Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   35335   clinical trials with a EudraCT protocol, of which   5785   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    Long-term extension of the multinational, double-blind, placebo controlled study EFC6049 (HMR1726D/3001) to document the safety of two doses of teriflunomide (7 and 14 mg) in patients with multiple sclerosis (MS) with relapses

    Summary
    EudraCT number
    2006-003361-14
    Trial protocol
    GB   AT   FI   DE   IT   SE   NL   PT   DK   CZ   EE  
    Global end of trial date
    23 Dec 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    25 Dec 2016
    First version publication date
    25 Dec 2016
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    LTS6050
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00803049
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    1 avenue Pierre Brossolette, Chilly-Mazarin, France, 91380
    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
    10 Feb 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Dec 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To document the long-term safety and tolerability of two doses of teriflunomide (7 mg/day and 14 mg/day) in  MS subjects with relapses.
    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
    16 Oct 2006
    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
    Netherlands: 25
    Country: Number of subjects enrolled
    Norway: 7
    Country: Number of subjects enrolled
    Poland: 91
    Country: Number of subjects enrolled
    Portugal: 4
    Country: Number of subjects enrolled
    Sweden: 10
    Country: Number of subjects enrolled
    United Kingdom: 40
    Country: Number of subjects enrolled
    Austria: 17
    Country: Number of subjects enrolled
    Czech Republic: 17
    Country: Number of subjects enrolled
    Denmark: 5
    Country: Number of subjects enrolled
    Estonia: 8
    Country: Number of subjects enrolled
    Finland: 18
    Country: Number of subjects enrolled
    France: 93
    Country: Number of subjects enrolled
    Germany: 62
    Country: Number of subjects enrolled
    Italy: 40
    Country: Number of subjects enrolled
    Canada: 139
    Country: Number of subjects enrolled
    Chile: 35
    Country: Number of subjects enrolled
    Russian Federation: 66
    Country: Number of subjects enrolled
    Switzerland: 3
    Country: Number of subjects enrolled
    Turkey: 10
    Country: Number of subjects enrolled
    Ukraine: 47
    Country: Number of subjects enrolled
    United States: 5
    Worldwide total number of subjects
    742
    EEA total number of subjects
    437
    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)
    742
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    The study was conducted at 117 centers in 21 countries between 16 October 2006 and 23 December 2015. A total of 742 subjects who completed study EFC6049 (2004-000555-42), entered in this extension study. Out of 742 subjects, 740 were treated and 2 subjects discontinued the study without receiving study treatment.

    Pre-assignment
    Screening details
    Subjects who received placebo in EFC6049 study were randomized in 1:1 ratio to receive either teriflunomide 7 or 14 mg/day and, those who received teriflunomide 7 or 14 mg/day in EFC6049 received same double-blind treatment in this extension study until 292 weeks from the first subject enrolled or until teriflunomide was commercially available.

    Period 1
    Period 1 title
    Overall Period
    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
    Placebo/Teriflunomide 7 mg
    Arm description
    Subjects who completed treatment of placebo (for teriflunomide) tablet once daily (QD) for 108 weeks in EFC6049 study, received teriflunomide tablet 7 mg QD for 288 weeks in this extension study.
    Arm type
    Experimental

    Investigational medicinal product name
    Teriflunomide
    Investigational medicinal product code
    HMR1726
    Other name
    Aubagio
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Teriflunomide 7 mg administered QD orally for 288 weeks.

    Arm title
    Teriflunomide 7 mg/7 mg
    Arm description
    Subjects who completed treatment of teriflunomide 7 mg tablet QD for 108 weeks in EFC6049 study, continued their treatment with teriflunomide 7 mg tablet QD for 288 weeks in this extension study.
    Arm type
    Experimental

    Investigational medicinal product name
    Teriflunomide
    Investigational medicinal product code
    HMR1726
    Other name
    Aubagio
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Teriflunomide 7 mg administered QD orally for 288 weeks.

    Arm title
    Placebo/Teriflunomide 14 mg
    Arm description
    Subjects who completed treatment of placebo (for teriflunomide tablet) QD for 108 weeks in EFC6049 study, received teriflunomide 14 mg tablet QD for 288 weeks in this extension study.
    Arm type
    Experimental

    Investigational medicinal product name
    Teriflunomide
    Investigational medicinal product code
    HMR1726
    Other name
    Aubagio
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Teriflunomide 14 mg administered QD orally for 288 weeks.

    Arm title
    Teriflunomide 14 mg/14 mg
    Arm description
    Subjects who completed treatment of teriflunomide 14 mg tablet QD for 108 weeks in EFC6049 study, continued their treatment with teriflunomide 14 mg tablet QD orally for 288 weeks in this extension study.
    Arm type
    Experimental

    Investigational medicinal product name
    Teriflunomide
    Investigational medicinal product code
    HMR1726
    Other name
    Aubagio
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Teriflunomide 14 mg administered QD orally for 288 weeks.

    Number of subjects in period 1
    Placebo/Teriflunomide 7 mg Teriflunomide 7 mg/7 mg Placebo/Teriflunomide 14 mg Teriflunomide 14 mg/14 mg
    Started
    129
    252
    108
    253
    Treated
    129
    252
    108
    251
    Completed
    68
    134
    64
    151
    Not completed
    61
    118
    44
    102
         Progressive disease
             6
             10
             6
             6
         Randomized but not treated
             -
             -
             -
             2
         Death
             2
             1
             -
             2
         Protocol violation
             -
             1
             1
             -
         Lack of efficacy
             10
             19
             6
             13
         Other than specified above
             3
             9
             2
             5
         Consent withdrawn by subject
             19
             43
             16
             44
         Adverse Event
             21
             33
             13
             27
         Lost to follow-up
             -
             2
             -
             3

    Baseline characteristics

    Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Placebo/Teriflunomide 7 mg
    Reporting group description
    Subjects who completed treatment of placebo (for teriflunomide) tablet once daily (QD) for 108 weeks in EFC6049 study, received teriflunomide tablet 7 mg QD for 288 weeks in this extension study.

    Reporting group title
    Teriflunomide 7 mg/7 mg
    Reporting group description
    Subjects who completed treatment of teriflunomide 7 mg tablet QD for 108 weeks in EFC6049 study, continued their treatment with teriflunomide 7 mg tablet QD for 288 weeks in this extension study.

    Reporting group title
    Placebo/Teriflunomide 14 mg
    Reporting group description
    Subjects who completed treatment of placebo (for teriflunomide tablet) QD for 108 weeks in EFC6049 study, received teriflunomide 14 mg tablet QD for 288 weeks in this extension study.

    Reporting group title
    Teriflunomide 14 mg/14 mg
    Reporting group description
    Subjects who completed treatment of teriflunomide 14 mg tablet QD for 108 weeks in EFC6049 study, continued their treatment with teriflunomide 14 mg tablet QD orally for 288 weeks in this extension study.

    Reporting group values
    Placebo/Teriflunomide 7 mg Teriflunomide 7 mg/7 mg Placebo/Teriflunomide 14 mg Teriflunomide 14 mg/14 mg Total
    Number of subjects
    129 252 108 253 742
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    39.6 ± 8.5 38 ± 8.8 37.6 ± 8.5 38.6 ± 8.4 -
    Gender categorical
    Units: Subjects
        Female
    94 175 85 182 536
        Male
    35 77 23 71 206

    End points

    Close Top of page
    End points reporting groups
    Reporting group title
    Placebo/Teriflunomide 7 mg
    Reporting group description
    Subjects who completed treatment of placebo (for teriflunomide) tablet once daily (QD) for 108 weeks in EFC6049 study, received teriflunomide tablet 7 mg QD for 288 weeks in this extension study.

    Reporting group title
    Teriflunomide 7 mg/7 mg
    Reporting group description
    Subjects who completed treatment of teriflunomide 7 mg tablet QD for 108 weeks in EFC6049 study, continued their treatment with teriflunomide 7 mg tablet QD for 288 weeks in this extension study.

    Reporting group title
    Placebo/Teriflunomide 14 mg
    Reporting group description
    Subjects who completed treatment of placebo (for teriflunomide tablet) QD for 108 weeks in EFC6049 study, received teriflunomide 14 mg tablet QD for 288 weeks in this extension study.

    Reporting group title
    Teriflunomide 14 mg/14 mg
    Reporting group description
    Subjects who completed treatment of teriflunomide 14 mg tablet QD for 108 weeks in EFC6049 study, continued their treatment with teriflunomide 14 mg tablet QD orally for 288 weeks in this extension study.

    Subject analysis set title
    Teriflunomide 7 mg/7 mg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects who received Teriflunomide 7 mg treatment in EFC6049 study were continued to receive the same treatment in this extension study. Teriflunomide 7 mg once daily (QD), orally for 288 weeks. Included 1 subject from Placebo/Teriflunomide 14 mg and 1 subject from Teriflunomide 14 mg/14 mg arm.

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

    Close Top of page
    End point title
    Percentage of Subjects With Treatment Emergent Adverse Events (TEAEs) [1] [2]
    End point description
    Adverse event (AE): any untoward medical occurrence in a subject who received investigational medicinal product (IMP) without regard to possibility of causal relationship with this treatment. TEAEs: AEs developed/worsened/became serious during on-treatment period (from time of first dose of study drug [in LTS6050] up to 4 weeks (28 days) after last dose of study drug). Serious adverse event (SAE): any untoward medical occurrence resulted in any of following outcomes: death, life-threatening, required initial/prolonged in-patient hospitalization, persistent/significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. Any TEAE included both serious & non-serious AEs. Safety population: all subjects randomized in LTS6050 study & exposed to IMP during LTS6050 study treatment period, regardless of amount of treatment administered. Safety analysis was conducted as treatment received. Here, 99999 = percentage of subjects was 0 for this arm.
    End point type
    Primary
    End point timeframe
    Baseline (LTS6050) up to 28 days after last dose of study drug up to 450 weeks
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    Placebo/Teriflunomide 7 mg Placebo/Teriflunomide 14 mg Teriflunomide 14 mg/14 mg Teriflunomide 7 mg/7 mg
    Number of subjects analysed
    129
    107
    250
    254
    Units: percentage of subjects
    number (not applicable)
        Any TEAE
    93.8
    94.4
    91.2
    91.3
        Any Treatment Emergent SAE
    24.8
    21.5
    24.8
    28
        Any TEAE Leading to Death
    2.3
    99999
    0.8
    0.8
        Any TEAE Leading to Permanent Discontinuation
    17.1
    12.1
    10.8
    12.2
    No statistical analyses for this end point

    Secondary: Time to 12 Week Sustained Disability Progression (DP): Kaplan-Meier Estimates of the Rate of DP

    Close Top of page
    End point title
    Time to 12 Week Sustained Disability Progression (DP): Kaplan-Meier Estimates of the Rate of DP
    End point description
    Sustained DP: sustained increase of at least 1 point from baseline(EFC6049)expanded disability status scale(EDSS)score(0.5 point for subjects with baseline EDSS>5.5)persisting for at least 12weeks. Probability of DP at 12weeks estimated by Kaplan-Meier method on time to DP: date of first DP minus(-)date of randomization in EFC6049 study +1 day. Subjects free of DP(no DP observed on treatment)censored at date of last on-treatment EDSS evaluation in LTS6050.Kaplan-Meier method consists in computing probabilities of non-occurrence of event at any observed time of event and multiplying successive probabilities for time ≤t by any earlier computed probabilities to estimate probability of being event-free for amount of time t. Analysis for end point performed on combined data of EFC6049&LTS6050 study, as pre-specified in protocol. Intent-to-treat(ITT)(EFC6049+LTS6050) population: all subjects randomized in both(EFC6049&LTS6050)studies that had at least 1-day IMP exposure during both studies.
    End point type
    Secondary
    End point timeframe
    Up to 10.8 years (EFC6049: 108 weeks + LTS6050: 450 weeks)
    End point values
    Placebo/Teriflunomide 7 mg Teriflunomide 7 mg/7 mg Placebo/Teriflunomide 14 mg Teriflunomide 14 mg/14 mg
    Number of subjects analysed
    129
    252
    108
    251
    Units: Probability
        number (confidence interval 95%)
    0.544 (0.441 to 0.646)
    0.494 (0.423 to 0.565)
    0.627 (0.444 to 0.811)
    0.473 (0.403 to 0.543)
    Statistical analysis title
    Placebo/Teriflunomide7mg vs. Teriflunomide 7mg/7mg
    Statistical analysis description
    Analysis was performed using Log-rank test with treatment, EDSS strata at baseline and region as covariates. Estimation was performed using Cox proportional hazard model with treatment, EDSS strata at baseline and region as covariates.
    Comparison groups
    Placebo/Teriflunomide 7 mg v Teriflunomide 7 mg/7 mg
    Number of subjects included in analysis
    381
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.2079 [3]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.824
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.602
         upper limit
    1.128
    Notes
    [3] - Threshold for significance at 0.05 level.
    Statistical analysis title
    Placebo/Teriflunomide14mg vs. Teriflunomide14/14mg
    Statistical analysis description
    Analysis was performed using Log-rank test with treatment, EDSS strata at baseline and region as covariates. Estimation was performed using Cox proportional hazard model with treatment, EDSS strata at baseline and region as covariates.
    Comparison groups
    Placebo/Teriflunomide 14 mg v Teriflunomide 14 mg/14 mg
    Number of subjects included in analysis
    359
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.3039 [4]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.825
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.591
         upper limit
    1.152
    Notes
    [4] - Threshold for significance at 0.05 level.
    Statistical analysis title
    Teriflunomide 7mg/7mg vs. Teriflunomide 14mg/14 mg
    Statistical analysis description
    Analysis was performed using Log-rank test with treatment, EDSS strata at baseline and region as covariates. Estimation was performed using Cox proportional hazard model with treatment, EDSS strata at baseline and region as covariates.
    Comparison groups
    Teriflunomide 7 mg/7 mg v Teriflunomide 14 mg/14 mg
    Number of subjects included in analysis
    503
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.8271 [5]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.963
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.736
         upper limit
    1.26
    Notes
    [5] - Threshold for significance at 0.05 level.

    Secondary: Time to 24 Week Sustained Disability Progression (DP): Kaplan-Meier Estimates of the Rate of DP

    Close Top of page
    End point title
    Time to 24 Week Sustained Disability Progression (DP): Kaplan-Meier Estimates of the Rate of DP
    End point description
    Sustained DP: sustained increase of at least 1 point from baseline (EFC6049) EDSS score (0.5 point for subjects with baseline EDSS>5.5) persisting for at least 24 weeks. Probability of DP at 24 weeks estimated by Kaplan-Meier method on time to DP: date of first DP minus (-) date of randomization in EFC6049 study +1 day. Subjects free of DP (no DP observed on treatment) censored at date of last on-treatment EDSS evaluation in LTS6050. Kaplan-Meier method consists in computing probabilities of non-occurrence of event at any observed time of event and multiplying successive probabilities for time ≤t by any earlier computed probabilities to estimate the probability of being event-free for amount of time t. Analysis for this end point performed on combined data of EFC6049 & LTS6050 study, as pre-specified in protocol. ITT (EFC6049 + LTS6050) population: all subjects randomized in both EFC6049 & LTS6050 studies that had at least 1-day IMP exposure during both EFC6049 & LTS6050 study.
    End point type
    Secondary
    End point timeframe
    Up to 10.8 years (EFC6049: 108 weeks + LTS6050: 450 weeks)
    End point values
    Placebo/Teriflunomide 7 mg Teriflunomide 7 mg/7 mg Placebo/Teriflunomide 14 mg Teriflunomide 14 mg/14 mg
    Number of subjects analysed
    129
    252
    108
    251
    Units: Probability
        number (confidence interval 95%)
    0.444 (0.338 to 0.55)
    0.434 (0.363 to 0.504)
    0.518 (0.411 to 0.624)
    0.438 (0.367 to 0.509)
    Statistical analysis title
    Placebo/Teriflunomide7mg vs. Teriflunomide 7mg/7mg
    Statistical analysis description
    Analysis was performed using Log-rank test with treatment, EDSS strata at baseline and region as covariates. Estimation was performed using Cox proportional hazard model with treatment, EDSS strata at baseline and region as covariates.
    Comparison groups
    Placebo/Teriflunomide 7 mg v Teriflunomide 7 mg/7 mg
    Number of subjects included in analysis
    381
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.8017 [6]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.961
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.678
         upper limit
    1.362
    Notes
    [6] - Threshold for significance at 0.05 level.
    Statistical analysis title
    Placebo/Teriflunomide14mg vs. Teriflunomide14/14mg
    Statistical analysis description
    Analysis was performed using Log-rank test with treatment, EDSS strata at baseline and region as covariates. Estimation was performed using Cox proportional hazard model with treatment, EDSS strata at baseline and region as covariates.
    Comparison groups
    Placebo/Teriflunomide 14 mg v Teriflunomide 14 mg/14 mg
    Number of subjects included in analysis
    359
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1866 [7]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.79
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.559
         upper limit
    1.117
    Notes
    [7] - Threshold for significance at 0.05 level.
    Statistical analysis title
    Placebo/Teriflunomide7mg vs. Teriflunomide 14/14mg
    Statistical analysis description
    Analysis was performed using Log-rank test with treatment, EDSS strata at baseline and region as covariates. Estimation was performed using Cox proportional hazard model with treatment, EDSS strata at baseline and region as covariates.
    Comparison groups
    Teriflunomide 7 mg/7 mg v Teriflunomide 14 mg/14 mg
    Number of subjects included in analysis
    503
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.8763 [8]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.767
         upper limit
    1.357
    Notes
    [8] - Threshold for significance at 0.05 level.

    Secondary: Percentage of Subjects Free of Sustained Disability Progression (DP)

    Close Top of page
    End point title
    Percentage of Subjects Free of Sustained Disability Progression (DP)
    End point description
    Sustained DP was defined as sustained increase of at least 1 point from EFC6049 baseline EDSS score (0.5 point for subjects with baseline EDSS>5.5) persisting for at least 12 weeks & 24 weeks. EDSS: an ordinal scale in half-point increments that qualifies disability in subjects with MS. It consists of 8 ordinal rating scales assessing seven functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder, cerebral) as well as ambulation. EDSS total score ranges from 0 (normal neurological examination) to 10 (death due to MS), where higher scores indicates worse neurological function. Percentage of subjects who were considered as free of DP confirmed after 12 week & 24 week sustained progression were reported. Analysis for this end point was performed on the combined data of EFC6049 & LTS6050 study, as pre-specified in the protocol. ITT(EFC6049 + LTS6050)population.
    End point type
    Secondary
    End point timeframe
    Up to 10.8 years since EFC6049 randomization (EFC6049: 108 weeks + LTS6050: 450 weeks)
    End point values
    Placebo/Teriflunomide 7 mg Teriflunomide 7 mg/7 mg Placebo/Teriflunomide 14 mg Teriflunomide 14 mg/14 mg
    Number of subjects analysed
    129
    252
    108
    251
    Units: Percentage of Subjects
    number (not applicable)
        Free of DP Sustained for 12 Weeks
    45.6
    50.6
    37.3
    52.7
        Free of DP Sustained for 24 Weeks
    55.6
    56.6
    48.2
    56.2
    No statistical analyses for this end point

    Secondary: Annualized MS Relapse Rate (ARR): Poisson Regression Estimates

    Close Top of page
    End point title
    Annualized MS Relapse Rate (ARR): Poisson Regression Estimates
    End point description
    ARR was obtained from the total number of confirmed relapses that occurred during the treatment period divided by the sum of treatment durations in LTS6050 study only. Each episode of relapse - appearance, or worsening of a clinical symptom that was stable for at least 30 days, that persisted for a minimum of 24 hours in the absence of fever - was to be confirmed by an increase in EDSS score or Functional System scores. To account for the different treatment duration among participants, a Poisson regression model with robust error variance was used (total number of confirmed relapses as response variable; log-transformed treatment duration as "offset" variable; treatment group, region of enrolment and baseline EDSS stratum as covariates). ITT(LTS6050) population: all subjects who were randomized in the LTS6050 study and had at least 1-day IMP exposure during the LTS6050 study.
    End point type
    Secondary
    End point timeframe
    Up to 8 years since LTS6050 randomization
    End point values
    Placebo/Teriflunomide 7 mg Teriflunomide 7 mg/7 mg Placebo/Teriflunomide 14 mg Teriflunomide 14 mg/14 mg
    Number of subjects analysed
    129
    252
    108
    251
    Units: relapses per subject-year
        number (confidence interval 95%)
    0.216 (0.162 to 0.288)
    0.183 (0.149 to 0.225)
    0.176 (0.132 to 0.236)
    0.16 (0.129 to 0.198)
    No statistical analyses for this end point

    Secondary: Magnetic Resonance Imaging (MRI) Assessment: Change From Baseline in Total Volume of Abnormal Lesions (Burden of Disease [BOD]) at Week 192 Since LTS6050 Randomization

    Close Top of page
    End point title
    Magnetic Resonance Imaging (MRI) Assessment: Change From Baseline in Total Volume of Abnormal Lesions (Burden of Disease [BOD]) at Week 192 Since LTS6050 Randomization
    End point description
    BOD was assessed by cerebral MRI and defined as the total volume of all abnormal brain tissue (calculated as the sum of the total volume of T2-lesion component and T1-hypointense lesion component). ITT (LTS6050 population). Number of subjects analyzed=subjects with available data for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 192
    End point values
    Placebo/Teriflunomide 7 mg Teriflunomide 7 mg/7 mg Placebo/Teriflunomide 14 mg Teriflunomide 14 mg/14 mg
    Number of subjects analysed
    49
    99
    36
    103
    Units: millilitres (ml)
        arithmetic mean (standard deviation)
    5.307 ± 9.088
    3.969 ± 11.135
    3.72 ± 6.696
    3.943 ± 9.685
    No statistical analyses for this end point

    Adverse events

    Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    All AEs were collected from signature of informed consent form up to 28 days after the last dose of study drug up to Week 450, regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported AEs are TEAEs that is AEs that developed/worsened during the 'on treatment period' (the time from the first dose of study treatment to 4 weeks [28 days] after the last dose of study treatment). Analysis was performed on safety population and was conducted as per the treatment received.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Placebo/Teriflunomide 7 mg
    Reporting group description
    Subjects who completed placebo (for teriflunomide) tablet once daily (QD) for 108 weeks in EFC6049 study received teriflunomide tablet 7 mg QD for 288 weeks in this extension study.

    Reporting group title
    Teriflunomide 7 mg/7 mg
    Reporting group description
    Subjects who completed teriflunomide 7 mg tablet QD for 108 weeks in EFC6049 study continued their treatment with teriflunomide 7 mg tablet QD for 288 weeks in this extension study. Included 2 subjects randomized in placebo and teriflunomide 14 mg arm respectively in EFC6049 study, incorrectly received at least 1 dose of teriflunomide 7 mg. In LTS6050 study, same subjects received correct dose of teriflunomide 14 mg but consistently included in Teriflunomide 7 mg/7 mg arm for safety analysis.

    Reporting group title
    Placebo/Teriflunomide 14 mg
    Reporting group description
    Subjects who completed placebo (for teriflunomide tablet) QD for 108 weeks in EFC6049 study received teriflunomide 14 mg tablet QD for 288 weeks in this extension study. Excluded 1 subject randomized in placebo arm in EFC6049 study, incorrectly received at least 1 dose of teriflunomide 7 mg. In LTS6050 study, same subject received 14 mg dose but consistently included in teriflunomide 7 mg/7 mg arm for safety analysis.

    Reporting group title
    Teriflunomide 14 mg/14 mg
    Reporting group description
    Subjects who completed teriflunomide 14 mg tablet QD for 108 weeks in EFC6049 study continued their treatment with teriflunomide 14 mg tablet QD orally for 288 weeks in this extension study. Excluded 1 subject randomized in 14 mg arm in EFC6049 study, incorrectly received at least 1 dose of teriflunomide 7 mg. In LTS6050 study, same subject received correct dose of 14 mg but consistently included in Teriflunomide 7 mg arm for safety analysis.

