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    Clinical Trial Results:
    A Phase IIb, Randomized, Double-blind Study in Subjects with Rheumatoid Arthritis Evaluating the Safety and Efficacy of Evobrutinib Compared with Placebo in Subjects with an Inadequate Response to Methotrexate

    Summary
    EudraCT number
    		 2017-000384-32
    Trial protocol
    		 BG   CZ  
    Global end of trial date
    23 Sep 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Sep 2020
    First version publication date
    20 Sep 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MS200527-0060
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03233230
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck KGaA, Darmstadt, Germany
    Sponsor organisation address
    Frankfurter Strasse 250, Darmstadt, Germany, 64293
    Public contact
    Communication Centre, Merck KGaA, Darmstadt, Germany, +41 6151725200, service@merckgroup.com
    Scientific contact
    Communication Centre, Merck 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
    23 Sep 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Sep 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study was to evaluate the efficacy and dose response of 12 weeks of treatment with M2951 compared with placebo in rheumatoid arthritis (RA) subjects with inadequate response to methotrexate (MTX-IR) on stable methotrexate (MTX) therapy by assessment of the signs and symptoms of RA, as measured by ACR20 response assessed using hsCRP at Week 12.
    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
    18 Sep 2017
    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
    Argentina: 44
    Country: Number of subjects enrolled
    Bulgaria: 35
    Country: Number of subjects enrolled
    Chile: 22
    Country: Number of subjects enrolled
    Colombia: 36
    Country: Number of subjects enrolled
    Czech Republic: 17
    Country: Number of subjects enrolled
    Mexico: 27
    Country: Number of subjects enrolled
    Poland: 49
    Country: Number of subjects enrolled
    Russian Federation: 28
    Country: Number of subjects enrolled
    Serbia: 26
    Country: Number of subjects enrolled
    South Africa: 9
    Country: Number of subjects enrolled
    Ukraine: 84
    Country: Number of subjects enrolled
    United States: 13
    Worldwide total number of subjects
    390
    EEA total number of subjects
    101
    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)
    327
    From 65 to 84 years
    63
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 933 subjects with rheumatoid arthritis were screened. Out of which, 390 subjects were randomized in ratio of 1:1:1:1 to 1 of the 4 treatment groups: Placebo; M2951 25 milligrams (mg) once daily (QD), M2951 75 mg QD and M2951 50 mg twice daily (BID).

    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
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects received placebo matched to M2951 orally for 12 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to M2951 was administered orally.

    Arm title
    		 M2951 25 mg QD
    Arm description
    		 Subjects received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Evobruitnib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg of M2951 was administered orally once daily for 12 weeks.

    Arm title
    		 M2951 75 mg QD
    Arm description
    		 Subjects received 75 mg of M2951 orally QD for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Evobrutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    75 mg of M2951 was administered orally once daily for 12 weeks.

    Arm title
    		 M2951 50 mg BID
    Arm description
    		 Subjects received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Evobrutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50 mg of M2951 was administered orally twice daily for 12 weeks.

    Number of subjects in period 1
    		Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Started
    97
    98
    96
    99
    Completed
    82
    83
    84
    91
    Not completed
    15
    15
    12
    8
         Consent withdrawn by subject
    2
    2
    -
    1
         Adverse event, non-fatal
    6
    3
    6
    3
         Unspecified
    5
    5
    5
    3
         Lost to follow-up
    -
    3
    -
    -
         Protocol deviation
    1
    2
    1
    1
         Lack of efficacy
    1
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to M2951 orally for 12 weeks.

    Reporting group title
    M2951 25 mg QD
    Reporting group description
    		 Subjects received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks.

    Reporting group title
    M2951 75 mg QD
    Reporting group description
    		 Subjects received 75 mg of M2951 orally QD for 12 weeks.

    Reporting group title
    M2951 50 mg BID
    Reporting group description
    		 Subjects received 50 mg of M2951 orally twice daily (BID) for 12 weeks.

    Reporting group values
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID Total
    Number of subjects
    		 97 98 96 99 390
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 52.9 ( 12.24 ) 50.9 ( 13.15 ) 53.3 ( 11.33 ) 53.7 ( 12.13 ) -
    Sex: Female, Male
    Units: subjects
        Female
    		 77 82 76 77 312
        Male
    		 20 16 20 22 78
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0
        Asian
    		 1 1 1 0 3
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0
        Black or African American
    		 1 2 0 0 3
        White
    		 92 94 91 97 374
        More than one race
    		 0 0 0 0 0
        Unknown or Not Reported
    		 3 1 4 2 10
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 32 33 35 38 138
        Not Hispanic or Latino
    		 65 65 61 61 252
        Unknown or Not Reported
    		 0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to M2951 orally for 12 weeks.

    Reporting group title
    M2951 25 mg QD
    Reporting group description
    		 Subjects received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks.

    Reporting group title
    M2951 75 mg QD
    Reporting group description
    		 Subjects received 75 mg of M2951 orally QD for 12 weeks.

    Reporting group title
    M2951 50 mg BID
    Reporting group description
    		 Subjects received 50 mg of M2951 orally twice daily (BID) for 12 weeks.

    Primary: Percentage of Subjects Who Achieved American College of Rheumatology 20 Percent (%) Response Criteria (ACR20) Assessed Using High-Sensitivity C-reactive Protein (hsCRP) at Week 12

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    End point title
    		 Percentage of Subjects Who Achieved American College of Rheumatology 20 Percent (%) Response Criteria (ACR20) Assessed Using High-Sensitivity C-reactive Protein (hsCRP) at Week 12
    End point description
    ACR20 response: a subject has at least 20% improvement in both tender joint counts (based on a total of 68 joints) and swollen joint counts (based on a total of 66 joints) together with 20% improvement in at least 3 of the following: 1) subject's assessment of pain; 2) subject's global assessment of disease activity; 3) physician's global assessment of disease activity; 4) subject's assessment of physical function measured by Health Assessment Questionnaire-Disability Index (HAQ-DI); and 5) acute phase reactant as measured by high-sensitivity C-reactive protein (hsCRP). Percentage of subjects with ACR20 response using hsCRP = Number of subjects with ACR20 response using hsCRP divided by total modified intent-to-treat (mITT) subjects * 100. mITT analysis set included all randomized subjects who received at least one dose of Investigational Medicinal Product (IMP) (M2951 or placebo).
    End point type
    Primary
    End point timeframe
    Week 12
    End point values
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Number of subjects analysed
    97
    98
    96
    99
    Units: percentage of subjects
        number (not applicable)
    49.5
    59.2
    51.0
    59.6
    Statistical analysis title
    		 Placebo vs M2951 25 mg QD
    Comparison groups
    Placebo v M2951 25 mg QD
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1746
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.84
         upper limit
    		 2.61
    Statistical analysis title
    		 Placebo vs M2951 75 mg QD
    Comparison groups
    Placebo v M2951 75 mg QD
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8283
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 1.87
    Statistical analysis title
    		 Placebo vs M2951 50 mg BID
    Comparison groups
    Placebo v M2951 50 mg BID
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1298
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 2.74

    Secondary: Percentage of Subjects with Low Disease Activity Score (DAS28 Less Than [<] 3.2) Based on 28 Joint Count-High-Sensitivity C-reactive Protein (DAS28-hsCRP) at Week 12

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    End point title
    		 Percentage of Subjects with Low Disease Activity Score (DAS28 Less Than [<] 3.2) Based on 28 Joint Count-High-Sensitivity C-reactive Protein (DAS28-hsCRP) at Week 12
    End point description
    DAS based on a 28 joint count hsCRP consisted of composite numerical score of following variables: tender joint count (TJC28), swollen joint count (SJC28), hsCRP (mg/mL), and subject's global assessment of disease activity. DAS28-hsCRP was calculated using following formula: DAS28-hsCRP equals to (=) 0.56*square root (sqrt) (TJC28) plus (+) 0.28*sqrt (SJC28) + 0.36*natural log(hsCRP+1) + 0.014* subject's global assessment of disease activity + 0.96. Scores ranged 0-9.4, where lower scores indicated less disease activity. Percentage of subjects with low DAS28 < 3.2 based on DAS28- hsCRP at Week 12 were reported. mITT analysis set included all randomized subjects who received at least one dose of IMP (M2951 or placebo).
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Number of subjects analysed
    97
    98
    96
    99
    Units: percentage of subjects
        number (not applicable)
    7.2
    20.4
    24.0
    20.2
    Statistical analysis title
    		 Placebo vs M2951 25 mg QD
    Comparison groups
    Placebo v M2951 25 mg QD
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0077
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response rate difference
    Point estimate
    0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.04
         upper limit
    		 0.23
    Statistical analysis title
    		 Placebo vs M2951 75 mg QD
    Comparison groups
    Placebo v M2951 75 mg QD
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0013
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response rate difference
    Point estimate
    0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.07
         upper limit
    		 0.27
    Statistical analysis title
    		 Placebo vs M2951 50 mg BID
    Comparison groups
    Placebo v M2951 50 mg BID
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.008
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response rate difference
    Point estimate
    0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.04
         upper limit
    		 0.23

    Secondary: Percentage of Subjects with Remission Disease Activity Score (DAS28 Less Than [<] 2.6) Based on a 28 Joint Count-High-Sensitivity C-reactive Protein (DAS28-hsCRP) at Week 12

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    End point title
    		 Percentage of Subjects with Remission Disease Activity Score (DAS28 Less Than [<] 2.6) Based on a 28 Joint Count-High-Sensitivity C-reactive Protein (DAS28-hsCRP) at Week 12
    End point description
    DAS based on a 28 joint count hsCRP consisted of composite numerical score of following variables: tender joint count (TJC28), swollen joint count (SJC28), hsCRP (mg/mL), and subject's global assessment of disease activity. DAS28-hsCRP was calculated using following formula: DAS28-hsCRP equals to (=) 0.56*square root (sqrt) (TJC28) plus (+) 0.28*sqrt (SJC28) + 0.36*natural log(hsCRP+1) + 0.014* subject's global assessment of disease activity + 0.96. Scores ranged 0-9.4, where lower scores indicated less disease activity. A DAS28 score less than (<) 2.6 indicated clinical remission. Percentage of subjects with low DAS28 < 2.6 based on DAS28- hsCRP at Week 12 were reported. mITT analysis set included all randomized subjects who received at least one dose of IMP (M2951 or placebo).
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Number of subjects analysed
    97
    98
    96
    99
    Units: percentage of subjects
        number (not applicable)
    1.0
    10.2
    10.4
    10.1
    Statistical analysis title
    		 Placebo vs M2951 25 mg QD
    Comparison groups
    Placebo v M2951 25 mg QD
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0056
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response rate difference
    Point estimate
    0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.03
         upper limit
    		 0.17
    Statistical analysis title
    		 Placebo vs M2951 75 mg QD
    Comparison groups
    Placebo v M2951 75 mg QD
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response rate difference
    Point estimate
    0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.03
         upper limit
    		 0.17
    Statistical analysis title
    		 Placebo vs M2951 50 mg BID
    Comparison groups
    Placebo v M2951 50 mg BID
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0053
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response rate difference
    Point estimate
    0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.03
         upper limit
    		 0.17

    Secondary: Percentage of Subjects Achieving American College of Rheumatology 50% Response Criteria (ACR50)

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    End point title
    		 Percentage of Subjects Achieving American College of Rheumatology 50% Response Criteria (ACR50)
    End point description
    ACR50 response: a subject has at least 50% improvement in both tender joint counts (based on a total of 68 joints) and swollen joint counts (based on a total of 66 joints) together with 50% improvement in at least 3 of the following: 1) subject's assessment of pain; 2) subjects's global assessment of disease activity; 3) physician's global assessment of disease activity; 4) subjects's assessment of physical function measured by HAQ-DI; and 5) acute phase reactant as measured by hsCRP. Percentage of subjects with ACR50 response = Number of subjects with ACR50 response divided by total mITT subjects * 100. mITT analysis set included all randomized subjects who received at least one dose of IMP (M2951 or placebo).
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Number of subjects analysed
    97
    98
    96
    99
    Units: percentage of subjects
        number (not applicable)
    19.6
    28.6
    27.1
    26.3
    Statistical analysis title
    		 Placebo vs M2951 25 mg QD
    Comparison groups
    Placebo v M2951 25 mg QD
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1419
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response rate difference
    Point estimate
    0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.03
         upper limit
    		 0.21
    Statistical analysis title
    		 Placebo vs M2951 75 mg QD
    Comparison groups
    Placebo v M2951 75 mg QD
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2202
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response rate difference
    Point estimate
    0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.05
         upper limit
    		 0.19
    Statistical analysis title
    		 Placebo vs M2951 50 mg BID
    Comparison groups
    Placebo v M2951 50 mg BID
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2328
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response rate difference
    Point estimate
    0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.05
         upper limit
    		 0.19

    Secondary: Percentage of Subjects Achieving American College of Rheumatology 70% Response Criteria (ACR70) Assessed Using High-Sensitivity C-reactive Protein (hsCRP)

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    End point title
    		 Percentage of Subjects Achieving American College of Rheumatology 70% Response Criteria (ACR70) Assessed Using High-Sensitivity C-reactive Protein (hsCRP)
    End point description
    ACR70 response: a subject has at least 70% improvement ACR70 response in both tender joint counts (based on a total of 68 joints) and swollen joint counts (based on a total of 66 joints) together with 70% improvement in at least 3 of the following: 1) subject's assessment of pain; 2) subject's global assessment of disease activity; 3) physician's global assessment of disease activity; 4) subject's assessment of physical function measured by HAQ-DI; and 5) acute phase reactant as measured by hsCRP. Percentage of subjects with ACR70 response = Number of subjects with ACR70 response divided by total mITT subjects * 100. mITT analysis set included all randomized subjects who received at least one dose of IMP (M2951 or placebo).
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Number of subjects analysed
    97
    98
    96
    99
    Units: percentage of subjects
        number (not applicable)
    5.2
    11.2
    10.4
    10.1
    Statistical analysis title
    		 Placebo vs M2951 25 mg QD
    Comparison groups
    Placebo v M2951 25 mg QD
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1232
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response rate difference
    Point estimate
    0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.02
         upper limit
    		 0.15
    Statistical analysis title
    		 Placebo vs M2951 75 mg QD
    Comparison groups
    Placebo v M2951 75 mg QD
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1725
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response rate difference
    Point estimate
    0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.03
         upper limit
    		 0.14
    Statistical analysis title
    		 Placebo vs M2951 50 mg BID
    Comparison groups
    Placebo v M2951 50 mg BID
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1795
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response rate difference
    Point estimate
    0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.03
         upper limit
    		 0.13

    Secondary: Number of Subjects with Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs 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) and Serious TEAEs According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)
    End point description
    Adverse event (AE) was defined as any untoward medical occurrence in subject, which does not necessarily have causal relationship with treatment. A serious AE was defined as an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged insubject hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs: events between first dose of study drug that were absent before treatment/that worsened relative to pre-treatment state up to 16 weeks. TEAEs included both Serious TEAEs and non-serious TEAEs. Number of subjects with TEAEs and serious TEAEs were reported. The safety analysis set (SAF) included all subjects who received at least 1 dose of IMP (M2951 or placebo).
    End point type
    Secondary
    End point timeframe
    up to Week 16
    End point values
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Number of subjects analysed
    97
    98
    96
    99
    Units: subjects
        TEAEs
    44
    48
    48
    50
        Serious TEAEs
    2
    2
    2
    1
    No statistical analyses for this end point

    Secondary: Number of Subjects with Treatment-Emergent Adverse Events (TEAEs) by 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) by Severity According to National Cancer Institute-Common Terminology Criteria for Adverse Events version 4.03 (NCI-CTCAE v4.03)
    End point description
    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 by severity were reported. The SAF included all subjects who received at least 1 dose of IMP (M2951 or placebo).
    End point type
    Secondary
    End point timeframe
    up to Week 16
    End point values
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Number of subjects analysed
    97
    98
    96
    99
    Units: subjects
        Grade 1
    33
    42
    37
    40
        Grade 2
    19
    14
    23
    17
        Grade 3
    2
    5
    1
    1
        Grade 4
    0
    1
    0
    0
        Grade 5
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects with Clinically Significant Change from Baseline in Vital Signs

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    End point title
    		 Number of Subjects with Clinically Significant Change from Baseline in Vital Signs
    End point description
    Vital signs included body temperature, systolic and diastolic blood pressure, pulse rate, respiratory rate, weight and height. Clinical significance was determined by the investigator. The number of subjects with clinically significant changes from baseline in vital signs were reported. The SAF included all subjects who received at least 1 dose of IMP (M2951 or placebo).
    End point type
    Secondary
    End point timeframe
    up to Week 16
    End point values
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Number of subjects analysed
    97
    98
    96
    99
    Units: subjects
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects with Clinically Significant Change from Baseline in Laboratory Parameters

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    End point title
    		 Number of Subjects with Clinically Significant Change from Baseline in Laboratory Parameters
    End point description
    Laboratory investigation included hematology, biochemistry, urinalysis and coagulation. Clinical significance was determined by the investigator. The number of subjects with clinically significant changes from baseline in laboratory parameters were reported. The SAF included all subjects who received at least 1 dose of IMP (M2951 or placebo).
    End point type
    Secondary
    End point timeframe
    up to Week16
    End point values
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Number of subjects analysed
    97
    98
    96
    99
    Units: subjects
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects with Clinically Significant Change from Baseline in 12-Lead Electrocardiogram (ECG) Findings

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    End point title
    		 Number of Subjects with Clinically Significant Change from Baseline in 12-Lead Electrocardiogram (ECG) Findings
    End point description
    12-lead ECG recordings included rhythm, heart rate (as measured by RR interval), PR interval, QRS duration, and QT interval. The corrected QT interval (QTcF) was calculated using Fridericia’s formula. 12-lead ECG recordings were obtained after the subjects have rested for at least 10 minutes in semisupine position. Clinical significance was determined by the investigator. The number of subjects with clinically significant changes from baseline in 12-lead ECG findings were reported. The SAF included all subjects who received at least 1 dose of IMP (M2951 or placebo).
    End point type
    Secondary
    End point timeframe
    up to Week 16
    End point values
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Number of subjects analysed
    97
    98
    96
    99
    Units: subjects
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Change from Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 2, 4, 8, 12 and 16

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    End point title
    		 Change from Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 2, 4, 8, 12 and 16
    End point description
    Change in the serum levels of IgG, IgA, IgM from baseline were assessed. SAF included all subjects who received at least 1 dose of IMP (M2951 or placebo). Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint and "n" signifies those subjects who were evaluable for the specified category at given time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, 4, 8, 12 and 16
    End point values
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Number of subjects analysed
    95
    96
    95
    99
    Units: gram per liter (g/L)
    arithmetic mean (standard deviation)
        IgG: Week 2 (n = 95, 96, 95, 99)
    -0.02 ( 1.083 )
    -0.07 ( 1.042 )
    -0.21 ( 0.968 )
    -0.09 ( 1.062 )
        IgG: Week 4 (n = 94, 94, 93, 96)
    -0.05 ( 1.465 )
    -0.15 ( 1.576 )
    -0.34 ( 1.254 )
    -0.17 ( 1.168 )
        IgG: Week 8 (n = 90, 94, 87, 95)
    0.12 ( 1.513 )
    -0.28 ( 2.052 )
    -0.37 ( 1.565 )
    -0.35 ( 2.037 )
        IgG: Week 12 (n = 83, 89, 81, 88)
    0.47 ( 1.617 )
    -0.17 ( 2.080 )
    -0.33 ( 1.493 )
    -0.23 ( 1.781 )
        IgG: Week 16 (n = 60, 60, 63, 67)
    0.08 ( 1.829 )
    -0.14 ( 2.349 )
    -0.14 ( 1.808 )
    0.06 ( 1.960 )
        IgA: Week 2 (n = 95, 96, 95, 99)
    -0.01 ( 0.253 )
    -0.15 ( 1.187 )
    0.00 ( 0.242 )
    0.03 ( 0.369 )
        IgA: Week 4 (n = 94, 94, 93, 96)
    -0.05 ( 0.326 )
    -0.01 ( 0.359 )
    -0.05 ( 0.333 )
    0.02 ( 0.396 )
        IgA: Week 8 (n = 90, 94, 87, 95)
    -0.02 ( 0.346 )
    -0.16 ( 1.322 )
    -0.06 ( 0.373 )
    0.07 ( 0.567 )
        IgA: Week 12 (n = 83, 89, 81, 88)
    0.02 ( 0.373 )
    0.01 ( 0.444 )
    -0.08 ( 0.388 )
    0.05 ( 0.545 )
        IgA: Week 16 (n = 60, 60, 63, 67)
    0.01 ( 0.466 )
    0.07 ( 0.465 )
    -0.11 ( 0.380 )
    0.05 ( 0.478 )
        IgM: Week 2 (n = 95, 96, 95, 99)
    -0.04 ( 0.198 )
    -0.04 ( 0.183 )
    -0.03 ( 0.281 )
    -0.01 ( 0.323 )
        IgM: Week 4 (n = 94, 94, 93, 96)
    -0.04 ( 0.199 )
    -0.11 ( 0.224 )
    -0.11 ( 0.217 )
    -0.05 ( 0.385 )
        IgM: Week 8 (n = 90, 94, 87, 95)
    -0.03 ( 0.310 )
    -0.20 ( 0.243 )
    -0.23 ( 0.327 )
    -0.10 ( 0.485 )
        IgM: Week 12 (n = 83, 89, 81, 88)
    -0.01 ( 0.265 )
    -0.20 ( 0.309 )
    -0.25 ( 0.296 )
    -0.17 ( 0.406 )
        IgM: Week 16 (n = 60, 60, 63, 67)
    -0.16 ( 0.776 )
    -0.12 ( 0.436 )
    -0.22 ( 0.246 )
    -0.12 ( 0.487 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in B Cell Count at Week 2, 4, 8, 12 and 16

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    End point title
    		 Change from Baseline in B Cell Count at Week 2, 4, 8, 12 and 16
    End point description
    Flow cytometry analysis of lymphocyte populations using four-color fluorescence-activated cell sorting was performed for the analysis of B cell counts. The SAF included all subjects who received at least 1 dose of IMP (M2951 or placebo). Here, "Number of Subjects Analyzed" specifies those subjects who were evaluable for this endpoint and "n" signified those subjects who were evaluable for the specified category at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, 4, 8, 12 and 16
    End point values
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Number of subjects analysed
    90
    90
    92
    97
    Units: cells per microliter (cells/microliter)
    arithmetic mean (standard deviation)
        Week 2: (n = 87, 90, 92, 97)
    -13 ( 111.0 )
    264 ( 1832.7 )
    161 ( 648.3 )
    74 ( 144.8 )
        Week 4: (n = 90, 90, 91, 93)
    -20 ( 115.7 )
    71 ( 130.1 )
    66 ( 145.3 )
    93 ( 137.6 )
        Week 8: (n = 81, 90, 82, 91)
    -21 ( 87.5 )
    35 ( 103.1 )
    56 ( 188.1 )
    59 ( 145.4 )
        Week 12: (n = 82, 85, 77, 83)
    -22 ( 136.4 )
    41 ( 111.8 )
    51 ( 156.2 )
    54 ( 145.0 )
        Week 16: (n = 56, 58, 60, 64)
    -20 ( 121.9 )
    -3 ( 108.5 )
    -40 ( 133.5 )
    -19 ( 235.6 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Remission Assessed by American College of Rheumatology-European League Against Rheumatism (ACR-EULAR) Boolean at Week 12

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    End point title
    		 Percentage of Subjects Remission Assessed by American College of Rheumatology-European League Against Rheumatism (ACR-EULAR) Boolean at Week 12
    End point description
    ACR-EULAR Boolean remission was when a subject satisfied all of the following: tender joint count, swollen joint count (both based on a 28-joint assessment), C-reactive Protein (in milligrams per deciliter [mg/dL]), and subject's global assessment (visual analog scale [VAS]: 0 centimeter (cm) [very well] to 10 cm [worst], higher scores indicated worse health condition) and all scores were less than or equal to (<=) 1. Percentage of subjects with ACR-EULAR Boolean Remission were reported. The mITT analysis set included all randomized subjects who received at least one dose of IMP (M2951 or placebo).
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Number of subjects analysed
    97
    98
    96
    99
    Units: percentage of subjects
        number (not applicable)
    0.0
    0.0
    1.0
    3.0
    Statistical analysis title
    		 Placebo vs M2951 25 mg QD
    Comparison groups
    Placebo v M2951 25 mg QD
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Response rate difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 0.04
    Statistical analysis title
    		 Placebo vs M2951 75 mg QD
    Comparison groups
    Placebo v M2951 75 mg QD
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Response rate difference
    Point estimate
    0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.03
         upper limit
    		 0.06
    Statistical analysis title
    		 Placebo vs M2951 50 mg BID
    Comparison groups
    Placebo v M2951 50 mg BID
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Response rate difference
    Point estimate
    0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.01
         upper limit
    		 0.09

    Secondary: Percentage of Subjects with Clinical Disease Activity Index (CDAI) Score Less Than or Equal to [=<] 2.8 at Week 12

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    End point title
    		 Percentage of Subjects with Clinical Disease Activity Index (CDAI) Score Less Than or Equal to [=<] 2.8 at Week 12
    End point description
    CDAI: a composite index (without acute-phase reactant) for assessing disease activity. The CDAI was calculated based on following formula: CDAI = 28 joint count for swelling (SJC28) + 28 joint count for tenderness (TJC28) + GH + PhGA where, GH = general health component of the Disease Activity Score [DAS] (i.e., Subject's Global Assessment of Disease Activity, assessed using a scale of 0 to 10 centimeter (cm) Visual Analogue Scale (VAS) where 0 = very well and 10 = very poor activity and PhGA = Physician's Global Assessment of Disease Activity assessed using a scale of 0 to 10 cm VAS, where 0 = very well and 10 = very poor activity. The total CDAI score ranges from 0 to 76, where 0 (none) to 76 (extreme disease activity). CDAI score =< 2.8 indicated clinical remission. Percentage of subjects with CDAI score =< 2.8 were reported. The mITT analysis set included all randomized subjects who received at least one dose of IMP (M2951 or placebo).
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Number of subjects analysed
    97
    98
    96
    99
    Units: percentage of subjects
        number (not applicable)
    1.0
    4.1
    6.3
    3.0
    Statistical analysis title
    		 Placebo vs M2951 25 mg QD
    Comparison groups
    Placebo v M2951 25 mg QD
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Response rate difference
    Point estimate
    0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.02
         upper limit
    		 0.09
    Statistical analysis title
    		 Placebo vs M2951 75 mg QD
    Comparison groups
    Placebo v M2951 75 mg QD
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Response rate difference
    Point estimate
    0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.12
    Statistical analysis title
    		 Placebo vs M2951 50 mg BID
    Comparison groups
    Placebo v M2951 50 mg BID
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Response rate difference
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.03
         upper limit
    		 0.08

    Secondary: Percentage of Subjects with Simplified Disease Activity Index (SDAI) Score Less Than or Equal to [=<] 3.3 at Week 12

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    End point title
    		 Percentage of Subjects with Simplified Disease Activity Index (SDAI) Score Less Than or Equal to [=<] 3.3 at Week 12
    End point description
    SDAI was calculated based on following formula: SDAI = 28 joint count for swelling (SJC28) + 28 joint count for tenderness (TJC28)+ GH+PGA+ hsCRP where, GH = general health component of the Disease Activity Score [DAS] (i.e., Subject's Global Assessment of Disease Activity, assessed using a scale of 0 to 10 centimeter (cm) Visual Analogue Scale (VAS) where 0 = very well and 10 = very poor activity and PhGA = Physician's Global Assessment of Disease Activity assessed using a scale of 0 to 10 cm VAS, where 0 = very well and 10 = very poor activity. The total SDAI score ranges from 0 to 86, where 0 (none) to 86 (extreme disease activity). SDAI score =< 3.3 indicated clinical remission. Percentage of subjects with SDAI score =< 3.3 at Week 12 were reported. The mITT analysis set included all randomized subjects who received at least one dose of IMP (M2951 or placebo).
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Number of subjects analysed
    97
    98
    96
    99
    Units: percentage of subjects
        number (not applicable)
    0.0
    3.1
    4.2
    3.0
    Statistical analysis title
    		 Placebo vs M2951 25 mg QD
    Comparison groups
    Placebo v M2951 25 mg QD
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Response rate difference
    Point estimate
    0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.01
         upper limit
    		 0.09
    Statistical analysis title
    		 Placebo vs M2951 75 mg QD
    Comparison groups
    Placebo v M2951 75 mg QD
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Response rate difference
    Point estimate
    0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.1
    Statistical analysis title
    		 Placebo vs M2951 50 mg BID
    Comparison groups
    Placebo v M2951 50 mg BID
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Response rate difference
    Point estimate
    0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.01
         upper limit
    		 0.09

    Secondary: Percentage of Subjects with Good or Moderate European League Against Rheumatism (EULAR) Responses at Week 12

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    End point title
    		 Percentage of Subjects with Good or Moderate European League Against Rheumatism (EULAR) Responses at Week 12
    End point description
    EULAR Responder index based on 28 joint counts categorizes clinical response based on improvement since baseline in DAS28-CRP. DAS28-CRP scores range from 0-9.4, where lower scores indicated less disease activity. High disease activity: DAS28-CRP >5.1, low disease activity: DAS28-CRP <3.2, and remission: DAS28-CRP <2.6. EULAR DAS28-CRP responder index: good (absolute: <3.2 or >1.2 improvement from baseline), moderate (absolute: 3.2-5.1 or 0.6-1.2 improvement from baseline), or no response (absolute: >5.1 or <0.6 improvement from baseline). Percentage of subjects with DAS28-CRP based EULAR response =(number of subjects with specific response)/(number of subjects analyzed in the group) * 100. The mITT analysis set included all randomized subjects who received at least one dose of IMP (M2951 or placebo).
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Number of subjects analysed
    97
    98
    96
    99
    Units: percentage of subjects
        number (not applicable)
    54.6
    65.3
    66.7
    71.7
    Statistical analysis title
    		 Placebo vs M2951 25 mg QD
    Comparison groups
    Placebo v M2951 25 mg QD
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Response rate difference
    Point estimate
    0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.03
         upper limit
    		 0.24
    Statistical analysis title
    		 Placebo vs M2951 75 mg QD
    Comparison groups
    Placebo v M2951 75 mg QD
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Response rate difference
    Point estimate
    0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.02
         upper limit
    		 0.25
    Statistical analysis title
    		 Placebo vs M2951 50 mg BID
    Comparison groups
    Placebo v M2951 50 mg BID
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Response rate difference
    Point estimate
    0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.05
         upper limit
    		 0.31

    Secondary: American College of Rheumatology (ACR) Hybrid Scores Computed Using High-Sensitivity C-reactive Protein (hsCRP)

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    End point title
    		 American College of Rheumatology (ACR) Hybrid Scores Computed Using High-Sensitivity C-reactive Protein (hsCRP)
    End point description
    Hybrid ACR combines the ACR 20/50/70 response with the mean percent change in all 7 ACR core components, thus providing a percent improvement from baseline on a continuous scale. For each subject, the mean percent improvement from baseline across the 7 ACR core set measures (TJC, SJC, Subject's Global Assessment of Disease Activity, Physician's Global Assessment of Disease Activity, disability index of the Health Assessment Questionnaire [HAQ], and C-reactive protein [CRP]) was calculated (a positive change indicates improvement, and the maximum worst change is limited to -100%) and the ACR20, ACR50, and ACR70 response was determined. The hybrid ACR was determined from a reference table taking into account both ACR response and mean percent improvement in the core set measures. Scores can range from -100% (maximal worsening) to 100% (maximal improvement). mITT analysis set was used. "Number of Subjects Analyzed" = subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Number of subjects analysed
    96
    97
    96
    98
    Units: percent change
        arithmetic mean (standard deviation)
    26.51 ( 25.779 )
    34.66 ( 29.033 )
    33.09 ( 27.724 )
    36.99 ( 26.241 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Disease Activity Score (DAS) Based on a 28 Joint Count-High-Sensitivity C-reactive Protein (DAS28-hsCRP) at Week 12

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    End point title
    		 Change from Baseline in Disease Activity Score (DAS) Based on a 28 Joint Count-High-Sensitivity C-reactive Protein (DAS28-hsCRP) at Week 12
    End point description
    DAS28 was a composite score used for measuring disease activity in subjects with rheumatoid arthritis. The calculation was based on the tender joint count (out of 28 joints), swollen joint count (out of 28 joints), hs-CRP (milligrams per liter [mg/L]) and Subject's Global Assessment of Disease Activity. Total DAS28-hsCRP score ranged from 0 (none) to 9.4 (extreme disease activity). DAS28-hsCRP < 3.2 implied low disease activity and >= 3.2 to <= 5.1 implied moderate disease activity, > 5.1 implied high disease activity. DAS28-hsCRP = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.36 * ln(hsCRP in mg/L +1) + 0.014 * Subject's Global Assessment of Disease Activity + 0.96; ln = natural logarithm, sqrt = square root. The mITT analysis set included all randomized subjects who received at least one dose of IMP (M2951 or placebo). Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Number of subjects analysed
    96
    97
    96
    98
    Units: units on a scale
        arithmetic mean (standard deviation)
    -1.21 ( 1.048 )
    -1.45 ( 1.230 )
    -1.62 ( 1.257 )
    -1.75 ( 1.229 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Clinical Disease Activity Index (CDAI) at Week 12

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    End point title
    		 Change from Baseline in Clinical Disease Activity Index (CDAI) at Week 12
    End point description
    The CDAI was a composite index (without acute-phase reactant) for assessing disease activity. The CDAI was calculated based on following formula: CDAI = 28 joint count for swelling (SJC28) + 28 joint count for tenderness (TJC28) + GH + PhGA where, GH = general health component of the DAS (i.e., Subject's Global Assessment of Disease Activity, assessed using a scale of 0 to 10 centimeter (cm) Visual Analogue Scale (VAS) where 0 = very well and 10 = very poor activity and PhGA = Physician's Global Assessment of Disease Activity assessed using a scale of 0 to 10 cm VAS, where 0 = very well and 10 = very poor activity. The total CDAI score ranges from 0 to 76, where 0 (none) to 76 (extreme disease activity). CDAI score =< 2.8 indicated clinical remission. The mITT analysis set included all randomized subjects who received at least one dose of IMP (M2951 or placebo). Here, “Number of Subjects Analyzed” signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Number of subjects analysed
    96
    97
    96
    98
    Units: units on a scale
        arithmetic mean (standard deviation)
    -16.9 ( 13.09 )
    -18.0 ( 13.00 )
    -18.9 ( 14.33 )
    -20.3 ( 13.90 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Simplified Disease Activity Index (SDAI) at Week 12

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    End point title
    		 Change from Baseline in Simplified Disease Activity Index (SDAI) at Week 12
    End point description
    SDAI was numerical sum of 5 outcome parameters: 28 joint count for swelling (SJC28) + 28 joint count for tenderness (TJC28)+ GH+PGA+ hsCRP where, GH = general health component of the DAS (i.e., Subject's Global Assessment of Disease Activity, assessed using a scale of 0 to 10 centimeter (cm) Visual Analogue Scale (VAS) where 0 = very well and 10 = very poor activity and PhGA = Physician's Global Assessment of Disease Activity assessed using a scale of 0 to 10 cm VAS, where 0 = very well and 10 = very poor activity. The total SDAI score ranges from 0 to 86, where 0 (none) to 86 (extreme disease activity). SDAI score =< 3.3 indicated clinical remission. The mITT analysis set included all randomized subjects who received at least one dose of IMP (M2951 or placebo). Here, “Number of Subjects Analyzed” signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Number of subjects analysed
    96
    97
    96
    98
    Units: units on a scale
        arithmetic mean (standard deviation)
    -17.000 ( 13.5175 )
    -18.647 ( 13.5957 )
    -19.404 ( 14.1591 )
    -21.053 ( 14.3720 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 12

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    End point title
    		 Change from Baseline in Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 12
    End point description
    Sixty-eight joints were assessed and classified as tender/not tender and Sixty –six joints were classified as swollen/not swollen by pressure and joint manipulation on physical examination. The mITT analysis set included all randomized subjects who received at least one dose of IMP (M2951 or placebo). Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Number of subjects analysed
    96
    97
    96
    98
    Units: joints
    arithmetic mean (standard deviation)
        TJC: Week 12
    -11 ( 12.0 )
    -11 ( 10.6 )
    -13 ( 13.2 )
    -12 ( 10.8 )
        SJC: Week 12
    -7 ( 7.5 )
    -8 ( 6.1 )
    -8 ( 7.7 )
    -8 ( 6.6 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Subject's Global Assessment of Disease Activity Based on Visual Analog Scale (VAS) Score at Week 12

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    End point title
    		 Change from Baseline in Subject's Global Assessment of Disease Activity Based on Visual Analog Scale (VAS) Score at Week 12
    End point description
    The subject's overall assessment of disease activity was recorded using the 100 millimeter (mm) horizontal visual analog scale (VAS). The scale ranged from 0-100 mm, where 0 indicated no disease activity (symptom free and no arthritis symptoms) and 100 represented maximum disease activity (maximum arthritis disease activity). The mITT analysis set included all randomized subjects who received at least one dose of IMP (M2951 or placebo). Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Number of subjects analysed
    96
    97
    96
    98
    Units: millimeter (mm)
        arithmetic mean (standard deviation)
    -20 ( 29.6 )
    -19 ( 27.9 )
    -17 ( 29.6 )
    -25 ( 25.7 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Subject's Assessment of Pain Based on Visual Analog Scale (VAS) Score at Week 12

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    End point title
    		 Change from Baseline in Subject's Assessment of Pain Based on Visual Analog Scale (VAS) Score at Week 12
    End point description
    The subjects were asked to assess their level of pain by marking a vertical tick on a 100 mm horizontal VAS scale. The scale ranged from 0-100 mm, where 0 indicated no pain and 100 indicated worst possible pain. The mITT analysis set included all randomized subjects who received at least one dose of IMP (M2951 or placebo). Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Number of subjects analysed
    96
    97
    95
    98
    Units: millimeter
        arithmetic mean (standard deviation)
    -21 ( 24.7 )
    -24 ( 26.9 )
    -22 ( 24.7 )
    -25 ( 26.6 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Total Score at Week 12

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    End point title
    		 Change from Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Total Score at Week 12
    End point description
    HAQ-DI score was an evaluation of the functional status for a subject. The 20-question instrument assess the degree of difficulty a subject had in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily living). Responses in each functional area were scored from 0, indicated no difficulty, to 3, indicated inability to perform a task in that area. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range: 0-3 where 0 = least difficulty and 3 = extreme difficulty. The mITT analysis set included all randomized subjects who received at least one dose of IMP (M2951 or placebo). Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Number of subjects analysed
    96
    97
    95
    98
    Units: units on a scale
        arithmetic mean (standard deviation)
    -0.38 ( 0.567 )
    -0.58 ( 0.662 )
    -0.40 ( 0.658 )
    -0.52 ( 0.616 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Physician's Global Assessment of Disease Activity Scale Based on Visual Analog Scale (VAS) Score at Week 12

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    End point title
    		 Change from Baseline in Physician's Global Assessment of Disease Activity Scale Based on Visual Analog Scale (VAS) Score at Week 12
    End point description
    The Physician's Global Assessment of Disease Activity was recorded using the 100 mm horizontal VAS. Physician rated subject's arthritis disease activity on a scale ranged from 0-100 mm, where 0 indicated no disease activity (no arthritis) and 100 represented maximum disease activity (maximum arthritis). The mITT analysis set included all randomized subjects who received at least one dose of IMP (M2951 or placebo). Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Number of subjects analysed
    96
    97
    96
    98
    Units: millimeter
        arithmetic mean (standard deviation)
    -29 ( 21.2 )
    -33 ( 26.5 )
    -34 ( 26.1 )
    -37 ( 25.3 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in High-Sensitivity C-Reactive Protein (hsCRP) at Week 12

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    End point title
    		 Change from Baseline in High-Sensitivity C-Reactive Protein (hsCRP) at Week 12
    End point description
    hsCRP was the American College of Rheumatology (ACR) Core Set measure of acute phase reactant. It was measured at the central laboratory to help assess the effect of M2951 on the subject's rheumatoid arthritis. The mITT analysis set included all randomized subjects who received at least one dose of IMP (M2951 or placebo). Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Number of subjects analysed
    96
    97
    96
    99
    Units: milligram per liter (mg/L)
        arithmetic mean (standard deviation)
    -1.11 ( 25.925 )
    -6.42 ( 23.280 )
    -5.45 ( 28.807 )
    -7.69 ( 23.007 )
    No statistical analyses for this end point

    Secondary: Percent Change from Baseline in Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 12

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    End point title
    		 Percent Change from Baseline in Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 12
    End point description
    Sixty-eight joints were assessed and classified as tender/not tender and Sixty –six joints were classified as swollen/not swollen by pressure and joint manipulation on physical examination. The mITT analysis set included all randomized subjects who received at least one dose of IMP (M2951 or placebo). Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Number of subjects analysed
    96
    97
    96
    98
    Units: percent change
    arithmetic mean (standard deviation)
        TJC
    -39 ( 45.6 )
    -46 ( 44.2 )
    -51 ( 42.8 )
    -49 ( 37.5 )
        SJC
    -46 ( 52.7 )
    -53 ( 42.6 )
    -56 ( 40.3 )
    -58 ( 43.8 )
    No statistical analyses for this end point

    Secondary: Percent Change from Baseline in Subject's Global Assessment of Disease Activity Based on Visual Analog Scale (VAS) Score at Week 12

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    End point title
    		 Percent Change from Baseline in Subject's Global Assessment of Disease Activity Based on Visual Analog Scale (VAS) Score at Week 12
    End point description
    The subject's overall assessment of disease activity was recorded using the 100 millimeter (mm) horizontal visual analog scale (VAS). The scale ranged from 0-100 mm, where 0 indicated no disease activity (symptom free and no arthritis symptoms) and 100 represented maximum disease activity (maximum arthritis disease activity). The mITT analysis set included all randomized subjects who received at least one dose of IMP (M2951 or placebo). Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Number of subjects analysed
    96
    96
    96
    98
    Units: percent change
        arithmetic mean (standard deviation)
    -13 ( 111.0 )
    -21 ( 69.3 )
    -13 ( 65.7 )
    -33 ( 35.9 )
    No statistical analyses for this end point

    Secondary: Percent Change from Baseline in Subject's Assessment of Pain Based on Visual Analog Scale (VAS) Score at Week 12

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    End point title
    		 Percent Change from Baseline in Subject's Assessment of Pain Based on Visual Analog Scale (VAS) Score at Week 12
    End point description
    The subjects were asked to assess their level of pain by marking a vertical tick on a 100 mm horizontal VAS scale. The scale ranged from 0-100 mm, where 0 indicated no pain and 100 indicated worst possible pain. The mITT analysis set included all randomized subjects who received at least one dose of IMP (M2951 or placebo). Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Number of subjects analysed
    96
    97
    95
    99
    Units: percent change
        arithmetic mean (standard deviation)
    -23 ( 65.0 )
    -32 ( 38.4 )
    -29 ( 40.5 )
    -32 ( 48.4 )
    No statistical analyses for this end point

    Secondary: Percent Change from Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Total Score at Week 12

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    End point title
    		 Percent Change from Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Total Score at Week 12
    End point description
    HAQ-DI score was an evaluation of the functional status for a subject. The 20-question instrument assess the degree of difficulty a subject had in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily living). Responses in each functional area were scored from 0, indicated no difficulty, to 3, indicated inability to perform a task in that area. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range: 0-3 where 0 = least difficulty and 3 = extreme difficulty. The mITT analysis set included all randomized subjects who received at least one dose of IMP (M2951 or placebo). Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Number of subjects analysed
    95
    97
    95
    98
    Units: percent change
        arithmetic mean (standard deviation)
    -20.09 ( 40.084 )
    -31.85 ( 37.124 )
    -21.27 ( 44.571 )
    -27.12 ( 42.624 )
    No statistical analyses for this end point

    Secondary: Percent Change from Baseline in Physician's Global Assessment of Disease Activity Scale Based on Visual Analog Scale (VAS) Score at Week 12

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    End point title
    		 Percent Change from Baseline in Physician's Global Assessment of Disease Activity Scale Based on Visual Analog Scale (VAS) Score at Week 12
    End point description
    The Physician's Global Assessment of Disease Activity was recorded using the 100 mm horizontal VAS. Physician rated subject's arthritis disease activity on a scale ranged from 0-100 mm, where 0 indicated no disease activity (no arthritis) and 100 represented maximum disease activity (maximum arthritis). The mITT analysis set included all randomized subjects who received at least one dose of IMP (M2951 or placebo). Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Number of subjects analysed
    96
    97
    96
    98
    Units: percent change
        arithmetic mean (standard deviation)
    -42 ( 31.4 )
    -44 ( 51.9 )
    -47 ( 34.9 )
    -52 ( 33.5 )
    No statistical analyses for this end point

    Secondary: Percent Change from Baseline in High-Sensitivity C-Reactive Protein (hsCRP) at Week 12

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    End point title
    		 Percent Change from Baseline in High-Sensitivity C-Reactive Protein (hsCRP) at Week 12
    End point description
    hsCRP was the American College of Rheumatology (ACR) Core Set measure of acute phase reactant. It was measured at the central laboratory to help assess the effect of M2951 on the subject's rheumatoid arthritis. The mITT analysis set included all randomized subjects who received at least one dose of IMP (M2951 or placebo). Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Number of subjects analysed
    96
    97
    96
    99
    Units: percent change
        arithmetic mean (standard deviation)
    95.01 ( 380.161 )
    10.93 ( 167.257 )
    182.57 ( 1775.154 )
    -13.91 ( 105.688 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Synovitis Score According to the Outcomes Measures in Rheumatology Clinical Trials Rheumatoid Arthritis Magnetic Resonance Imaging Scoring System (OMERACT RAMRIS) at Week 12

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    End point title
    		 Change from Baseline in Synovitis Score According to the Outcomes Measures in Rheumatology Clinical Trials Rheumatoid Arthritis Magnetic Resonance Imaging Scoring System (OMERACT RAMRIS) at Week 12
    End point description
    A total of 8 joints in the hand and wrist were evaluated for RAMRIS synovitis. Individual joint scores were assessed on a scale of 0 (no synovitis) to 3 (67 to 100 percent volume enhancement). The final synovitis score was the sum of the individual joint scores. The total score from 8 joints ranges from 0 to 24, with 0 implying normal (no synovitis) and 24 implying 67 to 100 percent volume enhancement. The Magnetic Resonance Imaging (MRI) analysis set included all randomized subjects who have at least at least 1 pre-dose and 1 post-dose MRI assessment. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Number of subjects analysed
    44
    49
    47
    51
    Units: units on a scale
        arithmetic mean (standard deviation)
    0 ( 1.9 )
    -1 ( 2.5 )
    -1 ( 3.4 )
    -1 ( 2.4 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Bone Marrow Edema (Osteitis) Score According to the Outcomes Measures in Rheumatology Clinical Trials Rheumatoid Arthritis Magnetic Resonance Imaging Scoring System (OMERACT RAMRIS) at Week 12

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    End point title
    		 Change from Baseline in Bone Marrow Edema (Osteitis) Score According to the Outcomes Measures in Rheumatology Clinical Trials Rheumatoid Arthritis Magnetic Resonance Imaging Scoring System (OMERACT RAMRIS) at Week 12
    End point description
    A total of 25 locations in the hand and wrist were evaluated for RAMRIS bone edema or osteitis. Individual location scores range from 0 (no edema) to 3 (67 to 100 percent involvement of original articular bone) based on the proportion of estimated originally non-eroded bone involved. The final bone edema or osteitis score is the sum of the individual location scores. The total score from the 25 locations ranges from 0 to 75, with 0 implying no bone edema or osteitis and 75 implying 67 to 100 percent involvement of original articular bone. The Magnetic Resonance Imaging (MRI) analysis set included all randomized subjects who have at least at least 1 pre-dose and 1 post-dose MRI assessment. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Number of subjects analysed
    44
    49
    47
    51
    Units: units on a scale
        arithmetic mean (standard deviation)
    -1 ( 5.8 )
    0 ( 4.6 )
    0 ( 5.4 )
    0 ( 4.0 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Physical Function Using Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 12

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    End point title
    		 Change from Baseline in Physical Function Using Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 12
    End point description
    The HAQ-DI questionnaire assessed the subject's self-perception on the degree of difficulty [0 (without any difficulty), 1 (with some difficulty), 2 (with much difficulty), and 3 (unable to do)] when dressing and grooming, arising, eating, walking, hygiene, reaching, gripping, and performing other daily activities. Scores for each functional area were averaged to calculate HAQ-DI scores, which ranged from 0 (no disability) to 3 (worst disability). A decrease in HAQ-DI score indicated an improvement in the subject's condition. Quality of Life (QoL) Analysis Set: all randomized subjects who have received at least 1 dose of IMP (M2951 or placebo) and had at least 1 Baseline and 1 post baseline QoL assessment. "Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Number of subjects analysed
    87
    93
    86
    92
    Units: units on a scale
        arithmetic mean (standard deviation)
    -0.41 ( 0.543 )
    -0.61 ( 0.637 )
    -0.45 ( 0.657 )
    -0.53 ( 0.631 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Short-Form (SF-36) Health Survey Physical Component Score and Mental Component Score at Week 12

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    End point title
    		 Change from Baseline in the Short-Form (SF-36) Health Survey Physical Component Score and Mental Component Score at Week 12
    End point description
    SF-36: a standardized survey evaluating 8 aspects of functional health and well-being. These 8 subscales were summarized as relating to either physical health/mental health. Physical component summary (PCS) was based primarily on physical functioning, role-physical, bodily pain and general health scales and mental component summary (MCS) encompasses vitality, social functioning, role-emotional, and mental health scales. Score from mental health, role emotional, social functioning, and vitality domains were averaged to calculate MCS. Total score range for MCS was 0-100 (100 = highest level of mental functioning). Score from physical function, role physical, bodily pain, and general health domains were averaged to calculate PCS. Total score range for PCS was 0-100 (100 = highest level of physical functioning). QoL analysis set was used. Here, "Number of Subjects Analyzed" = subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Number of subjects analysed
    87
    93
    86
    92
    Units: units on a scale
    arithmetic mean (standard deviation)
        PCS
    5.9 ( 7.10 )
    7.1 ( 8.50 )
    6.4 ( 8.50 )
    7.1 ( 8.28 )
        MCS
    4.9 ( 11.46 )
    5.7 ( 8.41 )
    5.0 ( 11.72 )
    4.7 ( 8.95 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Score at Week 12

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    End point title
    		 Change from Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Score at Week 12
    End point description
    The FACIT-Fatigue score was calculated according to a 13-item questionnaire that assess self-reported fatigue and its impact upon daily activities and function. It uses a 5-point Likert-type scale (0 = not at all; 1 = a little bit; 2 = somewhat; 3 = quite a bit; 4 = very much). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worse possible score) to 52 (best score). A higher score reflected an improvement in the subject's health status. Quality of Life (QoL) Analysis Set: all randomized subjects who have received at least 1 dose of IMP (M2951 or placebo) and had at least 1 Baseline and 1 post baseline QoL assessment. "Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Number of subjects analysed
    87
    93
    86
    92
    Units: units on a scale
        arithmetic mean (standard deviation)
    9 ( 11.4 )
    10 ( 9.4 )
    9 ( 9.0 )
    8 ( 10.7 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    up to Week 16
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to M2951 orally for 12 weeks.

    Reporting group title
    M2951 25 mg QD
    Reporting group description
    		 Subjects received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks.

    Reporting group title
    M2951 75 mg QD
    Reporting group description
    		 Subjects received 75 mg of M2951 orally QD for 12 weeks.

    Reporting group title
    M2951 50 mg BID
    Reporting group description
    		 Subjects received 50 mg of M2951 orally twice daily (BID) for 12 weeks.

    Serious adverse events
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 97 (2.06%)
    2 / 98 (2.04%)
    2 / 96 (2.08%)
    1 / 99 (1.01%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Tibia fracture
         subjects affected / exposed
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    1 / 96 (1.04%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Lymphoedema
         subjects affected / exposed
    1 / 97 (1.03%)
    1 / 98 (1.02%)
    0 / 96 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis superficial
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 98 (0.00%)
    0 / 96 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 98 (1.02%)
    0 / 96 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    0 / 96 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 98 (0.00%)
    0 / 96 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Osteomyelitis
         subjects affected / exposed
    0 / 97 (0.00%)
    0 / 98 (0.00%)
    1 / 96 (1.04%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 98 (1.02%)
    0 / 96 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 97 (11.34%)
    13 / 98 (13.27%)
    8 / 96 (8.33%)
    17 / 99 (17.17%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 97 (5.15%)
    6 / 98 (6.12%)
    5 / 96 (5.21%)
    8 / 99 (8.08%)
         occurrences all number
    5
    6
    5
    8
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 97 (6.19%)
    2 / 98 (2.04%)
    3 / 96 (3.13%)
    7 / 99 (7.07%)
         occurrences all number
    6
    2
    3
    7
    Metabolism and nutrition disorders
    Dyslipidaemia
         subjects affected / exposed
    0 / 97 (0.00%)
    5 / 98 (5.10%)
    0 / 96 (0.00%)
    2 / 99 (2.02%)
         occurrences all number
    0
    5
    0
    2

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Dec 2017
    • added fasting requirements • reduced the treatment Period from 24 weeks to 12 weeks • removed rescue therapy • increased safety monitoring by adding visits at Week 6 and Week 10 during the Treatment Period, and reduced the length of the Open Label Extension (OLE) Period from 24 months to 12 months
    12 Jul 2018
    After receiving feedback from multiple regulatory agencies, the study Sponsor decided not to initiate the Open Label Extension Period outside the US.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    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
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