Phase IIb Study of Evobrutinib in Subjects With Rheumatoid Arthritis

• ClinicalTrials.gov Identifier: NCT03233230
• Recruitment Status: Completed
• First Posted: July 28, 2017
• Results First Posted: September 28, 2020
• Last Update Posted: September 28, 2020
• Sponsor: EMD Serono Research & Development Institute, Inc.
• Collaborator: Merck KGaA, Darmstadt, Germany
• Information provided by (Responsible Party): EMD Serono ( EMD Serono Research & Development Institute, Inc. )

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
Rheumatoid Arthritis	Drug: M2591 25 mg QD; Drug: M2951 75 mg QD; Drug: M2951 50 mg BID; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• 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: September 18, 2017
• Actual Primary Completion Date: September 23, 2019
• Actual Study Completion Date: September 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 Name: Evobrutinib
Experimental: M2951 75 mg QD	Drug: M2951 75 mg QD; Participants received 75 mg of M2951 orally QD for 12 weeks.; Other Name: 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 Name: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

United States, Arizona

Arizona Arthritis & Rheumatology Associates, P.C.

Phoenix, Arizona, United States, 85032

Arizona Arthritis & Rheumatology Research, PLLC

Phoenix, Arizona, United States, 85037

United States, California

East Bay Rheumatology Medical Group, Inc.

San Leandro, California, United States, 94578

United States, Florida

Omega Research Consultants

DeBary, Florida, United States, 32713

Clinical Research of West Florida, Inc.

Tampa, Florida, United States, 33603

McIlwain Medical Group, PA

Tampa, Florida, United States, 33614

United States, North Carolina

Medication Management, LLC

Greensboro, North Carolina, United States, 27410

United States, Texas

Arthritis Clinic Of Central Texas

San Marcos, Texas, United States, 78666

Argentina

Hospital Italiano de La Plata

La Plata, Buenos Aires, Argentina, B1900AXI

Instituto de Investigaciones Clinicas

Mar del Plata, Buenos Aires, Argentina, B7600FZ

Instituto Medico CER

Quilmes, Buenos Aires, Argentina, B1878DVB

Instituto de Investigaciones Clinicas Quilmes

Quilmes, Buenos Aires, Argentina, B1878GEG

Centro Medico Privado de Reumatologia

Tucuman, San Miguel De Tucuman, Argentina, T4000AXL

Centro de Investigaciones Reumatológicas

San Miguel de Tucuman, Tucuman, Argentina, T4000BRD

Organizacion Medica de Investigacion (OMI)

Ciudad Autonoma Buenos Aires, Argentina, C1015ABO

APRILLUS

Ciudad Autonoma Buenos Aires, Argentina, C1046AAQ

Expertia S.A- Mautalen Salud e Investigación

Ciudad Autonoma Buenos Aires, Argentina, C1128AAE

Hospital General de Agudos Dr. J. M. Ramos Mejia

Ciudad Autonoma Buenos Aires, Argentina, C1221ADC

ILAIM-CEOM Inst. Latinoamericano de Inv. Medicas

Cordoba, Argentina, X5000BNB

Instituto Reumatológico Strusberg

Cordoba, Argentina, X5000EDC

Centro Polivalente de Asistencia e Inv. Clinica CER

San Juan, Argentina, 5400

Bulgaria

MHAT "Hadzhi Dimitar", OOD

Sliven, Bulgaria, 8800

DCC "Alexandrovska", EOOD

Sofia, Bulgaria, 1431

UMHAT "SofiaMed", OOD

Sofia, Bulgaria, 1797

Chile

Centro Medico Prosalud

Santiago, Chile, 7500000

Interin

Santiago, Chile, 7500010

BioMedica Research Group

Santiago, Chile, 7500710

Centro de Estudios Reumatologicos

Santiago, Chile, 7501126

Colombia

Centro de Reumatologia y Ortopedia SAS

Barranquilla, Colombia, 080001

Riesgo de Fractura S.A.

