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    Clinical Trial Results:
    A Phase III, Multicenter, Randomized, Parallel Group, Double Blind, Double Dummy, Active Controlled Study of Evobrutinib Compared With Teriflunomide, in Participants With Relapsing Multiple Sclerosis to Evaluate Efficacy and Safety (evolutionRMS 2)

    Summary
    EudraCT number
    2019-004980-36
    Trial protocol
    PT   LT   SK   LV   GR   BG   PL   NO   ES   DE   SI   IT   RO   CZ  
    Global end of trial date
    19 Mar 2024

    Results information
    Results version number
    v1(current)
    This version publication date
    21 Mar 2025
    First version publication date
    21 Mar 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MS200527_0082
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT04338061
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Merck Healthcare KGaA, Darmstadt Germany
    Sponsor organisation address
    Street Address: Frankfurter Strasse 250, Darmstadt, Germany, 64293
    Public contact
    Communication Centre, Merck Healthcare KGaA, Darmstadt, Germany, +49 6151725200, service@merckgroup.com
    Scientific contact
    Communication Centre, Merck Healthcare KGaA, Darmstadt Germany, +49 6151725200, service@merckgroup.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
    19 Mar 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Mar 2024
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The objective of this trial was to evaluate the efficacy and safety of evobrutinib administered orally twice daily versus Teriflunomide (Aubagio®), administered orally once daily in subjects with Relapsing Multiple Sclerosis (RMS). Subjects who complete the double-blind treatment period (DBTP) and double-blind extension period (DBEP) prior to approval of a separate long-term follow-up study in their country will get an option for evobrutinib treatment continuation through a 96-week open-label extension (OLE) period.
    Protection of trial subjects
    Subject protection was ensured by following high medical and ethical standards in accordance with the principles laid down in the Declaration of Helsinki, and that are consistent with Good Clinical Practice and applicable regulations.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    02 Jul 2020
    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
    Bulgaria: 74
    Country: Number of subjects enrolled
    Belarus: 54
    Country: Number of subjects enrolled
    Czechia: 5
    Country: Number of subjects enrolled
    Lithuania: 14
    Country: Number of subjects enrolled
    Latvia: 5
    Country: Number of subjects enrolled
    Moldova, Republic of: 12
    Country: Number of subjects enrolled
    Poland: 191
    Country: Number of subjects enrolled
    Romania: 7
    Country: Number of subjects enrolled
    Russian Federation: 161
    Country: Number of subjects enrolled
    Slovakia: 15
    Country: Number of subjects enrolled
    Ukraine: 351
    Country: Number of subjects enrolled
    Switzerland: 4
    Country: Number of subjects enrolled
    Germany: 19
    Country: Number of subjects enrolled
    Spain: 36
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    Greece: 9
    Country: Number of subjects enrolled
    Italy: 23
    Country: Number of subjects enrolled
    Portugal: 10
    Country: Number of subjects enrolled
    Slovenia: 1
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    United States: 55
    Country: Number of subjects enrolled
    Brazil: 27
    Country: Number of subjects enrolled
    India: 4
    Country: Number of subjects enrolled
    Mexico: 7
    Country: Number of subjects enrolled
    Malaysia: 23
    Country: Number of subjects enrolled
    Philippines: 1
    Country: Number of subjects enrolled
    Puerto Rico: 1
    Country: Number of subjects enrolled
    Saudi Arabia: 4
    Country: Number of subjects enrolled
    Singapore: 2
    Country: Number of subjects enrolled
    Thailand: 1
    Country: Number of subjects enrolled
    Türkiye: 23
    Country: Number of subjects enrolled
    South Africa: 18
    Worldwide total number of subjects
    1166
    EEA total number of subjects
    414
    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)
    1166
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 1581 subjects with relapsing multiple sclerosis (RMS) were screened in this trial. Out of which 1166 subjects were randomized at a ratio of 1:1 (583 per treatment group) in this trial.

    Period 1
    Period 1 title
    Double-blind Treatment Period: 156 weeks
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Data analyst, Assessor, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Teriflunomide
    Arm description
    Participants received Teriflunomide at a dose of 14 milligrams (mg) orally once daily up to 156 weeks in Double blind treatment period (DBTP) followed by once daily oral doses of Teriflunomide 14 mg up to 96 weeks in double blind extension (DBE) period.
    Arm type
    Active comparator

    Investigational medicinal product name
    Teriflunomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received Teriflunomide at a dose of 14 mg orally once daily up to 156 weeks in Double blind treatment period (DBTP).

    Arm title
    Evobrutinib
    Arm description
    Participants received Evobrutinib at a dose of 45 mg orally twice daily up to 156 weeks in Double blind treatment period (DBTP) followed by twice daily oral doses of Evobrutinib 45 mg up to 96 weeks in double blind extension (DBE) period.
    Arm type
    Experimental

    Investigational medicinal product name
    Evobrutinib
    Investigational medicinal product code
    M2951
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received Evobrutinib at a dose of 45 mg orally twice daily up to 156 weeks in Double blind treatment period (DBTP).

    Number of subjects in period 1
    Teriflunomide Evobrutinib
    Started
    583
    583
    Completed
    409
    410
    Not completed
    174
    173
         Consent withdrawn by subject
    59
    52
         Randomized, but not treated
    -
    2
         Other Reasons
    17
    22
         Adverse event, non-fatal
    67
    70
         Protocol Non-Compliance
    9
    8
         Lost to follow-up
    11
    3
         Lack of efficacy
    11
    16
    Period 2
    Period 2 title
    Double-blind Extension Period: 96 weeks
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Teriflunomide
    Arm description
    Participants received Teriflunomide at a dose of 14 milligrams (mg) orally once daily up to 156 weeks in Double blind treatment period (DBTP) followed by once daily oral doses of Teriflunomide 14 mg up to 96 weeks in double blind extension (DBE) period.
    Arm type
    Active comparator

    Investigational medicinal product name
    Teriflunomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received Teriflunomide at a dose of 14 mg orally once daily up to 96 weeks in double blind extension (DBE) period.

    Arm title
    Evobrutinib
    Arm description
    Participants received Evobrutinib at a dose of 45 mg orally twice daily up to 156 weeks in Double blind treatment period (DBTP) followed by twice daily oral doses of Evobrutinib 45 mg up to 96 weeks in double blind extension (DBE) period.
    Arm type
    Experimental

    Investigational medicinal product name
    Evobrutinib
    Investigational medicinal product code
    M2951
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received Evobrutinib at a dose of 45 mg orally twice daily up to 96 weeks in double blind extension (DBE) period.

    Number of subjects in period 2 [1]
    Teriflunomide Evobrutinib
    Started
    390
    389
    Completed
    381
    377
    Not completed
    9
    12
         Consent withdrawn by subject
    2
    1
         Adverse event, non-fatal
    1
    1
         Other Reasons
    4
    8
         Protocol Non-Compliance
    1
    -
         Lost to follow-up
    1
    2
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: only 779 subjects (390 in Teriflunomide and 389 in Evobrutinib) started the DBE period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Teriflunomide
    Reporting group description
    Participants received Teriflunomide at a dose of 14 milligrams (mg) orally once daily up to 156 weeks in Double blind treatment period (DBTP) followed by once daily oral doses of Teriflunomide 14 mg up to 96 weeks in double blind extension (DBE) period.

    Reporting group title
    Evobrutinib
    Reporting group description
    Participants received Evobrutinib at a dose of 45 mg orally twice daily up to 156 weeks in Double blind treatment period (DBTP) followed by twice daily oral doses of Evobrutinib 45 mg up to 96 weeks in double blind extension (DBE) period.

    Reporting group values
    Teriflunomide Evobrutinib Total
    Number of subjects
    583 583 1166
    Age categorical
    Units: Subjects
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    37 ( 9.5 ) 36 ( 9.1 ) -
    Sex: Female, Male
    Units: subjects
        Female
    370 413 783
        Male
    213 170 383
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    30 51 81
        Not Hispanic or Latino
    553 531 1084
        Unknown or Not Reported
    0 1 1
    Race
    Units: Subjects
        American Indian or Alaska Native
    1 1 2
        Asian
    17 15 32
        Black or African American
    4 4 8
        White
    551 556 1107
        More than one race
    7 2 9
        Unknown or Not Reported
    3 4 7
        Native Hawaiian or Other Pacific Islander
    0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Teriflunomide
    Reporting group description
    Participants received Teriflunomide at a dose of 14 milligrams (mg) orally once daily up to 156 weeks in Double blind treatment period (DBTP) followed by once daily oral doses of Teriflunomide 14 mg up to 96 weeks in double blind extension (DBE) period.

    Reporting group title
    Evobrutinib
    Reporting group description
    Participants received Evobrutinib at a dose of 45 mg orally twice daily up to 156 weeks in Double blind treatment period (DBTP) followed by twice daily oral doses of Evobrutinib 45 mg up to 96 weeks in double blind extension (DBE) period.
    Reporting group title
    Teriflunomide
    Reporting group description
    Participants received Teriflunomide at a dose of 14 milligrams (mg) orally once daily up to 156 weeks in Double blind treatment period (DBTP) followed by once daily oral doses of Teriflunomide 14 mg up to 96 weeks in double blind extension (DBE) period.

    Reporting group title
    Evobrutinib
    Reporting group description
    Participants received Evobrutinib at a dose of 45 mg orally twice daily up to 156 weeks in Double blind treatment period (DBTP) followed by twice daily oral doses of Evobrutinib 45 mg up to 96 weeks in double blind extension (DBE) period.

    Primary: Double Blind Treatment Period (DBTP) and Double Blind Extension (DBE) Period: Annualized Relapse Rate (ARR)

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    End point title
    Double Blind Treatment Period (DBTP) and Double Blind Extension (DBE) Period: Annualized Relapse Rate (ARR) [1]
    End point description
    The qualifying relapse is the occurrence of new or worsening neurological symptoms attributable to Multiple Sclerosis (MS) (for more than [>] 24 hours, no fever, infection, injury, adverse events (AEs), and preceded by a stable or improving neurological state for more than or equal to [>=] 30 days). Full Analysis Set (FAS) included all subjects who were randomized to study treatment.
    End point type
    Primary
    End point timeframe
    Baseline up to 170 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: Only descriptive statistical data was planned to be reported for this endpoint.
    End point values
    Teriflunomide Evobrutinib
    Number of subjects analysed
    583
    583
    Units: relapses per year
        arithmetic mean (confidence interval 95%)
    0.11 (0.09 to 0.13)
    0.11 (0.09 to 0.13)
    No statistical analyses for this end point

    Secondary: DBTP and DBE Period: Percentage of Subjects Without 24-Week Confirmed Disability Progression (CDP) as Measured by Expanded Disability Status Scale (EDSS)

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    End point title
    DBTP and DBE Period: Percentage of Subjects Without 24-Week Confirmed Disability Progression (CDP) as Measured by Expanded Disability Status Scale (EDSS)
    End point description
    Disability progression was defined as increase in EDSS of greater than or equal to [>=] 1 point from baseline EDSS score, if EDSS score at baseline is 5.0 or less and an increase of >=0.5 point, if the baseline score is 5.5. Disability progression is considered sustained for 24 weeks when the initial increase in the EDSS is confirmed at a regularly scheduled visit at least 24 weeks after the initial documentation of neurological worsening. The total EDSS score ranges from 0 (normal) to 10 (death due to multiple sclerosis). Kaplan-Meier method was used to estimate the percentage of subjects without 24-week CDP. Full Analysis Set (FAS) included all subjects who were randomized to study treatment. The result reported for this endpoint are the results from data of combined DBTP and DBE periods.
    End point type
    Secondary
    End point timeframe
    Week 96 and Week 156 (combined DBTP and DBE periods)
    End point values
    Teriflunomide Evobrutinib
    Number of subjects analysed
    583
    583
    Units: percentage of subjects
    number (confidence interval 95%)
        Week 96
    91.6 (88.7 to 93.8)
    93.6 (91.0 to 95.5)
        Week 156
    89.7 (86.5 to 92.2)
    90.9 (87.8 to 93.3)
    No statistical analyses for this end point

    Secondary: DBTP and DBE Period: Percentage of Subjects Without 12-Week Confirmed Disability Progression (CDP) as Measured by Expanded Disability Status Scale (EDSS)

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    End point title
    DBTP and DBE Period: Percentage of Subjects Without 12-Week Confirmed Disability Progression (CDP) as Measured by Expanded Disability Status Scale (EDSS)
    End point description
    Disability progression was defined as increase in EDSS of greater than or equal to [>=] 1 point from baseline EDSS score, if EDSS score at baseline is 5.0 or less and an increase of >=0.5 point, if the baseline score is 5.5. Disability progression is considered sustained for 12 weeks when the initial increase in the EDSS is confirmed at a regularly scheduled visit at least 12 weeks after the initial documentation of neurological worsening. The total EDSS score ranges from 0 (normal) to 10 (death due to multiple sclerosis). Kaplan-Meier method was used to estimate the percentage of subjects without 12-week CDP. Full Analysis Set (FAS) included all subjects who were randomized to study treatment. The result reported for this endpoint are the results from data of combined DBTP and DBE periods.
    End point type
    Secondary
    End point timeframe
    Week 96 and Week 156 (combined DBTP and DBE periods)
    End point values
    Teriflunomide Evobrutinib
    Number of subjects analysed
    583
    583
    Units: percentage of subjects
    number (confidence interval 95%)
        Week 96
    88.9 (85.7 to 91.4)
    91.8 (88.9 to 93.9)
        Week 156
    82.3 (76.0 to 87.1)
    85.0 (77.8 to 90.0)
    No statistical analyses for this end point

    Secondary: DBTP and DBE Period: Percentage of Subjects with 24-Week Confirmed Disability Improvement (CDI) as Measured by Expanded Disability Status Scale (EDSS)

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    End point title
    DBTP and DBE Period: Percentage of Subjects with 24-Week Confirmed Disability Improvement (CDI) as Measured by Expanded Disability Status Scale (EDSS)
    End point description
    Disability improvement was defined as a reduction of 1 point from Baseline EDSS score when the Baseline score is >= 2 and less than or equal to [<=] 6 and a reduction of 0.5 point from Baseline EDSS score when the Baseline score is >= 6.5 and <= 9.5. Disability improvement is considered sustained when the initial reduction in the EDSS score is confirmed at a regularly scheduled visit at least 24 weeks after the initial reduction. The total EDSS score ranges from 0 (normal) to 10 (death due to multiple sclerosis). Kaplan-Meier method was used to estimate the percentage of subjects with 12-week CDI. Full Analysis Set (FAS) included all subjects who were randomized to study treatment. The result reported for this endpoint are the results from data of combined DBTP and DBE periods.
    End point type
    Secondary
    End point timeframe
    Week 96 and Week 156 (combined DBTP and DBE periods)
    End point values
    Teriflunomide Evobrutinib
    Number of subjects analysed
    583
    583
    Units: percentage of subjects
    number (confidence interval 95%)
        Week 96
    11.4 (8.6 to 15.0)
    7.6 (5.4 to 10.7)
        Week 156
    12.5 (9.5 to 16.4)
    8.4 (6.0 to 11.6)
    No statistical analyses for this end point

    Secondary: DBTP and DBE Period: Change From Baseline in Patient Reported Outcomes Measurement Information System (PROMIS) Physical Function (PF) Score at Week 48, Week 96, Week 120, Week 144 and Week 156

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    End point title
    DBTP and DBE Period: Change From Baseline in Patient Reported Outcomes Measurement Information System (PROMIS) Physical Function (PF) Score at Week 48, Week 96, Week 120, Week 144 and Week 156
    End point description
    Physical function was assessed with PROMISnq Short Form v2.0 – Physical Function – Multiple Sclerosis 15a (PROMISnq PF(MS) 15a). PROMISnq PF(MS) 15a assesses a subject's abilities and limitations with respect to everyday physical activities. Results are reported as a T-score. In the general population, T-scores have a mean of 50, standard deviation of 10, and range from 10 to 65. Higher T-scores represent higher physical function. Change from baseline in PROMIS PF score was analyzed using Mixed Effect Model for Repeated Measures (MMRM) to evaluate the result of the 2 periods (DBTP and DBE). FAS was used. Here, number of subjects analyzed signifies those subjects who were evaluable for this endpoint. Here, "9999" = Week 156 is not evaluable in the modelling due to the lack of subjects in some of the covariate categories at that visit. The result reported for this endpoint are the results from data of combined DBTP and DBE periods.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48, Week 96, Week 120, Week 144 and Week 156 (Combined DBTP and DBE periods)
    End point values
    Teriflunomide Evobrutinib
    Number of subjects analysed
    572
    572
    Units: units on a scale
    least squares mean (confidence interval 95%)
        Week 48
    0.25 (-0.22 to 0.72)
    0.31 (-0.16 to 0.78)
        Week 96
    -0.31 (-0.88 to 0.26)
    -0.45 (-1.03 to 0.13)
        Week 120
    -0.56 (-1.23 to 0.11)
    -0.19 (-0.86 to 0.48)
        Week 144
    -0.38 (-1.12 to 0.35)
    -0.57 (-1.31 to 0.17)
        Week 156
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    No statistical analyses for this end point

    Secondary: DBTP and DBE Period: Change From Baseline in Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Score at Week 48, Week 96, Week 120, Week 144 and Week 156

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    End point title
    DBTP and DBE Period: Change From Baseline in Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Score at Week 48, Week 96, Week 120, Week 144 and Week 156
    End point description
    PROMIS Fatigue score was assessed with PROMIS Short Form v1.0 – Fatigue – Multiple Sclerosis 8a (PROMIS Fatigue (MS) 8a). PROMIS Fatigue (MS) 8a assesses level of fatigue and its interference on daily activities. Results are reported as a T-score. In the general population, T-scores have a mean of 50, standard deviation of 10, and range from 33 to 85. Higher T-scores represent higher fatigue. Change from baseline in PROMIS fatigue score was analyzed using Mixed Effect Model for Repeated Measures (MMRM) to evaluate the result of the 2 periods (DBTP and DBE). Full Analysis Set (FAS) included all subjects who were randomized to study treatment. Here, number of subjects analyzed signifies those subjects who were evaluable for this endpoint. The result reported for this endpoint are the results from data of combined DBTP and DBE periods.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48, Week 96, Week 120, Week 144 and Week 156 (combined DBTP and DBE periods)
    End point values
    Teriflunomide Evobrutinib
    Number of subjects analysed
    572
    572
    Units: units on a scale
    least squares mean (confidence interval 95%)
        Week 48
    -2.20 (-2.81 to -1.60)
    -2.59 (-3.19 to -1.98)
        Week 96
    -2.17 (-2.85 to -1.49)
    -2.12 (-2.81 to -1.44)
        Week 120
    -2.24 (-3.00 to -1.48)
    -2.59 (-3.35 to -1.83)
        Week 144
    -2.41 (-3.35 to -1.48)
    -2.16 (-3.10 to -1.22)
        Week 156
    -2.21 (-3.62 to -0.81)
    -2.34 (-3.83 to -0.86)
    No statistical analyses for this end point

    Secondary: DBTP and DBE Period: Total number of T1 Gadolinium-positive (Gd+) lesions

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    End point title
    DBTP and DBE Period: Total number of T1 Gadolinium-positive (Gd+) lesions
    End point description
    Analysis of Gadolinium-positive T1 lesions was done using magnetic resonance imaging (MRI) scans. Full Analysis Set (FAS) included all subjects who were randomized to study treatment. Here, number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to 170 weeks
    End point values
    Teriflunomide Evobrutinib
    Number of subjects analysed
    544
    544
    Units: lesions per scan
        arithmetic mean (confidence interval 95%)
    0.29 (0.24 to 0.34)
    0.51 (0.43 to 0.60)
    No statistical analyses for this end point

    Secondary: DBTP and DBE Period: New or Enlarging T2 Lesions Rate

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    End point title
    DBTP and DBE Period: New or Enlarging T2 Lesions Rate
    End point description
    Analysis of new or enlarging T2 lesions rate was done using magnetic resonance imaging (MRI) scans. Negative binomial model for lesion count (summed over scans) includes treatment and covariates based on randomization strata and baseline volume of T2 lesion (continuous), with offset equal to the log of the time in years between the last available MRI scan and the baseline scan. Full Analysis Set (FAS) included all subjects who were randomized to study treatment. Here, number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to 170 weeks
    End point values
    Teriflunomide Evobrutinib
    Number of subjects analysed
    544
    544
    Units: lesions per year
        arithmetic mean (confidence interval 95%)
    6.88 (6.01 to 7.87)
    6.17 (5.38 to 7.07)
    No statistical analyses for this end point

    Secondary: DBTP Period: Neurofilament Light Chain (NfL) Concentration at Week 12

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    End point title
    DBTP Period: Neurofilament Light Chain (NfL) Concentration at Week 12
    End point description
    NfL is a biomarker of neuro-axonal damage whose concentration was assessed in blood at Week 12. Full Analysis Set (FAS) included all subjects who were randomized to study treatment. Here, number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    Teriflunomide Evobrutinib
    Number of subjects analysed
    544
    544
    Units: nanogram per liter (ng/L)
        geometric mean (confidence interval 95%)
    13.09 (12.69 to 13.50)
    12.51 (12.13 to 12.90)
    No statistical analyses for this end point

    Secondary: DBTP and DBE Periods: Number of Subjects with Treatment-Emergent Adverse Events (TEAEs) and Adverse Events of Special Interest (AESIs)

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    End point title
    DBTP and DBE Periods: Number of Subjects with Treatment-Emergent Adverse Events (TEAEs) and Adverse Events of Special Interest (AESIs)
    End point description
    Adverse event (AE): Any untoward medical occurrence in a participant which does not necessarily have a causal relationship with the study drug. Serious AE: an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs: those AEs with an onset date on or after the date of first study intervention administration, or AEs present prior to any study intervention administration but exacerbating after. TEAEs included both Serious TEAEs and non-serious TEAEs. AESIs included liver AEs (possible drug-induced, non-infectious, non-alcoholic, and immune-mediated), infections (serious and opportunistic infections), lipase and amylase elevation, and seizure. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to 170 weeks
    End point values
    Teriflunomide Evobrutinib
    Number of subjects analysed
    583
    581
    Units: subjects
        Subjects with TEAEs
    524
    508
        Subjects with AESIs
    144
    135
    No statistical analyses for this end point

    Secondary: DBTP and DBE periods: Number of Subjects with Treatment-Emergent Adverse Events (TEAEs) by Severity

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    End point title
    DBTP and DBE periods: Number of Subjects with Treatment-Emergent Adverse Events (TEAEs) by Severity
    End point description
    Severity of adverse events (AE) were assessed by the investigator per the National Cancer Institute- Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0. Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Death. Number of subjects with Grades 1, 2, 3, 4 and 5 were reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to 170 weeks
    End point values
    Teriflunomide Evobrutinib
    Number of subjects analysed
    583
    581
    Units: subjects
        Subjects with Grade 1
    41
    59
        Subjects with Grade 2
    389
    351
        Subjects with Grade 3
    87
    92
        Subjects with Grade 4
    7
    6
        Subjects with Grade 5
    0
    0
    No statistical analyses for this end point

    Secondary: DBTP and DBE Periods: Change From Baseline in Vital Signs: Diastolic Blood Pressure and Systolic Blood Pressure

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    End point title
    DBTP and DBE Periods: Change From Baseline in Vital Signs: Diastolic Blood Pressure and Systolic Blood Pressure
    End point description
    Diastolic blood pressure and systolic blood pressure were measured after at least 5 minutes of rest for the subject in a quiet sitting without distractions. Changes in vital signs: diastolic blood pressure and systolic blood pressure from Baseline up to 170 weeks were reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to 170 weeks
    End point values
    Teriflunomide Evobrutinib
    Number of subjects analysed
    457
    454
    Units: millimeter of mercury (mmHg)
    arithmetic mean (standard deviation)
        Systolic Blood Pressure
    2.4 ( 11.0 )
    1.0 ( 11.50 )
        Diastolic Blood Pressure
    1.4 ( 8.73 )
    -0.5 ( 8.38 )
    No statistical analyses for this end point

    Secondary: DBTP and DBE Periods: Change From Baseline in Vital Signs: Weight

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    End point title
    DBTP and DBE Periods: Change From Baseline in Vital Signs: Weight
    End point description
    Changes in vital signs: weight from baseline up to 170 weeks was reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to 170 weeks
    End point values
    Teriflunomide Evobrutinib
    Number of subjects analysed
    457
    454
    Units: kilograms (kg)
        arithmetic mean (standard deviation)
    -0.51 ( 5.447 )
    1.06 ( 5.310 )
    No statistical analyses for this end point

    Secondary: DBTP and DBE Periods: Change From Baseline in Vital Signs: Respiratory Rate

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    End point title
    DBTP and DBE Periods: Change From Baseline in Vital Signs: Respiratory Rate
    End point description
    Respiratory rate was measured after at least 5 minutes of rest for the subject in a quiet sitting without distractions. Changes in vital signs: respiratory rate from baseline up to 170 weeks was reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to 170 weeks
    End point values
    Teriflunomide Evobrutinib
    Number of subjects analysed
    457
    454
    Units: breaths per minute
        arithmetic mean (standard deviation)
    -0.3 ( 1.75 )
    -0.5 ( 1.87 )
    No statistical analyses for this end point

    Secondary: DBTP and DBE Periods: Change From Baseline in Vital Signs: Pulse Rate

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    End point title
    DBTP and DBE Periods: Change From Baseline in Vital Signs: Pulse Rate
    End point description
    Pulse rate was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions. Changes in vital signs: pulse rate from baseline up to 170 weeks was reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to 170 weeks
    End point values
    Teriflunomide Evobrutinib
    Number of subjects analysed
    457
    454
    Units: beats per minute
        arithmetic mean (standard deviation)
    2.2 ( 10.19 )
    3.0 ( 10.15 )
    No statistical analyses for this end point

    Secondary: DBTP and DBE Periods: Change From Baseline in Vital Signs: Temperature

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    End point title
    DBTP and DBE Periods: Change From Baseline in Vital Signs: Temperature
    End point description
    Temperature was measured after at least 5 minutes of rest for the subject in a quiet sitting without distractions. Changes in vital signs: Temperature from baseline up to 170 weeks was reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to 170 weeks
    End point values
    Teriflunomide Evobrutinib
    Number of subjects analysed
    457
    454
    Units: degree Celsius
        arithmetic mean (standard deviation)
    -0.02 ( 0.340 )
    -0.03 ( 0.350 )
    No statistical analyses for this end point

    Secondary: DBTP and DBE Periods: Change From Baseline in Electrocardiograms (ECGs): Heart Rate

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    End point title
    DBTP and DBE Periods: Change From Baseline in Electrocardiograms (ECGs): Heart Rate
    End point description
    Heart rate was measured after at least 5 minutes of rest for the subject in a quiet sitting without distractions. Changes in vital signs: heart rate from Baseline up to 170 weeks was reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to 170 weeks
    End point values
    Teriflunomide Evobrutinib
    Number of subjects analysed
    77
    69
    Units: beats per minute
        arithmetic mean (standard deviation)
    -0.1 ( 10.36 )
    2.6 ( 10.20 )
    No statistical analyses for this end point

