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Phase IIb Study of Evobrutinib in Subjects With Rheumatoid Arthritis

Sponsor
EMD Serono Research & Development Institute, Inc. (Industry)
Overall Status
Completed
CT.gov ID
NCT03233230
Collaborator
Merck KGaA, Darmstadt, Germany (Industry)
390
Enrollment
98
Locations
4
Arms
24.1
Actual Duration (Months)
4
Patients Per Site
0.2
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study was to determine the efficacy, dose response, and safety of M52951 in participants with Rheumatoid Arthritis (RA), and to consider a dose to took forward into Phase III development.

Condition or Disease Intervention/Treatment Phase
  • Drug: M2591 25 mg QD
  • Drug: M2951 75 mg QD
  • Drug: M2951 50 mg BID
  • Drug: Placebo
 Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
390 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Phase IIb, Randomized, Double-blind Study in Subjects With Rheumatoid Arthritis Evaluating the Safety and Efficacy of Evobrutinib Compared With Placebo in Subjects With an Inadequate Response to Methotrexate
Actual Study Start Date :
Sep 18, 2017
Actual Primary Completion Date :
Sep 23, 2019
Actual Study Completion Date :
Sep 23, 2019

Arms and Interventions

Arm Intervention/Treatment
Placebo Comparator: Placebo

Drug: Placebo
Participants received placebo matched to M2951 orally for 12 weeks.
Experimental: M2951 25 mg QD

Drug: M2591 25 mg QD
Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks.
Other Names:
  • Evobrutinib

    		•
    Experimental: M2951 75 mg QD

    Drug: M2951 75 mg QD
    Participants received 75 mg of M2951 orally QD for 12 weeks.
    Other Names:
  • Evobrutinib

    		•
    Experimental: M2951 50 mg BID

    Drug: M2951 50 mg BID
    Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Other Names:
  • Evobrutinib

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Percentage of Participants Who Achieved American College of Rheumatology 20 Percent (%) Response Criteria (ACR20) Assessed Using High-Sensitivity C-reactive Protein (hsCRP) at Week 12 [Week 12]

      ACR20 response: a participant has at least 20% improvement in both tender joint counts (based on a total of 68 joints) and swollen joint counts (based on a total of 66 joints) together with 20% improvement in at least 3 of the following: 1) 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). Percentage of participants with ACR20 response using hsCRP = Number of participants with ACR20 response using hsCRP divided by total modified intent-to-treat (mITT) participants * 100.

    Secondary Outcome Measures

    1. Percentage of Participants With Low Disease Activity Score (DAS28 Less Than [<] 3.2) Based on 28 Joint Count-High-Sensitivity C-reactive Protein (DAS28-hsCRP) at Week 12 [Week 12]

      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) + 0.36*natural log(hsCRP+1) + 0.014* participant's global assessment of disease activity + 0.96. Scores ranged 0-9.4, where lower scores indicated less disease activity. Percentage of participants with low DAS28 < 3.2 based on DAS28- hsCRP at Week 12 were reported.

    2. Percentage of Participants With Remission Disease Activity Score (DAS28 Less Than [<] 2.6) Based on a 28 Joint Count-High-Sensitivity C-reactive Protein (DAS28-hsCRP) at Week 12 [Week 12]

      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) + 0.36*natural log(hsCRP+1) + 0.014* participant's global assessment of disease activity + 0.96. Scores ranged 0-9.4, where lower scores indicated less disease activity. A DAS28 score less than (<) 2.6 indicated clinical remission. Percentage of participants with low DAS28 < 2.6 based on DAS28- hsCRP at Week 12 were reported.

    3. Percentage of Participants Achieving American College of Rheumatology 50% Response Criteria (ACR50) [Week 12]

      ACR50 response: a participant has at least 50% improvement in both tender joint counts (based on a total of 68 joints) and swollen joint counts (based on a total of 66 joints) together with 50% improvement in at least 3 of the following: 1) 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]. Percentage of participants with ACR50 response = Number of participants with ACR50 response divided by total mITT participants * 100.

    4. Percentage of Participants Achieving American College of Rheumatology 70% Response Criteria (ACR70) [Week 12]

      ACR70 response: a participant has at least 70% improvement ACR70 response in both tender joint counts (based on a total of 68 joints) and swollen joint counts (based on a total of 66 joints) together with 70% improvement in at least 3 of the following: 1) 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]. Percentage of participants with ACR70 response = Number of participants with ACR70 response divided by total mITT participants * 100.

    5. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03) [up to Week 16]

      Adverse event (AE) was defined as any untoward medical occurrence in a participant, which does not necessarily have causal relationship with treatment. A serious AE was defined as an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inparticipant hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs: events between first dose of study drug that were absent before treatment/that worsened relative to pre-treatment state up to 16 weeks. TEAEs included both serious TEAEs and non-serious TEAEs. Number of participants with TEAEs and serious TEAEs were reported.

    6. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Severity According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03) [up to Week 16]

      Severity of TEAEs were graded using NCI-CTCAE v4.03 toxicity grades, as follows: Grade 1= Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Life-threatening and Grade 5 = Death. Number of participants with TEAEs by severity were reported.

    7. Number of Participants With Clinically Significant Change From Baseline in Vital Signs [up to Week 16]

      Vital signs included body temperature, systolic and diastolic blood pressure, pulse rate, respiratory rate, weight and height. Clinical significance was determined by the investigator. The number of participants with clinically significant changes from baseline in vital signs were reported.

    8. Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters [up to Week 16]

      Laboratory investigation included hematology, biochemistry, urinalysis and coagulation. Clinical significance was determined by the investigator. The number of participants with clinically significant changes from baseline in laboratory parameters were reported.

    9. Number of Participants With Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings [up to Week 16]

      12-lead ECG recordings included rhythm, heart rate (as measured by RR interval), PR interval, QRS duration, and QT interval. The corrected QT interval (QTcF) was calculated using Fridericia's formula. 12-lead ECG recordings were obtained after the participants have rested for at least 10 minutes in semisupine position. Clinical significance was determined by the investigator. The number of participants with clinically significant changes from baseline in 12-lead ECG findings were reported.

    10. Change From Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 2, 4, 8, 12 and 16 [Baseline, Week 2, 4, 8, 12 and 16]

      Change in the serum levels of IgG, IgA, IgM were assessed.

    11. Change From Baseline in B Cell Count at Week 2, 4, 8, 12 and 16 [Baseline, Week 2, 4, 8, 12 and 16]

      Flow cytometry analysis of lymphocyte populations using four-color fluorescence-activated cell sorting was performed for the analysis of B cell counts.

    12. Percentage of Participants With Remission Assessed by American College of Rheumatology-European League Against Rheumatism (ACR-EULAR) Boolean at Week 12 [Week 12]

      ACR-EULAR Boolean remission was when a participant satisfied all of the following: tender joint count, swollen joint count (both based on a 28-joint assessment), C-reactive Protein (in milligrams per deciliter [mg/dL]), and participant's global assessment (visual analog scale [VAS]: 0 centimeter (cm) [very well] to 10 cm [worst], higher scores indicated worse health condition) and all scores were less than or equal to (<=) 1. Percentage of participants with ACR-EULAR Boolean Remission were reported.

    13. Percentage of Participants With Clinical Disease Activity Index (CDAI) Score Less Than or Equal to [=<] 2.8 at Week 12 [Week 12]

      CDAI: a composite index (without acute-phase reactant) for assessing disease activity. The CDAI was calculated based on following formula: CDAI = 28 joint count for swelling (SJC28) + 28 joint count for tenderness (TJC28) + GH + PhGA where, GH = general health component of the Disease Activity Score [DAS] (i.e., Participant's Global Assessment of Disease Activity, assessed using a scale of 0 to 10 centimeter (cm) Visual Analogue Scale (VAS) where 0 = very well and 10 = very poor activity and PhGA = Physician's Global Assessment of Disease Activity assessed using a scale of 0 to 10 cm VAS, where 0 = very well and 10 = very poor activity. The total CDAI score ranges from 0 to 76, where 0 (none) to 76 (extreme disease activity). CDAI score =< 2.8 indicated clinical remission. Percentage of participants with CDAI score =< 2.8 were reported.

    14. Percentage of Participants With Simplified Disease Activity Index (SDAI) Score Less Than or Equal to [=<] 3.3 at Week 12 [Week 12]

      SDAI was calculated based on following formula: SDAI = 28 joint count for swelling (SJC28) + 28 joint count for tenderness (TJC28) + GH + PGA + hsCRP where, GH = general health component of the Disease Activity Score [DAS] (i.e., Participant's Global Assessment of Disease Activity, assessed using a scale of 0 to 10 centimeter (cm) Visual Analogue Scale (VAS) where 0 = very well and 10 = very poor activity and PhGA = Physician's Global Assessment of Disease Activity assessed using a scale of 0 to 10 cm VAS, where 0 = very well and 10 = very poor activity. The total SDAI score ranges from 0 to 86, where 0 (none) to 86 (extreme disease activity). SDAI score =< 3.3 indicated clinical remission. Percentage of participants with SDAI score =< 3.3 at Week 12 were reported.

    15. Percentage of Participants With Good or Moderate European League Against Rheumatism (EULAR) Responses at Week 12 [Week 12]

      EULAR Responder index based on 28 joint counts categorizes clinical response based on improvement since baseline in DAS28-CRP. DAS28-CRP scores range from 0-9.4, where lower scores indicated less disease activity. High disease activity: DAS28-CRP >5.1, low disease activity: DAS28-CRP <3.2, and remission: DAS28-CRP <2.6. EULAR DAS28-CRP responder index: good (absolute: <3.2 or >1.2 improvement from baseline), moderate (absolute: 3.2-5.1 or 0.6-1.2 improvement from baseline), or no response (absolute: >5.1 or <0.6 improvement from baseline). Percentage of Participants With Good or Moderate EULAR Responses were reported.