Bogota, Colombia, 110221

Simedics Ips Sas

Bogotá, Colombia, 111211

Centro de Investigacion en Reumatologia y Especialidades Medicas SAS. CIREEM

Bogotá, Colombia

Servimed S.A.S.

Bucaramanga, Colombia, 680003

Clinica de Artritis Temprana S.A.

Cali, Colombia, 76001

Czechia

Revmatolog, s.r.o

Jihlava, Czechia, 586 01

ARTROSCAN s.r.o.

Ostrava - Trebovice, Czechia, 722 00

CCBR Ostrava s.r.o.

Ostrava, Czechia, 702 00

CLINTRIAL s.r.o.

Praha 10, Czechia, 100 00

Thomayerova nemocnice

Praha 4 - Krc, Czechia, 140 59

MUDR. Zuzana URBANOVA Revmatologie

Praha 4 Nusle, Czechia, 140 00

MUDR. Zuzana URBANOVA Revmatologie

Praha 4, Czechia, 140 00

MEDICAL PLUS s.r.o.

Uherske Hradiste, Czechia, 686 01

PV-MEDICAL s.r.o.

Zlin, Czechia, 760 01

Mexico

Centro Investigacion en Artritis y Osteoporosis S.C.

Mexicali, Baja California Norte, Mexico, 21200

RM Pharma Specialists SA de CV

Mexico, Distrito Federal, Mexico, 03100

Clinica de Investigacion en Reumatologia y Obesidad S.C.

Guadalajara, Jalisco, Mexico, 44650

Investigacion y Biomedicina de Chihuahua, S.C.

Chihuahua, Mexico, 31000

Centro de Investigacion y Atencion Integral Durango CIAID

Durango, Mexico, 34270

Poland

ClinicMed Daniluk, Nowak Spółka Jawna

Bialystok, Poland, 15-879

Centrum Reumatologiczne Indywidualna Specjalistyczna Praktyka Lekarska lek. Barbara Bazela

Elblag, Poland, 82-300

MCBK Iwona Czajkowska Anna Podrażka- Szczepaniak S.C.

Grodzisk Mazowiecki, Poland, 05-825

Care Clinic

Katowice, Poland, 40-060

Silmedic sp. z o.o

Katowice, Poland, 40-282

GLOBE CLINICAL RESEARCH (Globe Badania Kliniczne Sp z o.o.)

Klodzko, Poland, 57-300

Indywidualna Specjalistyczna Praktyka Lekarska Maciej Zymla

Knurow, Poland, 44-190

Malopolskie Centrum Medyczne s.c.

Krakow, Poland, 30-510

Grazyna Pulka Specjalistyczny Osrodek "ALL-MED"

Krakow, Poland, 31-024

Centrum Badan Klinicznych S.C.

Poznan, Poland, 60-773

RCMed

Sochaczew, Poland, 96-500

Centrum Medyczne AMED

Warsaw, Poland, 03-291

Medycyna Kliniczna

Warszawa, Poland, 00-660

Rheuma Medicus Zaklad Opieki Zdrowotnej

Warszawa, Poland, 02-118

Wojskowy Instytut Medyczny

Warszawa, Poland, 04-141

Reum-Medica S.C Eliza Roszkowska

Wroclaw, Poland, 50-244

Russian Federation

Research Institute of Emergency Medical Care

St. Petersburg, Saint Petersburg, Russian Federation, 192242

Limited Liability Company "Centre of Medical Common Practice"

Novosibirsk, Russian Federation, 630091

Ultramed

Omsk, Russian Federation, 644024

SPb SBIH "Clinical Rheumatological Hospital # 25"

Saint-Petersburg, Russian Federation, 190068

LLC Medical Sanitary Unit#157

Saint-Petersburg, Russian Federation, 196066

NIH "Departmental Hospital on Station Smolensk of OJSC "Russian Railways"

Smolensk, Russian Federation, 214025

SAIH of Yaroslavl region "Clinical Hospital of Emergency Medical Care n.a. N. V. Solovyev"

Yaroslavl, Russian Federation, 150003

SBHI of Yaroslavl Region "Clinical Hospital # 8"

Yaroslavl, Russian Federation, 150003

Serbia

Institute of Rheumatology_Site 1

Belgrade, Serbia, 11000

Military Medical Academy

Belgrade, Serbia, 11000

Clinical Center Bezanijska kosa

Belgrade, Serbia, 11080

Institute of Treatment and Rehabilitation "Niska Banja"

Niska Banja, Serbia, 18205

General Hospital "Dr Laza K. Lazarevic" Sabac

Sabac, Serbia, 15000

South Africa

Wits Clinical Research

Johannesburg, Gauteng, South Africa, 2193

Clinresco Centres (Pty) Ltd

Kempton Park, Gauteng, South Africa, 1619

Emmed Research

Pretoria, Gauteng, South Africa, 0002

University of Pretoria Clinical Research Unit

Pretoria, Gauteng, South Africa, 0002

Naidoo, A

Durban, KwaZulu-Natal, South Africa, 4319

Arthritis Clinical Research Trial Unit

Cape Town, Western Cape, South Africa, 7405

Winelands Medical Research Centre

Stellenbosch, Western Cape, South Africa, 7600

Ukraine

Regional CH Dep of Rheumatology SHEI Ivano-Frankivsk NMU

Ivano-Frankivsk, Ukraine, 76008

GI L.T.Malaya Therapy National Institute of the NAMS of Ukraine

Kharkiv, Ukraine, 61039

Communal Institution of Healthcare Kharkiv City Clinical Hospital #8

Kharkiv, Ukraine, 61176

Medical Center Medical Clinic Blagomed LLC

Kyiv, Ukraine, 01601

Med Center 'Ok!Clinic+' of International Institute of Clinical Trials LLC

Kyiv, Ukraine, 02091

Medical Center of Revmotsentr LLC

Kyiv, Ukraine, 04070

SI D.F.Chebotariov Institute of Gerontology of NAMSU

Kyiv, Ukraine, 04114

CH of State Border Service of Ukraine (Military Base 2522) Dept of Therapy, D.Halytskyi Lviv NMU

Lviv, Ukraine, 79049

M.V. Sklifosovskyi Poltava RCH Dept of Rheumatology HSEIU UMSA

Poltava, Ukraine, 36011

A.Novak Transcarpathian Regional Clinical Hospital

Uzhgorod, Ukraine, 88000

National Pirogov Memorial Medical University

Vinnytsia, Ukraine, 21018

CI City Hospital #1

Zaporizhzhia, Ukraine, 69104

CI Zaporizhzhia Regional Clinical Hospital of ZRC

Zaporizhzhia, Ukraine, 69600

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)

Documents provided by EMD Serono ( EMD Serono Research & Development Institute, Inc. ):

Study Protocol  [PDF] July 12, 2018

Statistical Analysis Plan  [PDF] October 14, 2019

More Information

Additional Information:

Trial Awareness and Transparency website 

US Medical Information website, Medical Resources 

• Responsible Party: EMD Serono Research & Development Institute, Inc.
• ClinicalTrials.gov Identifier: NCT03233230
• Other Study ID Numbers: MS200527-0060; 2017-000384-32 ( EudraCT Number )
• First Posted: July 28, 2017
• Results First Posted: September 28, 2020
• Last Update Posted: September 28, 2020
• Last Verified: August 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Per company policy, following approval of a new product or a new indication for an approved product in both the EU and the US, EMD Serono will share study protocols, anonymized patient level and study level data and redacted clinical study reports from clinical trials in patients with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website https://www.emdgroup.com/en/research/our-approach-to-research-and-development/healthcare/clinical-trials/commitment-responsible-data-sharing.html

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by EMD Serono ( 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; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases