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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 an Interferon Beta 1a (Avonex®), in Participants with Relapsing Multiple Sclerosis to Evaluate Efficacy and Safety

    Summary
    EudraCT number
    2018-004701-11
    Trial protocol
    BG  
    Global end of trial date
    16 Apr 2020

    Results information
    Results version number
    v2(current)
    This version publication date
    11 Sep 2021
    First version publication date
    20 Jun 2021
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    MS200527_0073
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT04032158
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Merck Healthcare KGaA, Darmstadt Germany
    Sponsor organisation address
    Frankfurter Strasse 250, Darmstadt, Germany, 64293
    Public contact
    Communication Center, Merck Healthcare KGaA, Darmstadt Germany, +49 6151 72 5200, service@merckgroup.com
    Scientific contact
    Communication Center, 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
    16 Apr 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Apr 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The purpose of this study was to evaluate the the efficacy and safety of evobrutinib administered orally twice daily versus Interferon-beta-1a (Avonex®), once a week intramuscularly in subjects with Relapsing Multiple Sclerosis (RMS).
    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
    26 Aug 2019
    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
    United States: 3
    Worldwide total number of subjects
    3
    EEA total number of subjects
    0
    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)
    3
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    This study was to be conducted in 2 periods; double blind period and open label extension period. However, due to early termination of the study, sponsor decided not to conduct the open label extension period.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Carer, Assessor, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Evobrutinib + Avonex® matched Placebo
    Arm description
    Subjects received active evobrutinib twice daily (BID) along with concomitant intramuscular (IM) injection of placebo matched to Avonex® once a week. Treatment period was planned to be of 96 weeks.
    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
    Subjects received active evobrutinib BID

    Investigational medicinal product name
    Avonex® matched Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subject received IM injection of placebo matched to Avonex® once a week

    Arm title
    Avonex® + Evobrutinib matched Placebo
    Arm description
    Subjects received IM injection of active Avonex® once a week along with concomitant placebo matched to evobrutinib BID. Treatment period was planned to be of 96 weeks.
    Arm type
    Active comparator

    Investigational medicinal product name
    Evobrutinib matched Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subject received placebo matched to evobrutinib BID.

    Investigational medicinal product name
    Avonex®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received IM injection of active Avonex® once a week.

    Number of subjects in period 1
    Evobrutinib + Avonex® matched Placebo Avonex® + Evobrutinib matched Placebo
    Started
    2
    1
    Completed
    0
    0
    Not completed
    2
    1
         Study Termination
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Evobrutinib + Avonex® matched Placebo
    Reporting group description
    Subjects received active evobrutinib twice daily (BID) along with concomitant intramuscular (IM) injection of placebo matched to Avonex® once a week. Treatment period was planned to be of 96 weeks.

    Reporting group title
    Avonex® + Evobrutinib matched Placebo
    Reporting group description
    Subjects received IM injection of active Avonex® once a week along with concomitant placebo matched to evobrutinib BID. Treatment period was planned to be of 96 weeks.

    Reporting group values
    Evobrutinib + Avonex® matched Placebo Avonex® + Evobrutinib matched Placebo Total
    Number of subjects
    2 1 3
    Age Categorical
    Units: Years
        <=18 years
    0 0 0
        Between 18 and 65 years
    2 1 3
        >=65 years
    0 0 0
    Sex: Female, Male
    Units: Subjects
        Female
    1 1 2
        Male
    1 0 1
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 0 0
        Asian
    0 0 0
        Native Hawaiian or Other Pacific Islander
    0 0 0
        Black or African American
    0 1 1
        White
    2 0 2
        More than one race
    0 0 0
        Unknown or Not Reported
    0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Evobrutinib + Avonex® matched Placebo
    Reporting group description
    Subjects received active evobrutinib twice daily (BID) along with concomitant intramuscular (IM) injection of placebo matched to Avonex® once a week. Treatment period was planned to be of 96 weeks.

    Reporting group title
    Avonex® + Evobrutinib matched Placebo
    Reporting group description
    Subjects received IM injection of active Avonex® once a week along with concomitant placebo matched to evobrutinib BID. Treatment period was planned to be of 96 weeks.

