A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Retreatment With Rituximab in Subjects With Rheumatoid Arthritis Receiving Background Methotrexate
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 559
- 主要终点
- Retreated Subjects With an American College of Rheumatology 20% (ACR20) Response at Week 48 Relative to Baseline
研究概览
简要总结
This is a Phase III, randomized, double-blind, placebo-controlled, multicenter study evaluating the efficacy of retreatment with rituximab in subjects with active rheumatoid arthritis (RA) who are receiving Methotrexate (MTX).
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
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Signed informed consent form
- •Ability and willingness to comply with the requirements of the study protocol
- •Age 18-80 years
- •Diagnosis of RA for at least 6 months
- •Receiving treatment for RA on an outpatient basis
- •Documented moderate to severe active RA activity at screening and Day 1
- •Documented inadequate response to previous or current treatment with one or more of the following: etanercept, infliximab, and/or adalimumab because of toxicity or inadequate efficacy
- •Use of MTX 10-25 mg/wk for ≥ 12 weeks prior to Day 1 at a stable dose for ≥ 4 weeks
- •Willingness to receive oral folic acid
- •If taking a background corticosteroid, use of the corticosteroid must be at a stable dose during the 4 weeks prior to Day 1
- •Use of one NSAID is permitted if the dose is stable for ≥ 2 weeks prior to Day 1
- •For men and women of reproductive potential, willingness to use a reliable means of contraception for ≥ 30 days prior to Day 1 and for the study duration or the duration that the subject's peripheral CD19 B cells are depleted, whichever is longer
排除标准
- •Rheumatic autoimmune disease other than RA or significant systemic involvement secondary to RA; Secondary Sjogren's syndrome with RA is permitted.
- •History of or current inflammatory joint disease other than RA or other systemic rheumatic disorder (e.g., systemic lupus erythematosus, inflammatory bowel disease, scleroderma, inflammatory myopathy, or overlap syndrome)
- •History of deep space/tissue infection within 52 weeks prior to Day 1
- •Diagnosis of juvenile idiopathic arthritis (JIA), juvenile rheumatoid arthritis (JRA), and/or RA before age 16
- •Functional Class IV, as defined by the ACR Classification of Functional Status in Rheumatoid Arthritis
- •Any surgical procedure, including bone/joint surgery/synovectomy (including joint fusion or replacement), within 12 weeks prior to Day 1 or planned within 48 weeks after Day 1
- •Known hypersensitivity to any component of a humanized or murine monoclonal antibody
- •Receipt of any vaccination within 4 weeks prior to Day 1
- •Significant cardiac or pulmonary disease, including obstructive pulmonary disease
- •Evidence of significant uncontrolled concomitant disease, such as, but not limited to nervous system, renal, hepatic, endocrine, or gastrointestinal disorders
- •Known active bacterial, viral, fungal, mycobacterial, or other infection (including tuberculosis or atypical mycobacterial disease but excluding fungal infections of the nail beds) or any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of Day 1 or oral antibiotics within 2 weeks of Day 1
- •History of serious recurrent or chronic infection (a chest X-ray will be performed at screening if one has not been performed within 12 weeks of screening that showed no clinically significant abnormality)
- •History of or currently active primary or secondary immunodeficiency, including HIV infection
- •History of cancer, including solid tumors and hematologic malignancies (except basal cell or squamous cell carcinoma of the skin that has been excised and cured)
- •History of significant cytopenias or other bone marrow disorders
- •History of alcohol, drug, or chemical abuse within 24 weeks prior to Day 1
- •Pregnancy or lactation
- •Neuropathies and neurovasculopathies that might interfere with pain evaluation
- •Poor peripheral venous access
- •Intolerance or contraindications to oral or IV corticosteroids
- •Positive hepatitis B surface antigen or hepatitis C antibody serology
- •For women of childbearing potential (including those who have had a tubal ligation), a positive serum pregnancy test at screening
- •Current use of any DMARD other than MTX
- •Concurrent treatment with any biologic agent
- •Treatment with any investigational agent within 4 weeks prior to Day 1 or five half-lives of the investigational drug (whichever is longer)
- •Any previous treatment with rituximab or other cell-depleting therapies, including CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19, anti-CD11a, anti-CD22, anti-BLys/ BAFF, and other anti-CD20 agents
- •Previous treatment with a co-stimulation blocking agent, including abatacept
- •Previous treatment with an anti-<alpha> 4 integrin agent, including natalizumab
- •Previous treatment within 6 months of screening with IV & globulin or the Prosorba(R) Column
- •Intra-articular or parenteral corticosteroids within 4 weeks prior to Day 1
研究组 & 干预措施
Arm A: Rituximab Retreatment
1000 mg rituximab intravenous initial treatment on day 1 and day 15 plus 10-25 mg/week methotrexate followed by re-treatment during weeks 24 -40 consisting of two additional doses of 1000 mg rituximab 14 days apart plus 10-25 mg/week methotrexate.
干预措施: rituximab (Drug)
Arm A: Rituximab Retreatment
1000 mg rituximab intravenous initial treatment on day 1 and day 15 plus 10-25 mg/week methotrexate followed by re-treatment during weeks 24 -40 consisting of two additional doses of 1000 mg rituximab 14 days apart plus 10-25 mg/week methotrexate.
干预措施: methotrexate (Drug)
Arm A: Rituximab Retreatment
1000 mg rituximab intravenous initial treatment on day 1 and day 15 plus 10-25 mg/week methotrexate followed by re-treatment during weeks 24 -40 consisting of two additional doses of 1000 mg rituximab 14 days apart plus 10-25 mg/week methotrexate.
干预措施: folate (Drug)
Arm B: Placebo Retreatment
1000 mg rituximab intravenous initial treatment on day 1 and day 15 plus 10-25 mg/week methotrexate followed by retreatment during weeks 24 -40 consisting of two doses of placebo 14 days apart plus 10-25 mg/week methotrexate.
干预措施: placebo (Drug)
Arm B: Placebo Retreatment
1000 mg rituximab intravenous initial treatment on day 1 and day 15 plus 10-25 mg/week methotrexate followed by retreatment during weeks 24 -40 consisting of two doses of placebo 14 days apart plus 10-25 mg/week methotrexate.
干预措施: methotrexate (Drug)
Arm B: Placebo Retreatment
1000 mg rituximab intravenous initial treatment on day 1 and day 15 plus 10-25 mg/week methotrexate followed by retreatment during weeks 24 -40 consisting of two doses of placebo 14 days apart plus 10-25 mg/week methotrexate.
干预措施: folate (Drug)
结局指标
主要结局
Retreated Subjects With an American College of Rheumatology 20% (ACR20) Response at Week 48 Relative to Baseline
时间窗: 48 Weeks
ACR20 response was defined as a ≥ 20% improvement compared with baseline in both tender joint count (TJC) \[68 joints\] and swollen joint count (SJC) \[66 joints\] as well as a ≥ 20% improvement in three of five additional measurements: 1) Physician's Global Assessment of disease activity \[visual analog scale: 0=no disease activity to 100=maximum disease activity\]; 2) Patient's Global Assessment of Disease Activity \[visual analog scale: 0=no disease activity to 100=maximum disease activity\]; 3) Patient's Assessment of Pain \[visual analog scale: 0=no pain to 100=unbearable pain\]; 4) Health Assessment Questionnaire \[20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do\] and 5) erythrocyte sedimentation rate.
次要结局
- Percentage of Retreated Subjects With a European League Against Rheumatism (EULAR) Response at Week 48(Baseline, Week 48)
- Change From Baseline in American College of Rheumatology (ACR) Core Set Component: Subject's Global Assessment of Disease Activity at Week 48(Baseline, Week 48)
- Change From Baseline in American College of Rheumatology (ACR) Core Set Component: Subject's Assessment of Pain at Week 48(Baseline, Week 48)
- Change From Baseline in American College of Rheumatology (ACR) Core Set Component: C-Reactive Protein at Week 48(Baseline, Week 48)
- Change From Baseline in American College of Rheumatology (ACR) Core Set Component: Erythrocyte Sedimentation (ESR) at Week 48(Baseline, Week 48)
- Change From Baseline in Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) at Week 48 in Retreated Subjects(Baseline, Week 48)
- Percentage of Retreated Subjects Achieving DAS28-ESR Low Disease at Week 48(Week 48)
- Change From Baseline in Disease Activity Score (DAS28-CRP) at Week 48(Baseline, Week 48)
- Change From Baseline in American College of Rheumatology (ACR) Core Set Component: Swollen Joint Count at Week 48(Baseline, Week 48)
- Change From Baseline in American College of Rheumatology (ACR) Core Set Component: Tender Joint Count at Week 48(Baseline, Week 48)
- Change From Baseline in American College of Rheumatology (ACR) Core Set Component: Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 48(Baseline, Week 48)
- Change From Baseline in American College of Rheumatology (ACR) Core Set Component: Physician's Global Assessment of Disease Activity at Week 48(Baseline, Week 48)
- Retreated Subjects With American College of Rheumatology 50% (ACR50) Response and American College of Rheumatology 70% (ACR70) Response at Week 48 Relative to Baseline(Baseline, Week 48)
- Change From Baseline in the Disease Activity Score Using 28 Joint Counts (DAS28-ESR) at Week 48(48 weeks)
- Change From Baseline in SF-36 Health Summary Scores at Week 48 in Retreated Subjects(Baseline, Week 48)
- Percentage of Retreated Subjects Achieving DAS28-ESR Remission at Week 48(Week 48)
- Percentage of Retreated Subjects With a Change ≥ 0.22 From Baseline in HAQ-DI at Week 48(Baseline, Week 48)
- Percentage of Retreated Subjects With a Change ≥ 0.3 From Baseline in HAQ-DI at Week 48(Baseline, Week 48)
- ACRn in Retreated Subjects at Week 48(Baseline, Week 48)