    Secondary: DBTP and DBE Periods: Change From Baseline in Electrocardiograms (ECGs): QT Interval - Fridericia's Correction Formula, PR Interval and QRS Duration

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    End point title
    DBTP and DBE Periods: Change From Baseline in Electrocardiograms (ECGs): QT Interval - Fridericia's Correction Formula, PR Interval and QRS Duration
    End point description
    QT Interval - Fridericia's Correction Formula, PR Interval and QRS Duration was measured after at least 5 minutes of rest for the subject in a quiet sitting without distractions. Changes in vital signs: QT Interval - Fridericia's Correction Formula, PR Interval and QRS Duration from baseline up to 170 weeks were reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to 170 weeks
    End point values
    Teriflunomide Evobrutinib
    Number of subjects analysed
    77
    69
    Units: milliseconds (msec)
    arithmetic mean (standard deviation)
        QT Interval - Fridericia's Correction Formula
    -2.14 ( 16.459 )
    -0.07 ( 14.935 )
        PR Interval
    -4.2 ( 16.82 )
    -3.1 ( 14.51 )
        QRS Duration
    -2.8 ( 6.77 )
    -1.1 ( 8.94 )
    No statistical analyses for this end point

    Secondary: DBTP and DBE Periods: Change From Baseline in Hematology Parameter: Hemoglobin and Erythrocytes Mean Corpuscular Hemoglobin (HGB) Concentration

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    End point title
    DBTP and DBE Periods: Change From Baseline in Hematology Parameter: Hemoglobin and Erythrocytes Mean Corpuscular Hemoglobin (HGB) Concentration
    End point description
    Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the hematology parameters: erythrocytes mean corpuscular HGB concentration (Con.) and hemoglobin. Changes in hematology parameters: erythrocytes mean corpuscular HGB concentration and hemoglobin from baseline up to 170 weeks were reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, number of subjects analyzed signifies those subjects who were evaluable for this endpoint and “n"= subjects who were evaluable for the specified categories.
    End point type
    Secondary
    End point timeframe
    Baseline up to 170 weeks
    End point values
    Teriflunomide Evobrutinib
    Number of subjects analysed
    447
    436
    Units: gram per liter (g/L)
    arithmetic mean (standard deviation)
        Erythrocytes Mean Corpuscular HGB Con.: n=438, 428
    0.0 ( 11.07 )
    -1.9 ( 12.42 )
        Hemoglobin: n = 447, 436
    -3.4 ( 11.40 )
    -3.4 ( 11.43 )
    No statistical analyses for this end point

    Secondary: DBTP and DBE Periods: Change From Baseline in Hematology Parameter: Platelets, Leukocytes, Neutrophils, Eosinophils, Basophils, Monocytes, Lymphocytes and Reticulocytes

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    End point title
    DBTP and DBE Periods: Change From Baseline in Hematology Parameter: Platelets, Leukocytes, Neutrophils, Eosinophils, Basophils, Monocytes, Lymphocytes and Reticulocytes
    End point description
    Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the hematology parameters: Platelets, Leukocytes, Neutrophils, Eosinophils, Basophils, Monocytes, Lymphocytes and Reticulocytes. Changes in hematology parameters: Platelets, Leukocytes, Neutrophils, Eosinophils, Basophils, Monocytes, Lymphocytes and Reticulocytes from baseline up to 170 weeks were reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, number of subjects analyzed signifies those subjects who were evaluable for this endpoint and “n"= subjects who were evaluable for the specified categories.
    End point type
    Secondary
    End point timeframe
    Baseline up to 170 weeks
    End point values
    Teriflunomide Evobrutinib
    Number of subjects analysed
    446
    437
    Units: 10^9 cells per liter
    arithmetic mean (standard deviation)
        Platelets: n = 441, 432
    -8.4 ( 48.38 )
    9.8 ( 52.24 )
        Leukocytes: n = 446, 437
    -0.39 ( 1.954 )
    0.24 ( 1.883 )
        Neutrophils: n = 331, 324
    -0.471 ( 1.7550 )
    0.156 ( 1.7796 )
        Eosinophils: n = 438, 431
    0.0198 ( 0.14809 )
    0.0238 ( 0.14945 )
        Basophils: n = 438, 431
    -0.0081 ( 0.03882 )
    -0.0042 ( 0.03902 )
        Monocytes: n = 438, 432
    0.0797 ( 0.19710 )
    0.0772 ( 0.20715 )
        Lymphocytes: n = 442, 434
    -0.0241 ( 0.57564 )
    0.0311 ( 0.57810 )
        Reticulocytes: n = 436, 430
    2.001 ( 23.3886 )
    -0.841 ( 20.2200 )
    No statistical analyses for this end point

    Secondary: DBTP and DBE Periods: Change From Baseline in Hematology Parameters: Hematocrit

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    End point title
    DBTP and DBE Periods: Change From Baseline in Hematology Parameters: Hematocrit
    End point description
    Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the hematology parameter: Hematocrit. Changes in hematology parameter: Hematocrit from baseline up to 170 weeks was reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to 170 weeks
    End point values
    Teriflunomide Evobrutinib
    Number of subjects analysed
    442
    431
    Units: percentage of cells
        arithmetic mean (standard deviation)
    -0.0107 ( 0.03199 )
    -0.0085 ( 0.03311 )
    No statistical analyses for this end point

    Secondary: DBTP and DBE Periods: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin

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    End point title
    DBTP and DBE Periods: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin
    End point description
    Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the hematology parameter: Erythrocytes Mean Corpuscular Hemoglobin. Changes in hematology parameter: Erythrocytes Mean Corpuscular Hemoglobin from baseline up to 170 weeks was reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to 170 weeks
    End point values
    Teriflunomide Evobrutinib
    Number of subjects analysed
    443
    435
    Units: picogram
        arithmetic mean (standard deviation)
    -0.44 ( 1.603 )
    -0.93 ( 1.941 )
    No statistical analyses for this end point

    Secondary: DBTP and DBE Periods: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Volume

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    End point title
    DBTP and DBE Periods: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Volume
    End point description
    Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the hematology parameter: Erythrocytes Mean Corpuscular Volume. Changes in hematology parameter: Erythrocytes Mean Corpuscular Volume from baseline up to 170 weeks was reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to 170 weeks
    End point values
    Teriflunomide Evobrutinib
    Number of subjects analysed
    441
    431
    Units: femtoliters
        arithmetic mean (standard deviation)
    -1.48 ( 4.150 )
    -2.53 ( 5.217 )
    No statistical analyses for this end point

    Secondary: DBTP and DBE Periods: Change From Baseline in Biochemistry Parameters: Bilirubin and Creatinine

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    End point title
    DBTP and DBE Periods: Change From Baseline in Biochemistry Parameters: Bilirubin and Creatinine
    End point description
    Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the biochemistry parameters: Bilirubin and Creatinine. Changes in biochemistry parameters: Bilirubin and Creatinine from baseline up to 170 weeks were reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, number of subjects analyzed signifies those subjects who were evaluable for this endpoint and “n" = subjects who were evaluable for the specified categories.
    End point type
    Secondary
    End point timeframe
    Baseline up to 170 weeks
    End point values
    Teriflunomide Evobrutinib
    Number of subjects analysed
    455
    446
    Units: micromoles per liter (mcmol/L)
    arithmetic mean (standard deviation)
        Bilirubin: n = 455, 446
    -0.02 ( 4.649 )
    0.33 ( 4.212 )
        Creatinine: n = 449, 442
    1.6 ( 8.93 )
    2.4 ( 12.06 )
    No statistical analyses for this end point

    Secondary: DBTP and DBE Periods: Change From Baseline in Biochemistry Parameters: Aspartate Aminotransferase, Alanine Aminotransferase, Alkaline Phosphatase, Amylase, Lipase, Gamma Glutamyl Transferase and Lactate Dehydrogenase

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    End point title
    DBTP and DBE Periods: Change From Baseline in Biochemistry Parameters: Aspartate Aminotransferase, Alanine Aminotransferase, Alkaline Phosphatase, Amylase, Lipase, Gamma Glutamyl Transferase and Lactate Dehydrogenase
    End point description
    Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the biochemistry parameters: Aspartate Aminotransferase, Alanine Aminotransferase, Alkaline Phosphatase, Amylase, Lipase, Gamma Glutamyl Transferase and Lactate Dehydrogenase. Changes in biochemistry parameters: Aspartate Aminotransferase, Alanine Aminotransferase, Alkaline Phosphatase, Amylase, Lipase, Gamma Glutamyl Transferase and Lactate Dehydrogenase from baseline up to 170 weeks were reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, number of subjects analyzed signifies those subjects who were evaluable for this endpoint and “n" = subjects who were evaluable for the specified categories.
    End point type
    Secondary
    End point timeframe
    Baseline up to 170 weeks
    End point values
    Teriflunomide Evobrutinib
    Number of subjects analysed
    455
    446
    Units: units per liter (U/L)
    arithmetic mean (standard deviation)
        Aspartate Aminotransferase: n = 454, 444
    2.64 ( 15.365 )
    1.74 ( 13.219 )
        Alanine Aminotransferase: n = 455, 446
    4.40 ( 33.878 )
    2.75 ( 32.018 )
        Alkaline Phosphatase: n = 447, 445
    2.32 ( 15.875 )
    6.69 ( 15.659 )
        Amylase: n = 450, 441
    1.3 ( 14.42 )
    2.1 ( 15.91 )
        Lipase: n = 449, 442
    -0.3 ( 18.35 )
    2.3 ( 17.26 )
        Gamma Glutamyl Transferase: n = 359, 385
    3.71 ( 26.084 )
    1.98 ( 20.207 )
        Lactate Dehydrogenase: n = 436, 439
    7.08 ( 27.049 )
    -5.41 ( 27.637 )
    No statistical analyses for this end point

    Secondary: DBTP and DBE Periods: Change From Baseline in Biochemistry Parameters: Sodium, Potassium, Calcium, Magnesium, Glucose, Chloride, Urea Nitrogen, Phosphate, Bicarbonate and Corrected Calcium

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    End point title
    DBTP and DBE Periods: Change From Baseline in Biochemistry Parameters: Sodium, Potassium, Calcium, Magnesium, Glucose, Chloride, Urea Nitrogen, Phosphate, Bicarbonate and Corrected Calcium
    End point description
    Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the biochemistry parameters: Sodium, Potassium, Calcium, Magnesium, Glucose, Chloride, Urea Nitrogen, Phosphate, Bicarbonate and Corrected Calcium. Changes in biochemistry parameters: Sodium, Potassium, Calcium, Magnesium, Glucose, Chloride, Urea Nitrogen, Phosphate, Bicarbonate and Corrected Calcium from baseline up to 170 weeks were reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, number of subjects analyzed signifies those subjects who were evaluable for this endpoint and “n" = subjects who were evaluable for the specified categories.
    End point type
    Secondary
    End point timeframe
    Baseline up to 170 weeks
    End point values
    Teriflunomide Evobrutinib
    Number of subjects analysed
    450
    446
    Units: millimole per liter (mmol/L)
    arithmetic mean (standard deviation)
        Sodium: n = 448, 440
    0.9286 ( 2.56796 )
    0.7750 ( 3.21185 )
        Potassium: n = 449, 439
    0.0405 ( 0.48750 )
    0.0376 ( 0.44331 )
        Calcium: n = 448, 440
    -0.006 ( 0.1197 )
    -0.008 ( 0.1121 )
        Magnesium: n = 449, 441
    -0.002 ( 0.0656 )
    -0.006 ( 0.0667 )
        Glucose: n = 448, 440
    0.09 ( 0.949 )
    0.16 ( 0.812 )
        Chloride: n = 450, 440
    2.3 ( 3.30 )
    2.1 ( 3.53 )
        Urea Nitrogen: n = 447, 441
    0.126 ( 1.2759 )
    0.122 ( 1.1651 )
        Phosphate: n = 428, 434
    -0.047 ( 0.1944 )
    -0.024 ( 0.1799 )
        Bicarbonate: n = 324, 348
    0.44 ( 2.592 )
    0.17 ( 2.980 )
        Corrected Calcium: n = 446, 437
    0.0290 ( 0.10405 )
    0.0292 ( 0.09775 )
    No statistical analyses for this end point

    Secondary: DBTP and DBE Periods: Change From Baseline in Biochemistry Parameters: Total Protein and Albumin

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    End point title
    DBTP and DBE Periods: Change From Baseline in Biochemistry Parameters: Total Protein and Albumin
    End point description
    Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the biochemistry parameters: Total Protein and Albumin. Changes in biochemistry parameters: Total Protein and Albumin from baseline up to 170 weeks were reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, number of subjects analyzed signifies those subjects who were evaluable for this endpoint and “n" = subjects who were evaluable for the specified categories.
    End point type
    Secondary
    End point timeframe
    Baseline up to 170 weeks
    End point values
    Teriflunomide Evobrutinib
    Number of subjects analysed
    448
    444
    Units: gram per liter (g/L)
    arithmetic mean (standard deviation)
        Total protein: n = 448, 437
    -1.31 ( 4.905 )
    -0.59 ( 4.998 )
        Albumin: n = 448, 444
    -1.75 ( 3.497 )
    -1.83 ( 3.287 )
    No statistical analyses for this end point

    Secondary: DBTP and DBE Periods: Change From Baseline in Biochemistry Parameters: Glomerular Filtration Rate

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    End point title
    DBTP and DBE Periods: Change From Baseline in Biochemistry Parameters: Glomerular Filtration Rate
    End point description
    Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the biochemistry parameter: Glomerular Filtration Rate. Changes in biochemistry parameter: Glomerular Filtration Rate from baseline up to 170 weeks were reported. The Glomerular Filtration Rate will be measured as milliliter per minute per 1.73 square meter (mL/min/1.73m^2). Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to 170 weeks
    End point values
    Teriflunomide Evobrutinib
    Number of subjects analysed
    360
    351
    Units: mL/min/1.73m^2
        arithmetic mean (standard deviation)
    -4.7 ( 13.41 )
    -5.7 ( 13.81 )
    No statistical analyses for this end point

