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    Clinical Trial Results:
    A Phase 2 Study to Evaluate the Safety, Pharmacodynamics, Pharmacokinetics, and Exploratory Efficacy of GZ/SAR402671 in Enzyme Replacement Therapy (ERT) Treatment-naïve Adult Male Patients Diagnosed with Fabry Disease

    Summary
    EudraCT number
    2013-005324-41
    Trial protocol
    GB   CZ  
    Global end of trial date
    06 Sep 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    21 Sep 2017
    First version publication date
    21 Sep 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ACT13739
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02228460
    WHO universal trial number (UTN)
    U1111-1152-1456
    Sponsors
    Sponsor organisation name
    Genzyme Corporation
    Sponsor organisation address
    500 Kendall Street, Cambridge, MA, United States, 02142
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Sep 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Sep 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), and exploratory efficacy of GZ402671/SAR402671 in enzyme replacement therapy (ERT) treatment-naïve adult male subjects diagnosed with Fabry disease (FD).
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    11 Nov 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Russian Federation: 1
    Country: Number of subjects enrolled
    United States: 4
    Country: Number of subjects enrolled
    United Kingdom: 4
    Worldwide total number of subjects
    11
    EEA total number of subjects
    6
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    11
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects were enrolled in the study at 8 centers in 5 countries between 11 November 2014 and 06 September 2016. A total of 14 subjects were screened in the study.

    Pre-assignment
    Screening details
    Out of 14 screened subjects, 11 subjects were enrolled and treated in the study.

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

    Arms
    Arm title
    GZ/SAR402671
    Arm description
    GZ/SAR402671 15 mg once daily, orally for 26 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    GZ/SAR402671
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    GZ/SAR402671 capsule, once daily for 26 weeks.

    Number of subjects in period 1
    GZ/SAR402671
    Started
    11
    Completed
    9
    Not completed
    2
         Adverse event
             1
         Lost to follow-up
             1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    GZ/SAR402671
    Reporting group description
    GZ/SAR402671 15 mg once daily, orally for 26 weeks.

    Reporting group values
    GZ/SAR402671 Total
    Number of subjects
    11 11
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    26.5 ± 7.6 -
    Gender categorical
    Units: Subjects
        Female
    0 0
        Male
    11 11

    End points

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    End points reporting groups
    Reporting group title
    GZ/SAR402671
    Reporting group description
    GZ/SAR402671 15 mg once daily, orally for 26 weeks.

    Primary: Change From Baseline at Week 26 in Skin Globotriaosylceramide (GL-3) Score in Superficial Skin Capillary Endothelium: Number of Subjects in Categories of Shift in GL-3 Score From Baseline to Week 26

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    End point title
    Change From Baseline at Week 26 in Skin Globotriaosylceramide (GL-3) Score in Superficial Skin Capillary Endothelium: Number of Subjects in Categories of Shift in GL-3 Score From Baseline to Week 26 [1]
    End point description
    Skin biopsies taken at baseline and Week 26 were analyzed for cellular GL-3 accumulation (inclusions) by light microscopy. Three independent pathologists evaluated each biopsy using an inclusion severity score of 0 (none/trace), 1 (mild), 2 (moderate), and 3 (severe). A single score per subject per time point was derived by taking the score rated by a majority of the pathologists; if a majority score could not be derived, the median score was used. Data were summarized and reported in terms of number of subjects with shift from baseline GL-3 score to Week 26 GL-3 score. Any shift category of Baseline score/Week 26 score that was not observed is not reported. Shift to lower score from baseline to Week 26 indicates less severe condition at Week 26. Analysis was performed on Full Analysis Set (FAS) that included all subjects who received at least 1 dose of study treatment. Number of subjects analyzed=subjects with available data at both baseline and Week 26.
    End point type
    Primary
    End point timeframe
    Baseline, Week 26
    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: Single arm study. A McNemar test was used to assess the treatment effect based on paired pre-treatment and post-treatment (Week 26) frequencies of skin GL-3 score grouped into categories (0 to <2; 2 to 3) at the 5% significance level. p = 0.3173
    End point values
    GZ/SAR402671
    Number of subjects analysed
    9
    Units: subjects
        Baseline Score:1/Week 26 Score:1
    4
        Baseline Score:1/Week 26 Score:2
    1
        Baseline Score:2/Week 26 Score:1
    3
        Baseline Score:2/Week 26 Score:2
    1
    No statistical analyses for this end point

    Primary: Mean Change From Baseline at Week 26 in Skin GL-3 Score in Superficial Skin Capillary Endothelium

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    End point title
    Mean Change From Baseline at Week 26 in Skin GL-3 Score in Superficial Skin Capillary Endothelium [2]
    End point description
    Skin biopsies taken at baseline and Week 26 were analyzed for cellular GL-3 accumulation (inclusions) by light microscopy. Three independent pathologists evaluated each biopsy using an inclusion severity score of 0 (none/trace), 1 (mild), 2 (moderate), and 3 (severe). A single score per subject per time point was derived by taking the score rated by a majority of the pathologists; if a majority score could not be derived, the median score was used. Change from baseline in GL-3 score was obtained by subtracting baseline value from post-baseline value at Week 26. A negative change from baseline indicates less severe condition at Week 26. Analysis was performed on FAS. Number of subjects analyzed=subjects with available data at both baseline and Week 26.
    End point type
    Primary
    End point timeframe
    Baseline, Week 26
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Single arm study. A Wilcoxon signed rank test was used to assess the mean change from baseline to Week 26 in skin GL-3 score at the 5% significance level. p = 0.625
    End point values
    GZ/SAR402671
    Number of subjects analysed
    9
    Units: score on a scale
        arithmetic mean (confidence interval 95%)
    -0.22 (-0.73 to 0.29)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Plasma GL-3 Concentration at Week 26

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    End point title
    Change From Baseline in Plasma GL-3 Concentration at Week 26
    End point description
    Change from baseline in plasma GL-3 was obtained by subtracting baseline value from post-baseline value at Week 26. Concentration of GL-3 in plasma was determined using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Analysis was performed on FAS. Number of subjects analyzed = subjects with available data at both baseline and Week 26.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    GZ/SAR402671
    Number of subjects analysed
    9
    Units: mcg/mL
        arithmetic mean (standard deviation)
    -3.62 ± 1.07
    No statistical analyses for this end point

    Secondary: Change From Baseline in Plasma Lyso Globotriaosylceramide (Lyso-GL-3) Concentration at Week 26

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    End point title
    Change From Baseline in Plasma Lyso Globotriaosylceramide (Lyso-GL-3) Concentration at Week 26
    End point description
    Change from baseline in plasma Lyso-GL-3 was obtained by subtracting baseline value from post-baseline value at Week 26. Concentration of lyso-GL-3 in plasma was determined using a validated LC-MS/MS method. Analysis was performed on FAS. Number of subjects analyzed = subjects with available data at both baseline and Week 26.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    GZ/SAR402671
    Number of subjects analysed
    9
    Units: ng/mL
        arithmetic mean (standard deviation)
    -30.99 ± 22.83
    No statistical analyses for this end point

    Secondary: Change From Baseline in Plasma Glucosylceramide (GL-1) Concentration at Week 26

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    End point title
    Change From Baseline in Plasma Glucosylceramide (GL-1) Concentration at Week 26
    End point description
    Change from baseline in plasma GL-1 was obtained by subtracting baseline value from post-baseline value at Week 26. Concentration of GL-1 in plasma was determined using a validated LC-MS/MS method. Analysis was performed on FAS. Number of subjects analyzed = subjects with available data at both baseline and Week 26.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    GZ/SAR402671
    Number of subjects analysed
    9
    Units: mcg/mL
        arithmetic mean (standard deviation)
    -3.26 ± 1.43
    No statistical analyses for this end point

    Secondary: Change From Baseline at Week 26 in Skin GL-3 Score in Deep Vessels Endothelial Cells: Number of Subjects in Categories of Shift in GL-3 Score From Baseline to Week 26

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    End point title
    Change From Baseline at Week 26 in Skin GL-3 Score in Deep Vessels Endothelial Cells: Number of Subjects in Categories of Shift in GL-3 Score From Baseline to Week 26
    End point description
    Skin biopsies taken at baseline and Week 26 were analyzed for cellular GL-3 accumulation (inclusions) by light microscopy. Three independent pathologists evaluated each biopsy using an inclusion severity score of 0 (none/trace), 1 (mild), 2 (moderate), and 3 (severe). A single score per subject per time point was derived by taking the score rated by a majority of the pathologists; if a majority score could not be derived, the median score was used. Data were summarized and reported in terms of number of subjects with shift from baseline GL-3 score to Week 26 GL-3 score. Any shift category of Baseline score/Week 26 score that was not observed is not reported. Shift to lower score from baseline to Week 26 indicates less severe condition at Week 26. Analysis was performed on FAS. Number of subjects analyzed=subjects with available data at both baseline and Week 26.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    GZ/SAR402671
    Number of subjects analysed
    9
    Units: subjects
        Baseline Score:1/Week 26 Score:1
    1
        Baseline Score:2/Week 26 Score:1
    2
        Baseline Score:2/Week 26 Score:2
    6
    No statistical analyses for this end point

    Secondary: Change From Baseline at Week 26 in Skin GL-3 Score in Deep Vessels Smooth Muscle Cells: Number of Subjects in Categories of Shift in GL-3 Score From Baseline to Week 26

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    End point title
    Change From Baseline at Week 26 in Skin GL-3 Score in Deep Vessels Smooth Muscle Cells: Number of Subjects in Categories of Shift in GL-3 Score From Baseline to Week 26
    End point description
    Skin biopsies taken at baseline and Week 26 were analyzed for cellular GL-3 accumulation (inclusions) by light microscopy. Three independent pathologists evaluated each biopsy using an inclusion severity score of 0 (none/trace), 1 (mild), 2 (moderate), and 3 (severe). A single score per subject per time point was derived by taking the score rated by a majority of the pathologists; if a majority score could not be derived, the median score was used. Data were summarized and reported in terms of number of subjects with shift from baseline GL-3 score to Week 26 GL-3 score. Any shift category of Baseline score/Week 26 score that was not observed is not reported. Shift to lower score from baseline to Week 26 indicates less severe condition at Week 26. Analysis was performed on FAS. Number of subjects analyzed=subjects with available data at both baseline and Week 26.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    GZ/SAR402671
    Number of subjects analysed
    9
    Units: subjects
        Baseline Score:1.5/Week 26 Score:1.5
    2
        Baseline Score:2/Week 26 Score:2
    7
    No statistical analyses for this end point

    Secondary: Change From Baseline at Week 26 in Skin GL-3 Score in Perineurium Cells: Number of Subjects in Categories of Shift in GL-3 Score From Baseline to Week 26

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    End point title
    Change From Baseline at Week 26 in Skin GL-3 Score in Perineurium Cells: Number of Subjects in Categories of Shift in GL-3 Score From Baseline to Week 26
    End point description
    Skin biopsies taken at baseline and Week 26 were analyzed for cellular GL-3 accumulation (inclusions) by light microscopy. Three independent pathologists evaluated each biopsy using an inclusion severity score of 0 (none/trace), 1 (mild), 2 (moderate), and 3 (severe). A single score per subject per time point was derived by taking the score rated by a majority of the pathologists; if a majority score could not be derived, the median score was used. Data were summarized and reported in terms of number of subjects with shift from baseline GL-3 score to Week 26 GL-3 score. Any shift category of Baseline score/Week 26 score that was not observed is not reported. Shift to lower score from baseline to Week 26 indicates less severe condition at Week 26. Analysis was performed on FAS. Number of subjects analyzed=subjects with available data at both baseline and Week 26.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    GZ/SAR402671
    Number of subjects analysed
    9
    Units: subjects
        Baseline Score:1/Week 26 Score:2
    1
        Baseline Score:2/Week 26 Score:2
    8
    No statistical analyses for this end point

    Secondary: Change From Baseline in Urine Globotriaosylceramide (GL-3) Concentration at Week 26

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    End point title
    Change From Baseline in Urine Globotriaosylceramide (GL-3) Concentration at Week 26
    End point description
    Change from baseline in plasma GL-3 was obtained by subtracting baseline value from post-baseline value at Week 26. Concentration of GL-3 in urine was determined using a validated LC-MS/MS method. Analysis was performed on FAS. Number of subjects analyzed = subjects with available data at both baseline and Week 26.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    GZ/SAR402671
    Number of subjects analysed
    8
    Units: mg/mmol Cr
        arithmetic mean (standard deviation)
    -0.25 ± 0.19
    No statistical analyses for this end point

    Secondary: 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)
    End point description
    Any untoward medical occurrence in a subject who received study drug was considered an adverse event (AE) without regard to possibility of causal relationship with this treatment. TEAEs were defined as AEs that developed or worsened during on-treatment period (period from the first administration of study drug through the last administration of the study drug plus 30 days or end of study participation for subject, whichever occurs first). Analysis was performed on safety population defined as all enrolled subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline up to 212 days
    End point values
    GZ/SAR402671
    Number of subjects analysed
    11
    Units: subjects
    9
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK): Maximum Plasma Drug Concentration (Cmax) of GZ/SAR402671

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    End point title
    Pharmacokinetics (PK): Maximum Plasma Drug Concentration (Cmax) of GZ/SAR402671
    End point description
    Maximum plasma concentration observed for study drug was reported. Analysis was performed on PK population defined as all subjects for whom the primary PK data were considered sufficient and interpretable. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Day 1 (predose and 1, 2, 4, 8, 24 hours post-dose); Day 182 (predose and 1, 2, 4, 8, 24 hours postdose)
    End point values
    GZ/SAR402671
    Number of subjects analysed
    11
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1 (n=11)
    24.7 ± 5.89
        Day 182 (n=9)
    192 ± 96.4
    No statistical analyses for this end point

    Secondary: PK: Plasma Trough Concentration (Ctrough) of GZ/SAR402671

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    End point title
    PK: Plasma Trough Concentration (Ctrough) of GZ/SAR402671
    End point description
    Ctrough was defined as the plasma concentration of study drug observed just before treatment administration during repeated dosing. Analysis was performed on PK population. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Predose on Day 14, 28, 56, 84, 126 and 182
    End point values
    GZ/SAR402671
    Number of subjects analysed
    11
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 14 (n= 11)
    152 ± 68.9
        Day 28 (n= 11)
    165 ± 66.1
        Day 56 (n= 10)
    182 ± 90.3
        Day 84 (n= 10)
    164 ± 124
        Day 126 (n= 9)
    175 ± 94.7
        Day 182 (n= 9)
    164 ± 89.4
    No statistical analyses for this end point

    Secondary: PK: Time to Reach Maximum Plasma Drug Concentration (Tmax) of GZ/SAR402671

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    End point title
    PK: Time to Reach Maximum Plasma Drug Concentration (Tmax) of GZ/SAR402671
    End point description
    Tmax was defined as time to reach maximum plasma concentration of study drug. Analysis was performed on PK population. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Day 1 (predose and 1, 2, 4, 8, 24 hours post-dose); Day 182 (predose and 1, 2, 4, 8, 24 hours postdose)
    End point values
    GZ/SAR402671
    Number of subjects analysed
    11
    Units: hours
    median (full range (min-max))
        Day 1 (n= 11)
    8 (1.07 to 24)
        Day 182 (n= 9)
    4 (0 to 8)
    No statistical analyses for this end point

    Secondary: PK: Area Under Plasma Concentration Versus Time Curve From 0 to 24 Hours (AUC0-24) of GZ/SAR402671

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    End point title
    PK: Area Under Plasma Concentration Versus Time Curve From 0 to 24 Hours (AUC0-24) of GZ/SAR402671
    End point description
    Area under the plasma concentration versus time curve of study drug from time 0 to 24 hours (AUC0-24) was calculated using the trapezoidal method over the dosing interval. Analysis was performed on PK population. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Day 1 (predose and 1, 2, 4, 8, 24 hours post-dose); Day 182 (predose and 1, 2, 4, 8, 24 hours postdose)
    End point values
    GZ/SAR402671
    Number of subjects analysed
    11
    Units: ng*hour/mL
    arithmetic mean (standard deviation)
        Day 1 (n= 11)
    476 ± 125
        Day 182 (n= 9)
    4110 ± 2090
    No statistical analyses for this end point

    Secondary: PK: Terminal Half-life (t1/2z) of GZ/SAR402671

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    End point title
    PK: Terminal Half-life (t1/2z) of GZ/SAR402671
    End point description
    Plasma t1/2z was the time measured for the plasma concentration of drug to decrease by one half. The t1/2z was estimated based on 24-hour post-dose PK. Analysis was performed on PK population. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Day 1 (predose and 1, 2, 4, 8, 24 hours post-dose); Day 182 (predose and 1, 2, 4, 8, 24 hours postdose)
    End point values
    GZ/SAR402671
    Number of subjects analysed
    11
    Units: hours
    arithmetic mean (standard deviation)
        Day 1 (n= 4)
    86.8 ± 39.6
        Day 182 (n= 7)
    128 ± 59
    No statistical analyses for this end point

    Secondary: PK: Apparent Total Body Clearance of GZ/SAR402671 (CLss/F)

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    End point title
    PK: Apparent Total Body Clearance of GZ/SAR402671 (CLss/F)
    End point description
    Drug clearance was a quantitative measure of the rate at which a drug substance was removed from the blood. Analysis was performed on PK population. Number of subjects analyzed = subjects with available data for this end point.
    End point type
    Secondary
    End point timeframe
    Predose and 1, 2, 4, 8, 24 hours post-dose on Day 182
    End point values
    GZ/SAR402671
    Number of subjects analysed
    9
    Units: mL/hour
        arithmetic mean (standard deviation)
    7490 ± 10900
    No statistical analyses for this end point

    Secondary: PK: Apparent Volume of Distribution of GZ/SAR402671 (Vss/F) at Steady State

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    End point title
    PK: Apparent Volume of Distribution of GZ/SAR402671 (Vss/F) at Steady State
    End point description
    Volume of distribution at steady state was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of drug. Since the percent extrapolation of AUC for all subjects was >30%, AUC could not be determined and hence, Vss/F could not be calculated.
    End point type
    Secondary
    End point timeframe
    Predose and 1, 2, 4, 8, 24 hours post-dose on Day 182
    End point values
    GZ/SAR402671
    Number of subjects analysed
    0 [3]
    Units: Liters (L)
        arithmetic mean (standard deviation)
    ±
    Notes
    [3] - Since percent extrapolation of AUC for all subjects was >30%, hence Vss/F could not be calculated.
    No statistical analyses for this end point

    Secondary: PK: Cumulated Amount of GZ/SAR402671 Excreted in Urine From 0 to 24 Hours (Ae0-24)

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    End point title
    PK: Cumulated Amount of GZ/SAR402671 Excreted in Urine From 0 to 24 Hours (Ae0-24)
    End point description
    Ae0-24 was the cumulated amount of study drug excreted in urine during the time interval of 0 to 24 hours. Analysis was performed on PK population. Number of subjects analyzed = subjects with available data for this end point.
    End point type
    Secondary
    End point timeframe
    0-24 hours on Day 182
    End point values
    GZ/SAR402671
    Number of subjects analysed
    9
    Units: mcg
        arithmetic mean (standard deviation)
    3210 ± 1640
    No statistical analyses for this end point

    Secondary: PK: Percentage of Dose of GZ/SAR402671 Excreted in Urine From 0 to 24 Hours (fe0-24)

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    End point title
    PK: Percentage of Dose of GZ/SAR402671 Excreted in Urine From 0 to 24 Hours (fe0-24)
    End point description
    fe0-24 was the fraction of dose excreted in urine during the time interval of 0 to 24 hours. Analysis was performed on PK population. Number of subjects analyzed = subjects with available data for this end point.
    End point type
    Secondary
    End point timeframe
    0-24 hours on Day 182
    End point values
    GZ/SAR402671
    Number of subjects analysed
    9
    Units: percentage of dose
        arithmetic mean (standard deviation)
    21.4 ± 10.9
    No statistical analyses for this end point

    Secondary: PK: Renal Clearance of GZ/SAR402671 From 0 to 24 Hours (CLR)

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    End point title
    PK: Renal Clearance of GZ/SAR402671 From 0 to 24 Hours (CLR)
    End point description
    Renal clearance (CLR) was calculated by dividing the cumulative amount of drug excreted in urine during the dosing interval of 0-24 hours by area under the plasma drug concentration time-curve during the dosing interval of 0-24 hours. Analysis was performed on PK population. Number of subjects analyzed = subjects with available data for this end point.
    End point type
    Secondary
    End point timeframe
    0-24 hours on Day 182
    End point values
    GZ/SAR402671
    Number of subjects analysed
    9
    Units: mL/hour
        arithmetic mean (standard deviation)
    925 ± 407
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 212 days.
    Adverse event reporting additional description
    Reported AEs are TEAEs that is AEs developed/worsened during "on treatment period" (from first administration through last administration of study drug + 30 days or end of study participation for subject, whichever occurs first). Analysis was performed on safety population that included all enrolled subjects who received ≥1 dose of study drug.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    GZ/SAR402671
    Reporting group description
    GZ/SAR402671 15 mg once daily, orally for 26 weeks.

    Serious adverse events
    GZ/SAR402671
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 11 (27.27%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Blood and lymphatic system disorders
    Haemolysis
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Depressed Mood
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Floppy Infant
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    GZ/SAR402671
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 11 (81.82%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 11 (18.18%)
         occurrences all number
    2
    Influenza Like Illness
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    Feeling Hot
         subjects affected / exposed
    2 / 11 (18.18%)
         occurrences all number
    2
    Non-Cardiac Chest Pain
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    2 / 11 (18.18%)
         occurrences all number
    2
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    Depressed Mood
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Wound
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    Muscle Strain
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    Investigations
    Electrocardiogram T Wave Abnormal
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    Electrocardiogram Abnormal
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    Nuclear Magnetic Resonance Imaging Brain Abnormal
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    Vibration Test Abnormal
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 11 (18.18%)
         occurrences all number
    2
    Cough
         subjects affected / exposed
    2 / 11 (18.18%)
         occurrences all number
    2
    Oropharyngeal Pain
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    2
    Headache
         subjects affected / exposed
    4 / 11 (36.36%)
         occurrences all number
    5
    Dizziness
         subjects affected / exposed
    2 / 11 (18.18%)
         occurrences all number
    6
    Hypoaesthesia
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    2
    Migraine
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    2
    Paraesthesia
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    White Matter Lesion
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    Sinus Headache
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    Eye disorders
    Blepharitis
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    2
    Chalazion
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    Eye Pain
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    Lacrimation Increased
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    Lenticular Opacities
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    2
    Retinal Vascular Disorder
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    Vision Blurred
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    2 / 11 (18.18%)
         occurrences all number
    2
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    Dry Mouth
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    Oesophageal Discomfort
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    2 / 11 (18.18%)
         occurrences all number
    6
    Toothache
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    2 / 11 (18.18%)
         occurrences all number
    2
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    Angiokeratoma
         subjects affected / exposed
    2 / 11 (18.18%)
         occurrences all number
    2
    Hyperhidrosis
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal Chest Pain
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    Muscle Twitching
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    3
    Neck Pain
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    Pain In Extremity
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    Myalgia
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    Infections and infestations
    Ear Infection
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    Upper Respiratory Tract Infection
         subjects affected / exposed
    2 / 11 (18.18%)
         occurrences all number
    2
    Rhinitis
         subjects affected / exposed
    2 / 11 (18.18%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Aug 2014
    Following changes were made: - Added ophthalmology exam at Week 12, as requested by the Medicines and Healthcare products Regulatory Agency; - Exclusion of the use of grapefruit, grapefruit juice, or grapefruit products for 72 hours prior to administration of first dose of study drug and for duration of 26-week treatment period.

    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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