    Serious adverse events
    Placebo/Teriflunomide 7 mg Teriflunomide 7 mg/7 mg Placebo/Teriflunomide 14 mg Teriflunomide 14 mg/14 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    32 / 129 (24.81%)
    71 / 254 (27.95%)
    23 / 107 (21.50%)
    62 / 250 (24.80%)
         number of deaths (all causes)
    3
    2
    0
    2
         number of deaths resulting from adverse events
    3
    2
    0
    2
    Injury, poisoning and procedural complications
    Hand Fracture
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    2 / 250 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Accidental Overdose
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 254 (0.00%)
    1 / 107 (0.93%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ankle Fracture
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical Vertebral Fracture
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 129 (0.78%)
    2 / 254 (0.79%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral Neck Fracture
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ligament Rupture
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road Traffic Accident
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anastomotic Leak
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibula Fracture
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head Injury
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic Rupture
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    1 / 107 (0.93%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip Fracture
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    1 / 107 (0.93%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint Dislocation
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ligament Sprain
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower Limb Fracture
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meniscus Injury
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple Fractures
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    1 / 107 (0.93%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Patella Fracture
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural Pain
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius Fracture
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib Fracture
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia Fracture
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic Shock
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    1 / 107 (0.93%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wrist Fracture
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    4 / 129 (3.10%)
    3 / 254 (1.18%)
    3 / 107 (2.80%)
    6 / 250 (2.40%)
         occurrences causally related to treatment / all
    4 / 4
    2 / 3
    3 / 3
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic Enzyme Increased
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    2 / 250 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases Increased
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood Alkaline Phosphatase Increased
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood Pressure Increased
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gamma-Glutamyltransferase Increased
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lipase Increased
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial Infarction
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    3 / 250 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute Myocardial Infarction
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina Pectoris
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis Coronary Artery
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac Failure Acute
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Coronary Artery Disease
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac Arrest
         subjects affected / exposed
    2 / 129 (1.55%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Cardiac Valve Disease
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular Tachycardia
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Dolichocolon
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 129 (0.00%)
    2 / 254 (0.79%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular Accident
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraplegia
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uhthoff's Phenomenon
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ageusia
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    1 / 107 (0.93%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carpal Tunnel Syndrome
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    1 / 107 (0.93%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular Insufficiency
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial Neuralgia
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    1 / 107 (0.93%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracranial Aneurysm
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscle Spasticity
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    1 / 107 (0.93%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Posterior Reversible Encephalopathy Syndrome
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Uveitis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystoid Macular Oedema
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    1 / 107 (0.93%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal Detachment
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    1 / 107 (0.93%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    2 / 250 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal Hernia
         subjects affected / exposed
    0 / 129 (0.00%)
    2 / 254 (0.79%)
    0 / 107 (0.00%)
    2 / 250 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal Fissure
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal Fistula
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Crohn's Disease
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulum Intestinal
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal Ulcer Haemorrhage
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Large Intestine Perforation
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mechanical Ileus
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal Pain Upper
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis Microscopic
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric Ulcer Haemorrhage
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroduodenal Haemorrhage
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    1 / 107 (0.93%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoidal Haemorrhage
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hernial Eventration
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mesenteric Haematoma
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    1 / 107 (0.93%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mouth Swelling
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    1 / 107 (0.93%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder Prolapse
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 254 (0.00%)
    1 / 107 (0.93%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Mass
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary Retention
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Alopecia Areata
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Decubitus Ulcer
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    1 / 107 (0.93%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lichen Planus
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pustular Psoriasis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    1 / 107 (0.93%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral Disc Protrusion
         subjects affected / exposed
    2 / 129 (1.55%)
    5 / 254 (1.97%)
    0 / 107 (0.00%)
    2 / 250 (0.80%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rotator Cuff Syndrome
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthropathy
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    1 / 107 (0.93%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back Pain
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone Cyst
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    1 / 107 (0.93%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar Spinal Stenosis
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tenosynovitis
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Thyroiditis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes Mellitus Inadequate Control
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes Mellitus
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    1 / 107 (0.93%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Type 2 Diabetes Mellitus
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    1 / 107 (0.93%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Erysipelas
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    2 / 250 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    2 / 250 (0.80%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal Abscess
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 129 (0.00%)
    2 / 254 (0.79%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium Difficile Colitis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometritis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal Infection
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis A
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Perirectal Abscess
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 129 (0.00%)
    2 / 254 (0.79%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia Streptococcal
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory Tract Infection
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    1 / 107 (0.93%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous Abscess
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    1 / 107 (0.93%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vestibular Neuronitis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone Abscess
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bursitis Infective
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 129 (0.00%)
    2 / 254 (0.79%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infected Dermal Cyst
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oral Herpes
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia Bacterial
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative Wound Infection
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    2 / 129 (1.55%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tooth Abscess
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tubo-Ovarian Abscess
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound Infection
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    1 / 107 (0.93%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Venous Stenosis
         subjects affected / exposed
    0 / 129 (0.00%)
    3 / 254 (1.18%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicose Vein
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Mammoplasty
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteotomy
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Meningioma
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thyroid Neoplasm
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine Leiomyoma
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 254 (0.00%)
    2 / 107 (1.87%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basal Cell Carcinoma
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast Cancer
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholesteatoma
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    1 / 107 (0.93%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon Cancer Metastatic
