Open-Label, Phase IIIb Study to Evaluate the Efficacy and Safety of Subcutaneous (SC) Tocilizumab Monotherapy or Combination Therapy With Methotrexate (MTX) or Other Non-Biologic Disease Modifying Anti-Rheumatic Drugs (DMARDs) in Patients With Active Rheumatoid Arthritis (RA) Who Have an Inadequate Response to Current Non-Biologic DMARD Therapy or the First Anti-Tumour Necrosis Factor (Anti-TNF) Biologic Agent
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 162
- 试验地点
- 38
- 主要终点
- Change From Baseline in Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS28-ESR) at Week 2
研究概览
简要总结
This open-label study will evaluate the efficacy and safety of tocilizumab as monotherapy or in combination with methotrexate or other non-biologic disease modifying anti-rheumatic drugs (DMARDs) in participants with active rheumatoid arthritis (RA) and an inadequate response to current non-biologic DMARD therapy or the first anti-tumour necrosis factor (anti-TNF) agent. Participants will receive tocilizumab 162 milligrams (mg) subcutaneously once a week for 52 weeks.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Active RA according to the revised (1987) ACR criteria or EULAR/ACR (2010) criteria
- •Participants who have an inadequate response to current non-biologic DMARD therapy or the first anti-TNF agent (in monotherapy or in combination with MTX or other non-biologic DMARDs). Inadequate response to anti-TNF treatment is defined as DAS28 score improvement of less than 1.2 or participants achieving a DAS28 score improvement of 1.2 but not achieving low disease activity (current DAS28-ESR above 3.2) according to a treat-to-target strategy and have not been previously exposed to treatment with tocilizumab. Inadequate response to non-biologic DMARD therapy will be assessed according to local guidelines and the participants will need to be eligible for biologic therapy according to local guidelines
- •Oral corticosteroids (≤10 mg/day prednisone or equivalent) and non-steroidal anti-inflammatory drugs (NSAIDs; up to recommended dose) are permitted if on stable dose regimen for greater than or equal to [≥] 4 weeks prior to baseline
- •Permitted non-biologic DMARDs are allowed if on stable dose for at least 4 weeks prior to baseline
- •Receiving treatment on an outpatient basis, not including tocilizumab
- •Females of childbearing potential and males with female partners of childbearing potential must agree to use reliable means of contraception as defined by protocol during the study and for at least 3 months following the last dose of tocilizumab
排除标准
- •Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months following baseline
- •Rheumatic autoimmune disease other than RA
- •Functional Class IV as defined by the ACR Classification of Functional Status in Rheumatoid Arthritis
- •Diagnosis of juvenile idiopathic arthritis or juvenile RA and/or RA before the age of 16
- •Prior history of or current inflammatory joint disease other than RA
- •Exposure to tocilizumab either intravenous or SC at any time prior to baseline
- •Treatment with any investigational agent within 4 weeks (or 5 half-lives of the investigational drug, whichever is longer) of screening
- •Intra-articular or parenteral corticosteroids within 4 weeks prior to baseline
- •History of severe allergic or anaphylactic reactions to human, humanized or murine monoclonal antibodies
- •Known active current or history of recurrent infections
- •Major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks of screening
- •Active tuberculosis (TB) requiring treatment within the previous 3 years
- •Positive for hepatitis B or hepatitis C virus infection
- •Primary or secondary immunodeficiency (history of or currently active)
- •Pregnant or lactating women
- •Inadequate hematologic, renal or liver function
研究组 & 干预措施
Tocilizumab Monotherapy
Participants will receive a weekly SC injection of tocilizumab 162 mg as monotherapy for 52 weeks.
干预措施: Tocilizumab (Drug)
Tocilizumab in Combination With Methotrexate or Other DMARDs
Participants will receive a weekly SC injection of tocilizumab 162 mg in combination with methotrexate or other non-biologic DMARDs for 52 weeks.
干预措施: Tocilizumab (Drug)
Tocilizumab in Combination With Methotrexate or Other DMARDs
Participants will receive a weekly SC injection of tocilizumab 162 mg in combination with methotrexate or other non-biologic DMARDs for 52 weeks.
干预措施: DMARDs (Drug)
Tocilizumab in Combination With Methotrexate or Other DMARDs
Participants will receive a weekly SC injection of tocilizumab 162 mg in combination with methotrexate or other non-biologic DMARDs for 52 weeks.
干预措施: Oral Corticosteroids (Drug)
Tocilizumab in Combination With Methotrexate or Other DMARDs
Participants will receive a weekly SC injection of tocilizumab 162 mg in combination with methotrexate or other non-biologic DMARDs for 52 weeks.
干预措施: Methotrexate (Drug)
结局指标
主要结局
Change From Baseline in Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS28-ESR) at Week 2
时间窗: Baseline, Week 2
DAS28 was calculated from swollen joint count (SJC) and tender joint count (TJC) using 28 joints count, erythrocyte sedimentation rate (ESR; millimeters per hour \[mm/hour\]), and patient's global assessment of disease activity (measured on a 0 to 100 mm Visual Analog Scale \[VAS\] where 0 mm=no disease activity and 100 mm=worst disease activity). DAS28 scores were calculated as \[0.56 × square root of TJC\] + \[0.28 × square root of SJC\] + \[0.70 × natural log (ESR)\] + \[0.014 × VAS\]. Total score range: 0-10, higher score=higher disease activity. DAS28-ESR greater than or equal to (≥) 2.6 to less than or equal to (≤) 3.2 implied low disease activity, greater than (\>) 3.2 to ≤5.1 implied moderate disease activity, \>5.1 implied high/severe disease, and less than (\<) 2.6 implied clinical remission.
Change From Baseline in DAS28-ESR at Week 4
时间窗: Baseline, Week 4
DAS28 was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and patient's global assessment of disease activity (measured on a 0 to 100 mm VAS where 0 mm=no disease activity and 100 mm=worst disease activity). DAS28 scores were calculated as \[0.56 × square root of TJC\] + \[0.28 × square root of SJC\] + \[0.70 × natural log (ESR)\] + \[0.014 × VAS\]. Total score range: 0-10, higher score=higher disease activity. DAS28-ESR ≥2.6 to ≤3.2 implied low disease activity, \>3.2 to ≤5.1 implied moderate disease activity, \>5.1 implied high/severe disease, and \<2.6 implied clinical remission.
Change From Baseline in DAS28-ESR at Week 8
时间窗: Baseline, Week 8
DAS28 was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and patient's global assessment of disease activity (measured on a 0 to 100 mm VAS where 0 mm=no disease activity and 100 mm=worst disease activity). DAS28 scores were calculated as \[0.56 × square root of TJC\] + \[0.28 × square root of SJC\] + \[0.70 × natural log (ESR)\] + \[0.014 × VAS\]. Total score range: 0-10, higher score=higher disease activity. DAS28-ESR ≥2.6 to ≤3.2 implied low disease activity, \>3.2 to ≤5.1 implied moderate disease activity, \>5.1 implied high/severe disease, and \<2.6 implied clinical remission.
Change From Baseline in DAS28-ESR at Week 20
时间窗: Baseline, Week 20
DAS28 was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and patient's global assessment of disease activity (measured on a 0 to 100 mm VAS where 0 mm=no disease activity and 100 mm=worst disease activity). DAS28 scores were calculated as \[0.56 × square root of TJC\] + \[0.28 × square root of SJC\] + \[0.70 × natural log (ESR)\] + \[0.014 × VAS\]. Total score range: 0-10, higher score=higher disease activity. DAS28-ESR ≥2.6 to ≤3.2 implied low disease activity, \>3.2 to ≤5.1 implied moderate disease activity, \>5.1 implied high/severe disease, and \<2.6 implied clinical remission.
Change From Baseline in DAS28-ESR at Week 24
时间窗: Baseline, Week 24
DAS28 was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and patient's global assessment of disease activity (measured on a 0 to 100 mm VAS where 0 mm=no disease activity and 100 mm=worst disease activity). DAS28 scores were calculated as \[0.56 × square root of TJC\] + \[0.28 × square root of SJC\] + \[0.70 × natural log (ESR)\] + \[0.014 × VAS\]. Total score range: 0-10, higher score=higher disease activity. DAS28-ESR ≥2.6 to ≤3.2 implied low disease activity, \>3.2 to ≤5.1 implied moderate disease activity, \>5.1 implied high/severe disease, and \<2.6 implied clinical remission.
Change From Baseline in DAS28-ESR at Week 28
时间窗: Baseline, Week 28
DAS28 was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and patient's global assessment of disease activity (measured on a 0 to 100 mm VAS where 0 mm=no disease activity and 100 mm=worst disease activity). DAS28 scores were calculated as \[0.56 × square root of TJC\] + \[0.28 × square root of SJC\] + \[0.70 × natural log (ESR)\] + \[0.014 × VAS\]. Total score range: 0-10, higher score=higher disease activity. DAS28-ESR ≥2.6 to ≤3.2 implied low disease activity, \>3.2 to ≤5.1 implied moderate disease activity, \>5.1 implied high/severe disease, and \<2.6 implied clinical remission.
Change From Baseline in DAS28-ESR at Week 32
时间窗: Baseline, Week 32
DAS28 was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and patient's global assessment of disease activity (measured on a 0 to 100 mm VAS where 0 mm=no disease activity and 100 mm=worst disease activity). DAS28 scores were calculated as \[0.56 × square root of TJC\] + \[0.28 × square root of SJC\] + \[0.70 × natural log (ESR)\] + \[0.014 × VAS\]. Total score range: 0-10, higher score=higher disease activity. DAS28-ESR ≥2.6 to ≤3.2 implied low disease activity, \>3.2 to ≤5.1 implied moderate disease activity, \>5.1 implied high/severe disease, and \<2.6 implied clinical remission.
Change From Baseline in DAS28-ESR at Week 36
时间窗: Baseline, Week 36
DAS28 was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and patient's global assessment of disease activity (measured on a 0 to 100 mm VAS where 0 mm=no disease activity and 100 mm=worst disease activity). DAS28 scores were calculated as \[0.56 × square root of TJC\] + \[0.28 × square root of SJC\] + \[0.70 × natural log (ESR)\] + \[0.014 × VAS\]. Total score range: 0-10, higher score=higher disease activity. DAS28-ESR ≥2.6 to ≤3.2 implied low disease activity, \>3.2 to ≤5.1 implied moderate disease activity, \>5.1 implied high/severe disease, and \<2.6 implied clinical remission.
Change From Baseline in DAS28-ESR at Week 40
时间窗: Baseline, Week 40
DAS28 was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and patient's global assessment of disease activity (measured on a 0 to 100 mm VAS where 0 mm=no disease activity and 100 mm=worst disease activity). DAS28 scores were calculated as \[0.56 × square root of TJC\] + \[0.28 × square root of SJC\] + \[0.70 × natural log (ESR)\] + \[0.014 × VAS\]. Total score range: 0-10, higher score=higher disease activity. DAS28-ESR ≥2.6 to ≤3.2 implied low disease activity, \>3.2 to ≤5.1 implied moderate disease activity, \>5.1 implied high/severe disease, and \<2.6 implied clinical remission.
Change From Baseline in DAS28-ESR at Week 44
时间窗: Baseline, Week 44
DAS28 was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and patient's global assessment of disease activity (measured on a 0 to 100 mm VAS where 0 mm=no disease activity and 100 mm=worst disease activity). DAS28 scores were calculated as \[0.56 × square root of TJC\] + \[0.28 × square root of SJC\] + \[0.70 × natural log (ESR)\] + \[0.014 × VAS\]. Total score range: 0-10, higher score=higher disease activity. DAS28-ESR ≥2.6 to ≤3.2 implied low disease activity, \>3.2 to ≤5.1 implied moderate disease activity, \>5.1 implied high/severe disease, and \<2.6 implied clinical remission.
Change From Baseline in DAS28-ESR at Week 12
时间窗: Baseline, Week 12
DAS28 was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and patient's global assessment of disease activity (measured on a 0 to 100 mm VAS where 0 mm=no disease activity and 100 mm=worst disease activity). DAS28 scores were calculated as \[0.56 × square root of TJC\] + \[0.28 × square root of SJC\] + \[0.70 × natural log (ESR)\] + \[0.014 × VAS\]. Total score range: 0-10, higher score=higher disease activity. DAS28-ESR ≥2.6 to ≤3.2 implied low disease activity, \>3.2 to ≤5.1 implied moderate disease activity, \>5.1 implied high/severe disease, and \<2.6 implied clinical remission.
Change From Baseline in DAS28-ESR at Week 16
时间窗: Baseline, Week 16
DAS28 was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and patient's global assessment of disease activity (measured on a 0 to 100 mm VAS where 0 mm=no disease activity and 100 mm=worst disease activity). DAS28 scores were calculated as \[0.56 × square root of TJC\] + \[0.28 × square root of SJC\] + \[0.70 × natural log (ESR)\] + \[0.014 × VAS\]. Total score range: 0-10, higher score=higher disease activity. DAS28-ESR ≥2.6 to ≤3.2 implied low disease activity, \>3.2 to ≤5.1 implied moderate disease activity, \>5.1 implied high/severe disease, and \<2.6 implied clinical remission.
Change From Baseline in DAS28-ESR at Week 48
时间窗: Baseline, Week 48
DAS28 was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and patient's global assessment of disease activity (measured on a 0 to 100 mm VAS where 0 mm=no disease activity and 100 mm=worst disease activity). DAS28 scores were calculated as \[0.56 × square root of TJC\] + \[0.28 × square root of SJC\] + \[0.70 × natural log (ESR)\] + \[0.014 × VAS\]. Total score range: 0-10, higher score=higher disease activity. DAS28-ESR ≥2.6 to ≤3.2 implied low disease activity, \>3.2 to ≤5.1 implied moderate disease activity, \>5.1 implied high/severe disease, and \<2.6 implied clinical remission.
Change From Baseline in DAS28-ESR at Week 52
时间窗: Baseline, Week 52
DAS28 was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and patient's global assessment of disease activity (measured on a 0 to 100 mm VAS where 0 mm=no disease activity and 100 mm=worst disease activity). DAS28 scores were calculated as \[0.56 × square root of TJC\] + \[0.28 × square root of SJC\] + \[0.70 × natural log (ESR)\] + \[0.014 × VAS\]. Total score range: 0-10, higher score=higher disease activity. DAS28-ESR ≥2.6 to ≤3.2 implied low disease activity, \>3.2 to ≤5.1 implied moderate disease activity, \>5.1 implied high/severe disease, and \<2.6 implied clinical remission.
Change From Baseline in DAS28-ESR at Early Withdrawal
时间窗: Baseline, early withdrawal (up to Week 52)
DAS28 was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and patient's global assessment of disease activity (measured on a 0 to 100 mm VAS where 0 mm=no disease activity and 100 mm=worst disease activity). DAS28 scores were calculated as \[0.56 × square root of TJC\] + \[0.28 × square root of SJC\] + \[0.70 × natural log (ESR)\] + \[0.014 × VAS\]. Total score range: 0-10, higher score=higher disease activity. DAS28-ESR ≥2.6 to ≤3.2 implied low disease activity, \>3.2 to ≤5.1 implied moderate disease activity, \>5.1 implied high/severe disease, and \<2.6 implied clinical remission.
次要结局
- Number of Participants Achieving an American College of Rheumatology Criteria 20 (ACR20) Response(Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52))
- Number of Participants Achieving an ACR50 Response(Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52))
- Number of Participants With European League Against Rheumatism (EULAR) Response (Good, Moderate or No Response) Based on DAS28-ESR(Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52))
- Change From Baseline in Simplified Disease Activity Index (SDAI) at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at Early Withdrawal(Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52))
- Change From Baseline in Clinical Disease Activity Index (CDAI) at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at Early Withdrawal(Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52))
- Percent Change From Baseline in Total TJC on 68 Joints at Week 52(Baseline, Week 52)
- Change From Baseline in Total TJC on 28 Joints at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at Early Withdrawal(Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52))
- Percent Change From Baseline in Total SJC on 66 Joints at Week 52(Baseline, Week 52)
- Number of Participants Achieving an ACR70 Response(Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52))
- Number of Participants With Non-Biologic DMARD/Corticosteroid Dose Reductions and/or Discontinuation(Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, at early withdrawal (up to Week 52), follow-up Week 4 (up to Week 56), and follow-up Week 8 (up to Week 60))
- Percentage of Methotrexate Adherence as Assessed by Methotrexate Adherence Questionnaire(Baseline, Weeks 12, 24, 36, 52, and at early withdrawal (up to Week 52))
- Patient Global Assessment of Disease Activity VAS Score(Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52))
- Patient Pain VAS Score(Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52))
- Number of Participants Who Achieved Low Disease Activity as Defined by DAS28-ESR ≤3.2(Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52))
- Change From Baseline in Total SJC on 28 Joints at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at Early Withdrawal(Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52))
- Number of Participants Who Achieved Remission as Defined by DAS28-ESR <2.6(Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52))
- Health Assessment Questionnaire-Disability Index (HAQ-DI) Score(Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52))
- Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score(Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52))
- Number of Participants Compliant to Tocilizumab Treatment as Measured by Diary Cards and Return Records(Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52))
- Number of Participants With Anti-Tocilizumab Antibodies(Baseline, Weeks 12 and 24, at early withdrawal (up to Week 52), and follow-up visit (8 weeks after last dose of tocilizumab, up to 60 weeks))
- Serum Levels of Tocilizumab(Baseline, Weeks 12 and 24, at early withdrawal (up to Week 52), and follow-up visit (8 weeks after last dose of tocilizumab, up to 60 weeks))
- Serum Levels of Soluble Interleukin-6 Receptors (sIL-6Rs)(Baseline, Weeks 12 and 24, at early withdrawal (up to Week 52), and follow-up visit (8 weeks after last dose of tocilizumab, up to 60 weeks))