    Primary: Annualized Relapse Rate (ARR)

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    End point title
    Annualized Relapse Rate (ARR) [1]
    End point description
    The annualized relapse rate at 96 weeks was to be calculated based on qualified relapses. A qualifying relapse is the occurrence of new or worsening neurological symptoms attributable to MS. The relapse should be accompanied by an increase of 0.5 points or more on Expanded Disability Status Scale (EDSS), or 2 points increase on one of the Functional System Scores (FSS), or 1 point increase on at least two of the FSS. The increase in FSS scores must be related to the neurological symptoms which were reported as new or worsening. Following analysis of open label extension (OLE) data from RMS phase 2 study (MS200527- 0086), it was determined that a change in active comparator warranted in phase 3 RMS comprised of trial MS200527-0073. Consequently, this trial terminated early, therefore, it was decided as per Statistical Analysis Plan not to report the efficacy data for this study.
    End point type
    Primary
    End point timeframe
    At Week 96
    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: Data for efficacy analysis was not collected and evaluated due to early termination of study.
    End point values
    Evobrutinib + Avonex® matched Placebo Avonex® + Evobrutinib matched Placebo
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: per year
    Notes
    [2] - As per Statistical Analysis Plan, efficacy data were not reported.
    [3] - As per Statistical Analysis Plan, efficacy data were not reported.
    No statistical analyses for this end point

    Secondary: Time to First Occurrence of 12-Week Confirmed Expanded Disability Status Scale (EDSS) Progression

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    End point title
    Time to First Occurrence of 12-Week Confirmed Expanded Disability Status Scale (EDSS) Progression
    End point description
    EDSS is an ordinal scale in half-point increments that measures disability in subjects with MS. EDSS progression is defined as an increase of 1 point or more from Baseline EDSS score when the Baseline score is 5.0 or less, and an increase of 0.5 points or more when the Baseline score is 5.5 or greater. Time to first occurrence of 12-week confirmed EDSS progression is defined as the time from randomization to the first EDSS progression event that was confirmed at a regularly scheduled visit at least 12 weeks later. Following analysis of open label extension (OLE) data from RMS phase 2 study (MS200527- 0086), it was determined that a change in active comparator warranted in phase 3 RMS comprised of trial MS200527-0073. Consequently, this trial terminated early, therefore, it was decided as per Statistical Analysis Plan not to report the efficacy data for this study.
    End point type
    Secondary
    End point timeframe
    Baseline up to 96 weeks
    End point values
    Evobrutinib + Avonex® matched Placebo Avonex® + Evobrutinib matched Placebo
    Number of subjects analysed
    0 [4]
    0 [5]
    Units: Weeks
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [4] - As per Statistical Analysis Plan, efficacy data were not reported.
    [5] - As per Statistical Analysis Plan, efficacy data were not reported.
    No statistical analyses for this end point

    Secondary: Time to First Occurrence of 24-Week Confirmed Expanded Disability Status Scale (EDSS) Progression

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    End point title
    Time to First Occurrence of 24-Week Confirmed Expanded Disability Status Scale (EDSS) Progression
    End point description
    EDSS is an ordinal scale in half-point increments that measures disability in subjects with MS. EDSS progression is defined as an increase of 1 point or more from Baseline EDSS score when the Baseline score is 5.0 or less, and an increase of 0.5 points or more when the Baseline score is 5.5 or greater. Time to first occurrence of 24-week confirmed EDSS progression is defined as the time from randomization to the first EDSS progression event that was confirmed at a regularly scheduled visit at least 24 weeks later. Following analysis of open label extension (OLE) data from RMS phase 2 study (MS200527- 0086), it was determined that a change in active comparator warranted in phase 3 RMS comprised of trial MS200527-0073. Consequently, this trial terminated early, therefore, it was decided as per Statistical Analysis Plan not to report the efficacy data for this study.
    End point type
    Secondary
    End point timeframe
    Baseline up to 96 weeks
    End point values
    Evobrutinib + Avonex® matched Placebo Avonex® + Evobrutinib matched Placebo
    Number of subjects analysed
    0 [6]
    0 [7]
    Units: Weeks
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [6] - As per Statistical Analysis Plan, efficacy data were not reported.
    [7] - As per Statistical Analysis Plan, efficacy data were not reported.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Patient Reported Outcomes Measurement Information System (PROMIS) Physical Function (PF) Short Form Score at Week 96

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    End point title
    Change From Baseline in Patient Reported Outcomes Measurement Information System (PROMIS) Physical Function (PF) Short Form Score at Week 96
    End point description
    The PROMIS PF Short Form is specific to measuring the physical function domain of MS patients, with each item on the form scored on a T-score metric. Higher scores indicate higher PF. Change from baseline at Week 96 is the difference between the PROMIS PF scores at 96 weeks and at baseline. Following analysis of open label extension (OLE) data from RMS phase 2 study (MS200527- 0086), it was determined that a change in active comparator warranted in phase 3 RMS comprised of trial MS200527-0073. Consequently, this trial terminated early, therefore, it was decided as per Statistical Analysis Plan not to report the efficacy data for this study.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 96
    End point values
    Evobrutinib + Avonex® matched Placebo Avonex® + Evobrutinib matched Placebo
    Number of subjects analysed
    0 [8]
    0 [9]
    Units: T-score
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [8] - As per Statistical Analysis Plan, efficacy data were not reported.
    [9] - As per Statistical Analysis Plan, efficacy data were not reported.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Patient Reported Outcomes Measurement Information System (PROMIS) MS Fatigue Score at Week 96

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    End point title
    Change From Baseline in Patient Reported Outcomes Measurement Information System (PROMIS) MS Fatigue Score at Week 96
    End point description
    The PROMIS Fatigue Short Form is specific to measuring the fatigue domain of MS patients, with each item on the form scored on a T-score metric. Higher scores indicate higher fatigue. Change from baseline at Week 96 is the difference between the PROMIS Fatigue scores at 96 weeks and at baseline. Following analysis of open label extension (OLE) data from RMS phase 2 study (MS200527- 0086), it was determined that a change in active comparator warranted in phase 3 RMS comprised of trial MS200527-0073. Consequently, this trial terminated early, therefore, it was decided as per Statistical Analysis Plan not to report the efficacy data for this study.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 96
    End point values
    Evobrutinib + Avonex® matched Placebo Avonex® + Evobrutinib matched Placebo
    Number of subjects analysed
    0 [10]
    0 [11]
    Units: T-score
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [10] - As per Statistical Analysis Plan, efficacy data were not reported.
    [11] - As per Statistical Analysis Plan, efficacy data were not reported.
    No statistical analyses for this end point

    Secondary: Total Number of Gadolinium-Enhancing (Gd+) Time Constant 1 (T1) Lesions Assessed by Magnetic Resonance Imaging (MRI) Scans at Week 24, 48, and 96

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    End point title
    Total Number of Gadolinium-Enhancing (Gd+) Time Constant 1 (T1) Lesions Assessed by Magnetic Resonance Imaging (MRI) Scans at Week 24, 48, and 96
    End point description
    Total number of Gd+ T1 lesions was to be assessed using magnetic resonance imaging (MRI). Following analysis of open label extension (OLE) data from RMS phase 2 study (MS200527- 0086), it was determined that a change in active comparator warranted in phase 3 RMS comprised of trial MS200527-0073. Consequently, this trial terminated early, therefore, it was decided as per Statistical Analysis Plan not to report the efficacy data for this study.
    End point type
    Secondary
    End point timeframe
    At Week 24, 48 and 96
    End point values
    Evobrutinib + Avonex® matched Placebo Avonex® + Evobrutinib matched Placebo
    Number of subjects analysed
    0 [12]
    0 [13]
    Units: Lesion
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [12] - As per Statistical Analysis Plan, efficacy data were not reported.
    [13] - As per Statistical Analysis Plan, efficacy data were not reported.
    No statistical analyses for this end point

    Secondary: Total Number of New or Enlarging Time Constant 2 (T2) Lesions Assessed by Magnetic Resonance Imaging (MRI) Scans at Week 24, 48, and 96

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    End point title
    Total Number of New or Enlarging Time Constant 2 (T2) Lesions Assessed by Magnetic Resonance Imaging (MRI) Scans at Week 24, 48, and 96
    End point description
    Total number of new or enlarging T2 lesions was to be assessed using magnetic resonance imaging (MRI). Following analysis of open label extension (OLE) data from RMS phase 2 study (MS200527- 0086), it was determined that a change in active comparator warranted in phase 3 RMS comprised of trial MS200527-0073. Consequently, this trial terminated early, therefore, it was decided as per Statistical Analysis Plan not to report the efficacy data for this study.
    End point type
    Secondary
    End point timeframe
    At Week 24, 48 and 96
    End point values
    Evobrutinib + Avonex® matched Placebo Avonex® + Evobrutinib matched Placebo
    Number of subjects analysed
    0 [14]
    0 [15]
    Units: Lesion
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [14] - As per Statistical Analysis Plan, efficacy data were not reported.
    [15] - As per Statistical Analysis Plan, efficacy data were not reported.
    No statistical analyses for this end point

    Secondary: Number of Subjects with Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs and Adverse Events of Special Interest (AESIs)

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    End point title
    Number of Subjects with Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs and Adverse Events of Special Interest (AESIs)
    End point description
    AE is any untoward medical occurrence in subject administered a pharmaceutical product, regardless of causal relationship with treatment. Therefore, AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, regardless if it is considered related to the medicinal product. TEAE is an AE that started after study drug treatment or if the event was continuous from baseline & was serious, related to study drug, or resulted in death, discontinuation, interruption or reduction of study therapy. TEAEs includes both serious TEAEs & non-serious TEAEs. AESIs included liver AEs (possible drug-induced, non-infectious, non-alcoholic and immune-mediated) infections (serious and opportunistic infection), lipase and amylase elevation, & seizure. Number of subjects with AESIs are reported.
    End point type
    Secondary
    End point timeframe
    Baseline up to week 108
    End point values
    Evobrutinib + Avonex® matched Placebo Avonex® + Evobrutinib matched Placebo
    Number of subjects analysed
    2
    1
    Units: Subjects
        Subjects with AESIs
    0
    0
        Subjects with TEAEs
    2
    1
        Subjects with Serious TEAEs
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) Based on Severity According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)

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    End point title
    Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) Based on Severity According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)
    End point description
    TEAE is an AE that started after study drug treatment; or if the event was continuous from baseline and was serious, related to IMP, or resulted in death, discontinuation, interruption or reduction of study therapy. Severity of TEAEs were graded using NCI-CTCAE v4.03 toxicity grades, as follows: Grade 1= Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Life-threatening and Grade 5 = Death. Number of subjects with TEAEs based on severity were reported. SAF analysis set included all subjects who were administered any dose of any study intervention. SAF analysis set included all subjects who were administered any dose of any study intervention
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 108
    End point values
    Evobrutinib + Avonex® matched Placebo Avonex® + Evobrutinib matched Placebo
    Number of subjects analysed
    2
    1
    Units: Subjects
        Grade 1
    2
    0
        Grade 2
    0
    1
        Grade 3
    0
    0
        Grade 4
    0
    0
        Grade 5
    0
    0
    No statistical analyses for this end point

    Secondary: Vital Signs: Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)

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    End point title
    Vital Signs: Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)
    End point description
    DBP and SBP were measured in semi-supine position after 5 minutes rest for the subjects at indicated time points. SAF analysis set included all participants who were administered any dose of any study intervention. SAF analysis set included all participants who were administered any dose of any study intervention. No summary analysis was done. Following analysis of OLE data from RMS phase 2 study (MS200527- 0086), it was determined that a change in active comparator warranted in phase 3 RMS comprised of trial MS200527-0073. Consequently, this trial terminated early. Therefore, participant wise data reported and number analyzed= specific participant evaluated in respective arm at specified timepoint.
    End point type
    Secondary
    End point timeframe
    At Day 1, 83, 125 and 155
    End point values
    Evobrutinib + Avonex® matched Placebo Avonex® + Evobrutinib matched Placebo
    Number of subjects analysed
    2
    1
    Units: Millimeters of mercury (mmHg)
    number (not applicable)
        Subject 1 - DBP: Day 1
    0
    82
        Subject 1 - DBP: Day 83
    0
    87
        Subject 1 - DBP: Day 125
    0
    80
        Subject 1 - DBP: Day 155
    0
    75
        Subject 1 - SBP: Day 1
    0
    112
        Subject 1 - SBP: Day 83
    0
    120
        Subject 1 - SBP: Day 125
    0
    118
        Subject 1 - SBP: Day 155
    0
    109
        Subject 2 - DBP: Day 1
    84
    0
        Subject 2 - DBP: Day 83
    77
    0
        Subject 2 - DBP: Day 125
    84
    0
        Subject 2 - DBP: Day 155
    90
    0
        Subject 2 - SBP: Day 1
    124
    0
        Subject 2 - SBP: Day 83
    133
    0
        Subject 2 - SBP: Day 125
    138
    0
        Subject 2 - SBP: Day 155
    137
    0
        Subject 3 - DBP: Day 1
    65
    0
        Subject 3 - DBP: Day 83
    76
    0
        Subject 3 - SBP: Day 1
    101
    0
        Subject 3 - SBP: Day 83
    117
    0
    No statistical analyses for this end point