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Malignant Melanoma
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Squamous Cell Carcinoma Of The Cervix
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Social circumstances
    Miscarriage Of Partner
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion Spontaneous
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    2 / 250 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest Pain
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adverse Drug Reaction
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    General Physical Health Deterioration
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden Death
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicidal Ideation
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    2 / 250 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide Attempt
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 254 (0.00%)
    1 / 107 (0.93%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Affective Disorder
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bipolar Disorder
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Endometriosis
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    2 / 250 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast Hyperplasia
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Menorrhagia
         subjects affected / exposed
    0 / 129 (0.00%)
    2 / 254 (0.79%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine Haemorrhage
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast Cyst
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    1 / 107 (0.93%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical Polyp
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian Cyst
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    1 / 107 (0.93%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Premenstrual Cramps
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine Polyp
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Nasal Septum Deviation
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 254 (0.00%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial Lung Disease
         subjects affected / exposed
    0 / 129 (0.00%)
    0 / 254 (0.00%)
    1 / 107 (0.93%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    2 / 250 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis Chronic
         subjects affected / exposed
    1 / 129 (0.78%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic Steatosis
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatocellular Injury
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 254 (0.39%)
    0 / 107 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo/Teriflunomide 7 mg Teriflunomide 7 mg/7 mg Placebo/Teriflunomide 14 mg Teriflunomide 14 mg/14 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    107 / 129 (82.95%)
    195 / 254 (76.77%)
    95 / 107 (88.79%)
    197 / 250 (78.80%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    10 / 129 (7.75%)
    22 / 254 (8.66%)
    11 / 107 (10.28%)
    37 / 250 (14.80%)
         occurrences all number
    10
    22
    11
    37
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    17 / 129 (13.18%)
    37 / 254 (14.57%)
    17 / 107 (15.89%)
    26 / 250 (10.40%)
         occurrences all number
    17
    37
    17
    26
    Influenza Like Illness
         subjects affected / exposed
    1 / 129 (0.78%)
    6 / 254 (2.36%)
    1 / 107 (0.93%)
    13 / 250 (5.20%)
         occurrences all number
    1
    6
    1
    13
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    6 / 129 (4.65%)
    15 / 254 (5.91%)
    8 / 107 (7.48%)
    17 / 250 (6.80%)
         occurrences all number
    6
    15
    8
    17
    Depression
         subjects affected / exposed
    10 / 129 (7.75%)
    24 / 254 (9.45%)
    11 / 107 (10.28%)
    15 / 250 (6.00%)
         occurrences all number
    10
    24
    11
    15
    Anxiety
         subjects affected / exposed
    3 / 129 (2.33%)
    6 / 254 (2.36%)
    6 / 107 (5.61%)
    8 / 250 (3.20%)
         occurrences all number
    3
    6
    6
    8
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    9 / 129 (6.98%)
    20 / 254 (7.87%)
    8 / 107 (7.48%)
    34 / 250 (13.60%)
         occurrences all number
    9
    20
    8
    34
    Contusion
         subjects affected / exposed
    4 / 129 (3.10%)
    5 / 254 (1.97%)
    8 / 107 (7.48%)
    8 / 250 (3.20%)
         occurrences all number
    4
    5
    8
    8
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    18 / 129 (13.95%)
    36 / 254 (14.17%)
    18 / 107 (16.82%)
    32 / 250 (12.80%)
         occurrences all number
    18
    36
    18
    32
    Gamma-Glutamyltransferase Increased
         subjects affected / exposed
    4 / 129 (3.10%)
    16 / 254 (6.30%)
    2 / 107 (1.87%)
    12 / 250 (4.80%)
         occurrences all number
    4
    16
    2
    12
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    4 / 129 (3.10%)
    18 / 254 (7.09%)
    4 / 107 (3.74%)
    11 / 250 (4.40%)
         occurrences all number
    4
    18
    4
    11
    Blood Pressure Increased
         subjects affected / exposed
    8 / 129 (6.20%)
    10 / 254 (3.94%)
    5 / 107 (4.67%)
    7 / 250 (2.80%)
         occurrences all number
    8
    10
    5
    7
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 129 (0.78%)
    7 / 254 (2.76%)
    9 / 107 (8.41%)
    12 / 250 (4.80%)
         occurrences all number
    1
    7
    9
    12
    Neutropenia
         subjects affected / exposed
    2 / 129 (1.55%)
    6 / 254 (2.36%)
    6 / 107 (5.61%)
    6 / 250 (2.40%)
         occurrences all number
    2
    6
    6
    6
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    14 / 129 (10.85%)
    22 / 254 (8.66%)
    7 / 107 (6.54%)
    19 / 250 (7.60%)
         occurrences all number
    14
    22
    7
    19
    Nervous system disorders
    Headache
         subjects affected / exposed
    21 / 129 (16.28%)
    42 / 254 (16.54%)
    18 / 107 (16.82%)
    42 / 250 (16.80%)
         occurrences all number
    21
    42
    18
    42
    Paraesthesia
         subjects affected / exposed
    6 / 129 (4.65%)
    26 / 254 (10.24%)
    13 / 107 (12.15%)
    23 / 250 (9.20%)
         occurrences all number
    6
    26
    13
    23
    Dizziness
         subjects affected / exposed
    5 / 129 (3.88%)
    14 / 254 (5.51%)
    7 / 107 (6.54%)
    14 / 250 (5.60%)
         occurrences all number
    5
    14
    7
    14
    Hypoaesthesia
         subjects affected / exposed
    4 / 129 (3.10%)
    20 / 254 (7.87%)
    10 / 107 (9.35%)
    13 / 250 (5.20%)
         occurrences all number
    4
    20
    10
    13
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    16 / 129 (12.40%)
    24 / 254 (9.45%)
    19 / 107 (17.76%)
    30 / 250 (12.00%)
         occurrences all number
    16
    24
    19
    30
    Nausea
         subjects affected / exposed
    10 / 129 (7.75%)
    20 / 254 (7.87%)
    10 / 107 (9.35%)
    29 / 250 (11.60%)
         occurrences all number
    10
    20
    10
    29
    Constipation
         subjects affected / exposed
    4 / 129 (3.10%)
    10 / 254 (3.94%)
    7 / 107 (6.54%)
    15 / 250 (6.00%)
         occurrences all number
    4
    10
    7
    15
    Abdominal Pain Upper
         subjects affected / exposed
    3 / 129 (2.33%)
    16 / 254 (6.30%)
    4 / 107 (3.74%)
    10 / 250 (4.00%)
         occurrences all number
    3
    16
    4
    10
    Abdominal Pain
         subjects affected / exposed
    5 / 129 (3.88%)
    22 / 254 (8.66%)
    8 / 107 (7.48%)
    9 / 250 (3.60%)
         occurrences all number
    5
    22
    8
    9
    Toothache
         subjects affected / exposed
    2 / 129 (1.55%)
    13 / 254 (5.12%)
    3 / 107 (2.80%)
    9 / 250 (3.60%)
         occurrences all number
    2
    13
    3
    9
    Vomiting
         subjects affected / exposed
    8 / 129 (6.20%)
    8 / 254 (3.15%)
    5 / 107 (4.67%)
    8 / 250 (3.20%)
         occurrences all number
    8
    8
    5
    8
    Renal and urinary disorders
    Micturition Urgency
         subjects affected / exposed
    8 / 129 (6.20%)
    4 / 254 (1.57%)
    3 / 107 (2.80%)
    9 / 250 (3.60%)
         occurrences all number
    8
    4
    3
    9
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    2 / 129 (1.55%)
    7 / 254 (2.76%)
    1 / 107 (0.93%)
    15 / 250 (6.00%)
         occurrences all number
    2
    7
    1
    15
    Rash
         subjects affected / exposed
    6 / 129 (4.65%)
    11 / 254 (4.33%)
    6 / 107 (5.61%)
    14 / 250 (5.60%)
         occurrences all number
    6
    11
    6
    14
    Alopecia
         subjects affected / exposed
    11 / 129 (8.53%)
    12 / 254 (4.72%)
    18 / 107 (16.82%)
    6 / 250 (2.40%)
         occurrences all number
    11
    12
    18
    6
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    10 / 129 (7.75%)
    37 / 254 (14.57%)
    16 / 107 (14.95%)
    40 / 250 (16.00%)
         occurrences all number
    10
    37
    16
    40
    Pain In Extremity
         subjects affected / exposed
    14 / 129 (10.85%)
    27 / 254 (10.63%)
    20 / 107 (18.69%)
    32 / 250 (12.80%)
         occurrences all number
    14
    27
    20
    32
    Arthralgia
         subjects affected / exposed
    17 / 129 (13.18%)
    31 / 254 (12.20%)
    9 / 107 (8.41%)
    28 / 250 (11.20%)
         occurrences all number
    17
    31
    9
    28
    Musculoskeletal Pain
         subjects affected / exposed
    1 / 129 (0.78%)
    11 / 254 (4.33%)
    1 / 107 (0.93%)
    16 / 250 (6.40%)
         occurrences all number
    1
    11
    1
    16
    Muscle Spasms
         subjects affected / exposed
    6 / 129 (4.65%)
    12 / 254 (4.72%)
    4 / 107 (3.74%)
    13 / 250 (5.20%)
         occurrences all number
    6
    12
    4
    13
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    34 / 129 (26.36%)
    71 / 254 (27.95%)
    29 / 107 (27.10%)
    81 / 250 (32.40%)
         occurrences all number
    34
    71
    29
    81
    Influenza
         subjects affected / exposed
    19 / 129 (14.73%)
    39 / 254 (15.35%)
    20 / 107 (18.69%)
    37 / 250 (14.80%)
         occurrences all number
    19
    39
    20
    37
    Urinary Tract Infection
         subjects affected / exposed
    20 / 129 (15.50%)
    31 / 254 (12.20%)
    19 / 107 (17.76%)
    36 / 250 (14.40%)
         occurrences all number
    20
    31
    19
    36
    Sinusitis
         subjects affected / exposed
    7 / 129 (5.43%)
    16 / 254 (6.30%)
    5 / 107 (4.67%)
    28 / 250 (11.20%)
         occurrences all number
    7
    16
    5
    28
    Upper Respiratory Tract Infection
         subjects affected / exposed
    15 / 129 (11.63%)
    29 / 254 (11.42%)
    15 / 107 (14.02%)
    28 / 250 (11.20%)
         occurrences all number
    15
    29
    15
    28
    Bronchitis
         subjects affected / exposed
    10 / 129 (7.75%)
    17 / 254 (6.69%)
    9 / 107 (8.41%)
    26 / 250 (10.40%)
         occurrences all number
    10
    17
    9
    26
    Gastroenteritis
         subjects affected / exposed
    8 / 129 (6.20%)
    10 / 254 (3.94%)
    8 / 107 (7.48%)
    14 / 250 (5.60%)
         occurrences all number
    8
    10
    8
    14
    Cystitis
         subjects affected / exposed
    9 / 129 (6.98%)
    8 / 254 (3.15%)
    4 / 107 (3.74%)
    9 / 250 (3.60%)
         occurrences all number
    9
    8
    4
    9
    Respiratory Tract Infection
         subjects affected / exposed
    8 / 129 (6.20%)
    10 / 254 (3.94%)
    9 / 107 (8.41%)
    7 / 250 (2.80%)
         occurrences all number
    8
    10
    9
    7
    Oral Herpes
         subjects affected / exposed
    3 / 129 (2.33%)
    17 / 254 (6.69%)
    6 / 107 (5.61%)
    6 / 250 (2.40%)
         occurrences all number
    3
    17
    6
    6