    Secondary: DBTP and DBE Periods: Change From Baseline in Urinalyses Parameter: Potential of Hydrogen (pH) of Urine

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    End point title
    DBTP and DBE Periods: Change From Baseline in Urinalyses Parameter: Potential of Hydrogen (pH) of Urine
    End point description
    Urine samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the urinalyses parameter: pH. pH is measured on a numeric scale ranging from 0 to 14; values on the scale refer to the degree of alkalinity or acidity. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acid pH (5.0 - 6.0). Changes in urinalyses parameter: pH from baseline up to 170 weeks was reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to 170 weeks
    End point values
    Teriflunomide Evobrutinib
    Number of subjects analysed
    442
    438
    Units: pH
        arithmetic mean (standard deviation)
    -0.03 ( 0.936 )
    -0.04 ( 0.973 )
    No statistical analyses for this end point

    Secondary: DBTP and DBE Periods: Change From Baseline in Urinalyses Parameter: Specific Gravity of Urine

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    End point title
    DBTP and DBE Periods: Change From Baseline in Urinalyses Parameter: Specific Gravity of Urine
    End point description
    Urine samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the urinalyses parameter: Specific Gravity of Urine. Changes in urinalyses parameter: Specific Gravity of Urine from baseline up to 170 weeks was reported. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to 170 weeks
    End point values
    Teriflunomide Evobrutinib
    Number of subjects analysed
    436
    428
    Units: Kilogram per cubic meter
        arithmetic mean (standard deviation)
    -0.0015 ( 0.04460 )
    -0.0017 ( 0.03748 )
    No statistical analyses for this end point

    Secondary: DBTP and DBE Periods: Absolute Concentrations of Immunoglobulin (Ig) Levels

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    End point title
    DBTP and DBE Periods: Absolute Concentrations of Immunoglobulin (Ig) Levels
    End point description
    Absolute Concentrations serum levels of IgG, IgA, IgM were assessed. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    At Week 170
    End point values
    Teriflunomide Evobrutinib
    Number of subjects analysed
    319
    341
    Units: gram per liter (g/L)
    arithmetic mean (standard deviation)
        IgA
    1.899 ( 0.7787 )
    2.581 ( 1.1201 )
        IgG
    10.082 ( 2.1551 )
    10.990 ( 2.4844 )
        IgM
    1.251 ( 0.6445 )
    1.196 ( 0.6151 )
    No statistical analyses for this end point

    Secondary: DBTP and DBE Periods: Change from Baseline in Immunoglobulin (Ig) Levels

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    End point title
    DBTP and DBE Periods: Change from Baseline in Immunoglobulin (Ig) Levels
    End point description
    Change from baseline serum levels of IgG, IgA, IgM were assessed. Safety (SAF) analysis set included all subjects who received at least one dose of study treatment. Here, number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to 170 weeks
    End point values
    Teriflunomide Evobrutinib
    Number of subjects analysed
    319
    339
    Units: gram per liter (g/L)
    arithmetic mean (standard deviation)
        IgA
    -0.203 ( 0.5704 )
    0.500 ( 0.7197 )
        IgG
    -0.645 ( 1.6188 )
    0.146 ( 1.8712 )
        IgM
    -0.167 ( 0.5094 )
    -0.175 ( 0.3888 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 170 weeks
    Adverse event reporting additional description
    Safety (SAF) analysis set included all subjects who received at least one dose of study treatment.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Evobrutinib
    Reporting group description
    Subjects received Evobrutinib at a dose of 45 mg orally twice daily up to 156 weeks in Double blind treatment period (DBTP) followed by twice daily oral doses of Evobrutinib 45 mg up to 96 weeks in double blind extension (DBE) period.

    Reporting group title
    Teriflunomide
    Reporting group description
    Subjects received Teriflunomide at a dose of 14 milligrams (mg) orally once daily up to 156 weeks in Double blind treatment period (DBTP) followed by once daily oral doses of Teriflunomide 14 mg up to 96 weeks in double blind extension (DBE) period.

    Serious adverse events
    Evobrutinib Teriflunomide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    51 / 581 (8.78%)
    37 / 583 (6.35%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 581 (0.00%)
    1 / 583 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemangioma of liver
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 581 (0.00%)
    1 / 583 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    4 / 581 (0.69%)
    2 / 583 (0.34%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Synovial sarcoma
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papillary thyroid cancer
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 581 (0.00%)
    2 / 583 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Subgaleal haematoma
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 581 (0.00%)
    1 / 583 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Social circumstances
    Pregnancy of partner
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Miscarriage of partner
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine polyp
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 581 (0.00%)
    1 / 583 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine haemorrhage
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 581 (0.00%)
    1 / 583 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic ovarian cyst
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 581 (0.00%)
    1 / 583 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Genital haemorrhage
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 581 (0.00%)
    1 / 583 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometriosis
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 581 (0.00%)
    1 / 583 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial hyperplasia
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 581 (0.00%)
    1 / 583 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical polyp
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abnormal uterine bleeding
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 581 (0.00%)
    1 / 583 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory arrest
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 581 (0.00%)
    1 / 583 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax spontaneous
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 581 (0.00%)
    1 / 583 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paranasal sinus inflammation
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 581 (0.00%)
    1 / 583 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Emphysema
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 581 (0.00%)
    1 / 583 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Alcoholism
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 581 (0.00%)
    1 / 583 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropsychiatric symptoms
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mood disorder due to a general medical condition
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental disorder
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 581 (0.00%)
    1 / 583 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    7 / 581 (1.20%)
    3 / 583 (0.51%)
         occurrences causally related to treatment / all
    4 / 7
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    3 / 581 (0.52%)
    2 / 583 (0.34%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SARS-CoV-2 test positive
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 581 (0.00%)
    1 / 583 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Accidental overdose
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 581 (0.00%)
    2 / 583 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder injury
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carbon monoxide poisoning
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Craniocerebral injury
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial bones fracture
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 581 (0.00%)
    1 / 583 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 581 (0.00%)
    1 / 583 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scar
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal injury
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle injury
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint injury
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional hernia
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 581 (0.00%)
    1 / 583 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin abrasion
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract injury
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular pseudoaneurysm
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 581 (0.00%)
    1 / 583 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Autonomic neuropathy
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 581 (0.00%)
    1 / 583 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 581 (0.00%)
    1 / 583 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbosacral radiculopathy
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    2 / 581 (0.34%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 581 (0.00%)
    1 / 583 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple sclerosis relapse
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    3 / 581 (0.52%)
    1 / 583 (0.17%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    1 / 583 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 581 (0.00%)
    1 / 583 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Chalazion
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ileus spastic
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 581 (0.00%)
    1 / 583 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 581 (0.00%)
    1 / 583 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 581 (0.00%)
    1 / 583 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteonecrosis
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Symphysiolysis
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Acute sinusitis
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal abscess
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic tonsillitis
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis infective
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 581 (0.00%)
    1 / 583 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    2 / 581 (0.34%)
    2 / 583 (0.34%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    2 / 581 (0.34%)
    1 / 583 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    2 / 581 (0.34%)
    1 / 583 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 581 (0.00%)
    1 / 583 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    2 / 581 (0.34%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salpingo-oophoritis
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Electrolyte imbalance
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 581 (0.00%)
    1 / 583 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 581 (0.17%)
    0 / 583 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Evobrutinib Teriflunomide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    409 / 581 (70.40%)
    455 / 583 (78.04%)
    Investigations
    Lymphocyte count decreased
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    27 / 581 (4.65%)
    39 / 583 (6.69%)
         occurrences all number
    40
    73
    Lipase increased
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    33 / 581 (5.68%)
    33 / 583 (5.66%)
         occurrences all number
    55
    39
    Gamma-glutamyltransferase increased
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    31 / 581 (5.34%)
    29 / 583 (4.97%)
         occurrences all number
    37
    70
    Alanine aminotransferase increased
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    99 / 581 (17.04%)
    126 / 583 (21.61%)
         occurrences all number
    168
    227
    Aspartate aminotransferase increased
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    61 / 581 (10.50%)
    80 / 583 (13.72%)
         occurrences all number
    84
    123
    White blood cell count decreased
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    23 / 581 (3.96%)
    63 / 583 (10.81%)
         occurrences all number
    39
    122
    Neutrophil count decreased
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    40 / 581 (6.88%)
    92 / 583 (15.78%)
         occurrences all number
    52
    156
    Nervous system disorders
    Headache
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    96 / 581 (16.52%)
    103 / 583 (17.67%)
         occurrences all number
    198
    169
    General disorders and administration site conditions
    Fatigue
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    37 / 581 (6.37%)
    47 / 583 (8.06%)
         occurrences all number
    46
    66
    Blood and lymphatic system disorders
    Anaemia
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    34 / 581 (5.85%)
    23 / 583 (3.95%)
         occurrences all number
    54
    35
    Neutropenia
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    22 / 581 (3.79%)
    47 / 583 (8.06%)
         occurrences all number
    33
    112
    Gastrointestinal disorders
    Nausea
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    29 / 581 (4.99%)
    36 / 583 (6.17%)
         occurrences all number
    39
    39
    Diarrhoea
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    24 / 581 (4.13%)
    47 / 583 (8.06%)
         occurrences all number
    28
    59
    Skin and subcutaneous tissue disorders
    Alopecia
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    35 / 581 (6.02%)
    84 / 583 (14.41%)
         occurrences all number
    38
    87
    Musculoskeletal and connective tissue disorders
    Back pain
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    49 / 581 (8.43%)
    61 / 583 (10.46%)
         occurrences all number
    63
    79
    Pain in extremity
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    30 / 581 (5.16%)
    32 / 583 (5.49%)
         occurrences all number
    46
    40
    Infections and infestations
    Nasopharyngitis
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    58 / 581 (9.98%)
    67 / 583 (11.49%)
         occurrences all number
    89
    103
    COVID-19
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    105 / 581 (18.07%)
    121 / 583 (20.75%)
         occurrences all number
    119
    139
    Respiratory tract infection viral
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    23 / 581 (3.96%)
    37 / 583 (6.35%)
         occurrences all number
    36
    52
    Urinary tract infection
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    39 / 581 (6.71%)
    33 / 583 (5.66%)
         occurrences all number
    49
    46
    Upper respiratory tract infection
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    55 / 581 (9.47%)
    45 / 583 (7.72%)
         occurrences all number
    83
    81

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Dec 2020
    • To allow sufficient time for repeat laboratory results and other unanticipated events prior to randomization. • To clarify the process in the event of a female subject undergoing Accelerated elimination procedure (AEP). • To clarify that this is a safety visit safety follow-up (SFU) visit must be >= 28 days after last study intervention Clarification. • Assessment required at Week 108 for subjects for whom this is also D1 of the OLE.
    19 May 2021
    • To be aligned with the inclusion of an optional Interim analysis (IA) for Blinded Sample Size Re-estimation (BSSR). • Due to unexpectedly rapid enrollment, the trigger for the IA for Unblinded Sample Size Re-estimation (USSR) is projected to occur months after the completion of enrollment, considered too late to implement changes following outcome of IA from an operational perspective. The optional IA for BSSR, triggered prior to completion of enrollment, does not have this disadvantage. • To avoid variability in interpretation of ECGs by non-cardiologists and in reports obtained from the locally sourced ECG machines. • Due to the removal of the IA for USSR, the role played by the Independent Data Monitoring Committee (IDMC) in making the sample size increase recommendation is no longer required.
    03 Apr 2022
    • To ensure primary and important secondary endpoints are adequately powered despite loss of data from participants at sites in Ukraine, Russian Federation, and Belarus. • Due to the extended study duration and the planned transition of all eligible study completers to the long-term follow-up study under a new protocol, the OLE Period is no longer needed. • To ensure consistency after removal of the OLE Period, and to ensure consistency in evaluation of safety and efficacy for all subjects entering the long-term follow-up study. Furthermore, removal of the OLE Period and the mandatory AEP related to teriflunomide reduces the risk of unblinding due to the variable AEP duration. • CDI endpoint added to secondary endpoints to explore treatment effect on additional clinically relevant endpoint for disability. Week 12 NfL concentration added to investigate early impact of treatment on reducing neuronal damage.
    08 Dec 2022
    • Introduction of an OLE period for subjects completing the DBTP prior to approval of the long-term follow-up study in their country to enable an option for evobrutinib treatment continuation • Addition of the following exploratory endpoints: 1. Time to Progression Independent of Relapse Activity (PIRA) and time to Progression Independent of Relapse and Brain Magnetic Resonance (PIRMA) (to evaluate the effect of treatment on progression not driven by relapse events or MRI activity) 2. No evidence of progression (NEP) at Weeks 48, 96 3. Level of anti- Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) antibodies
    27 Apr 2023
    • To reflect recent update to risk profile of evobrutinib (i.e., important identified risk of drug-induced liver injury) by adapting liver-related eligibility criteria, monitoring, and discontinuation criteria as well as language on tolerability and safety of evobrutinib across the protocol. • To allow subjects to stay on blinded Investigational medicinal product (IMP) after DBTP in a DBE period to delay the switch of participants naïve to evobrutinib treatment to the OLE period. This will also allow to generate additional data on efficacy and safety over an extended period of time.

    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.
    Final Analysis represents analysis of cumulative data collected up to Primary Analysis trigger and beyond through DBE up to final database lock. Therefore, endpoints were evaluated considering a time period from start of DBTP to end of DBE Period.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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