    16. American College of Rheumatology (ACR) Hybrid Scores Computed Using High-Sensitivity C-reactive Protein (hsCRP) [Baseline, Week 12]

      The hybrid ACR combines the ACR 20/50/70 response with the mean percent change in all 7 ACR core components, thus providing a percent improvement from baseline on a continuous scale. For each participant, the mean percent improvement from baseline across the 7 ACR core set measures (tender joint count, swollen joint count, Patient's Global Assessment of Disease Activity, Physician's Global Assessment of Disease Activity, disability index of the Health Assessment Questionnaire [HAQ], and C-reactive protein [CRP]) was calculated (a positive change indicated improvement, and the maximum worst change was limited to -100%) and the ACR20, ACR50, and ACR70 response is determined. The hybrid ACR is determined from a reference table taking into account both ACR response and mean percent improvement in the core set measures. Scores can range from -100% (maximal worsening) to 100% (maximal improvement).

    17. Change From Baseline in Disease Activity Score (DAS) Based on a 28 Joint Count-High-Sensitivity C-reactive Protein (DAS28-hsCRP) at Week 12 [Baseline, Week 12]

      DAS28 was a composite score used for measuring disease activity in participants with rheumatoid arthritis. The calculation was based on the tender joint count (out of 28 joints), swollen joint count (out of 28 joints), hsCRP (milligrams per liter [mg/L]) and Participant's Global Assessment of Disease Activity. Total DAS28-hsCRP score ranged from 0 (none) to 9.4 (extreme disease activity). DAS28-hsCRP < 3.2 implied low disease activity and >= 3.2 to <= 5.1 implied moderate disease activity, > 5.1 implied high disease activity. DAS28-hsCRP = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.36*ln(hsCRP in mg/L +1) + 0.014* Participant's Global Assessment of Disease Activity + 0.96; ln = natural logarithm, sqrt = square root.

    18. Change From Baseline in Clinical Disease Activity Index (CDAI) at Week 12 [Baseline, Week 12]

      The CDAI was a composite index (without acute-phase reactant) for assessing disease activity. The CDAI was calculated based on following formula: CDAI = 28 joint count for swelling (SJC28) + 28 joint count for tenderness (TJC28) + GH + PhGA where, GH = general health component of the DAS (i.e., Participant's Global Assessment of Disease Activity, assessed using a scale of 0 to 10 centimeter (cm) Visual Analogue Scale (VAS) where 0 = very well and 10 = very poor activity and PhGA = Physician's Global Assessment of Disease Activity assessed using a scale of 0 to 10 cm VAS, where 0 = very well and 10 = very poor activity. The total CDAI score ranges from 0 to 76, where 0 (none) to 76 (extreme disease activity).

    19. Change From Baseline in Simplified Disease Activity Index (SDAI) at Week 12 [Baseline, Week 12]

      SDAI was numerical sum of 5 outcome parameters: 28 joint count for swelling (SJC28) + 28 joint count for tenderness (TJC28) + GH + PGA + hsCRP where, GH = general health component of the DAS (i.e., Participant's Global Assessment of Disease Activity, assessed using a scale of 0 to 10 centimeter (cm) Visual Analogue Scale (VAS) where 0 = very well and 10 = very poor activity and PhGA = Physician's Global Assessment of Disease Activity assessed using a scale of 0 to 10 cm VAS, where 0 = very well and 10 = very poor activity. The total SDAI score ranges from 0 to 86, where 0 (none) to 86 (extreme disease activity).

    20. Change From Baseline in Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 12 [Baseline, Week 12]

      Sixty-eight joints were assessed and classified as tender/not tender and Sixty-six joints were classified as swollen/not swollen by pressure and joint manipulation on physical examination.

    21. Change From Baseline in Participant's Global Assessment of Disease Activity Based on Visual Analog Scale (VAS) Score at Week 12 [Baseline, Week 12]

      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).

    22. Change From Baseline in Participant's Assessment of Pain Based on Visual Analog Scale (VAS) Score at Week 12 [Baseline, Week 12]

      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.

    23. Changes From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Total Score at Week 12 [Baseline, Week 12]

      HAQ-DI score was an evaluation of the functional status for a participant. The 20-question instrument assessed the degree of difficulty a person had in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily living). Responses in each functional area were scored from 0, indicated no difficulty, to 3, indicated inability to perform a task in that area. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range: 0-3 where 0 = least difficulty and 3 = extreme difficulty.

    24. Change From Baseline in Physician's Global Assessment of Disease Activity Scale Based on Visual Analog Scale (VAS) Score at Week 12 [Baseline, Week 12]

      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).

    25. Change From Baseline in High-Sensitivity C-reactive Protein (hsCRP) at Week 12 [Baseline, Week 12]

      hsCRP was the American College of Rheumatology (ACR) Core Set measure of acute phase reactant. It was measured at the central laboratory to help assess the effect of M2951 on the participant's rheumatoid arthritis.

    26. Percent Change From Baseline in Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 12 [Baseline, Week 12]

      Sixty-eight joints were assessed and classified as tender/not tender and Sixty-six joints were classified as swollen/not swollen by pressure and joint manipulation on physical examination.

    27. Percent Change From Baseline in Participant's Global Assessment of Disease Activity Based on Visual Analog Scale (VAS) Score at Week 12 [Baseline, Week 12]

      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).

    28. Percent Change From Baseline in Participant's Assessment of Pain Based on Visual Analog Scale (VAS) Score at Week 12 [Baseline, Week 12]

      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.

    29. Percent Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Total Score at Week 12 [Baseline, Week 12]

      HAQ-DI score was an evaluation of the functional status for a participant. The 20-question instrument assessed the degree of difficulty a person had in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily living). Responses in each functional area were scored from 0, indicated no difficulty, to 3, indicated inability to perform a task in that area. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range: 0-3 where 0 = least difficulty and 3 = extreme difficulty.

    30. Percent Change From Baseline in Physician's Global Assessment of Disease Activity Scale Based on Visual Analog Scale (VAS) Score at Week 12 [Baseline, Week 12]

      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).

    31. Percent Change From Baseline in High-Sensitivity C-reactive Protein (hsCRP) at Week 12 [Baseline, Week 12]

      hsCRP was the American College of Rheumatology (ACR) Core Set measure of acute phase reactant. It was measured at the central laboratory to help assess the effect of M2951 on the participant's rheumatoid arthritis.

    32. Change From Baseline in Synovitis Score According to the Outcomes Measures in Rheumatology Clinical Trials Rheumatoid Arthritis Magnetic Resonance Imaging Scoring System (OMERACT RAMRIS) at Week 12 [Baseline, Week 12]

      A total of 8 joints in the hand and wrist were evaluated for RAMRIS synovitis. Individual joint scores were assessed on a scale of 0 (no synovitis) to 3 (67 to 100 percent volume enhancement). The final synovitis score was the sum of the individual joint scores. The total score from 8 joints ranges from 0 to 24, with 0 implying normal (no synovitis) and 24 implying 67 to 100 percent volume enhancement.

    33. Change From Baseline in Bone Marrow Edema (Osteitis) Score According to the Outcomes Measures in Rheumatology Clinical Trials Rheumatoid Arthritis Magnetic Resonance Imaging Scoring System (OMERACT RAMRIS) at Week 12 [Baseline, Week 12]

      A total of 25 locations in the hand and wrist were evaluated for RAMRIS bone edema or osteitis. Individual location scores range from 0 (no edema) to 3 (67 to 100 percent involvement of original articular bone) based on the proportion of estimated originally non-eroded bone involved. The final bone edema or osteitis score is the sum of the individual location scores. The total score from the 25 locations ranges from 0 to 75, with 0 implying no bone edema or osteitis and 75 implying 67 to 100 percent involvement of original articular bone.

    34. Change From Baseline in Physical Function Using Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 12 [Baseline, Week 12]

      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.

    35. Change From Baseline in the Short-Form (SF-36) Health Survey Physical Component Score and Mental Component Score at Week 12 [Baseline, Week 12]

      The 36-Item Short-Form Health Survey (SF-36) was a standardized survey evaluating 8 aspects of functional health and well-being. These eight subscales were summarized as relating to either physical health or mental health. Physical component summary (PCS) was based primarily on physical functioning, role-physical, bodily pain, and general health scales and mental component summary (MCS) encompasses vitality, social functioning, role-emotional, and mental health scales. Score from mental health, role emotional, social functioning, and vitality domains were averaged to calculate MCS. Total score range for MCS was 0-100 (100 = highest level of mental functioning). Score from physical function, role physical, bodily pain, and general health domains were averaged to calculate PCS. Total score range for PCS was 0-100 (100 = highest level of physical functioning).

    36. Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Score at Week 12 [Baseline, Week 12]

      The FACIT-Fatigue score was calculated according to a 13-item questionnaire that assess self-reported fatigue and its impact upon daily activities and function. It uses a 5-point Likert-type scale (0 = not at all; 1 = a little bit; 2 = somewhat; 3 = quite a bit; 4 = very much). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worse possible score) to 52 (best score). A higher score reflected an improvement in the participant's health status.

    Eligibility Criteria

    Criteria

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

    • In Japan, if a participant is less than (<) 20 years, the written informed consent from the participant's parent or guardian will be required in addition to the participant's written consent.

    • Confirmed diagnosis of RA according to 2010 ACR/EULAR RA classification criteria of at least 6 months duration prior to Screening

    • Persistently active moderate to severe RA at both Screening and Randomization (if significant surgical treatment of a joint has been performed, that joint cannot be counted for entry or enrollment purposes), as defined by: >= 6 swollen joints (of 66 assessed) and >= 6 tender joints (of 68 assessed).

    • An hsCRP >= 5.0 milligram/liter (mg/L) at Screening

    • Treatment for >= 16 weeks with 7.5 to 25 mg/week Methotrexate (MTX) at a stable dose and route of administration (oral or parenteral) for at least 8 weeks prior to dosing with the Investigational Medicinal Product (IMP) and maintained throughout the trial

    • For participants entering the trial on MTX doses < 15 mg/week (< 10 mg/week in Japan), there must be clear documentation in the medical record that higher doses of MTX were not tolerated or that the dose of MTX is the highest acceptable dose based on local clinical practice guidelines.

    • For MRI Sub-study participants, participants must have palpable synovitis of the wrist and/or >= 1 of metacarpophalangeal joints 1 to 5, defined as loss of bony contours with palpable joint effusion and/or swelling, in the MRI-designated hand (that is., the hand being used in MRI assessments).

    Exclusion Criteria:

    • ACR functional class IV as defined by the ACR classification of functional status or wheelchair/bedbound

    • Use of oral corticosteroids greater than (>) 10 mg daily prednisone equivalent, or change in dose of corticosteroids within 2 weeks prior to Screening or during Screening

    • Use of injectable corticosteroids (including intra-articular corticosteroids) or intra-articular hyaluronic acid within 4 weeks prior to Screening or during Screening

    • Initiation or change in dose for nonsteroidal anti-inflammatory drugs (NSAIDs) (including low-dose aspirin and cyclooxygenase-2 inhibitors) within 2 weeks prior to dosing with the IMP

    • High potency opioid analgesics are prohibited within 2 weeks prior to Screening and during the trial; other analgesics are allowed (that is, acetaminophen, codeine, hydrocodone*, propoxyphene*, or tramadol), although not within 24 hours of study visits with clinical assessments (*not approved in Japan)

    • Current or prior treatment with any of the following:

    • Biologic Disease-modifying anti-rheumatic drugs (DMARDs) (approved or investigational), including but not limited to:

    • Tumor necrosis factor (TNF) antagonists or biosimilars of these agents (approved or investigational), or any investigational TNF antagonist

    • Interleukin-6 antagonists

    • Abatacept (CTLA4-Fc)

    • Anakinra* (IL-1 receptor antagonist) (*not approved in Japan)

    • B cell-depleting antibodies (example, rituximab, ocrelizumab*, ofatumumab, obinutuzumab*, ocaratuzumab*, veltuzumab*, or any biosimilars of these agents [approved or investigational]) (*not approved in Japan)

    • Anti-BLyS (B lymphocyte stimulator) agents (example, belimumab, tabalumab*) (*not approved in Japan)

    • Dual BLyS/A proliferation-inducing ligand (APRIL) neutralizing agents (that is, atacicept*, RCT-18*) (*not approved in Japan)

    • Targeted synthetic DMARDs, specifically:

    • Janus kinase inhibitors

    • Other Bruton's tyrosine kinase (BTK) inhibitors

    • Alkylating agents (example, chlorambucil*, cyclophosphamide) (*not approved in Japan).

    • The following restrictions on nonbiologic DMARD must be followed:

    • Auranofin (Ridaura), minocycline, penicillamine, sulfasalazine, cyclosporine, mycophenolate (mycophenolate sodium not approved in Japan), tacrolimus, azathioprine: must have been discontinued for 4 weeks prior to dosing with the IMP

    • Leflunomide (Arava) must have been discontinued 12 weeks prior to dosing with the IMP if no elimination procedure is followed. Alternately, it should have been discontinued with the following elimination procedure at least 4 weeks prior to dosing with the

    IMP:

    • Cholestyramine at a dosage of 8 gram 3 times a day for at least 24 hours, or activated charcoal at a dosage of 50 gram 4 times a day for at least 24 hours.

    • Injectable Gold (aurothioglucose* or aurothiomalate): must have been discontinued for 8 weeks prior to dosing with the IMP (*not approved in Japan)

    • Anti-malarials (hydroxychloroquine, chloroquine*) will be allowed in this trial. Participants may be taking oral hydroxychloroquine (=< 400 mg/day) or chloroquine (=< 250 mg/day), doses must have been stable for at least 12 weeks prior to dosing with the IMP, and will need to be continued at that stable dose for the duration of the trial. If discontinued prior to this trial, they must have been discontinued for 4 weeks prior to dosing with the IMP (*not approved in Japan).

    • For MRI Substudy:

    • Inability to comply with MRI scanning, including contraindications to MRI such as known allergy to gadolinium contrast media, claustrophobia (if the site does not have ability to scan extremities only), presence of a pacemaker, cochlear implants, ferromagnetic devices or clips, intracranial vascular clips, insulin pumps, and nerve stimulators.

    • More than 25% of applicable joints of the target hand and wrist having had prior surgery or showing maximum Genant-modified Sharp erosion (3.0) or joint-space narrowing (4.0) scores, based on single posteroanterior radiographs of target hand and wrist read centrally.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Arizona Arthritis & Rheumatology Associates, P.C. Phoenix Arizona United States 85032
    2 Arizona Arthritis & Rheumatology Research, PLLC Phoenix Arizona United States 85037
    3 East Bay Rheumatology Medical Group, Inc. San Leandro California United States 94578
    4 Omega Research Consultants DeBary Florida United States 32713
    5 Clinical Research of West Florida, Inc. Tampa Florida United States 33603
    6 McIlwain Medical Group, PA Tampa Florida United States 33614
    7 Medication Management, LLC Greensboro North Carolina United States 27410
    8 Arthritis Clinic Of Central Texas San Marcos Texas United States 78666
    9 Hospital Italiano de La Plata La Plata Buenos Aires Argentina B1900AXI
    10 Instituto de Investigaciones Clinicas Mar del Plata Buenos Aires Argentina B7600FZ
    11 Instituto Medico CER Quilmes Buenos Aires Argentina B1878DVB
    12 Instituto de Investigaciones Clinicas Quilmes Quilmes Buenos Aires Argentina B1878GEG
    13 Centro Medico Privado de Reumatologia Tucuman San Miguel De Tucuman Argentina T4000AXL
    14 Centro de Investigaciones Reumatológicas San Miguel de Tucuman Tucuman Argentina T4000BRD
    15 Organizacion Medica de Investigacion (OMI) Ciudad Autonoma Buenos Aires Argentina C1015ABO
    16 APRILLUS Ciudad Autonoma Buenos Aires Argentina C1046AAQ
    17 Expertia S.A- Mautalen Salud e Investigación Ciudad Autonoma Buenos Aires Argentina C1128AAE
    18 Hospital General de Agudos Dr. J. M. Ramos Mejia Ciudad Autonoma Buenos Aires Argentina C1221ADC
    19 ILAIM-CEOM Inst. Latinoamericano de Inv. Medicas Cordoba Argentina X5000BNB
    20 Instituto Reumatológico Strusberg Cordoba Argentina X5000EDC
    21 Centro Polivalente de Asistencia e Inv. Clinica CER San Juan Argentina 5400
    22 MHAT "Hadzhi Dimitar", OOD Sliven Bulgaria 8800
    23 DCC "Alexandrovska", EOOD Sofia Bulgaria 1431
    24 UMHAT "SofiaMed", OOD Sofia Bulgaria 1797
    25 Centro Medico Prosalud Santiago Chile 7500000
    26 Interin Santiago Chile 7500010
    27 BioMedica Research Group Santiago Chile 7500710
    28 Centro de Estudios Reumatologicos Santiago Chile 7501126
    29 Centro de Reumatologia y Ortopedia SAS Barranquilla Colombia 080001
    30 Riesgo de Fractura S.A. Bogota Colombia 110221
    31 Simedics Ips Sas Bogotá Colombia 111211
    32 Centro de Investigacion en Reumatologia y Especialidades Medicas SAS. CIREEM Bogotá Colombia
    33 Servimed S.A.S. Bucaramanga Colombia 680003
    34 Clinica de Artritis Temprana S.A. Cali Colombia 76001
    35 Revmatolog, s.r.o Jihlava Czechia 586 01
    36 ARTROSCAN s.r.o. Ostrava - Trebovice Czechia 722 00
    37 CCBR Ostrava s.r.o. Ostrava Czechia 702 00
    38 CLINTRIAL s.r.o. Praha 10 Czechia 100 00
    39 Thomayerova nemocnice Praha 4 - Krc Czechia 140 59
    40 MUDR. Zuzana URBANOVA Revmatologie Praha 4 Nusle Czechia 140 00
    41 MUDR. Zuzana URBANOVA Revmatologie Praha 4 Czechia 140 00
    42 MEDICAL PLUS s.r.o. Uherske Hradiste Czechia 686 01
    43 PV-MEDICAL s.r.o. Zlin Czechia 760 01
    44 Centro Investigacion en Artritis y Osteoporosis S.C. Mexicali Baja California Norte Mexico 21200
    45 RM Pharma Specialists SA de CV Mexico Distrito Federal Mexico 03100
    46 Clinica de Investigacion en Reumatologia y Obesidad S.C. Guadalajara Jalisco Mexico 44650
    47 Investigacion y Biomedicina de Chihuahua, S.C. Chihuahua Mexico 31000
    48 Centro de Investigacion y Atencion Integral Durango CIAID Durango Mexico 34270
    49 ClinicMed Daniluk, Nowak Spółka Jawna Bialystok Poland 15-879
    50 Centrum Reumatologiczne Indywidualna Specjalistyczna Praktyka Lekarska lek. Barbara Bazela Elblag Poland 82-300
    51 MCBK Iwona Czajkowska Anna Podrażka- Szczepaniak S.C. Grodzisk Mazowiecki Poland 05-825
    52 Care Clinic Katowice Poland 40-060
    53 Silmedic sp. z o.o Katowice Poland 40-282
    54 GLOBE CLINICAL RESEARCH (Globe Badania Kliniczne Sp z o.o.) Klodzko Poland 57-300
    55 Indywidualna Specjalistyczna Praktyka Lekarska Maciej Zymla Knurow Poland 44-190
    56 Malopolskie Centrum Medyczne s.c. Krakow Poland 30-510
    57 Grazyna Pulka Specjalistyczny Osrodek "ALL-MED" Krakow Poland 31-024
    58 Centrum Badan Klinicznych S.C. Poznan Poland 60-773
    59 RCMed Sochaczew Poland 96-500
    60 Centrum Medyczne AMED Warsaw Poland 03-291
    61 Medycyna Kliniczna Warszawa Poland 00-660
    62 Rheuma Medicus Zaklad Opieki Zdrowotnej Warszawa Poland 02-118
    63 Wojskowy Instytut Medyczny Warszawa Poland 04-141
    64 Reum-Medica S.C Eliza Roszkowska Wroclaw Poland 50-244
    65 Research Institute of Emergency Medical Care St. Petersburg Saint Petersburg Russian Federation 192242
    66 Limited Liability Company "Centre of Medical Common Practice" Novosibirsk Russian Federation 630091
    67 Ultramed Omsk Russian Federation 644024
    68 SPb SBIH "Clinical Rheumatological Hospital # 25" Saint-Petersburg Russian Federation 190068
    69 LLC Medical Sanitary Unit#157 Saint-Petersburg Russian Federation 196066
    70 NIH "Departmental Hospital on Station Smolensk of OJSC "Russian Railways" Smolensk Russian Federation 214025
    71 SAIH of Yaroslavl region "Clinical Hospital of Emergency Medical Care n.a. N. V. Solovyev" Yaroslavl Russian Federation 150003
    72 SBHI of Yaroslavl Region "Clinical Hospital # 8" Yaroslavl Russian Federation 150003
    73 Institute of Rheumatology_Site 1 Belgrade Serbia 11000
    74 Military Medical Academy Belgrade Serbia 11000
    75 Clinical Center Bezanijska kosa Belgrade Serbia 11080
    76 Institute of Treatment and Rehabilitation "Niska Banja" Niska Banja Serbia 18205
    77 General Hospital "Dr Laza K. Lazarevic" Sabac Sabac Serbia 15000
    78 Wits Clinical Research Johannesburg Gauteng South Africa 2193
    79 Clinresco Centres (Pty) Ltd Kempton Park Gauteng South Africa 1619
    80 Emmed Research Pretoria Gauteng South Africa 0002
    81 University of Pretoria Clinical Research Unit Pretoria Gauteng South Africa 0002
    82 Naidoo, A Durban KwaZulu-Natal South Africa 4319
    83 Arthritis Clinical Research Trial Unit Cape Town Western Cape South Africa 7405
    84 Winelands Medical Research Centre Stellenbosch Western Cape South Africa 7600
    85 Regional CH Dep of Rheumatology SHEI Ivano-Frankivsk NMU Ivano-Frankivsk Ukraine 76008
    86 GI L.T.Malaya Therapy National Institute of the NAMS of Ukraine Kharkiv Ukraine 61039
    87 Communal Institution of Healthcare Kharkiv City Clinical Hospital #8 Kharkiv Ukraine 61176
    88 Medical Center Medical Clinic Blagomed LLC Kyiv Ukraine 01601
    89 Med Center 'Ok!Clinic+' of International Institute of Clinical Trials LLC Kyiv Ukraine 02091
    90 Medical Center of Revmotsentr LLC Kyiv Ukraine 04070
    91 SI D.F.Chebotariov Institute of Gerontology of NAMSU Kyiv Ukraine 04114
    92 CH of State Border Service of Ukraine (Military Base 2522) Dept of Therapy, D.Halytskyi Lviv NMU Lviv Ukraine 79049
    93 M.V. Sklifosovskyi Poltava RCH Dept of Rheumatology HSEIU UMSA Poltava Ukraine 36011
    94 A.Novak Transcarpathian Regional Clinical Hospital Uzhgorod Ukraine 88000
    95 National Pirogov Memorial Medical University Vinnytsia Ukraine 21018
    96 CI City Hospital #1 Zaporizhzhia Ukraine 69104
    97 CI Zaporizhzhia Regional Clinical Hospital of ZRC Zaporizhzhia Ukraine 69600
    98 CI Zaporizhzhia Regional Clinical Hospital of ZRC Zaporizhzhya Ukraine 69600

    Sponsors and Collaborators

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

    Investigators

    • Study Director: Medical Responsible, EMD Serono Research & Development Institute, Inc.

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    EMD Serono Research & Development Institute, Inc.
    ClinicalTrials.gov Identifier:
    NCT03233230
    Other Study ID Numbers:
    • MS200527-0060
    • 2017-000384-32
    First Posted:
    Jul 28, 2017
    Last Update Posted:
    Sep 28, 2020
    Last Verified:
    Aug 1, 2020
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by EMD Serono Research & Development Institute, Inc.
    Rheumatoid Arthritis
    American College of Rheumatology
    High-sensitivity C-reactive protein
    Bruton's tyrosine kinase
    Additional relevant MeSH terms:
    Arthritis
    Arthritis, Rheumatoid

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail A total of 933 participants with rheumatoid arthritis were screened. Out of which, 390 participants were randomized in ratio of 1:1:1:1 to 1 of the 4 treatment groups: Placebo; M2951 25 milligrams (mg) once daily (QD), M2951 75 mg QD and M2951 50 mg twice daily (BID).
    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Period Title: Overall Study
    STARTED 97 98 96 99
    COMPLETED 82 83 84 91
    NOT COMPLETED 15 15 12 8

    Baseline Characteristics

    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID Total
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks. Total of all reporting groups
    Overall Participants 97 98 96 99 390
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    52.9
    (12.24)
    50.9
    (13.15)
    53.3
    (11.33)
    53.7
    (12.13)
    52.7
    (12.21)
    Sex: Female, Male (Count of Participants)
    Female
    77
    79.4%
    82
    83.7%
    76
    79.2%
    77
    77.8%
    312
    80%
    Male
    20
    20.6%
    16
    16.3%
    20
    20.8%
    22
    22.2%
    78
    20%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    32
    33%
    33
    33.7%
    35
    36.5%
    38
    38.4%
    138
    35.4%
    Not Hispanic or Latino
    65
    67%
    65
    66.3%
    61
    63.5%
    61
    61.6%
    252
    64.6%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Asian
    1
    1%
    1
    1%
    1
    1%
    0
    0%
    3
    0.8%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    1
    1%
    2
    2%
    0
    0%
    0
    0%
    3
    0.8%
    White
    92
    94.8%
    94
    95.9%
    91
    94.8%
    97
    98%
    374
    95.9%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    3
    3.1%
    1
    1%
    4
    4.2%
    2
    2%
    10
    2.6%

    Outcome Measures

    1. Primary Outcome
    Title Percentage of Participants Who Achieved American College of Rheumatology 20 Percent (%) Response Criteria (ACR20) Assessed Using High-Sensitivity C-reactive Protein (hsCRP) at Week 12
    Description ACR20 response: a participant has at least 20% improvement in both tender joint counts (based on a total of 68 joints) and swollen joint counts (based on a total of 66 joints) together with 20% improvement in at least 3 of the following: 1) 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). Percentage of participants with ACR20 response using hsCRP = Number of participants with ACR20 response using hsCRP divided by total modified intent-to-treat (mITT) participants * 100.
    Time Frame Week 12

    Outcome Measure Data

    Analysis Population Description
    The mITT analysis set included all randomized participants who received at least one dose of Investigational Medicinal Product (IMP) (M2951 or placebo).
    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Measure Participants 97 98 96 99
    Number [percentage of participants]
    49.5
    51%
    59.2
    60.4%
    51.0
    53.1%
    59.6
    60.2%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, M2951 25 mg QD
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1746
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 1.48
    Confidence Interval (2-Sided) 95%
    0.84 to 2.61
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, M2951 75 mg QD
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8283
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 1.06
    Confidence Interval (2-Sided) 95%
    0.61 to 1.87
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Placebo, M2951 50 mg BID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1298
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 1.55
    Confidence Interval (2-Sided) 95%
    0.88 to 2.74
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    Title Percentage of Participants With Low Disease Activity Score (DAS28 Less Than [<] 3.2) Based on 28 Joint Count-High-Sensitivity C-reactive Protein (DAS28-hsCRP) at Week 12
    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) + 0.36*natural log(hsCRP+1) + 0.014* participant's global assessment of disease activity + 0.96. Scores ranged 0-9.4, where lower scores indicated less disease activity. Percentage of participants with low DAS28 < 3.2 based on DAS28- hsCRP at Week 12 were reported.
    Time Frame Week 12

    Outcome Measure Data

    Analysis Population Description
    The mITT analysis set included all randomized participants who received at least one dose of IMP (M2951 or placebo).
    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Measure Participants 97 98 96 99
    Number [percentage of participants]
    7.2
    7.4%
    20.4
    20.8%
    24.0
    25%
    20.2
    20.4%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, M2951 25 mg QD
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0077
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Response rate difference
    Estimated Value 0.13
    Confidence Interval (2-Sided) 95%
    0.04 to 0.23
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, M2951 75 mg QD
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0013
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Response rate difference
    Estimated Value 0.17
    Confidence Interval (2-Sided) 95%
    0.07 to 0.27
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Placebo, M2951 50 mg BID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0080
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Response rate difference
    Estimated Value 0.13
    Confidence Interval (2-Sided) 95%
    0.04 to 0.23
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Secondary Outcome
    Title Percentage of Participants With Remission Disease Activity Score (DAS28 Less Than [<] 2.6) Based on a 28 Joint Count-High-Sensitivity C-reactive Protein (DAS28-hsCRP) at Week 12
    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) + 0.36*natural log(hsCRP+1) + 0.014* participant's global assessment of disease activity + 0.96. Scores ranged 0-9.4, where lower scores indicated less disease activity. A DAS28 score less than (<) 2.6 indicated clinical remission. Percentage of participants with low DAS28 < 2.6 based on DAS28- hsCRP at Week 12 were reported.
    Time Frame Week 12

    Outcome Measure Data

    Analysis Population Description
    The mITT analysis set included all randomized participants who received at least one dose of IMP (M2951 or placebo).
    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Measure Participants 97 98 96 99
    Number [percentage of participants]
    1.0
    1%
    10.2
    10.4%
    10.4
    10.8%
    10.1
    10.2%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, M2951 25 mg QD
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0056
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Response rate difference
    Estimated Value 0.09
    Confidence Interval (2-Sided) 95%
    0.03 to 0.17
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, M2951 75 mg QD
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0050
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Response rate difference
    Estimated Value 0.09
    Confidence Interval (2-Sided) 95%
    0.03 to 0.17
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Placebo, M2951 50 mg BID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0053
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Response rate difference
    Estimated Value 0.09
    Confidence Interval (2-Sided) 95%
    0.03 to 0.17
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    4. Secondary Outcome
    Title Percentage of Participants Achieving American College of Rheumatology 50% Response Criteria (ACR50)
    Description ACR50 response: a participant has at least 50% improvement in both tender joint counts (based on a total of 68 joints) and swollen joint counts (based on a total of 66 joints) together with 50% improvement in at least 3 of the following: 1) 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]. Percentage of participants with ACR50 response = Number of participants with ACR50 response divided by total mITT participants * 100.
    Time Frame Week 12

    Outcome Measure Data

    Analysis Population Description
    The mITT analysis set included all randomized participants who received at least one dose of IMP (M2951 or placebo).
    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Measure Participants 97 98 96 99
    Number [percentage of participants]
    19.6
    20.2%
    28.6
    29.2%
    27.1
    28.2%
    26.3
    26.6%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, M2951 25 mg QD
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1419
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Response rate difference
    Estimated Value 0.09
    Confidence Interval (2-Sided) 95%
    -0.03 to 0.21
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, M2951 75 mg QD
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2202
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Response rate difference
    Estimated Value 0.07
    Confidence Interval (2-Sided) 95%
    -0.05 to 0.19
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Placebo, M2951 50 mg BID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2328
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Response rate difference
    Estimated Value 0.07
    Confidence Interval (2-Sided) 95%
    -0.05 to 0.19
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    5. Secondary Outcome
    Title Percentage of Participants Achieving American College of Rheumatology 70% Response Criteria (ACR70)
    Description ACR70 response: a participant has at least 70% improvement ACR70 response in both tender joint counts (based on a total of 68 joints) and swollen joint counts (based on a total of 66 joints) together with 70% improvement in at least 3 of the following: 1) 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]. Percentage of participants with ACR70 response = Number of participants with ACR70 response divided by total mITT participants * 100.
    Time Frame Week 12

    Outcome Measure Data

    Analysis Population Description
    The mITT analysis set included all randomized participants who received at least one dose of IMP (M2951 or placebo).
    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Measure Participants 97 98 96 99
    Number [percentage of participants]
    5.2
    5.4%
    11.2
    11.4%
    10.4
    10.8%
    10.1
    10.2%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, M2951 25 mg QD
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1232
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Response rate difference
    Estimated Value 0.06
    Confidence Interval (2-Sided) 95%
    -0.02 to 0.15
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, M2951 75 mg QD
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1725
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Response rate difference
    Estimated Value 0.05
    Confidence Interval (2-Sided) 95%
    -0.03 to 0.14
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Placebo, M2951 50 mg BID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1795
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Response rate difference
    Estimated Value 0.05
    Confidence Interval (2-Sided) 95%
    -0.03 to 0.13
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    6. Secondary Outcome
    Title Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)
    Description Adverse event (AE) was defined as any untoward medical occurrence in a participant, which does not necessarily have causal relationship with treatment. A serious AE was defined as an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inparticipant hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs: events between first dose of study drug that were absent before treatment/that worsened relative to pre-treatment state up to 16 weeks. TEAEs included both serious TEAEs and non-serious TEAEs. Number of participants with TEAEs and serious TEAEs were reported.
    Time Frame up to Week 16

    Outcome Measure Data

    Analysis Population Description
    The safety analysis set (SAF) included all participants who received at least 1 dose of IMP (M2951 or placebo).
    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Measure Participants 97 98 96 99
    TEAEs
    44
    45.4%
    48
    49%
    48
    50%
    50
    50.5%
    Serious TEAEs
    2
    2.1%
    2
    2%
    2
    2.1%
    1
    1%
    7. Secondary Outcome
    Title Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Severity According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)
    Description Severity of TEAEs were graded using NCI-CTCAE v4.03 toxicity grades, as follows: Grade 1= Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Life-threatening and Grade 5 = Death. Number of participants with TEAEs by severity were reported.
    Time Frame up to Week 16

    Outcome Measure Data

    Analysis Population Description
    The SAF included all participants who received at least 1 dose of IMP (M2951 or placebo).
    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Measure Participants 97 98 96 99
    Grade 1
    33
    34%
    42
    42.9%
    37
    38.5%
    40
    40.4%
    Grade 2
    19
    19.6%
    14
    14.3%
    23
    24%
    17
    17.2%
    Grade 3
    2
    2.1%
    5
    5.1%
    1
    1%
    1
    1%
    Grade 4
    0
    0%
    1
    1%
    0
    0%
    0
    0%
    Grade 5
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    8. Secondary Outcome
    Title Number of Participants With Clinically Significant Change From Baseline in Vital Signs
    Description Vital signs included body temperature, systolic and diastolic blood pressure, pulse rate, respiratory rate, weight and height. Clinical significance was determined by the investigator. The number of participants with clinically significant changes from baseline in vital signs were reported.
    Time Frame up to Week 16

    Outcome Measure Data

    Analysis Population Description
    The SAF included all participants who received at least 1 dose of IMP (M2951 or placebo).
    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Measure Participants 97 98 96 99
    Count of Participants [Participants]
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    9. Secondary Outcome
    Title Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters
    Description Laboratory investigation included hematology, biochemistry, urinalysis and coagulation. Clinical significance was determined by the investigator. The number of participants with clinically significant changes from baseline in laboratory parameters were reported.
    Time Frame up to Week 16

    Outcome Measure Data

    Analysis Population Description
    The SAF included all participants who received at least 1 dose of IMP (M2951 or placebo).
    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Measure Participants 97 98 96 99
    Count of Participants [Participants]
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    10. Secondary Outcome
    Title Number of Participants With Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings
    Description 12-lead ECG recordings included rhythm, heart rate (as measured by RR interval), PR interval, QRS duration, and QT interval. The corrected QT interval (QTcF) was calculated using Fridericia's formula. 12-lead ECG recordings were obtained after the participants have rested for at least 10 minutes in semisupine position. Clinical significance was determined by the investigator. The number of participants with clinically significant changes from baseline in 12-lead ECG findings were reported.
    Time Frame up to Week 16

    Outcome Measure Data

    Analysis Population Description
    The SAF included all participants who received at least 1 dose of IMP (M2951 or placebo).
    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Measure Participants 97 98 96 99
    Count of Participants [Participants]
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    11. Secondary Outcome
    Title Change From Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 2, 4, 8, 12 and 16
    Description Change in the serum levels of IgG, IgA, IgM were assessed.
    Time Frame Baseline, Week 2, 4, 8, 12 and 16

    Outcome Measure Data

    Analysis Population Description
    The SAF included all participants who received at least 1 dose of IMP (M2951 or placebo). Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure and "Number Analyzed" signified those participants who were evaluable for the specified category at given time points.
    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Measure Participants 95 96 95 99
    IgG: Week 2
    -0.02
    (1.083)
    -0.07
    (1.042)
    -0.21
    (0.968)
    -0.09
    (1.062)
    IgG: Week 4
    -0.05
    (1.465)
    -0.15
    (1.576)
    -0.34
    (1.254)
    -0.17
    (1.168)
    IgG: Week 8
    0.12
    (1.513)
    -0.28
    (2.052)
    -0.37
    (1.565)
    -0.35
    (2.037)
    IgG: Week 12
    0.47
    (1.617)
    -0.17
    (2.080)
    -0.33
    (1.493)
    -0.23
    (1.781)
    IgG: Week 16
    0.08
    (1.829)
    -0.14
    (2.349)
    -0.14
    (1.808)
    0.06
    (1.960)
    IgA: Week 2
    -0.01
    (0.253)
    -0.15
    (1.187)
    0.00
    (0.242)
    0.03
    (0.369)
    IgA: Week 4
    -0.05
    (0.326)
    -0.01
    (0.359)
    -0.05
    (0.333)
    0.02
    (0.396)
    IgA: Week 8
    -0.02
    (0.346)
    -0.16
    (1.322)
    -0.06
    (0.373)
    0.07
    (0.567)
    IgA: Week 12
    0.02
    (0.373)
    0.01
    (0.444)
    -0.08
    (0.388)
    0.05
    (0.545)
    IgA: Week 16
    0.01
    (0.466)
    0.07
    (0.465)
    -0.11
    (0.380)
    0.05
    (0.478)
    IgM: Week 2
    -0.04
    (0.198)
    -0.04
    (0.183)
    -0.03
    (0.281)
    -0.01
    (0.323)
    IgM: Week 4
    -0.04
    (0.199)
    -0.11
    (0.224)
    -0.11
    (0.217)
    -0.05
    (0.385)
    IgM: Week 8
    -0.03
    (0.310)
    -0.20
    (0.243)
    -0.23
    (0.327)
    -0.10
    (0.485)
    IgM: Week 12
    -0.01
    (0.265)
    -0.20
    (0.309)
    -0.25
    (0.296)
    -0.17
    (0.406)
    IgM: Week 16
    -0.16
    (0.776)
    -0.12
    (0.436)
    -0.22
    (0.246)
    -0.12
    (0.487)
    12. Secondary Outcome
    Title Change From Baseline in B Cell Count at Week 2, 4, 8, 12 and 16
    Description Flow cytometry analysis of lymphocyte populations using four-color fluorescence-activated cell sorting was performed for the analysis of B cell counts.
    Time Frame Baseline, Week 2, 4, 8, 12 and 16

    Outcome Measure Data

    Analysis Population Description
    SAF included all participants who received at least 1 dose of IMP (M2951 or placebo). Here, "Overall Number of Participants Analyzed specifies those participants who were evaluable for this outcome measure and "Number Analyzed" signified those participants who were evaluable for the specified category at given time point.
    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Measure Participants 90 90 92 97
    Week 2
    -13
    (111.0)
    264
    (1832.7)
    161
    (648.3)
    74
    (144.8)
    Week 4
    -20
    (115.7)
    71
    (130.1)
    66
    (145.3)
    93
    (137.6)
    Week 8
    -21
    (87.5)
    35
    (103.1)
    56
    (188.1)
    59
    (145.4)
    Week 12
    -22
    (136.4)
    41
    (111.8)
    51
    (156.2)
    54
    (145.0)
    Week 16
    -20
    (121.9)
    -3
    (108.5)
    -40
    (133.5)
    -19
    (235.6)
    13. Secondary Outcome
    Title Percentage of Participants With Remission Assessed by American College of Rheumatology-European League Against Rheumatism (ACR-EULAR) Boolean at Week 12
    Description ACR-EULAR Boolean remission was when a participant satisfied all of the following: tender joint count, swollen joint count (both based on a 28-joint assessment), C-reactive Protein (in milligrams per deciliter [mg/dL]), and participant's global assessment (visual analog scale [VAS]: 0 centimeter (cm) [very well] to 10 cm [worst], higher scores indicated worse health condition) and all scores were less than or equal to (<=) 1. Percentage of participants with ACR-EULAR Boolean Remission were reported.
    Time Frame Week 12

    Outcome Measure Data

    Analysis Population Description
    The mITT analysis set included all randomized participants who received at least one dose of IMP (M2951 or placebo).
    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Measure Participants 97 98 96 99
    Number [percentage of participants]
    0.0
    0%
    0.0
    0%
    1.0
    1%
    3.0
    3%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, M2951 25 mg QD
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Response rate difference
    Estimated Value 0.00
    Confidence Interval (2-Sided) 95%
    -0.04 to 0.04
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, M2951 75 mg QD
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Response rate difference
    Estimated Value 0.01
    Confidence Interval (2-Sided) 95%
    -0.03 to 0.06
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Placebo, M2951 50 mg BID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Response rate difference
    Estimated Value 0.03
    Confidence Interval (2-Sided) 95%
    -0.01 to 0.09
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    14. Secondary Outcome
    Title Percentage of Participants With Clinical Disease Activity Index (CDAI) Score Less Than or Equal to [=<] 2.8 at Week 12
    Description CDAI: a composite index (without acute-phase reactant) for assessing disease activity. The CDAI was calculated based on following formula: CDAI = 28 joint count for swelling (SJC28) + 28 joint count for tenderness (TJC28) + GH + PhGA where, GH = general health component of the Disease Activity Score [DAS] (i.e., Participant's Global Assessment of Disease Activity, assessed using a scale of 0 to 10 centimeter (cm) Visual Analogue Scale (VAS) where 0 = very well and 10 = very poor activity and PhGA = Physician's Global Assessment of Disease Activity assessed using a scale of 0 to 10 cm VAS, where 0 = very well and 10 = very poor activity. The total CDAI score ranges from 0 to 76, where 0 (none) to 76 (extreme disease activity). CDAI score =< 2.8 indicated clinical remission. Percentage of participants with CDAI score =< 2.8 were reported.
    Time Frame Week 12

    Outcome Measure Data

    Analysis Population Description
    The mITT analysis set included all randomized participants who received at least one dose of IMP (M2951 or placebo).
    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Measure Participants 97 98 96 99
    Number [percentage of participants]
    1.0
    1%
    4.1
    4.2%
    6.3
    6.6%
    3.0
    3%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, M2951 25 mg QD
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Response rate difference
    Estimated Value 0.03
    Confidence Interval (2-Sided) 95%
    -0.02 to 0.09
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, M2951 75 mg QD
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Response rate difference
    Estimated Value 0.05
    Confidence Interval (2-Sided) 95%
    -0.00 to 0.12
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Placebo, M2951 50 mg BID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Response rate difference
    Estimated Value 0.02
    Confidence Interval (2-Sided) 95%
    -0.03 to 0.08
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    15. Secondary Outcome
    Title Percentage of Participants With Simplified Disease Activity Index (SDAI) Score Less Than or Equal to [=<] 3.3 at Week 12
    Description SDAI was calculated based on following formula: SDAI = 28 joint count for swelling (SJC28) + 28 joint count for tenderness (TJC28) + GH + PGA + hsCRP where, GH = general health component of the Disease Activity Score [DAS] (i.e., Participant's Global Assessment of Disease Activity, assessed using a scale of 0 to 10 centimeter (cm) Visual Analogue Scale (VAS) where 0 = very well and 10 = very poor activity and PhGA = Physician's Global Assessment of Disease Activity assessed using a scale of 0 to 10 cm VAS, where 0 = very well and 10 = very poor activity. The total SDAI score ranges from 0 to 86, where 0 (none) to 86 (extreme disease activity). SDAI score =< 3.3 indicated clinical remission. Percentage of participants with SDAI score =< 3.3 at Week 12 were reported.
    Time Frame Week 12

    Outcome Measure Data

    Analysis Population Description
    The mITT analysis set included all randomized participants who received at least one dose of IMP (M2951 or placebo).
    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Measure Participants 97 98 96 99
    Number [percentage of participants]
    0.0
    0%
    3.1
    3.2%
    4.2
    4.4%
    3.0
    3%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, M2951 25 mg QD
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Response rate difference
    Estimated Value 0.03
    Confidence Interval (2-Sided) 95%
    -0.01 to 0.09
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, M2951 75 mg QD
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Response rate difference
    Estimated Value 0.04
    Confidence Interval (2-Sided) 95%
    0.00 to 0.10
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Placebo, M2951 50 mg BID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Response rate difference
    Estimated Value 0.03
    Confidence Interval (2-Sided) 95%
    -0.01 to 0.09
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    16. Secondary Outcome
    Title Percentage of Participants With Good or Moderate European League Against Rheumatism (EULAR) Responses at Week 12
    Description EULAR Responder index based on 28 joint counts categorizes clinical response based on improvement since baseline in DAS28-CRP. DAS28-CRP scores range from 0-9.4, where lower scores indicated less disease activity. High disease activity: DAS28-CRP >5.1, low disease activity: DAS28-CRP <3.2, and remission: DAS28-CRP <2.6. EULAR DAS28-CRP responder index: good (absolute: <3.2 or >1.2 improvement from baseline), moderate (absolute: 3.2-5.1 or 0.6-1.2 improvement from baseline), or no response (absolute: >5.1 or <0.6 improvement from baseline). Percentage of Participants With Good or Moderate EULAR Responses were reported.
    Time Frame Week 12

    Outcome Measure Data

    Analysis Population Description
    The mITT analysis set included all randomized participants who received at least one dose of IMP (M2951 or placebo).
    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Measure Participants 97 98 96 99
    Number [percentage of participants]
    54.6
    56.3%
    65.3
    66.6%
    66.7
    69.5%
    71.7
    72.4%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, M2951 25 mg QD
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Response rate difference
    Estimated Value 0.11
    Confidence Interval (2-Sided) 95%
    -0.03 to 0.24
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, M2951 75 mg QD
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Response rate difference
    Estimated Value 0.12
    Confidence Interval (2-Sided) 95%
    -0.02 to 0.25
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Placebo, M2951 50 mg BID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Response rate difference
    Estimated Value 0.18
    Confidence Interval (2-Sided) 95%
    0.05 to 0.31
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    17. Secondary Outcome
    Title American College of Rheumatology (ACR) Hybrid Scores Computed Using High-Sensitivity C-reactive Protein (hsCRP)
    Description The hybrid ACR combines the ACR 20/50/70 response with the mean percent change in all 7 ACR core components, thus providing a percent improvement from baseline on a continuous scale. For each participant, the mean percent improvement from baseline across the 7 ACR core set measures (tender joint count, swollen joint count, Patient's Global Assessment of Disease Activity, Physician's Global Assessment of Disease Activity, disability index of the Health Assessment Questionnaire [HAQ], and C-reactive protein [CRP]) was calculated (a positive change indicated improvement, and the maximum worst change was limited to -100%) and the ACR20, ACR50, and ACR70 response is determined. The hybrid ACR is determined from a reference table taking into account both ACR response and mean percent improvement in the core set measures. Scores can range from -100% (maximal worsening) to 100% (maximal improvement).
    Time Frame Baseline, Week 12

    Outcome Measure Data

    Analysis Population Description
    The mITT analysis set included all randomized participants who received at least one dose of IMP (M2951 or placebo). Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.
    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Measure Participants 96 97 96 98
    Mean (Standard Deviation) [percent change]
    26.51
    (25.779)
    34.66
    (29.033)
    33.09
    (27.724)
    36.99
    (26.241)
    18. Secondary Outcome
    Title Change From Baseline in Disease Activity Score (DAS) Based on a 28 Joint Count-High-Sensitivity C-reactive Protein (DAS28-hsCRP) at Week 12
    Description DAS28 was a composite score used for measuring disease activity in participants with rheumatoid arthritis. The calculation was based on the tender joint count (out of 28 joints), swollen joint count (out of 28 joints), hsCRP (milligrams per liter [mg/L]) and Participant's Global Assessment of Disease Activity. Total DAS28-hsCRP score ranged from 0 (none) to 9.4 (extreme disease activity). DAS28-hsCRP < 3.2 implied low disease activity and >= 3.2 to <= 5.1 implied moderate disease activity, > 5.1 implied high disease activity. DAS28-hsCRP = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.36*ln(hsCRP in mg/L +1) + 0.014* Participant's Global Assessment of Disease Activity + 0.96; ln = natural logarithm, sqrt = square root.
    Time Frame Baseline, Week 12

    Outcome Measure Data

    Analysis Population Description
    The mITT analysis set included all randomized participants who received at least one dose of IMP (M2951 or placebo). Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.
    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Measure Participants 96 97 96 98
    Mean (Standard Deviation) [units on a scale]
    -1.21
    (1.048)
    -1.45
    (1.230)
    -1.62
    (1.257)
    -1.75
    (1.229)
    19. Secondary Outcome
    Title Change From Baseline in Clinical Disease Activity Index (CDAI) at Week 12
    Description The CDAI was a composite index (without acute-phase reactant) for assessing disease activity. The CDAI was calculated based on following formula: CDAI = 28 joint count for swelling (SJC28) + 28 joint count for tenderness (TJC28) + GH + PhGA where, GH = general health component of the DAS (i.e., Participant's Global Assessment of Disease Activity, assessed using a scale of 0 to 10 centimeter (cm) Visual Analogue Scale (VAS) where 0 = very well and 10 = very poor activity and PhGA = Physician's Global Assessment of Disease Activity assessed using a scale of 0 to 10 cm VAS, where 0 = very well and 10 = very poor activity. The total CDAI score ranges from 0 to 76, where 0 (none) to 76 (extreme disease activity).
    Time Frame Baseline, Week 12

    Outcome Measure Data

    Analysis Population Description
    The mITT analysis set included all randomized participants who received at least one dose of IMP (M2951 or placebo). Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.
    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Measure Participants 96 97 96 98
    Mean (Standard Deviation) [units on a scale]
    -16.9
    (13.09)
    -18.0
    (13.00)
    -18.9
    (14.33)
    -20.3
    (13.90)
    20. Secondary Outcome
    Title Change From Baseline in Simplified Disease Activity Index (SDAI) at Week 12
    Description SDAI was numerical sum of 5 outcome parameters: 28 joint count for swelling (SJC28) + 28 joint count for tenderness (TJC28) + GH + PGA + hsCRP where, GH = general health component of the DAS (i.e., Participant's Global Assessment of Disease Activity, assessed using a scale of 0 to 10 centimeter (cm) Visual Analogue Scale (VAS) where 0 = very well and 10 = very poor activity and PhGA = Physician's Global Assessment of Disease Activity assessed using a scale of 0 to 10 cm VAS, where 0 = very well and 10 = very poor activity. The total SDAI score ranges from 0 to 86, where 0 (none) to 86 (extreme disease activity).
    Time Frame Baseline, Week 12

    Outcome Measure Data

    Analysis Population Description
    The mITT analysis set included all randomized participants who received at least one dose of IMP (M2951 or placebo). Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.
    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Measure Participants 96 97 96 98
    Mean (Standard Deviation) [units on a scale]
    -17.000
    (13.5175)
    -18.647
    (13.5957)
    -19.404
    (14.1591)
    -21.053
    (14.3720)
    21. Secondary Outcome
    Title Change From Baseline in Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 12
    Description Sixty-eight joints were assessed and classified as tender/not tender and Sixty-six joints were classified as swollen/not swollen by pressure and joint manipulation on physical examination.
    Time Frame Baseline, Week 12

    Outcome Measure Data

    Analysis Population Description
    The mITT analysis set included all randomized participants who received at least one dose of IMP (M2951 or placebo). Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.
    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Measure Participants 96 97 96 98
    TJC
    -11
    (12.0)
    -11
    (10.6)
    -13
    (13.2)
    -12
    (10.8)
    SJC
    -7
    (7.5)
    -8
    (6.1)
    -8
    (7.7)
    -8
    (6.6)
    22. Secondary Outcome
    Title Change From Baseline in Participant's Global Assessment of Disease Activity Based on Visual Analog Scale (VAS) Score at Week 12
    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, Week 12

    Outcome Measure Data

    Analysis Population Description
    The mITT analysis set included all randomized participants who received at least one dose of IMP (M2951 or placebo). Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.
    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Measure Participants 96 97 96 98
    Mean (Standard Deviation) [millimeter (mm)]
    -20
    (29.6)
    -19
    (27.9)
    -17
    (29.6)
    -25
    (25.7)
    23. Secondary Outcome
    Title Change From Baseline in Participant's Assessment of Pain Based on Visual Analog Scale (VAS) Score at Week 12
    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, Week 12

    Outcome Measure Data

    Analysis Population Description
    The mITT analysis set included all randomized participants who received at least one dose of IMP (M2951 or placebo). Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.
    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Measure Participants 96 97 95 98
    Mean (Standard Deviation) [millimeter]
    -21
    (24.7)
    -24
    (26.9)
    -22
    (24.7)
    -25
    (26.6)
    24. Secondary Outcome
    Title Changes From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Total Score at Week 12
    Description HAQ-DI score was an evaluation of the functional status for a participant. The 20-question instrument assessed the degree of difficulty a person had in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily living). Responses in each functional area were scored from 0, indicated no difficulty, to 3, indicated inability to perform a task in that area. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range: 0-3 where 0 = least difficulty and 3 = extreme difficulty.
    Time Frame Baseline, Week 12

    Outcome Measure Data

    Analysis Population Description
    The mITT analysis set included all randomized participants who received at least one dose of IMP (M2951 or placebo). Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.
    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Measure Participants 96 97 95 98
    Mean (Standard Deviation) [units on a scale]
    -0.38
    (0.567)
    -0.58
    (0.662)
    -0.40
    (0.658)
    -0.52
    (0.616)
    25. Secondary Outcome
    Title Change From Baseline in Physician's Global Assessment of Disease Activity Scale Based on Visual Analog Scale (VAS) Score at Week 12
    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, Week 12

    Outcome Measure Data

    Analysis Population Description
    The mITT analysis set included all randomized participants who received at least one dose of IMP (M2951 or placebo). Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.
    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Measure Participants 96 97 96 98
    Mean (Standard Deviation) [millimeter]
    -29
    (21.2)
    -33
    (26.5)
    -34
    (26.1)
    -37
    (25.3)
    26. Secondary Outcome
    Title Change From Baseline in High-Sensitivity C-reactive Protein (hsCRP) at Week 12
    Description hsCRP was the American College of Rheumatology (ACR) Core Set measure of acute phase reactant. It was measured at the central laboratory to help assess the effect of M2951 on the participant's rheumatoid arthritis.
    Time Frame Baseline, Week 12

    Outcome Measure Data

    Analysis Population Description
    The mITT analysis set included all randomized participants who received at least one dose of IMP (M2951 or placebo). Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.
    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Measure Participants 96 97 96 99
    Mean (Standard Deviation) [milligram per liter (mg/L)]
    -1.11
    (25.925)
    -6.42
    (23.280)
    -5.45
    (28.807)
    -7.69
    (23.007)
    27. Secondary Outcome
    Title Percent Change From Baseline in Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 12
    Description Sixty-eight joints were assessed and classified as tender/not tender and Sixty-six joints were classified as swollen/not swollen by pressure and joint manipulation on physical examination.
    Time Frame Baseline, Week 12

    Outcome Measure Data

    Analysis Population Description
    The mITT analysis set included all randomized participants who received at least one dose of IMP (M2951 or placebo). Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.
    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Measure Participants 96 97 96 98
    TJC
    -39
    (45.6)
    -46
    (44.2)
    -51
    (42.8)
    -49
    (37.5)
    SJC
    -46
    (52.7)
    -53
    (42.6)
    -56
    (40.3)
    -58
    (43.8)
    28. Secondary Outcome
    Title Percent Change From Baseline in Participant's Global Assessment of Disease Activity Based on Visual Analog Scale (VAS) Score at Week 12
    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, Week 12

    Outcome Measure Data

    Analysis Population Description
    The mITT analysis set included all randomized participants who received at least one dose of IMP (M2951 or placebo). Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.
    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Measure Participants 96 96 96 98
    Mean (Standard Deviation) [percent change]
    -13
    (111.0)
    -21
    (69.3)
    -13
    (65.7)
    -33
    (35.9)
    29. Secondary Outcome
    Title Percent Change From Baseline in Participant's Assessment of Pain Based on Visual Analog Scale (VAS) Score at Week 12
    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, Week 12

    Outcome Measure Data

    Analysis Population Description
    The mITT analysis set included all randomized participants who received at least one dose of IMP (M2951 or placebo). Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.
    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Measure Participants 96 97 95 99
    Mean (Standard Deviation) [percent change]
    -23
    (65.0)
    -32
    (38.4)
    -29
    (40.5)
    -32
    (48.4)
    30. Secondary Outcome
    Title Percent Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Total Score at Week 12
    Description HAQ-DI score was an evaluation of the functional status for a participant. The 20-question instrument assessed the degree of difficulty a person had in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily living). Responses in each functional area were scored from 0, indicated no difficulty, to 3, indicated inability to perform a task in that area. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range: 0-3 where 0 = least difficulty and 3 = extreme difficulty.
    Time Frame Baseline, Week 12

    Outcome Measure Data

    Analysis Population Description
    The mITT analysis set included all randomized participants who received at least one dose of IMP (M2951 or placebo). Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.
    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Measure Participants 95 97 95 98
    Mean (Standard Deviation) [percent change]
    -20.09
    (40.084)
    -31.85
    (37.124)
    -21.27
    (44.571)
    -27.12
    (42.624)
    31. Secondary Outcome
    Title Percent Change From Baseline in Physician's Global Assessment of Disease Activity Scale Based on Visual Analog Scale (VAS) Score at Week 12
    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, Week 12

    Outcome Measure Data

    Analysis Population Description
    The mITT analysis set included all randomized participants who received at least one dose of IMP (M2951 or placebo). Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.
    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Measure Participants 96 97 96 98
    Mean (Standard Deviation) [percent change]
    -42
    (31.4)
    -44
    (51.9)
    -47
    (34.9)
    -52
    (33.5)
    32. Secondary Outcome
    Title Percent Change From Baseline in High-Sensitivity C-reactive Protein (hsCRP) at Week 12
    Description hsCRP was the American College of Rheumatology (ACR) Core Set measure of acute phase reactant. It was measured at the central laboratory to help assess the effect of M2951 on the participant's rheumatoid arthritis.
    Time Frame Baseline, Week 12

    Outcome Measure Data

    Analysis Population Description
    The mITT analysis set included all randomized participants who received at least one dose of IMP (M2951 or placebo). Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.
    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Measure Participants 96 97 96 99
    Mean (Standard Deviation) [percent change]
    95.01
    (380.161)
    10.93
    (167.257)
    182.57
    (1775.154)
    -13.91
    (105.688)
    33. Secondary Outcome
    Title Change From Baseline in Synovitis Score According to the Outcomes Measures in Rheumatology Clinical Trials Rheumatoid Arthritis Magnetic Resonance Imaging Scoring System (OMERACT RAMRIS) at Week 12
    Description A total of 8 joints in the hand and wrist were evaluated for RAMRIS synovitis. Individual joint scores were assessed on a scale of 0 (no synovitis) to 3 (67 to 100 percent volume enhancement). The final synovitis score was the sum of the individual joint scores. The total score from 8 joints ranges from 0 to 24, with 0 implying normal (no synovitis) and 24 implying 67 to 100 percent volume enhancement.
    Time Frame Baseline, Week 12

    Outcome Measure Data

    Analysis Population Description
    The Magnetic Resonance Imaging (MRI) analysis set included all randomized participants who have at least at least 1 pre-dose and 1 post-dose MRI assessment. Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.
    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Measure Participants 44 49 47 51
    Mean (Standard Deviation) [units on a scale]
    0
    (1.9)
    -1
    (2.5)
    -1
    (3.4)
    -1
    (2.4)
    34. Secondary Outcome
    Title Change From Baseline in Bone Marrow Edema (Osteitis) Score According to the Outcomes Measures in Rheumatology Clinical Trials Rheumatoid Arthritis Magnetic Resonance Imaging Scoring System (OMERACT RAMRIS) at Week 12
    Description A total of 25 locations in the hand and wrist were evaluated for RAMRIS bone edema or osteitis. Individual location scores range from 0 (no edema) to 3 (67 to 100 percent involvement of original articular bone) based on the proportion of estimated originally non-eroded bone involved. The final bone edema or osteitis score is the sum of the individual location scores. The total score from the 25 locations ranges from 0 to 75, with 0 implying no bone edema or osteitis and 75 implying 67 to 100 percent involvement of original articular bone.
    Time Frame Baseline, Week 12

    Outcome Measure Data

    Analysis Population Description
    The MRI analysis set included all randomized participants who have at least at least 1 pre-dose and 1 post-dose MRI assessment. Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.
    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Measure Participants 44 49 47 51
    Mean (Standard Deviation) [units on a scale]
    -1
    (5.8)
    0
    (4.6)
    0
    (5.4)
    0
    (4.0)
    35. Secondary Outcome
    Title Change From Baseline in Physical Function Using Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 12
    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, Week 12

    Outcome Measure Data

    Analysis Population Description
    Quality of Life (QoL) Analysis Set: all randomized participants who have received at least 1 dose of IMP (M2951 or placebo) and had at least 1 Baseline and 1 post baseline QoL assessment. "Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.
    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Measure Participants 87 93 86 92
    Mean (Standard Deviation) [units on a scale]
    -0.41
    (0.543)
    -0.61
    (0.637)
    -0.45
    (0.657)
    -0.53
    (0.631)
    36. Secondary Outcome
    Title Change From Baseline in the Short-Form (SF-36) Health Survey Physical Component Score and Mental Component Score at Week 12
    Description The 36-Item Short-Form Health Survey (SF-36) was a standardized survey evaluating 8 aspects of functional health and well-being. These eight subscales were summarized as relating to either physical health or mental health. Physical component summary (PCS) was based primarily on physical functioning, role-physical, bodily pain, and general health scales and mental component summary (MCS) encompasses vitality, social functioning, role-emotional, and mental health scales. Score from mental health, role emotional, social functioning, and vitality domains were averaged to calculate MCS. Total score range for MCS was 0-100 (100 = highest level of mental functioning). Score from physical function, role physical, bodily pain, and general health domains were averaged to calculate PCS. Total score range for PCS was 0-100 (100 = highest level of physical functioning).
    Time Frame Baseline, Week 12

    Outcome Measure Data

    Analysis Population Description
    QoL analysis set: all randomized participants who have received at least 1 dose of IMP (M2951 or placebo) and had at least 1 Baseline and 1 post baseline QoL assessment. Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.
    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Measure Participants 87 93 86 92
    PCS
    5.9
    (7.10)
    7.1
    (8.50)
    6.4
    (8.50)
    7.1
    (8.28)
    MCS
    4.9
    (11.46)
    5.7
    (8.41)
    5.0
    (11.72)
    4.7
    (8.95)
    37. Secondary Outcome
    Title Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Score at Week 12
    Description The FACIT-Fatigue score was calculated according to a 13-item questionnaire that assess self-reported fatigue and its impact upon daily activities and function. It uses a 5-point Likert-type scale (0 = not at all; 1 = a little bit; 2 = somewhat; 3 = quite a bit; 4 = very much). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worse possible score) to 52 (best score). A higher score reflected an improvement in the participant's health status.
    Time Frame Baseline, Week 12

    Outcome Measure Data

    Analysis Population Description
    QoL analysis set included all randomized participants who have received at least 1 dose of IMP (M2951 or placebo) and had at least 1 Baseline and 1 post Baseline QoL assessment. Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.
    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    Measure Participants 87 93 86 92
    Mean (Standard Deviation) [units on a scale]
    9
    (11.4)
    10
    (9.4)
    9
    (9.0)
    8
    (10.7)

    Adverse Events

    Time Frame up to Week 16
    Adverse Event Reporting Description
    Arm/Group Title Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Arm/Group Description Participants received placebo matched to M2951 orally for 12 weeks. Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. Participants received 75 mg of M2951 orally QD for 12 weeks. Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.
    All Cause Mortality
    Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/97 (0%) 0/98 (0%) 0/96 (0%) 0/99 (0%)
    Serious Adverse Events
    Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 2/97 (2.1%) 2/98 (2%) 2/96 (2.1%) 1/99 (1%)
    Hepatobiliary disorders
    Hepatotoxicity 0/97 (0%) 0/98 (0%) 0/96 (0%) 1/99 (1%)
    Immune system disorders
    Hypersensitivity 0/97 (0%) 1/98 (1%) 0/96 (0%) 0/99 (0%)
    Infections and infestations
    Osteomyelitis 0/97 (0%) 0/98 (0%) 1/96 (1%) 0/99 (0%)
    Sinusitis 0/97 (0%) 1/98 (1%) 0/96 (0%) 0/99 (0%)
    Injury, poisoning and procedural complications
    Tibia fracture 0/97 (0%) 0/98 (0%) 1/96 (1%) 0/99 (0%)
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease 1/97 (1%) 0/98 (0%) 0/96 (0%) 0/99 (0%)
    Vascular disorders
    Lymphoedema 0/97 (0%) 1/98 (1%) 0/96 (0%) 0/99 (0%)
    Thrombophlebitis superficial 1/97 (1%) 0/98 (0%) 0/96 (0%) 0/99 (0%)
    Other (Not Including Serious) Adverse Events
    Placebo M2951 25 mg QD M2951 75 mg QD M2951 50 mg BID
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 11/97 (11.3%) 13/98 (13.3%) 8/96 (8.3%) 17/99 (17.2%)
    Blood and lymphatic system disorders
    Anaemia 6/97 (6.2%) 2/98 (2%) 3/96 (3.1%) 7/99 (7.1%)
    Metabolism and nutrition disorders
    Dyslipidaemia 0/97 (0%) 5/98 (5.1%) 0/96 (0%) 2/99 (2%)
    Nervous system disorders
    Headache 5/97 (5.2%) 6/98 (6.1%) 5/96 (5.2%) 8/99 (8.1%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    Results Point of Contact

    Name/Title Communication Center
    Organization Merck KGaA, Darmstadt, Germany
    Phone +49-6151-72-5200
    Email service@emdgroup.com
    Responsible Party:
    EMD Serono Research & Development Institute, Inc.
    ClinicalTrials.gov Identifier:
    NCT03233230
    Other Study ID Numbers:
    • MS200527-0060
    • 2017-000384-32
    First Posted:
    Jul 28, 2017
    Last Update Posted:
    Sep 28, 2020
    Last Verified:
    Aug 1, 2020