NCT03233230已完成2 期
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
适应症
干预措施
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 390
- 试验地点
- 96
- 主要终点
- 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
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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).
排除标准
- •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.
研究组 & 干预措施
Placebo
Placebo Comparator
干预措施: Placebo (Drug)
M2951 25 mg QD
Experimental
干预措施: M2591 25 mg QD (Drug)
M2951 75 mg QD
Experimental
干预措施: M2951 75 mg QD (Drug)
M2951 50 mg BID
Experimental
干预措施: M2951 50 mg BID (Drug)
结局指标
主要结局
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
时间窗: 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.
次要结局
- 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)
- 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)
- Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters(up to Week 16)
- 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)
- Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Score at Week 12(Baseline, Week 12)
- Percentage of Participants Achieving American College of Rheumatology 50% Response Criteria (ACR50)(Week 12)
- Percentage of Participants Achieving American College of Rheumatology 70% Response Criteria (ACR70)(Week 12)
- 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)
- American College of Rheumatology (ACR) Hybrid Scores Computed Using High-Sensitivity C-reactive Protein (hsCRP)(Baseline, Week 12)
- 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)
- 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)
- Number of Participants With Clinically Significant Change From Baseline in Vital Signs(up to Week 16)
- Change From Baseline in B Cell Count at Week 2, 4, 8, 12 and 16(Baseline, Week 2, 4, 8, 12 and 16)
- Change From Baseline in the Short-Form (SF-36) Health Survey Physical Component Score and Mental Component Score at Week 12(Baseline, Week 12)
- Number of Participants With Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings(up to Week 16)
- Percentage of Participants With Good or Moderate European League Against Rheumatism (EULAR) Responses at Week 12(Week 12)
- Change From Baseline in Clinical Disease Activity Index (CDAI) at Week 12(Baseline, Week 12)
- Change From Baseline in Simplified Disease Activity Index (SDAI) at Week 12(Baseline, Week 12)
- Change From Baseline in Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 12(Baseline, Week 12)
- Change From Baseline in Participant's Global Assessment of Disease Activity Based on Visual Analog Scale (VAS) Score at Week 12(Baseline, Week 12)
- Change From Baseline in Participant's Assessment of Pain Based on Visual Analog Scale (VAS) Score at Week 12(Baseline, Week 12)
- Changes From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Total Score at Week 12(Baseline, Week 12)
- 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)
- Change From Baseline in High-Sensitivity C-reactive Protein (hsCRP) at Week 12(Baseline, Week 12)
- Percent Change From Baseline in Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 12(Baseline, Week 12)
- Percentage of Participants With Remission Assessed by American College of Rheumatology-European League Against Rheumatism (ACR-EULAR) Boolean at Week 12(Week 12)
- Percentage of Participants With Clinical Disease Activity Index (CDAI) Score Less Than or Equal to [=<] 2.8 at Week 12(Week 12)
- Percentage of Participants With Simplified Disease Activity Index (SDAI) Score Less Than or Equal to [=<] 3.3 at Week 12(Week 12)
- 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)
- Percent Change From Baseline in Participant's Assessment of Pain Based on Visual Analog Scale (VAS) Score at Week 12(Baseline, Week 12)
- Percent Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Total Score at Week 12(Baseline, Week 12)
- 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)
- Percent Change From Baseline in High-Sensitivity C-reactive Protein (hsCRP) at Week 12(Baseline, Week 12)
- 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)
- 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)
- Change From Baseline in Physical Function Using Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 12(Baseline, Week 12)
研究者
研究点 (96)
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