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    Clinical Trial Results:
    Phase IIa Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of M2951 in Subjects with Rheumatoid Arthritis on Stable Methotrexate Therapy

    Summary
    EudraCT number
    		 2016-000064-42
    Trial protocol
    		 SK   HU   CZ   BG  
    Global end of trial date
    14 Nov 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 May 2018
    First version publication date
    16 May 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MS200527-0081
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02784106
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck KGaA
    Sponsor organisation address
    Frankfurter Strasse 250, Darmstadt, Germany, 64293
    Public contact
    Communication Centre Merck KGaA, Merck KGaA, +49 6151725200, service@merckgroup.com
    Scientific contact
    Communication Centre Merck KGaA, Merck KGaA, +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
    14 Nov 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Nov 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of the study was to assess the efficacy of M2951 in participants with rheumatoid arthritis (RA) currently treated with stable dose of methotrexate (MTX).
    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
    31 Jul 2016
    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
    Ukraine: 15
    Country: Number of subjects enrolled
    United States: 12
    Country: Number of subjects enrolled
    Bulgaria: 5
    Country: Number of subjects enrolled
    Czech Republic: 2
    Country: Number of subjects enrolled
    Poland: 31
    Worldwide total number of subjects
    65
    EEA total number of subjects
    38
    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)
    57
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The study consisted of a 12-week double-blind period and a 26-week open-label extension period. Primary and secondary outcome measures were planned to be analyzed for double-blind treatment period only.

    Period 1
    Period 1 title
    Double-Blind Treatment Period (12 Weeks)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo: Double-Blind Treatment Period
    Arm description
    		 Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.

    Arm title
    		 M2951: Double-Blind Treatment Period
    Arm description
    		 Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    M2951
    Investigational medicinal product code
    Other name
    Evobrutinib
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 2 capsules of 25 milligrams(mg) of M2951 orally twice daily up to Day 84 during the double-blind treatment period.

    Number of subjects in period 1
    		Placebo: Double-Blind Treatment Period M2951: Double-Blind Treatment Period
    Started
    32
    33
    Completed
    24
    27
    Not completed
    8
    6
         Consent withdrawn by subject
    2
    1
         Adverse event, non-fatal
    3
    5
         Not specified
    2
    -
         Lack of efficacy
    1
    -
    Period 2
    Period 2 title
    Open-Label Extension Period (26 Weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo/M2951: Open-Label Extension Period
    Arm description
    		 Participants who received placebo matched to M2951 in double-blind treatment period, received 50 mg M2951 orally twice daily up to 26-weeks during the open-label extension period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    M2951
    Investigational medicinal product code
    Other name
    Evobrutinib
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants who received placebo in double-blind treatment period received 50 mg M2951 in the open-label extension period.

    Arm title
    		 M2951/M2951: Open-Label Extension Period
    Arm description
    		 Participants who received M2951 in double-blind treatment period, received 50 mg M2951 orally twice daily up to 26-weeks during the open-label extension period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    M2951
    Investigational medicinal product code
    Other name
    Evobrutinib
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants who received M2951 in double-blind treatment period received 50 mg M2951 in the open-label extension period.

    Number of subjects in period 2 [1]
    		Placebo/M2951: Open-Label Extension Period M2951/M2951: Open-Label Extension Period
    Started
    18
    21
    Completed
    15
    19
    Not completed
    3
    2
         Adverse event, non-fatal
    2
    1
         Lack of efficacy
    1
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: All participants who completed the double-blind treatment period didn't enter the open-lable extension period as this was optional.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo: Double-Blind Treatment Period
    Reporting group description
    		 Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.

    Reporting group title
    M2951: Double-Blind Treatment Period
    Reporting group description
    		 Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.

    Reporting group values
    		 Placebo: Double-Blind Treatment Period M2951: Double-Blind Treatment Period Total
    Number of subjects
    		 32 33 65
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53.1 ( 12.19 ) 53.8 ( 10.73 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 25 24 49
        Male
    		 7 9 16
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 1 1
        Black or African American
    		 1 1 2
        White
    		 31 31 62
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 1 1 2
        Not Hispanic or Latino
    		 31 32 63
        Unknown or Not Reported
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Placebo: Double-Blind Treatment Period
    Reporting group description
    		 Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.

    Reporting group title
    M2951: Double-Blind Treatment Period
    Reporting group description
    		 Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.
    Reporting group title
    Placebo/M2951: Open-Label Extension Period
    Reporting group description
    		 Participants who received placebo matched to M2951 in double-blind treatment period, received 50 mg M2951 orally twice daily up to 26-weeks during the open-label extension period.

    Reporting group title
    M2951/M2951: Open-Label Extension Period
    Reporting group description
    		 Participants who received M2951 in double-blind treatment period, received 50 mg M2951 orally twice daily up to 26-weeks during the open-label extension period.

    Primary: Proportion of Participants who Achieved American College of Rheumatology-20 (ACR20) Response

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    End point title
    		 Proportion of Participants who Achieved American College of Rheumatology-20 (ACR20) Response
    End point description
    ACR 20 response: greater than or equal to (>=) 20 percent (%) 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) participant's assessment of pain; 2) participant's global assessment of disease activity; 3) physician's global assessment of disease activity; 4) participant'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). The Modified Intent-to-Treat (mITT) Analysis Set included all participants who received at least 1 dose of M2951 or placebo and have at least 1 available ACR20 evaluation at a time point post-dose. Proportion of ACR20 responders = Number of participants with ACR20 response divided by total participants.
    End point type
    Primary
    End point timeframe
    Day 84
    End point values
    		 Placebo: Double-Blind Treatment Period M2951: Double-Blind Treatment Period
    Number of subjects analysed
    31
    33
    Units: proportion of participants
        number (not applicable)
    0.42
    0.52
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Placebo: Double-Blind Treatment Period v M2951: Double-Blind Treatment Period
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in Proportion of Responders
    Point estimate
    0.1
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.07
         upper limit
    		 0.25

    Secondary: Mean Change From Baseline in High-Sensitivity C-Reactive Protein (hsCRP) at Day 28

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    End point title
    		 Mean Change From Baseline in High-Sensitivity C-Reactive Protein (hsCRP) at Day 28
    End point description
    Mean change in the hsCRP concentration from baseline at Day 28 was reported. mITT analysis Set included all participants who received at least 1 dose of M2951 or placebo and have at least 1 available ACR20 evaluation at a time point post-dose. mITT analysis Set included all participants who received at least 1 dose of M2951 or placebo and have at least 1 available ACR20 evaluation at a time point post-dose.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 28
    End point values
    		 Placebo: Double-Blind Treatment Period M2951: Double-Blind Treatment Period
    Number of subjects analysed
    31
    33
    Units: milligram/milliliter (mg/mL)
        arithmetic mean (standard error)
    -0.80 ( 2.00 )
    -2.72 ( 1.93 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Placebo: Double-Blind Treatment Period v M2951: Double-Blind Treatment Period
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in Mean Changes
    Point estimate
    -1.93
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -5.54
         upper limit
    		 1.69

    Secondary: Proportion of Participants Achieving American College of Rheumatology-50 (ACR50) Response

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    End point title
    		 Proportion of Participants Achieving American College of Rheumatology-50 (ACR50) Response
    End point description
    ACR 50 response: >=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) participant's assessment of pain; 2) participant's global assessment of disease activity; 3) physician's global assessment of disease activity; 4) participant's assessment of physical function measured by HAQ-DI; and 5) acute phase reactant as measured by hsCRP. mITT analysis Set included all participants who received at least 1 dose of M2951 or placebo and have at least 1 available ACR20 evaluation at a time point post-dose. Proportion of ACR50 responders = Number of participants with ACR50 response divided by total participants.
    End point type
    Secondary
    End point timeframe
    Day 28, Day 56 and Day 84
    End point values
    		 Placebo: Double-Blind Treatment Period M2951: Double-Blind Treatment Period
    Number of subjects analysed
    31
    33
    Units: proportion of participants
    number (not applicable)
        Day 28
    0.10
    0.06
        Day 56
    0.23
    0.18
        Day 84
    0.23
    0.21
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Day 28
    Comparison groups
    Placebo: Double-Blind Treatment Period v M2951: Double-Blind Treatment Period
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in Proportion of Responders
    Point estimate
    -0.04
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.13
         upper limit
    		 0.06
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Day 56
    Comparison groups
    Placebo: Double-Blind Treatment Period v M2951: Double-Blind Treatment Period
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in Proportion of Responders
    Point estimate
    -0.04
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.18
         upper limit
    		 0.09
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Day 84
    Comparison groups
    Placebo: Double-Blind Treatment Period v M2951: Double-Blind Treatment Period
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in Proportion of Responders
    Point estimate
    -0.01
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.15
         upper limit
    		 0.12

    Secondary: Proportion of Participants Achieving American College of Rheumatology-70 (ACR70) Response

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    End point title
    		 Proportion of Participants Achieving American College of Rheumatology-70 (ACR70) Response
    End point description
    ACR 70 response: >=70% 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 >=70% improvement in at least 3 of the following: 1) participant's assessment of pain; 2) participant's global assessment of disease activity; 3) physician's global assessment of disease activity; 4) participant's assessment of physical function measured by HAQ-DI; and 5) acute phase reactant as measured by hsCRP. mITT analysis Set included all participants who received at least 1 dose of M2951 or placebo and have at least 1 available ACR20 evaluation at a time point post-dose. Proportion of ACR70 responders = Number of participants with ACR70 response divided by total participants.
    End point type
    Secondary
    End point timeframe
    Day 28, Day 56 and Day 84
    End point values
    		 Placebo: Double-Blind Treatment Period M2951: Double-Blind Treatment Period
    Number of subjects analysed
    31
    33
    Units: proportion of participants
    number (not applicable)
        Day 28
    0.00
    0.06
        Day 56
    0.03
    0.06
        Day 84
    0.13
    0.09
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Day 28
    Comparison groups
    Placebo: Double-Blind Treatment Period v M2951: Double-Blind Treatment Period
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Difference in Proportion of Responders
    Point estimate
    0.06
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.01
         upper limit
    		 0.14
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Day 56
    Comparison groups
    Placebo: Double-Blind Treatment Period v M2951: Double-Blind Treatment Period
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Difference in Proportion of Responders
    Point estimate
    0.03
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.05
         upper limit
    		 0.11
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Day 84
    Comparison groups
    Placebo: Double-Blind Treatment Period v M2951: Double-Blind Treatment Period
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in Proportion of Responders
    Point estimate
    -0.04
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.15
         upper limit
    		 0.07

    Secondary: Mean Change from Baseline in High-Sensitivity C-Reactive Protein (hsCRP) at Day 84

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    End point title
    		 Mean Change from Baseline in High-Sensitivity C-Reactive Protein (hsCRP) at Day 84
    End point description
    Mean change in the hsCRP concentration from baseline at Day 84 was reported. mITT analysis Set included all participants who received at least 1 dose of M2951 or placebo and have at least 1 available ACR20 evaluation at a time point post-dose.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 84
    End point values
    		 Placebo: Double-Blind Treatment Period M2951: Double-Blind Treatment Period
    Number of subjects analysed
    31
    33
    Units: mg/mL
        arithmetic mean (standard error)
    -2.14 ( 2.20 )
    -3.54 ( 2.13 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Placebo: Double-Blind Treatment Period v M2951: Double-Blind Treatment Period
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in Mean Changes
    Point estimate
    -1.4
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -5.37
         upper limit
    		 2.58

    Secondary: Mean Change from Baseline in Disease Activity Score Based on a 28 Joint Count High-Sensitivity C-Reactive Protein (DAS28-hsCRP) at Day 28 and 84

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    End point title
    		 Mean Change from Baseline in Disease Activity Score Based on a 28 Joint Count High-Sensitivity C-Reactive Protein (DAS28-hsCRP) at Day 28 and 84
    End point description
    Disease Activity Score (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 participant’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)+ 0.014* participant’s global assessment of disease activity + 0.36*natural log(hsCRP+1) +0.96. Scores ranged 1.0-9.4, where lower scores indicated less disease activity. mITT analysis Set included all participants who received at least 1 dose of M2951 or placebo and have at least 1 available ACR20 evaluation at a time point post-dose.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 28 and Day 84
    End point values
    		 Placebo: Double-Blind Treatment Period M2951: Double-Blind Treatment Period
    Number of subjects analysed
    31
    33
    Units: units on a scale
    arithmetic mean (standard error)
        Change at Day 28
    -0.79 ( 0.14 )
    -0.87 ( 0.13 )
        Change at Day 84
    -1.35 ( 0.20 )
    -1.28 ( 0.19 )
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Day 28
    Comparison groups
    Placebo: Double-Blind Treatment Period v M2951: Double-Blind Treatment Period
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in Mean Changes
    Point estimate
    -0.08
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.33
         upper limit
    		 0.16
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Day 84
    Comparison groups
    Placebo: Double-Blind Treatment Period v M2951: Double-Blind Treatment Period
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Difference in Mean Changes
    Point estimate
    0.07
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.29
         upper limit
    		 0.43

    Secondary: Proportion of Participants With Disease Activity Score- High Sensitivity C-Reactive Protein (DAS28-hsCRP) Value Less Than (<) 3.2

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    End point title
    		 Proportion of Participants With Disease Activity Score- High Sensitivity C-Reactive Protein (DAS28-hsCRP) Value Less Than (<) 3.2
    End point description
    DAS28-hsCRP consisted of composite score of following variables: TJC28, SJC28, hsCRP (mg/mL), and participant’s global assessment of disease activity. DAS28-hsCRP was calculated using following formula: DAS28-hsCRP =0.56* sqrt(TJC28) + 0.28*sqrt(SJC28)+ 0.014* participant’s global assessment of disease activity + 0.36*natural log(hsCRP+1) +0.96. Scores ranged 1.0-9.4, where lower scores indicated less disease activity. mITT analysis Set included all participants who received at least 1 dose of M2951 or placebo and have at least 1 available ACR20 evaluation at a time point post-dose. Proportion of participants with DAS28-hsCRP value <3.2 were reported.
    End point type
    Secondary
    End point timeframe
    Day 84
    End point values
    		 Placebo: Double-Blind Treatment Period M2951: Double-Blind Treatment Period
    Number of subjects analysed
    31
    33
    Units: proportion of participants
        number (not applicable)
    0.13
    0.21
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Placebo: Double-Blind Treatment Period v M2951: Double-Blind Treatment Period
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in Proportion of Participants
    Point estimate
    0.08
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 0.21

    Secondary: Proportion of Participants With Disease Activity Score- High Sensitivity C-Reactive Protein (DAS28-hsCRP) Value Less Than (<) 2.6

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    End point title
    		 Proportion of Participants With Disease Activity Score- High Sensitivity C-Reactive Protein (DAS28-hsCRP) Value Less Than (<) 2.6
    End point description
    DAS28 consisted of composite score of following variables: TJC28, SJC28, hsCRP (mg/mL), and participant’s global assessment of disease activity. DAS28-hsCRP was calculated using following formula: DAS28-hsCRP =0.56* sqrt (TJC28) + 0.28*sqrt(SJC28)+ 0.014* participant’s global assessment of disease activity + 0.36*natural log(hsCRP+1) +0.96. Scores ranged 1.0-9.4, where lower scores indicated less disease activity. mITT analysis Set included all participants who received at least 1 dose of M2951 or placebo and have at least 1 available ACR20 evaluation at a time point post-dose. Proportion of participants with DAS28-hsCRP value <2.6 were reported.
    End point type
    Secondary
    End point timeframe
    Day 84
    End point values
    		 Placebo: Double-Blind Treatment Period M2951: Double-Blind Treatment Period
    Number of subjects analysed
    31
    33
    Units: proportion of participants
        number (not applicable)
    0.10
    0.06
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Placebo: Double-Blind Treatment Period v M2951: Double-Blind Treatment Period
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in Proportion of Participants
    Point estimate
    -0.04
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.13
         upper limit
    		 0.06

    Secondary: Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Day 28 and 84

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    End point title
    		 Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Day 28 and 84
    End point description
    Erythrocyte sedimentation rate (ESR) is a type of blood test that measures how quickly erythrocytes (red blood cells) settle at the bottom of a test tube that contains a blood sample. Higher values indicate inflammation in the body. mITT analysis set included all participants who received at least 1 dose of M2951 or placebo and have at least 1 available ACR20 evaluation at a time point post-dose. Here “n" signified those participants who were evaluable for this endpoint at the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 28 and Day 84
    End point values
    		 Placebo: Double-Blind Treatment Period M2951: Double-Blind Treatment Period
    Number of subjects analysed
    31
    33
    Units: millimeter/hour (mm/hour)
    arithmetic mean (standard deviation)
        Change at Day 28 (n=29,32)
    -3 ( 36.9 )
    -7 ( 22.1 )
        Change at Day 84 (n=25,35)
    -3 ( 21.0 )
    -9 ( 21.1 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Anti-cyclic Citrullinated Peptide (anti-CCP) Antibody Levels at Day 28 and 84

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    End point title
    		 Change From Baseline in Anti-cyclic Citrullinated Peptide (anti-CCP) Antibody Levels at Day 28 and 84
    End point description
    Anti-cyclic citrullinated peptide (anti-CCP) is an antibody present in most rheumatoid arthritis participants. mITT analysis set included all participants who received at least 1 dose of M2951 or placebo and have at least 1 available ACR20 evaluation at a time point post-dose. Here “n" signified those participants who were evaluable for this endpoint at the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 28 and Day 84
    End point values
    		 Placebo: Double-Blind Treatment Period M2951: Double-Blind Treatment Period
    Number of subjects analysed
    31
    33
    Units: units/milliliter
    arithmetic mean (standard deviation)
        Change at Day 28 (n=29,32)
    168 ( 991.1 )
    -138 ( 720.9 )
        Change at Day 84 (n=25,25)
    301 ( 1282.6 )
    -396 ( 736.8 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Rheumatoid Factor (RF) at Day 28 and 84

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    End point title
    		 Change From Baseline in Rheumatoid Factor (RF) at Day 28 and 84
    End point description
    Rheumatoid Factor is an anti-body present in the blood. mITT analysis set included all participants who received at least 1 dose of M2951 or placebo and have at least 1 available ACR20 evaluation at a time point post-dose. Here “n" signified those participants who were evaluable for this endpoint at the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 28 and Day 84
    End point values
    		 Placebo: Double-Blind Treatment Period M2951: Double-Blind Treatment Period
    Number of subjects analysed
    31
    33
    Units: kiloUnit/Liter (kU/L)
    arithmetic mean (standard deviation)
        Change at Day 28 (n=29,32)
    -30 ( 124.2 )
    -7 ( 59.7 )
        Change at Day 84 (n=25,25)
    -34 ( 132.1 )
    -26 ( 79.9 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Global Assessment of Disease Activity Based on Visual Analog Scale (VAS) Score at Day 84

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    End point title
    		 Change From Baseline in Global Assessment of Disease Activity Based on Visual Analog Scale (VAS) Score at Day 84
    End point description
    The participant’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). mITT analysis set included all participants who received at least 1 dose of M2951 or placebo and have at least 1 available ACR20 evaluation at a time point post-dose. Here "Number of Subjects Analysed" signified those participants who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 84
    End point values
    		 Placebo: Double-Blind Treatment Period M2951: Double-Blind Treatment Period
    Number of subjects analysed
    25
    26
    Units: millimeter
        arithmetic mean (standard deviation)
    -21 ( 23.5 )
    -24 ( 24.6 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Self-assessment of Pain Based on Visual Analog Scale (VAS) Score at Day 84

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    End point title
    		 Change From Baseline in Self-assessment of Pain Based on Visual Analog Scale (VAS) Score at Day 84
    End point description
    The participants 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. mITT analysis set included all participants who received at least 1 dose of M2951 or placebo and have at least 1 available ACR20 evaluation at a time point post-dose. Here "Number of Subjects Analysed" signified those participants who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 84
    End point values
    		 Placebo: Double-Blind Treatment Period M2951: Double-Blind Treatment Period
    Number of subjects analysed
    25
    26
    Units: millimeter
        arithmetic mean (standard deviation)
    -19 ( 21.8 )
    -22 ( 22.0 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Self-assessment of Disability Using Health Assessment Questionnaire - Disability Index (HAQ-DI) Score at Day 84

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    End point title
    		 Change From Baseline in Self-assessment of Disability Using Health Assessment Questionnaire - Disability Index (HAQ-DI) Score at Day 84
    End point description
    The HAQ-DI questionnaire assessed the participant'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 participant's condition. mITT analysis set included all participants who received at least 1 dose of M2951 or placebo and have at least 1 available ACR20 evaluation at a time point post-dose. Here "Number of Subjects Analysed" signified those participants who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 84
    End point values
    		 Placebo: Double-Blind Treatment Period M2951: Double-Blind Treatment Period
    Number of subjects analysed
    25
    26
    Units: units on a scale
        arithmetic mean (standard deviation)
    -0.3 ( 0.44 )
    -0.3 ( 0.41 )
    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 Day 84

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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 Day 84
    End point description
    The Physician’s Global Assessment of Disease Activity was recorded using the 100 mm horizontal VAS. Physician rated participant’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). mITT analysis set included all participants who received at least 1 dose of M2951 or placebo and have at least 1 available ACR20 evaluation at a time point post-dose. Here "Number of Subjects Analysed" signified those participants who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 84
    End point values
    		 Placebo: Double-Blind Treatment Period M2951: Double-Blind Treatment Period
    Number of subjects analysed
    25
    26
    Units: millimeter
        arithmetic mean (standard deviation)
    -33 ( 20.3 )
    -30 ( 22.7 )
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
    End point description
    An Adverse event (AE) was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Treatment-emergent are events between first dose of study drug that were absent before treatment or that worsened relative to pre-treatment state. TEAEs included both Serious TEAEs and non-serious TEAEs. The Safety Analysis Set included all participants who received at least 1 dose of M2951 or placebo.
    End point type
    Secondary
    End point timeframe
    Baseline up to 16 Weeks
    End point values
    		 Placebo: Double-Blind Treatment Period M2951: Double-Blind Treatment Period
    Number of subjects analysed
    32
    33
    Units: participants
        TEAEs
    16
    22
        SAEs
    0
    1
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity

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    End point title
    		 Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity
    End point description
    Grade 3 and 4 TEAES as per National Cancer Institute Common Terminology Criteria for Adverse Experience version 4.03 (NCI-CTCAE v 4.03) were presented. Grade 3 refers to severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care and Activity of daily living (ADL).Grade 4 refers to Life-threatening consequences; where urgent intervention indicated. The Safety Analysis Set included all participants who received at least 1 dose of M2951 or placebo.
    End point type
    Secondary
    End point timeframe
    Baseline up to 16 Weeks
    End point values
    		 Placebo: Double-Blind Treatment Period M2951: Double-Blind Treatment Period
    Number of subjects analysed
    32
    33
    Units: participants
        NCI-CTCAE Severity grade >=3
    2
    3
        NCI-CTCAE Severity grade >=4
    0
    1
    No statistical analyses for this end point

    Secondary: Number of Participants With Grade 3 or Higher Clinically Significant Abnormality for Hematology, Biochemistry, Urinalysis or Coagulation

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    End point title
    		 Number of Participants With Grade 3 or Higher Clinically Significant Abnormality for Hematology, Biochemistry, Urinalysis or Coagulation
    End point description
    Clinically significant abnormalities for hematology, biochemistry or coagulation were graded with National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.03 toxicity grades, where Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening and Grade 5 = death. Participants with grade 3 or higher were reported. The Safety Analysis Set included all participants who received at least 1 dose of M2951 or placebo.
    End point type
    Secondary
    End point timeframe
    Baseline up to 16 Weeks
    End point values
    		 Placebo: Double-Blind Treatment Period M2951: Double-Blind Treatment Period
    Number of subjects analysed
    32
    33
    Units: participants
        Hematology
    2
    0
        Biochemistry
    4
    2
        Coagulation
    0
    0
        Urinalysis
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Clinically Significant Vital Signs Abnormalities

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    End point title
    		 Number of Participants With Clinically Significant Vital Signs Abnormalities
    End point description
    Vital sign assessment included blood pressure, pulse rate, respiratory rate and temperature. Clinical significance was determined by the investigator. The Safety Analysis Set included all participants who received at least 1 dose of M2951 or placebo.
    End point type
    Secondary
    End point timeframe
    Baseline up to 16 Weeks
    End point values
    		 Placebo: Double-Blind Treatment Period M2951: Double-Blind Treatment Period
    Number of subjects analysed
    32
    33
    Units: participants
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Clinically Significant 12-lead Electrocardiogram (ECG) Findings

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    End point title
    		 Number of Participants With Clinically Significant 12-lead Electrocardiogram (ECG) Findings
    End point description
    The 12-lead ECG recordings were obtained after 10 minutes of rest in a semi-supine position. The ECG parameters obtained directly from the computerized 12-lead ECG recordings included rhythm, ventricular rate, PR interval, QRS duration, and QT interval. Clinical significance was determined by the investigator. The Safety Analysis Set included all participants who received at least 1 dose of M2951 or placebo.
    End point type
    Secondary
    End point timeframe
    Baseline up to 16 Weeks
    End point values
    		 Placebo: Double-Blind Treatment Period M2951: Double-Blind Treatment Period
    Number of subjects analysed
    32
    33
    Units: participants
    0
    0
    No statistical analyses for this end point

    Secondary: Plasma Concentration of M2951

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    End point title
    		 Plasma Concentration of M2951 [1]
    End point description
    The Pharmacokinetic (PK) Analysis Set included all participants who receive at least 1 dose of M2951 and have at least 1 quantifiable M2951 plasma concentration at a scheduled PK time point post-dose. Here “n" signified those participants who were evaluable for this endpoint at the specified time point. "9999" represents statistical analysis was not applicable as mean concentration of the drug is zero.
    End point type
    Secondary
    End point timeframe
    Pre-dose at Day 1; 0.25, 0.5, 1.0, 2.0, 4.0, 6.0 hours post-dose at Day 1 and Day 29
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point was planned to be analyzed only for the double-blind treatment period arm.
    End point values
    		 M2951: Double-Blind Treatment Period
    Number of subjects analysed
    33
    Units: nanogram per milliliter (ng/mL)
    arithmetic mean (standard deviation)
        Day 1: Pre-Dose (n=33)
    0.00 ( 99999 )
        Day 1: 0.25 hours post-dose (n=33)
    10.3 ( 23.37 )
        Day 1: 0.5 hours post-dose (n=33)
    80.5 ( 136.9 )
        Day 1: 1 hour post-dose (n=33)
    160 ( 219.7 )
        Day 1: 2 hours post-dose (n=33)
    125 ( 111.9 )
        Day 1: 4 hours post-dose (n=33)
    47.3 ( 41.62 )
        Day 1: 6 hours post-dose (n=33)
    23.7 ( 20.92 )
        Day 29: 0.25 hours post-dose (n=28)
    22.0 ( 71.57 )
        Day 29: 0.5 hours post-dose (n=28)
    88.4 ( 114.1 )
        Day 29: 1 hour post-dose (n=28)
    120 ( 107.2 )
        Day 29: 2 hours post-dose (n=27)
    82.3 ( 53.82 )
        Day 29: 4 hours post-dose (n=28)
    62.1 ( 82.39 )
        Day 29: 6 hour post-dose (n=27)
    37.2 ( 43.96 )
    No statistical analyses for this end point

    Secondary: Area Under the Concentration-Time Curve From Time Zero to 6 Hours (AUC 0-6h) of M2951

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    End point title
    		 Area Under the Concentration-Time Curve From Time Zero to 6 Hours (AUC 0-6h) of M2951 [2]
    End point description
    PK analysis set included all participants who receive at least 1 dose of M2951 and have at least 1 quantifiable M2951 plasma concentration at a scheduled PK time point post-dose. Here “n" signified those participants who were evaluable for this endpoint at the specified time point.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0 hours post-dose at Day 1 and Day 29
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point was planned to be analyzed only for the double-blind treatment period arm.
    End point values
    		 M2951: Double-Blind Treatment Period
    Number of subjects analysed
    33
    Units: hours*nanogram/milliliter
    arithmetic mean (standard deviation)
        Day 1 (n=33)
    431 ( 390.9 )
        Day 29 (n=26)
    414 ( 268.4 )
    No statistical analyses for this end point

    Secondary: Maximum Observed Plasma Concentration (Cmax) of M2951

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    End point title
    		 Maximum Observed Plasma Concentration (Cmax) of M2951 [3]
    End point description
    PK analysis set included all participants who receive at least 1 dose of M2951 and have at least 1 quantifiable M2951 plasma concentration at a scheduled PK time point post-dose. Here “n" signified those participants who were evaluable for this endpoint at the specified time point.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0 hours post-dose at Day 1 and Day 29
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point was planned to be analyzed only for the double-blind treatment period arm.
    End point values
    		 M2951: Double-Blind Treatment Period
    Number of subjects analysed
    33
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1 (n=33)
    206 ( 214.7 )
        Day 29 (n=27)
    171 ( 130.1 )
    No statistical analyses for this end point

    Secondary: Plasma Concentration Observed Immediately Before Dosing on Day 29 (Cpre) of M2951

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    End point title
    		 Plasma Concentration Observed Immediately Before Dosing on Day 29 (Cpre) of M2951 [4]
    End point description
    PK analysis set included all participants who receive at least 1 dose of M2951 and have at least 1 quantifiable M2951 plasma concentration at a scheduled PK time point post-dose. Here “Number of Subjects Analyzed" signified those participants who were evaluable for this endpoint at the specified time point.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 29
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point was planned to be analyzed only for the double-blind treatment period arm.
    End point values
    		 M2951: Double-Blind Treatment Period
    Number of subjects analysed
    28
    Units: ng/mL
        arithmetic mean (standard deviation)
    5.47 ( 4.735 )
    No statistical analyses for this end point

    Secondary: Time to Reach Maximum Plasma Concentration (Tmax) of M2951

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    End point title
    		 Time to Reach Maximum Plasma Concentration (Tmax) of M2951 [5]
    End point description
    PK analysis set included all participants who receive at least 1 dose of M2951 and have at least 1 quantifiable M2951 plasma concentration at a scheduled PK time point post-dose. Here “n" signified those participants who were evaluable for this endpoint at the specified time point.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0 hours post-dose at Day 1 and Day 29
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point was planned to be analyzed only for the double-blind treatment period arm.
    End point values
    		 M2951: Double-Blind Treatment Period
    Number of subjects analysed
    33
    Units: hour
    median (full range (min-max))
        Day 1 (n=33)
    1.00 (0.50 to 4.00)
        Day 29 (n=27)
    1.00 (0.50 to 6.00)
    No statistical analyses for this end point

    Secondary: Accumulation Ratio for Area under the Concentration-Time Curve from Time Zero to 6 Hours (Racc [AUC0-6h]) of M2951

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    End point title
    		 Accumulation Ratio for Area under the Concentration-Time Curve from Time Zero to 6 Hours (Racc [AUC0-6h]) of M2951 [6]
    End point description
    Accumulation ratio for AUC was calculated as AUC 0-6h, Day 29 divided by AUC 0-6h, Day 1. PK analysis set included all participants who receive at least 1 dose of M2951 and have at least 1 quantifiable M2951 plasma concentration at a scheduled PK time point post-dose. Here “Number of Subjects Analyzed" signified those participants who were evaluable for this endpoint at the specified time point.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0 hours post-dose at Day 1 and Day 29
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point was planned to be analyzed only for the double-blind treatment period arm.
    End point values
    		 M2951: Double-Blind Treatment Period
    Number of subjects analysed
    26
    Units: ratio
        arithmetic mean (standard deviation)
    1.38 ( 1.134 )
    No statistical analyses for this end point

    Secondary: Accumulation Ratio for Observed Maximum Plasma Concentration (Racc [Cmax]) of M2951

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    End point title
    		 Accumulation Ratio for Observed Maximum Plasma Concentration (Racc [Cmax]) of M2951 [7]
    End point description
    Accumulation ratio for Cmax , was calculated as Cmax, Day 29 divided by Cmax, Day1. PK analysis set included all participants who receive at least 1 dose of M2951 and have at least 1 quantifiable M2951 plasma concentration at a scheduled PK time point post-dose. Here “Number of Subjects Analyzed" signified those participants who were evaluable for this endpoint at the specified time point.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0 hours post-dose at Day 1 and Day 29
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point was planned to be analyzed only for the double-blind treatment period arm.
    End point values
    		 M2951: Double-Blind Treatment Period
    Number of subjects analysed
    27
    Units: ratio
        arithmetic mean (standard deviation)
    1.52 ( 1.929 )
    No statistical analyses for this end point

    Secondary: Absolute Immunoglobulin Levels at Day 85

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    End point title
    		 Absolute Immunoglobulin Levels at Day 85
    End point description
    Following immunoglobulin levels were measured: Immunoglobulin A , Immunoglobulin G, Immunoglobulin G Subclass 1, Immunoglobulin G Subclass 2, Immunoglobulin G Subclass 3, Immunoglobulin G Subclass 4, Immunoglobulin M. The Pharmacodynamic (PD) Analysis Set included all participants who received at least 1 dose of M2951 or placebo and have at least 1 measured PD endpoint, not including Bruton’s tyrosine kinase(BTK) occupancy, at a scheduled PD time point post-dose. Here “Number of Subjects Analyzed" signified those participants who were evaluable for this endpoint at the specified time point.
    End point type
    Secondary
    End point timeframe
    Day 85
    End point values
    		 Placebo: Double-Blind Treatment Period M2951: Double-Blind Treatment Period
    Number of subjects analysed
    10
    12
    Units: gram/Liter
    arithmetic mean (standard deviation)
        Immunoglobulin A
    2.09 ( 0.968 )
    2.77 ( 1.323 )
        Immunoglobulin G
    10.61 ( 3.897 )
    9.88 ( 2.498 )
        Immunoglobulin G Subclass 1
    6.20 ( 2.338 )
    5.41 ( 1.574 )
        Immunoglobulin G Subclass 2
    3.59 ( 1.644 )
    3.74 ( 1.205 )
        Immunoglobulin G Subclass 3
    1.05 ( 0.551 )
    0.93 ( 0.510 )
        Immunoglobulin G Subclass 4
    0.394 ( 0.2474 )
    0.684 ( 0.6286 )
        Immunoglobulin M
    1.16 ( 0.365 )
    1.16 ( 0.642 )
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Immunoglobulin Levels at Day 85

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    End point title
    		 Absolute Change From Baseline in Immunoglobulin Levels at Day 85
    End point description
    Following immunoglobulin levels were measured: Immunoglobulin A , Immunoglobulin G, Immunoglobulin G Subclass 1, Immunoglobulin G Subclass 2, Immunoglobulin G Subclass 3, Immunoglobulin G Subclass 4, Immunoglobulin M. PD analysis set included all participants who received at least 1 dose of M2951 or placebo and have at least 1 measured PD endpoint, not including Bruton’s tyrosine kinase(BTK) occupancy, at a scheduled PD time point post-dose. Here “Number of Subjects Analyzed" signified those participants who were evaluable for this endpoint at the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 85
    End point values
    		 Placebo: Double-Blind Treatment Period M2951: Double-Blind Treatment Period
    Number of subjects analysed
    10
    12
    Units: gram/Liter
    arithmetic mean (standard deviation)
        Immunoglobulin A
    -0.07 ( 0.263 )
    -0.04 ( 0.133 )
        Immunoglobulin G
    0.02 ( 1.281 )
    -0.30 ( 0.517 )
        Immunoglobulin G Subclass 1
    0.11 ( 0.857 )
    -0.15 ( 0.410 )
        Immunoglobulin G Subclass 2
    -0.13 ( 0.477 )
    -0.17 ( 0.404 )
        Immunoglobulin G Subclass 3
    0.07 ( 0.214 )
    -0.04 ( 0.209 )
        Immunoglobulin G Subclass 4
    -0.028 ( 0.1073 )
    -0.046 ( 0.2576 )
        Immunoglobulin M
    -0.04 ( 0.177 )
    -0.25 ( 0.255 )
    No statistical analyses for this end point

    Secondary: Absolute B-Cell Levels at Day 85

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    End point title
    		 Absolute B-Cell Levels at Day 85
    End point description
    PD analysis set included all participants who received at least 1 dose of M2951 or placebo and have at least 1 measured PD endpoint, not including Bruton’s tyrosine kinase (BTK) occupancy, at a scheduled PD time point post-dose. Here “Number of Subjects Analyzed" signified those participants who were evaluable for this endpoint at the specified time point.
    End point type
    Secondary
    End point timeframe
    Day 85
    End point values
    		 Placebo: Double-Blind Treatment Period M2951: Double-Blind Treatment Period
    Number of subjects analysed
    12
    12
    Units: cells per micro-liter
        arithmetic mean (standard deviation)
    243 ( 265.0 )
    204 ( 154.0 )
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in B-cell Levels at Day 85

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    End point title
    		 Absolute Change From Baseline in B-cell Levels at Day 85
    End point description
    PD analysis set included all participants who received at least 1 dose of M2951 or placebo and have at least 1 measured PD endpoint, not including Bruton’s tyrosine kinase (BTK) occupancy, at a scheduled PD time point post-dose.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 85
    End point values
    		 Placebo: Double-Blind Treatment Period M2951: Double-Blind Treatment Period
    Number of subjects analysed
    12
    12
    Units: cells per micro-liter
        arithmetic mean (standard deviation)
    76 ( 242.0 )
    11 ( 73.2 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Double-Blind Period: Baseline up to 16 weeks; Open-Label Period: Baseline up to 30 weeks
    Adverse event reporting additional description
    MedDRA version for the double-blind treatment period is version 20.0 and MedDRA version for the open-label extension period is version 20.1
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20 , 20.1
    Reporting groups
    Reporting group title
    Placebo: Double-Blind Treatment Period
    Reporting group description
    		 Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.

    Reporting group title
    M2951: Double-Blind Treatment Period
    Reporting group description
    		 Participants received M2951 50 mg M2951 orally twice daily up to Day 84 during the double-blind treatment period.

    Reporting group title
    Placebo/M2951: Open Label Extension Period
    Reporting group description
    		 Participants who received placebo matched to M2951 in double-blind treatment period, received 50 mg M2951 orally twice daily up to 26-weeks during the open-label extension period.

    Reporting group title
    M2951/M2951: Open-Label Extension Period
    Reporting group description
    		 Participants who received M2951 in double-blind treatment period, received 50 mg M2951 orally twice daily up to 26-weeks during the open-label extension period.

    Serious adverse events
    		 Placebo: Double-Blind Treatment Period M2951: Double-Blind Treatment Period Placebo/M2951: Open Label Extension Period M2951/M2951: Open-Label Extension Period
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 33 (3.03%)
    0 / 18 (0.00%)
    0 / 21 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Nervous system disorders
    Vertigo CNS origin
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 33 (3.03%)
    0 / 18 (0.00%)
    0 / 21 (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
    Ear and labyrinth disorders
    Vestibular disorder
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 33 (3.03%)
    0 / 18 (0.00%)
    0 / 21 (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: Double-Blind Treatment Period M2951: Double-Blind Treatment Period Placebo/M2951: Open Label Extension Period M2951/M2951: Open-Label Extension Period
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 32 (40.63%)
    17 / 33 (51.52%)
    8 / 18 (44.44%)
    10 / 21 (47.62%)
    Investigations
    Lipase increased
         subjects affected / exposed
    2 / 32 (6.25%)
    3 / 33 (9.09%)
    0 / 18 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    3
    0
    0
    Blood glucose increased
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 33 (6.06%)
    0 / 18 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 32 (12.50%)
    1 / 33 (3.03%)
    1 / 18 (5.56%)
    0 / 21 (0.00%)
         occurrences all number
    4
    1
    1
    0
    Amylase increased
         subjects affected / exposed
    3 / 32 (9.38%)
    1 / 33 (3.03%)
    2 / 18 (11.11%)
    0 / 21 (0.00%)
         occurrences all number
    3
    1
    2
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 32 (9.38%)
    0 / 33 (0.00%)
    1 / 18 (5.56%)
    0 / 21 (0.00%)
         occurrences all number
    3
    0
    1
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 33 (0.00%)
    0 / 18 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 33 (6.06%)
    0 / 18 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    0
    2
    Blood and lymphatic system disorders
    Leukocytosis
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 33 (3.03%)
    0 / 18 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Neutropenia
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 33 (0.00%)
    0 / 18 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    3 / 32 (9.38%)
    3 / 33 (9.09%)
    0 / 18 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    3
    3
    0
    2
    Vomiting
         subjects affected / exposed
    1 / 32 (3.13%)
    2 / 33 (6.06%)
    0 / 18 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    1
    2
    0
    2
    Abdominal pain upper
         subjects affected / exposed
    2 / 32 (6.25%)
    2 / 33 (6.06%)
    0 / 18 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    2
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 33 (0.00%)
    1 / 18 (5.56%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 33 (0.00%)
    1 / 18 (5.56%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 33 (6.06%)
    0 / 18 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    0
    2
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 33 (0.00%)
    2 / 18 (11.11%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    2
    1
    Infections and infestations
    Viral upper respiratory tract infection
         subjects affected / exposed
    4 / 32 (12.50%)
    3 / 33 (9.09%)
    1 / 18 (5.56%)
    0 / 21 (0.00%)
         occurrences all number
    4
    3
    1
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 33 (6.06%)
    0 / 18 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    0
    2
    Gastroenteritis
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 33 (3.03%)
    0 / 18 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 33 (0.00%)
    0 / 18 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    0
    0
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 May 2016
    To modify the text for contraceptive measures to specify “highly effective” contraception, according to the definitions provided by the Clinical Trials Facilitation Group Guideline.
    02 Sep 2016
    To include an optional open label extension period for participants to continue receiving benefit from the Investigative Medicinal Product.

    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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