Safety and Efficacy Study of M2951 in Participants With Rheumatoid Arthritis

• Sponsor: EMD Serono Research & Development Institute, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02784106
• Collaborator: Merck KGaA, Darmstadt, Germany (Industry)
• Enrollment: 65
• Locations: 2
• Arms: 4
• Actual Duration (Months): 15.5
• Patients Per Site: 32.5
• Patients Per Site Per Month: 2.1

Study Details

Study Description

Brief Summary

M2951 is an investigational drug under evaluation for treatment of autoimmune and inflammatory disorders. The purpose of the study is to assess the efficacy of M2951 in participants with rheumatoid arthritis (RA) currently treated with stable dose of methotrexate (MTX).

Condition or Disease	Intervention/Treatment	Phase
Rheumatoid Arthritis	Drug: Placebo; Drug: M2951; Drug: M2951	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 65 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Jul 31, 2016
• Actual Primary Completion Date: Apr 30, 2017
• Actual Study Completion Date: Nov 14, 2017

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo: Double-Blind Treatment Period	Drug: Placebo; Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.
Experimental: M2951: Double-Blind Treatment Period	Drug: M2951; Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.; Other Names: Evobrutinib
Experimental: Placebo/M2951: Open Label Extension Period	Drug: M2951; Participants who received placebo matched to M2951 or M2951 in double-blind treatment period, received 50 mg M2951 orally twice daily up to 26-weeks during the open label extension period.; Other Names: Evobrutinib
Experimental: M2951/M2951: Open Label Extension Period	Drug: M2951; Participants who received placebo matched to M2951 or M2951 in double-blind treatment period, received 50 mg M2951 orally twice daily up to 26-weeks during the open label extension period.; Other Names: Evobrutinib

Outcome Measures

Primary Outcome Measures

1. Proportion of Participants Who Achieved American College of Rheumatology-20 (ACR20) Response [Day 84]

   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). Proportion of ACR20 responders = Number of participants with ACR20 response divided by total participants.

Secondary Outcome Measures

1. Mean Change From Baseline in High-Sensitivity C-Reactive Protein (hsCRP) at Day 28 [Baseline, Day 28]

   Mean change in the hsCRP concentration from baseline at Day 28 was reported.

2. Proportion of Participants Achieving American College of Rheumatology-50 (ACR50) Response [Day 28, Day 56 and Day 84]

   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. Proportion of ACR50 responders = Number of participants with ACR50 response divided by total participants.

3. Proportion of Participants Achieving American College of Rheumatology-70 (ACR70) Response [Day 28, Day 56 and Day 84]

   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. Proportion of ACR70 responders = Number of participants with ACR70 response divided by total participants.

4. Mean Change From Baseline in High-Sensitivity C-Reactive Protein (hsCRP) at Day 84 [Baseline, Day 84]

   Mean change in the hsCRP concentration from baseline at Day 84 was reported.

5. 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 [Baseline, Day 28 and Day 84]

   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.

6. Proportion of Participants With Disease Activity Score- High Sensitivity C-Reactive Protein (DAS28-hsCRP) Value Less Than (<) 3.2 [Day 84]

   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. Proportion of participants with DAS28-hsCRP value <3.2 were reported.

7. Proportion of Participants With Disease Activity Score- High Sensitivity C-Reactive Protein (DAS28-hsCRP) Value Less Than (<) 2.6 [Day 84]

   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. Proportion of participants with DAS28-hsCRP value <2.6 were reported.

8. Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Day 28 and 84 [Baseline, Day 28 and Day 84]

   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.

9. Change From Baseline in Anti-cyclic Citrullinated Peptide (Anti-CCP) Antibody Levels at Day 28 and 84 [Baseline, Day 28 and Day 84]

   Anti-cyclic citrullinated peptide (anti-CCP) is an antibody present in most rheumatoid arthritis participants.

10. Change From Baseline in Rheumatoid Factor (RF) at Day 28 and 84 [Baseline, Day 28 and Day 84]

    Rheumatoid Factor is an anti-body present in the blood.

11. Change From Baseline in Global Assessment of Disease Activity Based on Visual Analog Scale (VAS) Score at Day 84 [Baseline, Day 84]

    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).

12. Change From Baseline in Self-assessment of Pain Based on Visual Analog Scale (VAS) Score at Day 84 [Baseline, Day 84]

    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.

13. Change From Baseline in Self-assessment of Disability Using Health Assessment Questionnaire - Disability Index (HAQ-DI) Score at Day 84 [Baseline, Day 84]

    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.

14. Change From Baseline in Physician's Global Assessment of Disease Activity Scale Based on Visual Analog Scale (VAS) Score at Day 84 [Baseline, Day 84]

    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).

15. Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [Baseline up to 16 Weeks]

    An Adverse event (AE) was defined as any unfavorable 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.

16. Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity [Baseline up to 16 Weeks]

    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.

17. Number of Participants With Grade 3 or Higher Clinically Significant Abnormality for Hematology, Biochemistry, Urinalysis or Coagulation [Baseline up to 16 Weeks]

    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.

18. Number of Participants With Clinically Significant Vital Signs Abnormalities [Baseline up to 16 Weeks]

    Vital sign assessment included blood pressure, pulse rate, respiratory rate and temperature. Clinical significance was determined by the investigator.

19. Number of Participants With Clinically Significant 12-lead Electrocardiogram (ECG) Findings [Baseline up to 16 Weeks]

    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.

20. Plasma Concentration of M2951 [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]

21. Area Under the Concentration-Time Curve From Time Zero to 6 Hours (AUC 0-6h) of M2951 [Pre-dose, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0 hours post-dose at Day 1 and Day 29]

22. Maximum Observed Plasma Concentration (Cmax) of M2951 [Pre-dose, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0 hours post-dose at Day 1 and Day 29]

23. Plasma Concentration Observed Immediately Before Dosing on Day 29 (Cpre) of M2951 [Pre-dose on Day 29]

24. Time to Reach Maximum Plasma Concentration (Tmax) of M2951 [Pre-dose, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0 hours post-dose at Day 1 and Day 29]

25. Accumulation Ratio for Area Under the Concentration-Time Curve From Time Zero to 6 Hours (Racc [AUC0-6h]) of M2951 [Pre-dose, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0 hours post-dose at Day 1 and Day 29]

    Accumulation ratio for AUC was calculated as AUC 0-6h, Day 29 divided by AUC 0-6h, Day 1

26. Accumulation Ratio for Observed Maximum Plasma Concentration (Racc [Cmax]) of M2951 [Pre-dose, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0 hours post-dose at Day 1 and Day 29]

    Accumulation ratio for Cmax , was calculated as Cmax, Day 29 divided by Cmax, Day1

27. Absolute Immunoglobulin Levels at Day 85 [Baseline, Day 85]

    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.

28. Absolute Change From Baseline in Immunoglobulin Levels at Day 85 [Baseline, Day 85]

    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.

29. Absolute B-Cell Levels at Day 85 [Day 85]

30. Absolute Change From Baseline in B-cell Levels at Day 85 [Baseline, Day 85]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Men or women 18 to 75 years of age at the time of informed consent signature

• Confirmed diagnosis of RA according to 2010 American College of Rheumatology (ACR)/The European League Against Rheumatism (EULAR) RA classification criteria of at least 6 months duration

• Positive RF and/or anti-CCP (anti-cyclic citrullinated peptide)

• Persistently active disease defined as greater than equal to (>=) 6 swollen joints (of 66 counted) and >= 6 tender joints (of 68 counted)

• High-sensitivity C-reactive protein (hsCRP) >= 3.6 milligram per liter (mg/L)

• Treatment for >= 12 weeks with 10 to 25 mg/week MTX at a stable dose for at least 4 weeks prior to dosing with the investigational medicinal product (IMP) and maintained throughout the trial

• Women of childbearing potential must use acceptable methods of contraception for 4 weeks prior to randomization, throughout the trial, and for 90 days after the last dose of IMP. For the purposes of this trial

• Females who are postmenopausal (age-related amenorrhea >= 12 consecutive months and increased follicle-stimulating hormone [FSH] greater than (>) 40 milli international units per milliliter [mIU/mL]), or who have undergone hysterectomy or bilateral oophorectomy are exempt from pregnancy testing. If necessary to confirm postmenopausal status, an FSH will be drawn at Screening

• Acceptable contraception is defined as use of either 2 barrier methods (eg, female diaphragm and male condom), or 1 barrier method in conjunction with one of the following: spermicide, an intrauterine device, or hormonal contraceptives (implant or oral)

• Women of childbearing potential must have a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at Day 1/randomization before dosing.

Exclusion Criteria:

• Use of oral corticosteroids > 10 mg daily prednisone equivalent, use of injectable corticosteroids, or change in dose of corticosteroids within 2 weeks prior to Screening or during Screening

• Initiation or change in dose for nonsteroidal anti-inflammatory drugs (NSAIDs) within 2 weeks prior to Screening

• Treatment with tofacitinib, other Bruton's Tyrosine Kinase (BTK) inhibitors, or a biologic disease-modifying antirheumatic drug (DMARD; eg, anti-tumor necrosis factor alpha [anti-TNF-α], tocilizumab [anti-interleukin-6 receptor], abatacept [CTLA4-Fc]), or other immunosuppressive drugs(sulfasalazine would be acceptable at a stable dose) other than methotrexate within 3 months prior to Screening or during Screening

• Treatment with anti-CD20 therapy (eg, rituximab) within 12 months prior to Screening or during Screening

• Immunologic disorder other than Rheumatoid Arthritis (RA), with the exception of secondary Sjogren's syndrome associated with RA, and well-controlled diabetes or thyroid disorder, or any other condition requiring oral, intravenous, intramuscular, or intra-articular corticosteroid therapy

• Vaccination with live or live-attenuated virus vaccine within 1 month prior to Screening

• Active, clinically significant, viral, bacterial, or fungal infection, or any major episode of infection requiring hospitalization or treatment with parenteral anti-infectives within 4 weeks of Screening or during Screening, or completion of oral anti-infectives within 2 weeks before or during Screening, or a history of recurrent infections (ie, 3 or more of the same type of infection in a 12-month rolling period). Vaginal candidiasis, onychomycosis, and genital or oral herpes simplex virus considered by the Investigator to be sufficiently controlled would not be exclusionary

• History of or positive testing for human immunodeficiency virus (HIV), hepatitis C antibody and/or polymerase chain reaction, hepatitis B surface antigen (HBsAg) (+) and/or hepatitis B core total, and/or IgM antibody (+) at Screening

• History of or current diagnosis of active tuberculosis (TB); undergoing treatment for latent TB infection (LTBI); untreated LTBI (as determined by documented results within 3 months of the Screening Visit of a positive TB skin test with purified protein derivative with induration >= 5 millimeter (mm), a positive QuantiFERON-TB test or positive or borderline T-SPOT [Elispot] test); or positive QuantiFERON-TB test at Screening. Participants with documented completed appropriate LTBI treatment would not be excluded and are not required to be tested

• Participants with current household contacts with active TB will also be excluded

• Indeterminate QuantiFERON-TB or T-SPOT tests may be repeated once, and will be considered positive if retest results are positive or indeterminate

• History of cancer, except adequately treated basal cell or squamous cell carcinomas of the skin (no more than 3 lesions requiring treatment in lifetime) or carcinoma in situ/cervical intraepithelial neoplasia of the uterine cervix, unless considered cured

5 years

• Clinically significant abnormality on electrocardiogram (ECG), or an active infective process or any other clinically significant abnormality on Screening chest X-ray (CXR) taken within 4 weeks of the first dose, per Investigator opinion. If a CXR has been taken within the previous 3 months and results are available and normal, the CXR does not need to be carried out

• B cell (CD19) count less than (<) 50% of the lower limit of normal at Screening

• Significant cytopenia including absolute neutrophil count < 1,500/ mm^{3, platelet count < 100,000/mm}3, or absolute lymphocyte count < 1,000/mm^3

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	U.S. Medical Information	Billerica	Massachusetts	United States
2	Merck KGaA Communication Center	Darmstadt		Germany

Sponsors and Collaborators

• EMD Serono Research & Development Institute, Inc.
• Merck KGaA, Darmstadt, Germany

Investigators

• Study Director: Medical Responsible, EMD Serono Inc., a business of Merck KGaA, Darmstadt, Germany

Study Documents (Full-Text)

• Statistical Analysis Plan - Apr 18, 2017
• Study Protocol - Sep 2, 2016

More Information

Publications

None provided.

• Responsible Party: EMD Serono Research & Development Institute, Inc.
• ClinicalTrials.gov Identifier: NCT02784106
• Other Study ID Numbers: MS200527-0081; 2016-000064-42
• First Posted: May 26, 2016
• Last Update Posted: Jul 17, 2018
• Last Verified: Jun 1, 2018

• Keywords provided by EMD Serono Research & Development Institute, Inc.: Rheumatoid Arthritis; M2951; Bruton's Tyrosine Kinase (BTK)
• Additional relevant MeSH terms: Arthritis; Arthritis, Rheumatoid

Study Results

Participant Flow

Pre-assignment Detail	The study consisted of a 12-week double-blind treatment 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.

Arm/Group Title	Placebo: Double-Blind Treatment Period	M2951: Double-Blind Treatment Period	Placebo/M2951: Open-Label Extension Period	M2951/M2951: Open-Label Extension Period
Arm/Group Description	Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.	Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.	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.	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.
Period Title: Double-Blind Treatment Period (12 Weeks)
STARTED	32	33	0	0
COMPLETED	24	27	0	0
NOT COMPLETED	8	6	0	0
Period Title: Double-Blind Treatment Period (12 Weeks)
STARTED	0	0	18	21
COMPLETED	0	0	15	19
NOT COMPLETED	0	0	3	2

Baseline Characteristics

Arm/Group Title	Placebo: Double-Blind Treatment Period	M2951: Double-Blind Treatment Period	Total
Arm/Group Description	Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.	Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.	Total of all reporting groups
Overall Participants	32	33	65
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53.1 (12.19)	53.8 (10.73)	53.4 (11.39)
Sex: Female, Male (Count of Participants)
Female	25 78.1%	24 72.7%	49 75.4%
Male	7 21.9%	9 27.3%	16 24.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 3.1%	1 3%	2 3.1%
Not Hispanic or Latino	31 96.9%	32 97%	63 96.9%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	1 3%	1 1.5%
Black or African American	1 3.1%	1 3%	2 3.1%
White	31 96.9%	31 93.9%	62 95.4%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Proportion of Participants Who Achieved American College of Rheumatology-20 (ACR20) Response
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). Proportion of ACR20 responders = Number of participants with ACR20 response divided by total participants.
Time Frame	Day 84

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo: Double-Blind Treatment Period	M2951: Double-Blind Treatment Period
Arm/Group Description	Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.	Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.
Measure Participants	31	33
Number [proportion of participants]	0.42 1.3%	0.52 1.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo: Double-Blind Treatment Period, M2951: Double-Blind Treatment Period
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Proportion of Responders
	Estimated Value	0.10
	Confidence Interval	(2-Sided) 80%; -0.07 to 0.25
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Mean Change From Baseline in High-Sensitivity C-Reactive Protein (hsCRP) at Day 28
Description	Mean change in the hsCRP concentration from baseline at Day 28 was reported.
Time Frame	Baseline, Day 28

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo: Double-Blind Treatment Period	M2951: Double-Blind Treatment Period
Arm/Group Description	Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.	Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.
Measure Participants	31	33
Mean (Standard Error) [milligram/milliliter (mg/mL)]	-0.80 (2.00)	-2.72 (1.93)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo: Double-Blind Treatment Period, M2951: Double-Blind Treatment Period
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Mean Changes
	Estimated Value	-1.93
	Confidence Interval	(2-Sided) 80%; -5.54 to 1.69
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Proportion of Participants Achieving American College of Rheumatology-50 (ACR50) Response
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. Proportion of ACR50 responders = Number of participants with ACR50 response divided by total participants.
Time Frame	Day 28, Day 56 and Day 84

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo: Double-Blind Treatment Period	M2951: Double-Blind Treatment Period
Arm/Group Description	Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.	Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.
Measure Participants	31	33
Day 28	0.10 0.3%	0.06 0.2%
Day 56	0.23 0.7%	0.18 0.5%
Day 84	0.23 0.7%	0.21 0.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo: Double-Blind Treatment Period, M2951: Double-Blind Treatment Period
	Comments	Day 28
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Proportion of Responders
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 80%; -0.13 to 0.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo: Double-Blind Treatment Period, M2951: Double-Blind Treatment Period
	Comments	Day 56
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Proportion of Responders
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 80%; -0.18 to 0.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo: Double-Blind Treatment Period, M2951: Double-Blind Treatment Period
	Comments	Day 84
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Proportion of Responders
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 80%; -0.15 to 0.12
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Proportion of Participants Achieving American College of Rheumatology-70 (ACR70) Response
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. Proportion of ACR70 responders = Number of participants with ACR70 response divided by total participants.
Time Frame	Day 28, Day 56 and Day 84

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo: Double-Blind Treatment Period	M2951: Double-Blind Treatment Period
Arm/Group Description	Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.	Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.
Measure Participants	31	33
Day 28	0.00 0%	0.06 0.2%
Day 56	0.03 0.1%	0.06 0.2%
Day 84	0.13 0.4%	0.09 0.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo: Double-Blind Treatment Period, M2951: Double-Blind Treatment Period
	Comments	Day 28
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Proportion of Responders
	Estimated Value	0.06
	Confidence Interval	(2-Sided) 80%; 0.01 to 0.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo: Double-Blind Treatment Period, M2951: Double-Blind Treatment Period
	Comments	Day 56
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Proportion of Responders
	Estimated Value	0.03
	Confidence Interval	(2-Sided) 80%; -0.05 to 0.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo: Double-Blind Treatment Period, M2951: Double-Blind Treatment Period
	Comments	Day 84
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Proportion of Responders
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 80%; -0.15 to 0.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Mean Change From Baseline in High-Sensitivity C-Reactive Protein (hsCRP) at Day 84
Description	Mean change in the hsCRP concentration from baseline at Day 84 was reported.
Time Frame	Baseline, Day 84

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo: Double-Blind Treatment Period	M2951: Double-Blind Treatment Period
Arm/Group Description	Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.	Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.
Measure Participants	31	33
Mean (Standard Error) [mg/mL]	-2.14 (2.20)	-3.54 (2.13)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo: Double-Blind Treatment Period, M2951: Double-Blind Treatment Period
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Mean Changes
	Estimated Value	-1.40
	Confidence Interval	(2-Sided) 80%; -5.37 to 2.58
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

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
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.
Time Frame	Baseline, Day 28 and Day 84

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo: Double-Blind Treatment Period	M2951: Double-Blind Treatment Period
Arm/Group Description	Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.	Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.
Measure Participants	31	33
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 1

Statistical Analysis Overview	Comparison Group Selection	Placebo: Double-Blind Treatment Period, M2951: Double-Blind Treatment Period
	Comments	Day 28
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Mean Changes
	Estimated Value	-0.08
	Confidence Interval	(2-Sided) 80%; -0.33 to 0.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo: Double-Blind Treatment Period, M2951: Double-Blind Treatment Period
	Comments	Day 84
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Mean Changes
	Estimated Value	0.07
	Confidence Interval	(2-Sided) 80%; -0.29 to 0.43
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Proportion of Participants With Disease Activity Score- High Sensitivity C-Reactive Protein (DAS28-hsCRP) Value Less Than (<) 3.2
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. Proportion of participants with DAS28-hsCRP value <3.2 were reported.
Time Frame	Day 84

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo: Double-Blind Treatment Period	M2951: Double-Blind Treatment Period
Arm/Group Description	Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.	Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.
Measure Participants	31	33
Number [proportion of participants]	0.13 0.4%	0.21 0.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo: Double-Blind Treatment Period, M2951: Double-Blind Treatment Period
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Proportion of Participants
	Estimated Value	0.08
	Confidence Interval	(2-Sided) 80%; -0.04 to 0.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Proportion of Participants With Disease Activity Score- High Sensitivity C-Reactive Protein (DAS28-hsCRP) Value Less Than (<) 2.6
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. Proportion of participants with DAS28-hsCRP value <2.6 were reported.
Time Frame	Day 84

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo: Double-Blind Treatment Period	M2951: Double-Blind Treatment Period
Arm/Group Description	Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.	Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.
Measure Participants	31	33
Number [proportion of participants]	0.10 0.3%	0.06 0.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo: Double-Blind Treatment Period, M2951: Double-Blind Treatment Period
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Proportion of Participants
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 80%; -0.13 to 0.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Day 28 and 84
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.
Time Frame	Baseline, Day 28 and Day 84

Outcome Measure Data

Analysis Population Description

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 Analyzed" signified those participants who were evaluable for this endpoint at the specified time point.

Arm/Group Title	Placebo: Double-Blind Treatment Period	M2951: Double-Blind Treatment Period
Arm/Group Description	Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.	Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.
Measure Participants	31	33
Change at Day 28	-3 (36.9)	-7 (22.1)
Change at Day 84	-3 (21.0)	-9 (21.1)

10. Secondary Outcome

Title	Change From Baseline in Anti-cyclic Citrullinated Peptide (Anti-CCP) Antibody Levels at Day 28 and 84
Description	Anti-cyclic citrullinated peptide (anti-CCP) is an antibody present in most rheumatoid arthritis participants.
Time Frame	Baseline, Day 28 and Day 84

Outcome Measure Data

Analysis Population Description

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 Analyzed" signified those participants who were evaluable for this endpoint at the specified time point.

Arm/Group Title	Placebo: Double-Blind Treatment Period	M2951: Double-Blind Treatment Period
Arm/Group Description	Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.	Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.
Measure Participants	31	33
Change at Day 28	168 (991.1)	-138 (720.9)
Change at Day 84	301 (1282.6)	-396 (736.8)

11. Secondary Outcome

Title	Change From Baseline in Rheumatoid Factor (RF) at Day 28 and 84
Description	Rheumatoid Factor is an anti-body present in the blood.
Time Frame	Baseline, Day 28 and Day 84

Outcome Measure Data

Analysis Population Description

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 Analyzed" signified those participants who were evaluable for this endpoint at the specified time point.

Arm/Group Title	Placebo: Double-Blind Treatment Period	M2951: Double-Blind Treatment Period
Arm/Group Description	Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.	Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.
Measure Participants	31	33
Change at Day 28	-30 (124.2)	-7 (59.7)
Change at Day 84	-34 (132.1)	-26 (79.9)

12. Secondary Outcome

Title	Change From Baseline in Global Assessment of Disease Activity Based on Visual Analog Scale (VAS) Score at Day 84
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).
Time Frame	Baseline, Day 84

Outcome Measure Data

Analysis Population Description

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, "Overall Number of Participants Analyzed" signified those participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo: Double-Blind Treatment Period	M2951: Double-Blind Treatment Period
Arm/Group Description	Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.	Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.
Measure Participants	25	26
Mean (Standard Deviation) [millimeter]	-21 (23.5)	-24 (24.6)

13. Secondary Outcome

Title	Change From Baseline in Self-assessment of Pain Based on Visual Analog Scale (VAS) Score at Day 84
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.
Time Frame	Baseline, Day 84

Outcome Measure Data

Analysis Population Description

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, "Overall Number of Participants Analyzed" signified those participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo: Double-Blind Treatment Period	M2951: Double-Blind Treatment Period
Arm/Group Description	Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.	Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.
Measure Participants	25	26
Mean (Standard Deviation) [millimeter]	-19 (21.8)	-22 (22.0)

14. Secondary Outcome

Title	Change From Baseline in Self-assessment of Disability Using Health Assessment Questionnaire - Disability Index (HAQ-DI) Score at Day 84
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.
Time Frame	Baseline, Day 84

Outcome Measure Data

Analysis Population Description

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, "Overall Number of Participants Analyzed" signified those participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo: Double-Blind Treatment Period	M2951: Double-Blind Treatment Period
Arm/Group Description	Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.	Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.
Measure Participants	25	26
Mean (Standard Deviation) [units on a scale]	-0.3 (0.44)	-0.3 (0.41)

15. Secondary Outcome

Title	Change From Baseline in Physician's Global Assessment of Disease Activity Scale Based on Visual Analog Scale (VAS) Score at Day 84
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).
Time Frame	Baseline, Day 84

Outcome Measure Data

Analysis Population Description

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, "Overall Number of Participants Analyzed" signified those participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo: Double-Blind Treatment Period	M2951: Double-Blind Treatment Period
Arm/Group Description	Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.	Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.
Measure Participants	25	26
Mean (Standard Deviation) [millimeter]	-33 (20.3)	-30 (22.7)

16. Secondary Outcome

Title	Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Description	An Adverse event (AE) was defined as any unfavorable 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.
Time Frame	Baseline up to 16 Weeks

Outcome Measure Data

Analysis Population Description

The Safety Analysis Set included all participants who received at least 1 dose of M2951 or placebo.

Arm/Group Title	Placebo: Double-Blind Treatment Period	M2951: Double-Blind Treatment Period
Arm/Group Description	Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.	Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.
Measure Participants	32	33
TEAEs	16 50%	22 66.7%
SAEs	0 0%	1 3%

17. Secondary Outcome

Title	Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity
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.
Time Frame	Baseline up to 16 Weeks

Outcome Measure Data

Analysis Population Description

The Safety Analysis Set included all participants who received at least 1 dose of M2951 or placebo.

Arm/Group Title	Placebo: Double-Blind Treatment Period	M2951: Double-Blind Treatment Period
Arm/Group Description	Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.	Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.
Measure Participants	32	33
NCI-CTCAE Severity grade >=3	2 6.3%	3 9.1%
NCI-CTCAE Severity grade >=4	0 0%	1 3%

18. Secondary Outcome

Title	Number of Participants With Grade 3 or Higher Clinically Significant Abnormality for Hematology, Biochemistry, Urinalysis or Coagulation
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.
Time Frame	Baseline up to 16 Weeks

Outcome Measure Data

Analysis Population Description

The Safety Analysis Set included all participants who received at least 1 dose of M2951 or placebo.

Arm/Group Title	Placebo: Double-Blind Treatment Period	M2951: Double-Blind Treatment Period
Arm/Group Description	Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.	Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.
Measure Participants	32	33
Hematology	2 6.3%	0 0%
Biochemistry	4 12.5%	2 6.1%
Coagulation	0 0%	0 0%
Urinalysis	0 0%	0 0%

19. Secondary Outcome

Title	Number of Participants With Clinically Significant Vital Signs Abnormalities
Description	Vital sign assessment included blood pressure, pulse rate, respiratory rate and temperature. Clinical significance was determined by the investigator.
Time Frame	Baseline up to 16 Weeks

Outcome Measure Data

Analysis Population Description

The Safety Analysis Set included all participants who received at least 1 dose of M2951 or placebo.

Arm/Group Title	Placebo: Double-Blind Treatment Period	M2951: Double-Blind Treatment Period
Arm/Group Description	Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.	Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.
Measure Participants	32	33
Count of Participants [Participants]	0 0%	0 0%

20. Secondary Outcome

Title	Number of Participants With Clinically Significant 12-lead Electrocardiogram (ECG) Findings
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.
Time Frame	Baseline up to 16 Weeks

Outcome Measure Data

Analysis Population Description

The Safety Analysis Set included all participants who received at least 1 dose of M2951 or placebo.

Arm/Group Title	Placebo: Double-Blind Treatment Period	M2951: Double-Blind Treatment Period
Arm/Group Description	Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.	Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.
Measure Participants	32	33
Count of Participants [Participants]	0 0%	0 0%

21. Secondary Outcome

Title	Plasma Concentration of M2951
Time Frame	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

Outcome Measure Data

Analysis Population 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 "Number Analyzed" signified those participants who were evaluable for this endpoint at the specified time point.

Arm/Group Title	M2951: Double-Blind Treatment Period
Arm/Group Description	Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.
Measure Participants	33
Day 1: Pre-Dose:	0.00 (NA)
Day 1: 0.25 hours post-dose	10.3 (23.37)
Day 1: 0.5 hours post-dose	80.5 (136.9)
Day 1: 1 hour post-dose	160 (219.7)
Day 1: 2 hours post-dose	125 (111.9)
Day 1: 4 hours post-dose	47.3 (41.62)
Day 1: 6 hours post-dose	23.7 (20.92)
Day 29: 0.25 hours post-dose	22.0 (71.57)
Day 29: 0.5 hours post-dose	88.4 (114.1)
Day 29: 1 hour post-dose	120 (107.2)
Day 29: 2 hours post-dose	82.3 (53.82)
Day 29: 4 hours post-dose	62.1 (82.39)
Day 29: 6 hour post-dose	37.2 (43.96)

22. Secondary Outcome

Title	Area Under the Concentration-Time Curve From Time Zero to 6 Hours (AUC 0-6h) of M2951
Time Frame	Pre-dose, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0 hours post-dose at Day 1 and Day 29

Outcome Measure Data

Analysis Population 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 Analyzed" signified those participants who were evaluable for this endpoint at the specified time point.

Arm/Group Title	M2951: Double-Blind Treatment Period
Arm/Group Description	Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.
Measure Participants	33
Day 1	431 (390.9)
Day 29	414 (268.4)

23. Secondary Outcome

Title	Maximum Observed Plasma Concentration (Cmax) of M2951
Time Frame	Pre-dose, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0 hours post-dose at Day 1 and Day 29

Outcome Measure Data

Analysis Population 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 Analyzed" signified those participants who were evaluable for this endpoint at the specified time point.

Arm/Group Title	M2951: Double-Blind Treatment Period
Arm/Group Description	Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.
Measure Participants	33
Day 1	206 (214.7)
Day 29	171 (130.1)

24. Secondary Outcome

Title	Plasma Concentration Observed Immediately Before Dosing on Day 29 (Cpre) of M2951
Time Frame	Pre-dose on Day 29

Outcome Measure Data

Analysis Population 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, "Overall Number of Participants Analyzed" signified those participants who were evaluable for this outcome measure.

Arm/Group Title	M2951: Double-Blind Treatment Period
Arm/Group Description	Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.
Measure Participants	28
Mean (Standard Deviation) [ng/mL]	5.47 (4.735)

25. Secondary Outcome

Title	Time to Reach Maximum Plasma Concentration (Tmax) of M2951
Time Frame	Pre-dose, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0 hours post-dose at Day 1 and Day 29

Outcome Measure Data

Analysis Population 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 Analyzed" signified those participants who were evaluable for this endpoint at the specified time point.

Arm/Group Title	M2951: Double-Blind Treatment Period
Arm/Group Description	Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.
Measure Participants	33
Day 1	1.00
Day 29	1.00

26. Secondary Outcome

Title	Accumulation Ratio for Area Under the Concentration-Time Curve From Time Zero to 6 Hours (Racc [AUC0-6h]) of M2951
Description	Accumulation ratio for AUC was calculated as AUC 0-6h, Day 29 divided by AUC 0-6h, Day 1
Time Frame	Pre-dose, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0 hours post-dose at Day 1 and Day 29

Outcome Measure Data

Analysis Population 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, "Overall Number of Participants Analyzed" signified those participants who were evaluable for this outcome measure.

Arm/Group Title	M2951: Double-Blind Treatment Period
Arm/Group Description	Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.
Measure Participants	26
Mean (Standard Deviation) [ratio]	1.38 (1.134)

27. Secondary Outcome

Title	Accumulation Ratio for Observed Maximum Plasma Concentration (Racc [Cmax]) of M2951
Description	Accumulation ratio for Cmax , was calculated as Cmax, Day 29 divided by Cmax, Day1
Time Frame	Pre-dose, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0 hours post-dose at Day 1 and Day 29

Outcome Measure Data

Analysis Population 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, "Overall Number of Participants Analyzed" signified those participants who were evaluable for this outcome measure.

Arm/Group Title	M2951: Double-Blind Treatment Period
Arm/Group Description	Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.
Measure Participants	27
Mean (Standard Deviation) [ratio]	1.52 (1.929)

28. Secondary Outcome

Title	Absolute Immunoglobulin Levels at Day 85
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.
Time Frame	Baseline, Day 85

Outcome Measure Data

Analysis Population 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 BTK occupancy, at a scheduled PD time point post-dose. Here, "Overall Number of Participants Analyzed" signified those participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo: Double-Blind Treatment Period	M2951: Double-Blind Treatment Period
Arm/Group Description	Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.	Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.
Measure Participants	10	12
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)

29. Secondary Outcome

Title	Absolute Change From Baseline in Immunoglobulin Levels at Day 85
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.
Time Frame	Baseline, Day 85

Outcome Measure Data

Analysis Population 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 BTK occupancy, at a scheduled PD time point post-dose. Here, "Overall Number of Participants Analyzed" signified those participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo: Double-Blind Treatment Period	M2951: Double-Blind Treatment Period
Arm/Group Description	Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.	Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.
Measure Participants	10	12
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)

30. Secondary Outcome

Title	Absolute B-Cell Levels at Day 85
Time Frame	Day 85

Outcome Measure Data

Analysis Population 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 BTK occupancy, at a scheduled PD time point post-dose. Here, "Overall Number of Participants Analyzed" signified those participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo: Double-Blind Treatment Period	M2951: Double-Blind Treatment Period
Arm/Group Description	Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.	Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.
Measure Participants	12	12
Mean (Standard Deviation) [cells per micro-liter]	243 (265.0)	204 (154.0)

31. Secondary Outcome

Title	Absolute Change From Baseline in B-cell Levels at Day 85
Time Frame	Baseline, Day 85

Outcome Measure Data

Analysis Population 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 BTK occupancy, at a scheduled PD time point post-dose. Here, "Overall Number of Participants Analyzed" signified those participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo: Double-Blind Treatment Period	M2951: Double-Blind Treatment Period
Arm/Group Description	Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.	Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.
Measure Participants	12	12
Mean (Standard Deviation) [cells per micro-liter]	76 (242.0)	11 (73.2)

Adverse Events

Time Frame	Double-Blind Period: Baseline up to 16 weeks; Open-Label Period: Baseline up to 30 weeks
Adverse Event Reporting 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
Arm/Group Title	Placebo: Double-Blind Treatment Period		M2951: Double-Blind Treatment Period		Placebo/M2951: Open-Label Extension Period		M2951/M2951: Open-Label Extension Period
Arm/Group Description	Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period.		Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period.		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.		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.
All Cause Mortality
	Placebo: Double-Blind Treatment Period		M2951: Double-Blind Treatment Period		Placebo/M2951: Open-Label Extension Period		M2951/M2951: Open-Label Extension Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/32 (0%)		0/33 (0%)		0/18 (0%)		0/21 (0%)
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
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/32 (0%)		1/33 (3%)		0/18 (0%)		0/21 (0%)
Ear and labyrinth disorders
Vestibular disorder	0/32 (0%)		1/33 (3%)		0/18 (0%)		0/21 (0%)
Nervous system disorders
Vertigo CNS origin	0/32 (0%)		1/33 (3%)		0/18 (0%)		0/21 (0%)
Other (Not Including 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
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/32 (40.6%)		17/33 (51.5%)		8/18 (44.4%)		10/21 (47.6%)
Blood and lymphatic system disorders
Leukocytosis	2/32 (6.3%)		1/33 (3%)		0/18 (0%)		0/21 (0%)
Neutropenia	2/32 (6.3%)		0/33 (0%)		0/18 (0%)		0/21 (0%)
Gastrointestinal disorders
Nausea	3/32 (9.4%)		3/33 (9.1%)		0/18 (0%)		2/21 (9.5%)
Vomiting	1/32 (3.1%)		2/33 (6.1%)		0/18 (0%)		2/21 (9.5%)
Abdominal pain upper	2/32 (6.3%)		2/33 (6.1%)		0/18 (0%)		0/21 (0%)
Infections and infestations
Viral upper respiratory tract infection	4/32 (12.5%)		3/33 (9.1%)		1/18 (5.6%)		0/21 (0%)
Respiratory tract infection	0/32 (0%)		2/33 (6.1%)		0/18 (0%)		2/21 (9.5%)
Gastroenteritis	2/32 (6.3%)		1/33 (3%)		0/18 (0%)		0/21 (0%)
Nasopharyngitis	0/32 (0%)		0/33 (0%)		0/18 (0%)		3/21 (14.3%)
Investigations
Lipase increased	2/32 (6.3%)		3/33 (9.1%)		0/18 (0%)		0/21 (0%)
Blood glucose increased	0/32 (0%)		2/33 (6.1%)		0/18 (0%)		0/21 (0%)
Alanine aminotransferase increased	4/32 (12.5%)		1/33 (3%)		1/18 (5.6%)		0/21 (0%)
Amylase increased	3/32 (9.4%)		1/33 (3%)		2/18 (11.1%)		0/21 (0%)
Aspartate aminotransferase increased	3/32 (9.4%)		0/33 (0%)		1/18 (5.6%)		0/21 (0%)
Musculoskeletal and connective tissue disorders
Pain in extremity	0/32 (0%)		2/33 (6.1%)		0/18 (0%)		2/21 (9.5%)
Rheumatoid arthritis	0/32 (0%)		0/33 (0%)		2/18 (11.1%)		1/21 (4.8%)
Nervous system disorders
Headache	0/32 (0%)		2/33 (6.1%)		0/18 (0%)		2/21 (9.5%)
Psychiatric disorders
Anxiety	0/32 (0%)		0/33 (0%)		1/18 (5.6%)		0/21 (0%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	0/32 (0%)		0/33 (0%)		1/18 (5.6%)		0/21 (0%)
Vascular disorders
Hypertension	2/32 (6.3%)		0/33 (0%)		0/18 (0%)		0/21 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.