    Secondary: Vital Signs: Pulse Rate and Respiratory Rate

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    End point title
    Vital Signs: Pulse Rate and Respiratory Rate
    End point description
    Pulse rate and Respiration rate was measured in semi-supine position after 5 minutes rest for the subjects at indicated time points. SAF analysis set included all participants who were administered any dose of any study intervention. No summary analysis was done. Following analysis of OLE data from RMS phase 2 study (MS200527- 0086), it was determined that a change in active comparator warranted in phase 3 RMS comprised of trial MS200527-0073. Consequently, this trial terminated early. Therefore, participant wise data reported and number analyzed= specific participant evaluated in respective arm at specified timepoint.
    End point type
    Secondary
    End point timeframe
    At Day 1, 83, 125 and 155
    End point values
    Evobrutinib + Avonex® matched Placebo Avonex® + Evobrutinib matched Placebo
    Number of subjects analysed
    2
    1
    Units: breaths/minute
    number (not applicable)
        Subject 1 - Pulse rate: Day 1
    0
    71
        Subject 1 - Pulse rate: Day 83
    0
    69
        Subject 1 - Pulse rate: Day 125
    0
    72
        Subject 1 - Pulse rate: Day 155
    0
    75
        Subject 1 - Respiratory rate: Day 1
    0
    20
        Subject 1 - Respiratory rate: Day 83
    0
    18
        Subject 1 - Respiratory rate: Day 125
    0
    18
        Subject 1 - Respiratory rate: Day 155
    0
    20
        Subject 2 - Pulse rate: Day 1
    71
    0
        Subject 2 - Pulse rate: Day 83
    66
    0
        Subject 2 - Pulse rate: Day 125
    82
    0
        Subject 2 - Pulse rate: Day 155
    82
    0
        Subject 2 - Respiratory rate: Day 1
    18
    0
        Subject 2 - Respiratory rate: Day 83
    20
    0
        Subject 2 - Respiratory rate: Day 125
    18
    0
        Subject 2 - Respiratory rate: Day 155
    20
    0
        Subject 3 - Pulse rate: Day 1
    76
    0
        Subject 3 - Pulse rate: Day 83
    75
    0
        Subject 3 - Respiratory rate: Day 1
    18
    0
        Subject 3 - Respiratory rate: Day 83
    18
    0
    No statistical analyses for this end point

    Secondary: Vital Signs: Temperature

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    End point title
    Vital Signs: Temperature
    End point description
    Temperature was measured in semi-supine position after 5 minutes rest for the participants at indicated time points. SAF analysis set included all subjects who were administered any dose of any study intervention. SAF analysis set included all participants who were administered any dose of any study intervention. No summary analysis was done. Following analysis of OLE data from RMS phase 2 study (MS200527- 0086), it was determined that a change in active comparator warranted in phase 3 RMS comprised of trial MS200527-0073. Consequently, this trial terminated early. Therefore, participant wise data reported and number analyzed= specific participant evaluated in respective arm at specified timepoint.
    End point type
    Secondary
    End point timeframe
    At Day 1, 83, 125 and 155
    End point values
    Evobrutinib + Avonex® matched Placebo Avonex® + Evobrutinib matched Placebo
    Number of subjects analysed
    2
    1
    Units: Degree Celsius
    number (not applicable)
        Subject 1: Day 1
    0
    35.7
        Subject 1: Day 83
    0
    36.4
        Subject 1: Day 125
    0
    36.9
        Subject 1: Day 155
    0
    36.4
        Subject 2: Day 1
    36.9
    0
        Subject 2: Day 83
    36.7
    0
        Subject 2: Day 125
    36.9
    0
        Subject 2: Day 155
    36.8
    0
        Subject 3: Day 1
    36.5
    0
        Subject 3: Day 83
    37.0
    0
    No statistical analyses for this end point

    Secondary: Vital Signs: Weight

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    End point title
    Vital Signs: Weight
    End point description
    SAF analysis set included all subjects who were administered any dose of any study intervention. SAF analysis set included all participants who were administered any dose of any study intervention. No summary analysis was done. Following analysis of OLE data from RMS phase 2 study (MS200527- 0086), it was determined that a change in active comparator warranted in phase 3 RMS comprised of trial MS200527-0073. Consequently, this trial terminated early. Therefore, participant wise data reported and number analyzed= specific participant evaluated in respective arm at specified timepoint.
    End point type
    Secondary
    End point timeframe
    At Day 1, 83, 125 and 155
    End point values
    Evobrutinib + Avonex® matched Placebo Avonex® + Evobrutinib matched Placebo
    Number of subjects analysed
    2
    1
    Units: kilogram (kg)
    number (not applicable)
        Subject 1: Day 1
    0
    75.7
        Subject 1: Day 83
    0
    74.9
        Subject 1: Day 125
    0
    77.3
        Subject 1: Day 155
    0
    77.2
        Subject 2: Day 1
    89.0
    0
        Subject 2: Day 83
    89.0
    0
        Subject 2: Day 125
    92.2
    0
        Subject 2: Day 155
    92.1
    0
        Subject 3: Day 1
    40.8
    0
        Subject 3: Day 83
    40.3
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects with Abnormal Lab Values

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    End point title
    Number of Subjects with Abnormal Lab Values
    End point description
    The total number of subjects with laboratory test abnormalities was assessed. Clinical laboratory tests included hematology, coagulation, biochemistry and urinalysis. SAF analysis set included all subjects who were administered any dose of any study intervention.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 108
    End point values
    Evobrutinib + Avonex® matched Placebo Avonex® + Evobrutinib matched Placebo
    Number of subjects analysed
    2
    1
    Units: Subjects
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects with Clinically Significant Electrocardiogram (ECG) Abnormalities

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    End point title
    Number of Subjects with Clinically Significant Electrocardiogram (ECG) Abnormalities
    End point description
    ECG parameters included heart rhythm, heart rate, QRS intervals, QT intervals, RR intervals and corrected QT (QTc) intervals. Clinical meaningful was determined by the investigator. SAF analysis set included all participants who were administered any dose of any study intervention.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 108
    End point values
    Evobrutinib + Avonex® matched Placebo Avonex® + Evobrutinib matched Placebo
    Number of subjects analysed
    2
    1
    Units: Subjects
    0
    0
    No statistical analyses for this end point

    Secondary: Absolute Concentrations of Immunoglobulin (Ig) A Level

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    End point title
    Absolute Concentrations of Immunoglobulin (Ig) A Level
    End point description
    SAF analysis set included all participants who were administered any dose of any study intervention. No summary analysis was done. Following analysis of OLE data from RMS phase 2 study (MS200527- 0086), it was determined that a change in active comparator warranted in phase 3 RMS comprised of trial MS200527-0073. Consequently, this trial terminated early. Therefore, participant wise data reported and number analyzed= specific participant evaluated in respective arm at specified timepoint.
    End point type
    Secondary
    End point timeframe
    At Day 1, 83, 125 and 155
    End point values
    Evobrutinib + Avonex® matched Placebo Avonex® + Evobrutinib matched Placebo
    Number of subjects analysed
    2
    1
    Units: grams per liter (g/L)
    number (not applicable)
        Subject 1: Day 1
    0
    2.09
        Subject 1: Day 83
    0
    2.64
        Subject 1: Day 125
    0
    2.64
        Subject 1: Day 155
    0
    2.78
        Subject 2: Day 1
    1.64
    0
        Subject 2: Day 83
    1.85
    0
        Subject 2: Day 125
    2.2
    0
        Subject 2: Day 155
    2.15
    0
        Subject 3: Day 1
    2.09
    0
        Subject 3: Day 125
    1.84
    0
    No statistical analyses for this end point

    Secondary: Absolute Concentrations of Immunoglobulin (Ig) E Level

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    End point title
    Absolute Concentrations of Immunoglobulin (Ig) E Level
    End point description
    Absolute concentrations of Immunoglobulin (Ig) E was reported. SAF analysis set included all participants who were administered any dose of any study intervention. No summary analysis was done. Following analysis of OLE data from RMS phase 2 study (MS200527- 0086), it was determined that a change in active comparator warranted in phase 3 RMS comprised of trial MS200527-0073. Consequently, this trial terminated early. Therefore, participant wise data reported and number analyzed= specific participant evaluated in respective arm at specified timepoint.
    End point type
    Secondary
    End point timeframe
    At Day 1, 83, 125 and 155
    End point values
    Evobrutinib + Avonex® matched Placebo Avonex® + Evobrutinib matched Placebo
    Number of subjects analysed
    2
    1
    Units: International unit per milliliter(IU/mL)
    number (not applicable)
        Subject 1: Day 1
    0
    61
        Subject 1: Day 83
    0
    108
        Subject 1: Day 125
    0
    55.2
        Subject 1: Day 155
    0
    71.9
        Subject 2: Day 1
    10.7
    0
        Subject 2: Day 83
    12.3
    0
        Subject 2: Day 125
    14.9
    0
        Subject 2: Day 155
    11.4
    0
        Subject 3: Day 1
    27.6
    0
        Subject 3: Day 125
    23.5
    0
    No statistical analyses for this end point

    Secondary: Absolute Concentrations of Immunoglobulin (Ig) G Level

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    End point title
    Absolute Concentrations of Immunoglobulin (Ig) G Level
    End point description
    Absolute concentrations of Immunoglobulin (Ig) G was reported. SAF analysis set included all participants who were administered any dose of any study intervention. No summary analysis was done. Following analysis of OLE data from RMS phase 2 study (MS200527- 0086), it was determined that a change in active comparator warranted in phase 3 RMS comprised of trial MS200527-0073. Consequently, this trial terminated early. Therefore, participant wise data reported and number analyzed= specific participant evaluated in respective arm at specified timepoint.
    End point type
    Secondary
    End point timeframe
    At Day 1, 83, 125 and 155
    End point values
    Evobrutinib + Avonex® matched Placebo Avonex® + Evobrutinib matched Placebo
    Number of subjects analysed
    2
    1
    Units: grams per liter (g/L)
    number (not applicable)
        Subject 1: Day 1
    0
    16.49
        Subject 1: Day 83
    0
    21.77
        Subject 1: Day 125
    0
    19.34
        Subject 1: Day 155
    0
    19.62
        Subject 2: Day 1
    9.46
    0
        Subject 2: Day 83
    10.26
    0
        Subject 2: Day 125
    11.23
    0
        Subject 2: Day 155
    11.18
    0
        Subject 3: Day 1
    12.52
    0
        Subject 3: Day 125
    11.41
    0
    No statistical analyses for this end point

    Secondary: Absolute Concentrations of Immunoglobulin (Ig) M Level

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    End point title
    Absolute Concentrations of Immunoglobulin (Ig) M Level
    End point description
    Absolute concentrations of Immunoglobulin (Ig) M was reported. SAF analysis set included all participants who were administered any dose of any study intervention. No summary analysis was done. Following analysis of OLE data from RMS phase 2 study (MS200527- 0086), it was determined that a change in active comparator warranted in phase 3 RMS comprised of trial MS200527-0073. Consequently, this trial terminated early. Therefore, participant wise data reported and number analyzed= specific participant evaluated in respective arm at specified timepoint.
    End point type
    Secondary
    End point timeframe
    At Day 1, 83, 125 and 155
    End point values
    Evobrutinib + Avonex® matched Placebo Avonex® + Evobrutinib matched Placebo
    Number of subjects analysed
    2
    1
    Units: grams per liter (g/L)
    number (not applicable)
        Subject 1: Day 1
    0
    0.97
        Subject 1: Day 83
    0
    1.47
        Subject 1: Day 125
    0
    1.35
        Subject 1: Day 155
    0
    1.43
        Subject 2: Day 1
    1.08
    0
        Subject 2: Day 83
    0.84
    0
        Subject 2: Day 125
    0.78
    0
        Subject 2: Day 155
    1
    0
        Subject 3: Day 1
    2.22
    0
        Subject 3: Day 125
    1.91
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline in Immunoglobulin (Ig) A Level

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    End point title
    Change From Baseline in Immunoglobulin (Ig) A Level
    End point description
    Change from baseline in immunoglobulin (Ig) A level was reported. SAF analysis set included all participants who were administered any dose of any study intervention. No summary analysis was done. Following analysis of OLE data from RMS phase 2 study (MS200527- 0086), it was determined that a change in active comparator warranted in phase 3 RMS comprised of trial MS200527-0073. Consequently, this trial terminated early. Therefore, participant wise data reported and number analyzed= specific participant evaluated in respective arm at specified timepoint.
    End point type
    Secondary
    End point timeframe
    At Day 1, 83, 125 and 155
    End point values
    Evobrutinib + Avonex® matched Placebo Avonex® + Evobrutinib matched Placebo
    Number of subjects analysed
    2
    1
    Units: grams per liter (g/L)
    number (not applicable)
        Subject 1: Day 83
    0
    0.55
        Subject 1: Day 125
    0
    0.55
        Subject 1: Day 155
    0
    0.69
        Subject 2: Day 83
    0.21
    0
        Subject 2: Day 125
    0.56
    0
        Subject 2: Subject 155
    0.51
    0
        Subject 3: Day 125
    -0.25
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline in Immunoglobulin (Ig) E Level

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    End point title
    Change From Baseline in Immunoglobulin (Ig) E Level
    End point description
    Change from baseline in immunoglobulin (Ig) E level was reported. SAF analysis set included all participants who were administered any dose of any study intervention. No summary analysis was done. Following analysis of OLE data from RMS phase 2 study (MS200527- 0086), it was determined that a change in active comparator warranted in phase 3 RMS comprised of trial MS200527-0073. Consequently, this trial terminated early. Therefore, participant wise data reported and number analyzed= specific participant evaluated in respective arm at specified timepoint.
    End point type
    Secondary
    End point timeframe
    At Day 1, 83, 125 and 155
    End point values
    Evobrutinib + Avonex® matched Placebo Avonex® + Evobrutinib matched Placebo
    Number of subjects analysed
    2
    1
    Units: International unit per milliliter(IU/mL)
    number (not applicable)
        Subject 1: Day 83
    0
    47
        Subject 1: Day 125
    0
    -5.8
        Subject 1: Day 155
    0
    10.9
        Subject 2: Day 83
    1.6
    0
        Subject 2: Day 125
    4.2
    0
        Subject 2: Day 155
    0.7
    0
        Subject 3: Day 125
    -4.1
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline in Immunoglobulin (Ig) G Level

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    End point title
    Change From Baseline in Immunoglobulin (Ig) G Level
    End point description
    SAF analysis set included all participants who were administered any dose of any study intervention. No summary analysis was done. Following analysis of OLE data from RMS phase 2 study (MS200527- 0086), it was determined that a change in active comparator warranted in phase 3 RMS comprised of trial MS200527-0073. Consequently, this trial terminated early. Therefore, participant wise data reported and number analyzed= specific participant evaluated in respective arm at specified timepoint.
    End point type
    Secondary
    End point timeframe
    At Day 1, 83, 125 and 155
    End point values
    Evobrutinib + Avonex® matched Placebo Avonex® + Evobrutinib matched Placebo
    Number of subjects analysed
    2
    1
    Units: grams per liter (g/L)
    number (not applicable)
        Subject 1: Day 83
    0
    5.28
        Subject 1: Day 125
    0
    2.85
        Subject 1: Day 155
    0
    3.13
        Subject 2: Day 83
    0.8
    0
        Subject 2: Day 125
    1.77
    0
        Subject 2: Day 155
    1.72
    0
        Subject 3: Day 125
    -1.11
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline in Immunoglobulin (Ig) M Level

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    End point title
    Change From Baseline in Immunoglobulin (Ig) M Level
    End point description
    Change from baseline in immunoglobulin (Ig) M level was reported. SAF analysis set included all participants who were administered any dose of any study intervention. No summary analysis was done. Following analysis of OLE data from RMS phase 2 study (MS200527- 0086), it was determined that a change in active comparator warranted in phase 3 RMS comprised of trial MS200527-0073. Consequently, this trial terminated early. Therefore, participant wise data reported and number analyzed= specific participant evaluated in respective arm at specified timepoint.
    End point type
    Secondary
    End point timeframe
    At Day 1, 83, 125 and 155
    End point values
    Evobrutinib + Avonex® matched Placebo Avonex® + Evobrutinib matched Placebo
    Number of subjects analysed
    2
    1
    Units: grams per liter (g/L)
    number (not applicable)
        Subject 1: Day 83
    0
    0.5
        Subject 1: Day 125
    0
    0.38
        Subject 1: Day 155
    0
    0.46
        Subject 2: Day 83
    -0.24
    0
        Subject 2: Day 125
    -0.3
    0
        Subject 2: Day 155
    -0.08
    0
        Subject 3: Day 125
    -0.31
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to Week 108
    Adverse event reporting additional description
    SAF analysis set included all subjects who were administered any dose of any study intervention.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Evobrutinib + Avonex® matched Placebo
    Reporting group description
    Subjects received active evobrutinib twice daily (BID) along with concomitant intramuscular (IM) injection of placebo matched to Avonex® once a week. Treatment period was planned to be of 96 weeks.

    Reporting group title
    Avonex® + Evobrutinib matched Placebo
    Reporting group description
    Subjects received IM injection of active Avonex® once a week along with concomitant placebo matched to evobrutinib BID. Treatment period was planned to be of 96 weeks.

    Serious adverse events
    Evobrutinib + Avonex® matched Placebo Avonex® + Evobrutinib matched Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Evobrutinib + Avonex® matched Placebo Avonex® + Evobrutinib matched Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 2 (100.00%)
    1 / 1 (100.00%)
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    1
    Nervous system disorders
    Tension headache
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    1
    Paraesthesia
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Drug eruption
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    Influenza like illness
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Tinea cruris
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    Petechiae
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Pain in jaw
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Sep 2019
    -Restructured text on discontinuation of Study Intervention -Clarified the statistical approach towards primary and secondary endpoints -Adjusted Exclusion Criteria -Clarified the use of concomitant therapy

    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.
    Following analysis of open label extension (OLE) data from RMS phase 2 study (MS200527- 0086), it was determined that a change in active comparator warranted in phase 3 RMS comprised of trial MS200527-0073. Consequently, this trial terminated early.
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