaluation of disease progression of Fabry symptoms as AEs • Changed definition of serious AEs to reflect Food and Drug Administration revisions. Clarified reporting timelines. • Clarified responsibilities of investigator and sponsor.
    20 Nov 2012
    This description includes cummulative changes from Amendment 4 (dated 1 November 2012) and Amendment 4.1 (dated 20 November 2012): • Revised description of contraception requirements • Added optional blood draw for GLA genotyping • Allowed for potential future genetic testing.

    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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