    More information

    Close Top of page

    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Feb 2007
    Following changes were made: - Standardized and revised of 11-day washout procedure for all the subjects. - Safety parameters and monitoring were clarified. - Laboratory parameters and follow-up were clarified.
    08 Sep 2008
    Following changes were made: - Changed inclusion/exclusion criteria to exclude newly enrolled HIVpositive subjects from the study. All subjects were to sign a consent form for HIV testing. Previously enrolled subjects newly diagnosed with HIV were to consider discontinuation but were allowed to remain if they were not severely immunodeficient, did not require anti-retroviral nucleoside analogs, and were willing to undergo safety monitoring. - Addition of yearly HIV testing for HIV risk assessment; subjects instructed to report symptoms suggestive of immunodeficiency. - Contraception requirements to reflect ICH-M3 guidelines were updated. - Implementation of EDSS assessment after treatment discontinuation for at least 24 weeks from first increase onset to document disability progression after discontinuation. - Clarifications for harmonization of protocols within the teriflunomide development program.
    27 Apr 2010
    Following change was made: - Primary and secondary efficacy variables were modified for consistency with the previous EFC6049 study.
    10 Feb 2011
    Following changes were made: - Modified laboratory safety monitoring intervals based on the available safety profiles. - Modified the concomitant medications based on the updated drug interactions data (CYP2C9 substrates and CYP inducers). - Removed routine PK sampling but maintained unscheduled PK for safety, based on the available PK data. Appendix G of the protocol (Pharmacokinetic specifications [centrifugation/shipment] for plasma samples analyzed for teriflunomide) was removed since the central lab manual with the updated information was provided separately. - Added “peripheral neuropathy confirmed by nerve conduction studies” to the alert terms due to the potential risk of this event. - To shorten the washout (WO) period from 16 weeks to 4 weeks in order to allow subjects to terminate treatment more rapidly and move more quickly to new therapeutic and life projects, and to make laboratory information available immediately at the end of the drug elimination procedure.
    30 Jan 2012
    Following changes were made: - Extended the current extension study. - Stopped performing MRI for all subjects. - Sufficient MRI information had been obtained in this uncontrolled extension. - Modified the concomitant treatments based on the updated drug interactions data. - Modified components of follow up visits. - Vital sign was measured at follow up visits to document how blood pressure and heart rate evolved after discontinuation of teriflunomide.
    15 May 2012
    Following changes were made: - Modified the concomitant treatments based on the updated drug interactions data. - Modified components of follow up visits. - Vital sign was measured at follow up visits to document how blood pressure and heart rate evolved after discontinuation of teriflunomide.
    24 Jan 2013
    Following changes were made: - Reduction of scheduled study visits and visit contents. Clinical visits occurred only every 24 weeks up to the end of treatment, and included the following: - Adverse event reporting, concomitant medication, - Vital signs, physical examination, - Dispense study drugs: Accountability/Compliance, - EDSS / FS, - Clinical laboratory only at EOT visit. - New information regarding potential drug interactions.
    13 Jul 2013
    Following change was made: - To provide extension in the study.

    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
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2019 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA