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    Clinical Trial Results:
    Exploratory Open Label Study to Investigate the Effect of Teriflunomide on Immune Cell Subsets in the Blood of subjects With Relapsing Forms of Multiple Sclerosis

    Summary
    EudraCT number
    2012-005324-16
    Trial protocol
    BE   NL   DE  
    Global end of trial date
    22 Jan 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    16 Apr 2016
    First version publication date
    16 Apr 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    LPS13539
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01863888
    WHO universal trial number (UTN)
    U1111-1139-8802
    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
    30 Mar 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Jan 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To measure the effect of teriflunomide on lymphocytes subsets in subjects with relapsing forms of multiple sclerosis (RMS) as compared with baseline values and those of a reference population of untreated healthy subjects.
    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
    10 Oct 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 10
    Country: Number of subjects enrolled
    Belgium: 19
    Country: Number of subjects enrolled
    Germany: 41
    Worldwide total number of subjects
    70
    EEA total number of subjects
    70
    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)
    70
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 9 centers in 3 countries (for RMS subjects) and at a single site in Germany (for healthy subjects). A total of 87 subjects (56 RMS subjects and 31 healthy subjects) were screened between 10 October 2013 and 24 June 2014.

    Pre-assignment
    Screening details
    Of 56 RMS subjects screened, 50 were included and treated in the treatment arm. Of 31 healthy subjects screened, 20 were included in the healthy subjects' arm. 17 subjects (6 RMS subjects and 11 healthy subjects) were screen failure due to unmet inclusion criteria.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    RMS Subjects
    Arm description
    Subjects with RMS received teriflunomide 14 mg once daily for 24 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Teriflunomide
    Investigational medicinal product code
    HMR1726
    Other name
    AUBAGIO®
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Teriflunomide 14 mg administered orally once daily.

    Arm title
    Healthy Subjects
    Arm description
    Untreated Healthy subjects followed for 24 weeks.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    RMS Subjects Healthy Subjects
    Started
    50
    20
    Completed
    43
    20
    Not completed
    7
    0
         Other than specified
    2
    -
         Adverse event
    1
    -
         Lack of efficacy
    3
    -
         Consent withdrawn by subject
    1
    -
    Period 2
    Period 2 title
    Optional Extension Period (RMS Subjects)
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    RMS Subjects
    Arm description
    Subjects who could not receive the commercial drug due to unavailability at the time of completion of 24 week treatment period, were proposed the extension study and received teriflunomide 14 mg once daily till the availability of commercial teriflunomide.
    Arm type
    Experimental

    Investigational medicinal product name
    Teriflunomide
    Investigational medicinal product code
    HMR1726
    Other name
    AUBAGIO®
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Teriflunomide 14 mg administered orally once daily.

    Number of subjects in period 2 [1]
    RMS Subjects
    Started
    20
    Completed
    19
    Not completed
    1
         Adverse event
    1
    Notes
    [1] - 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: Only subjects who could not receive the commercial drug due to unavailability at the time of completion of 24 weeks treatment period, were proposed to continue in the extension study.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    RMS Subjects
    Reporting group description
    Subjects with RMS received teriflunomide 14 mg once daily for 24 weeks.

    Reporting group title
    Healthy Subjects
    Reporting group description
    Untreated Healthy subjects followed for 24 weeks.

    Reporting group values
    RMS Subjects Healthy Subjects Total
    Number of subjects
    50 20 70
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    40.7 ± 9.4 42.2 ± 8 -
    Gender categorical
    Units: Subjects
        Female
    35 14 49
        Male
    15 6 21

    End points

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    End points reporting groups
    Reporting group title
    RMS Subjects
    Reporting group description
    Subjects with RMS received teriflunomide 14 mg once daily for 24 weeks.

    Reporting group title
    Healthy Subjects
    Reporting group description
    Untreated Healthy subjects followed for 24 weeks.
    Reporting group title
    RMS Subjects
    Reporting group description
    Subjects who could not receive the commercial drug due to unavailability at the time of completion of 24 week treatment period, were proposed the extension study and received teriflunomide 14 mg once daily till the availability of commercial teriflunomide.

    Primary: Change From Baseline In Lymphocytes Subsets

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    End point title
    Change From Baseline In Lymphocytes Subsets [1]
    End point description
    Least square (LS) mean was estimated using mixed effect model with repeated measures (MMRM) approach adjusted on baseline. Analysis was performed on Per Protocol (PP) population consisted of all RMS subjects and healthy subjects with no major pharmacodynamics ­related protocol deviations who had at the very minimum pharmacodynamics evaluations at baseline and week 24. Number of subjects analyzed=subjects with available data for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12, Week 24.
    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: Only descriptive statistics were performed, treated and untreated arms were not compared.
    End point values
    RMS Subjects Healthy Subjects
    Number of subjects analysed
    38
    19
    Units: Percentage of Lymphocytes (in % PBMCs)
    least squares mean (standard error)
        At Week 12
    -3.32 ± 1.3
    3.36 ± 1.07
        At Week 24
    -3.05 ± 1.43
    2.04 ± 1.38
    No statistical analyses for this end point

    Primary: Change from Baseline in T-Cells Subset Parameters

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    End point title
    Change from Baseline in T-Cells Subset Parameters [2]
    End point description
    Analysis was performed on PP population. Number of subjects analyzed=subjects with available data for this endpoint. Here 'n' signifies number of subjects with available data for T-cells subset parameters.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12, Week 24.
    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: Only descriptive statistics were performed, treated and untreated arms were not compared.
    End point values
    RMS Subjects Healthy Subjects
    Number of subjects analysed
    38
    19
    Units: Percentage of T cell subsets
    median (full range (min-max))
        CD4+ (in % of CD3+) at Week 12 (n=38,19)
    1.9 (-8 to 10)
    -0.8 (-21 to 2)
        CD4+ (in % of CD3+) at Week 24 (n=38,19)
    1.6 (-15 to 6)
    -0.8 (-25 to 4)
        HLADR+(in % CD4+) at Week 12 (n=38,19)
    1 (-3 to 5)
    0.9 (0 to 7)
        HLADR+(in % CD4+) at Week 24 (n=38,19)
    0 (-5 to 6)
    0.4 (-4 to 6)
        CD69+ (in % of CD4+) at Week 12 (n=38,19)
    0.2 (-5 to 5)
    0.2 (0 to 1)
        CD69+ (in % of CD4+) at Week 24 (n=38,19)
    0.2 (-6 to 2)
    0.2 (-1 to 3)
        Th17 (in % CD4+) at Week 12 (n=32,19)
    0 (0 to 1)
    0 (0 to 0)
        Th17 (in % CD4+) at Week 24 (n=32,19)
    0 (0 to 1)
    0 (0 to 0)
        Th1 (in % CD4+) at Week 12 (n=32,19)
    -0.5 (-3 to 3)
    0.8 (-3 to 2)
        Th1 (in % CD4+) at Week 24 (n=32,19)
    -0.4 (-5 to 2)
    0.7 (-2 to 3)
        CD8+ (in % of CD3+) at Week 12 (n=38,19)
    -1.5 (-9 to 5)
    0.9 (-2 to 21)
        CD8+ (in % of CD3+) at Week 24 (n=38,19)
    -1 (-6 to 16)
    0.6 (-4 to 24)
        HLADR+ (in % CD8+) at Week 12 (n=38,19)
    -2.2 (-21 to 12)
    3.3 (-1 to 62)
        HLADR+ (in % CD8+) at Week 24 (n=38,19)
    -4.8 (-22 to 18)
    1.4 (-9 to 21)
        CD69+ (in % of CD8+) at Week 12 (n=38,19)
    2.4 (-21 to 30)
    3.5 (-35 to 10)
        CD69+ (in % of CD8+) at Week 24 (n=38,19)
    7 (-28 to 44)
    4.7 (-33 to 18)
    No statistical analyses for this end point

    Primary: Change from Baseline in T-Cells Subset Parameters (Continued)

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    End point title
    Change from Baseline in T-Cells Subset Parameters (Continued) [3]
    End point description
    LS mean was estimated using a MMRM approach adjusted on baseline. Analysis was performed on PP population. Number of subjects analyzed=subjects with available data for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12, Week 24
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics were performed, treated and untreated arms were not compared.
    End point values
    RMS Subjects Healthy Subjects
    Number of subjects analysed
    38
    19
    Units: Percentage of T cell subsets
    least squares mean (standard error)
        FoxP3+ (in % of CD4+) at Week 12
    0.28 ± 0.28
    0.03 ± 0.14
        FoxP3+ (in % of CD4+) at Week 24
    0.31 ± 0.26
    -0.35 ± 0.19
        Helios+FoxP3+ (in % of CD4) at Week 12
    0.1 ± 0.22
    -0.15 ± 0.15
        Helios+FoxP3+ (in % of CD4) at Week 24
    0.01 ± 0.19
    -0.25 ± 0.15
        Helios-FoxP3+ (in % of CD4+) at Week 12
    0.18 ± 0.08
    0.19 ± 0.14
        Helios-FoxP3+ (in % of CD4+) at Week 24
    0.29 ± 0.1
    -0.08 ± 0.08
    No statistical analyses for this end point

    Primary: Change from Baseline in T-cells Subset Parameters [CD4+/CD8+ Ratio]

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    End point title
    Change from Baseline in T-cells Subset Parameters [CD4+/CD8+ Ratio] [4]
    End point description
    A CD4+ (in % of CD3+)/CD8+ (in % of CD3+) ratio was performed. Analysis was performed on PP population. Number of subjects analyzed=subjects with available data for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12, Week 24
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics were performed, treated and untreated arms were not compared.
    End point values
    RMS Subjects Healthy Subjects
    Number of subjects analysed
    38
    19
    Units: Ratio
    median (full range (min-max))
        At Week 12
    0.9 (-8 to 9)
    -0.3 (-15 to 2)
        At Week 24
    0.6 (-6 to 24)
    -0.3 (-15 to 3)
    No statistical analyses for this end point

    Primary: Change from Baseline in NK Cells Subset Parameters

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    End point title
    Change from Baseline in NK Cells Subset Parameters [5]
    End point description
    Analysis was performed on PP population. Number of subjects analyzed=subjects with available data for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12, Week 24.
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics were performed, treated and untreated arms were not compared.
    End point values
    RMS Subjects Healthy Subjects
    Number of subjects analysed
    38
    19
    Units: Percentage of NK cells
    median (full range (min-max))
        NK cells (in % of lymphocytes) at Week 12
    -0.2 (-12 to 11)
    0.3 (-6 to 10)
        NK cells (in % of lymphocytes) at Week 24
    0.3 (-22 to 9)
    1.1 (-10 to 10)
        CD56dimCD16+ (in % of NK cells) at Week 12
    0.1 (-39 to 23)
    4.1 (-6 to 22)
        CD56dimCD16+ (in % of NK cells) at Week 24
    0.4 (-27 to 35)
    8.1 (-5 to 21)
    No statistical analyses for this end point

    Primary: Change from Baseline in NK Cells Subset Parameters (Continued)

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    End point title
    Change from Baseline in NK Cells Subset Parameters (Continued) [6]
    End point description
    LS mean was estimated using a MMRM approach adjusted on baseline. Analysis was performed on PP population. Number of subjects analyzed=subjects with available data for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12, Week 24
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics were performed, treated and untreated arms were not compared.
    End point values
    RMS Subjects Healthy Subjects
    Number of subjects analysed
    38
    19
    Units: Percentage of NK cells
    least squares mean (standard error)
        CD56brightCD16/ dim (in % of NK cells) at Week 12
    0.13 ± 0.86
    -0.9 ± 0.52
        CD56brightCD16/ dim (in % of NK cells) at Week 24
    1.9 ± 0.95
    -0.37 ± 0.61
        CD69+ (in % of CD56brightCD16/ dim) at Week 12
    3.37 ± 1.29
    1.7 ± 1.28
        CD69+ (in % of CD56brightCD16/ dim) at Week 24
    3.5 ± 0.93
    5.5 ± 1.64
        CD69+ (in % of CD56dimCD16+) at Week 12
    7.14 ± 2.46
    1.9 ± 1.67
        CD69+ (in % of CD56dimCD16+) at Week 24
    2.48 ± 1.58
    8.85 ± 3.54
    No statistical analyses for this end point

    Primary: Change from Baseline in NKT Cells Subset Parameters

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    End point title
    Change from Baseline in NKT Cells Subset Parameters [7]
    End point description
    Analysis was performed on PP population. Number of subjects analyzed=subjects with available data for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12, Week 24
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics were performed, treated and untreated arms were not compared.
    End point values
    RMS Subjects Healthy Subjects
    Number of subjects analysed
    38
    19
    Units: Percentage of NKT cells
    median (full range (min-max))
        CD3+CD56+ (in % of lymphocytes) at Week 12
    -0.1 (-2 to 1)
    0 (-1 to 3)
        CD3+CD56+ (in % of lymphocytes) at Week 24
    -0.1 (-4 to 2)
    0.2 (0 to 1)
    No statistical analyses for this end point

    Primary: Change from Baseline in B Cells Subset Parameters

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    End point title
    Change from Baseline in B Cells Subset Parameters [8]
    End point description
    Analysis was performed on PP population. Number of subjects analyzed=subjects with available data for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12, Week 24
    Notes
    [8] - 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: Only descriptive statistics were performed, treated and untreated arms were not compared.
    End point values
    RMS Subjects Healthy Subjects
    Number of subjects analysed
    38
    19
    Units: Percentage of B cells
    median (full range (min-max))
        CD19+ (in % of lymphocytes) at Week 12
    -1.8 (-23 to 14)
    -1.8 (-7 to 1)
        CD19+ (in % of lymphocytes) at Week 24
    -2 (-25 to 13)
    -1.3 (-8 to 2)
    No statistical analyses for this end point

    Secondary: Change from Baseline in Total Number of Different CD8+ T-Cell Clones

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    End point title
    Change from Baseline in Total Number of Different CD8+ T-Cell Clones
    End point description
    Analysis was performed on PP population. Number of subjects analyzed=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 24.
    End point values
    RMS Subjects Healthy Subjects
    Number of subjects analysed
    15
    10
    Units: Number of clones
    median (full range (min-max))
        At Week 12
    -280001 (-1621815 to 424421)
    500907.5 (-191690 to 2455942)
        At Week 24
    -592877 (-1333858 to 527410)
    814545 (-266108 to 2422501)
    No statistical analyses for this end point

    Secondary: Change from Baseline in Total Number of Unique CD8+ T-Cell Clones

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    End point title
    Change from Baseline in Total Number of Unique CD8+ T-Cell Clones
    End point description
    LS mean was estimated using a MMRM approach adjusted on baseline. Analysis was performed on PP population. Number of subjects analyzed=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 24.
    End point values
    RMS Subjects Healthy Subjects
    Number of subjects analysed
    15
    10
    Units: Number of clones
    least squares mean (standard error)
        At Week 12
    -30177 ± 15416.73
    21400.8 ± 9996.99
        At Week 24
    -28535.6 ± 9172.9
    27884.1 ± 11043.98
    No statistical analyses for this end point

    Secondary: Change from Baseline in Proliferating CD8+ T Cells

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    End point title
    Change from Baseline in Proliferating CD8+ T Cells
    End point description
    LS mean was estimated using a MMRM approach adjusted on baseline. Analysis was performed on PP population. Number of subjects analyzed=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 24.
    End point values
    RMS Subjects Healthy Subjects
    Number of subjects analysed
    33
    18
    Units: Percentage of T cells
    least squares mean (standard error)
        At Week 12
    -0.86 ± 1.13
    -2.01 ± 1.31
        At Week 24
    -1.53 ± 1.01
    -1.29 ± 0.58
    No statistical analyses for this end point

    Secondary: Change from Baseline in Proliferating CD8+ T Cells Upon in-vitro Exposure to 100µM Teriflunomide

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    End point title
    Change from Baseline in Proliferating CD8+ T Cells Upon in-vitro Exposure to 100µM Teriflunomide
    End point description
    LS mean was estimated using a MMRM approach adjusted on baseline. Analysis was performed on PP population. Number of subjects analyzed=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, in-vitro exposure.
    End point values
    RMS Subjects Healthy Subjects
    Number of subjects analysed
    25
    17
    Units: Percentage of T cells
        least squares mean (standard error)
    -32.15 ± 2.15
    -34.5 ± 1.74
    No statistical analyses for this end point

    Secondary: Change from Baseline in Cytokine Production Interleukin-2 (IL-2) Upon anti-CD3/CD28 Induction for 24 hours

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    End point title
    Change from Baseline in Cytokine Production Interleukin-2 (IL-2) Upon anti-CD3/CD28 Induction for 24 hours
    End point description
    Induction of cytokine production by anti- CD3/CD28 was assessed from samples of subjects at baseline, week 12 and week 24. Analysis was performed on PP population. Number of subjects analyzed=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 24
    End point values
    RMS Subjects Healthy Subjects
    Number of subjects analysed
    25
    13
    Units: pg/mL
    median (full range (min-max))
        At Week 12
    -93 (-894 to 724)
    -29 (-434 to 4013)
        At Week 24
    -147 (-2758 to 715)
    -165 (-718 to 525)
    No statistical analyses for this end point

    Secondary: Change from Baseline in Cytokine Production Tumor Necrosis Factor (TNFα) Upon anti-CD3/CD28 Induction for 24 hours

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    End point title
    Change from Baseline in Cytokine Production Tumor Necrosis Factor (TNFα) Upon anti-CD3/CD28 Induction for 24 hours
    End point description
    LS mean was estimated using a MMRM approach adjusted on baseline. Analysis was performed on PP population. Number of subjects analyzed=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 24
    End point values
    RMS Subjects Healthy Subjects
    Number of subjects analysed
    26
    13
    Units: pg/mL
    least squares mean (standard error)
        At Week 12
    -216.21 ± 135.15
    -674.46 ± 243.56
        At Week 24
    -459.64 ± 106.84
    -1361.38 ± 117.16
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AE) were collected from signature of informed consent form up to final visit of the subject regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported AEs and deaths were AEs developed/worsened and deaths occurred during 'treatment-emergent period’(time from administration of first investigational study drug to last dose of study drug in extension period for those who entered in extension or to last data[lab,vital signs or AE] available for those who did not enter in extension period.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    RMS Subjects
    Reporting group description
    Subjects with RMS who received at least one dose of teriflunomide 14 mg once daily during the study period (safety population). (Median exposure for main study period is 168 days and for extension period is 140 days)

    Reporting group title
    Healthy Subjects
    Reporting group description
    Untreated healthy subjects followed for 24 weeks.

    Serious adverse events
    RMS Subjects Healthy Subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 50 (8.00%)
    0 / 20 (0.00%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Tendon Rupture
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-Reactive Protein Increased
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Uterine Leiomyoma
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 20 (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
    Oedema
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden Death
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic Steatosis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    RMS Subjects Healthy Subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    36 / 50 (72.00%)
    0 / 20 (0.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 20 (0.00%)
         occurrences all number
    3
    0
    Investigations
    Lipase Increased
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 20 (0.00%)
         occurrences all number
    4
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 50 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    5
    0
    Paraesthesia
         subjects affected / exposed
    7 / 50 (14.00%)
    0 / 20 (0.00%)
         occurrences all number
    8
    0
    Gastrointestinal disorders
    Abdominal Pain Upper
         subjects affected / exposed
    7 / 50 (14.00%)
    0 / 20 (0.00%)
         occurrences all number
    7
    0
    Diarrhoea
         subjects affected / exposed
    10 / 50 (20.00%)
    0 / 20 (0.00%)
         occurrences all number
    11
    0
    Nausea
         subjects affected / exposed
    6 / 50 (12.00%)
    0 / 20 (0.00%)
         occurrences all number
    7
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    15 / 50 (30.00%)
    0 / 20 (0.00%)
         occurrences all number
    15
    0
    Pruritus
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 20 (0.00%)
         occurrences all number
    3
    0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 20 (0.00%)
         occurrences all number
    3
    0
    Pain In Extremity
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 20 (0.00%)
         occurrences all number
    3
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    7 / 50 (14.00%)
    0 / 20 (0.00%)
         occurrences all number
    7
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Oct 2013
    -Inclusion criteria was changed to define a wash-out period before switching to the study treatment teriflunomide.

    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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