Prospective, Multicentre, Placebo-controlled, Double-blind Interventional Study to Compare the Efficacy of Maintenance Treatment With Tocilizumab With or Without Glucocorticoid Discontinuation in Rheumatoid Arthritis Patients
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 314
- 试验地点
- 39
- 主要终点
- Change From Baseline in Disease Activity Score in 28 Joints - Erythrocyte Sedimentation Rate (DAS28-ESR) at Week 24 Post-randomization
研究概览
简要总结
This Phase IIIb/IV, two-arm, randomized, double-blind, placebo-controlled, parallel-group, international, multicenter trial compares the change in disease activity (as assessed by Disease Activity Score in 28 joints [DAS28] erythrocyte sedimentation rate [ESR]) from randomization to Week 24 post-randomization, in participants with stable low disease activity [LDA] (DAS28 ESR score less than or equal to [<=] 3.2) who receive tocilizumab, and have been randomized to either continue or taper prednisone in a double-blinded fashion.
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Tocilizumab-experienced participants:
- •Comply with the requirements of the study protocol (including treatment on an outpatient basis)
- •Rheumatoid arthritis (RA) of greater than or equal to (>=) 6 months duration diagnosed according to the revised 1987 American College of Rheumatology (ACR) criteria or 2010 ACR / European League Against Rheumatism (EULAR) criteria
- •Have received tocilizumab either subcutaneous (162 milligram [mg] once in a week) or intravenously (8 milligram per kilogram [mg/kg] once every 4 weeks) for the treatment of RA for at least 24 weeks prior to randomization
- •Have received 5 - 15 milligrams per day [mg/day] of glucocorticoids (prednisone or equivalent) for the treatment of RA for at least 20 weeks prior to screening
- •Currently receiving 5 mg/day of prednisone
- •Have attained and maintained LDA (DAS28 ESR score <=3.2) or remission (DAS28 ESR score less than [<] 2.6) for at least 4 weeks prior to randomization
- •Tocilizumab-naïve participants:
- •Comply with the requirements of the study protocol (including treatment on an outpatient basis)
- •RA of >=6 months duration diagnosed according to the revised 1987 ACR criteria or 2010 ACR / EULAR criteria
- •Have active RA (defined as DAS28 ESR score greater than [>] 3.2)
- •Are considered by the investigator as inadequate responders to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) or biologic disease-modifying anti-rheumatic drugs (bDMARDs)
- •Are receiving 5 - 15 mg/day prednisone (or equivalent) for the treatment of RA
排除标准
- •Major surgery (including joint surgery) within 8 weeks prior to screening, or planned major surgery during the study and up to 6 months after randomization
- •Pregnant women or nursing (breastfeeding) mothers
- •In females of childbearing potential, a positive serum pregnancy test at screening
- •Females of childbearing potential unwilling or unable to use a reliable means of contraception (for example, physical barrier [participant or partner], contraceptive pill or patch, spermicide and barrier, or intrauterine device) during study treatment and for a minimum of 3 months after the last dose of tocilizumab
- •Body weight of >=150 kilogram (kg)
- •Lack of peripheral venous access
- •Disease-related
- •RA of functional Class 4, as defined by the ACR Classification of Functional Status in Rheumatoid Arthritis
- •Rheumatic autoimmune disease other than RA, including systemic lupus erythematosus, mixed connective tissue disease, scleroderma, polymyositis, or significant systemic involvement secondary to RA (for example, vasculitis, pulmonary fibrosis, or Felty syndrome). Secondary Sjögren syndrome with RA may be allowed per the discretion of the investigator
- •Diagnosed with juvenile idiopathic arthritis or juvenile RA and/or RA before the age of 16 years
- •Prior or current inflammatory joint disease other than RA (for example, gout, Lyme disease, sero-negative spondyloarthropathy, including reactive arthritis, psoriatic arthritis, arthropathy of inflammatory bowel disease), or prior or current joint infections
- •Previous history of primary or secondary adrenal insufficiency
- •Previous or Concomitant Prohibited Therapy
- •Treatment with any investigational agent within 4 weeks (or 5 half-lives of the investigational drug, whichever is longer) of screening
- •Previous treatment with any cell-depleting therapies, including investigational agents or approved therapies (for example, CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19, anti-CD20)
- •Treatment with intravenous gamma globulin, plasmapheresis or Prosorba column within 6 months of screening
- •Intraarticular (IA) or parenteral glucocorticoids for the treatment of RA within 4 weeks prior to screening
- •Previous treatment with glucocorticoids for conditions other than RA, at any dose and in any formulation used continuously for >1 week, during the last 1 year prior to screening. Topical glucocorticoid creams or ointments for the treatment of skin conditions (for example eczema) are allowed
- •Immunization with a live/attenuated vaccine within 30 days prior to screening. Participants must agree not to take live attenuated vaccines (including seasonal nasal flu vaccine, varicella vaccine for shingles or chickenpox, vaccines for measles, mumps or rubella without or with varicella [MMR or MMRV], oral polio vaccine and vaccines for yellow fever), within 30 days before the Screening Visit, throughout the duration of the trial and for 60 days following the last dose of study drug
- •Any previous treatment with alkylating agents such as chlorambucil or with total lymphoid irradiation
- •Laboratory Exclusion Criteria
- •Inadequate haematological, renal and liver function
- •Positive hepatitis B surface antigen or hepatitis C antibody Previous or Concomitant Conditions
- •History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies
- •Evidence of current serious uncontrolled cardiovascular (including uncontrolled hyperlipidemia), nervous system, pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes mellitus) or gastrointestinal (GI) disease
- •Current liver disease as determined by the investigator
- •History of diverticulitis, peptic ulcer disease, diverticulosis requiring antibiotic treatment, or chronic ulcerative lower GI disease such as Crohn's disease, ulcerative colitis, or other symptomatic lower gastrointestinal conditions that might predispose to perforations
- •Known active current or history of recurrent bacterial, viral, fungal, mycobacterial, or other opportunistic infections (including, but not limited to, tuberculosis [TB] and atypical mycobacterial disease, hepatitis B and C, Epstein-Barr virus, cytomegalovirus and herpes zoster, but excluding fungal infections of nail beds)
- •Neuropathies or other conditions that might interfere with pain evaluation unless related to primary disease under investigation
- •Any major episode of infection requiring hospitalization or treatment with intravenous antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior to screening
- •Active TB requiring treatment within the previous 3 years (participants previously treated for TB with no recurrence within 3 years are permitted). All Track tocilizumab-naïve participants must be screened for latent TB and if positive, should be treated following local practice guidelines prior to initiating tocilizumab
- •History of or currently active, primary or secondary immunodeficiency
- •Evidence of active malignant disease, malignancies diagnosed within the previous 10 years (including haematological malignancies and solid tumours, except basal and squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that was excised and cured), or breast cancer diagnosed within the previous 20 years
- •History of alcohol, drug or chemical abuse within 1 year prior to screening
- •Pre-existing central nervous system (CNS) demyelination or seizure disorders
- •Any medical or psychological condition that in the opinion of the principal investigator would interfere with safe completion of the trial
研究组 & 干预措施
Tocilizumab+prednisone (constant dose)
Participants will receive tocilizumab at a dose of 162 milligram (mg) once a week subcutaneously; and prednisone at a dose of 5 milligram per day (mg/day) or matching placebo orally for 24 weeks.
干预措施: Placebo matched to prednisone (Drug)
Tocilizumab+prednisone (constant dose)
Participants will receive tocilizumab at a dose of 162 milligram (mg) once a week subcutaneously; and prednisone at a dose of 5 milligram per day (mg/day) or matching placebo orally for 24 weeks.
干预措施: Prednisone (Drug)
Tocilizumab+prednisone (constant dose)
Participants will receive tocilizumab at a dose of 162 milligram (mg) once a week subcutaneously; and prednisone at a dose of 5 milligram per day (mg/day) or matching placebo orally for 24 weeks.
干预措施: Tocilizumab (Biological)
Tocilizumab+prednisone (tapering dose)
Participants will receive tocilizumab at a dose of 162 milligram (mg) once a week subcutaneously; and prednisone at a dose of 5 milligram per day (mg/day) with 1 mg decrements every 4 weeks or matching placebo orally for 24 weeks.
干预措施: Placebo matched to prednisone (Drug)
Tocilizumab+prednisone (tapering dose)
Participants will receive tocilizumab at a dose of 162 milligram (mg) once a week subcutaneously; and prednisone at a dose of 5 milligram per day (mg/day) with 1 mg decrements every 4 weeks or matching placebo orally for 24 weeks.
干预措施: Prednisone (Drug)
Tocilizumab+prednisone (tapering dose)
Participants will receive tocilizumab at a dose of 162 milligram (mg) once a week subcutaneously; and prednisone at a dose of 5 milligram per day (mg/day) with 1 mg decrements every 4 weeks or matching placebo orally for 24 weeks.
干预措施: Tocilizumab (Biological)
结局指标
主要结局
Change From Baseline in Disease Activity Score in 28 Joints - Erythrocyte Sedimentation Rate (DAS28-ESR) at Week 24 Post-randomization
时间窗: Baseline to Week 24
The DAS28 is a combined index for measuring disease activity in rheumatic arthritis (RA) and includes swollen and tender joint count, erythrocyte sedimentation rate (ESR), and general health (GH) status. The index is calculated with the following formula: DAS28 = (0.56 × √(TJC28)) + (0.28 × √(SJC28)) + (0.7 × log(ESR)) + (0.014 × GH), where TJC28 = tender joint count and SJC28 = swollen joint count, each on 28 joints. GH = a patient's global assessment of disease activity in the previous 24 hours on a 100-millimeter (mm) visual analog scale (left end = no disease activity \[symptom-free and no arthritis symptoms\], right end = maximum disease activity \[maximum arthritis disease activity\]). When ESR equaled 0 mm/hr, it was set to 1 mm/hr. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity. A positive change in score indicates worsening, and a negative change indicates improvement.
次要结局
- Treatment Success(Week 24)
- Time to First RA Flare(Randomization to 24 weeks)
- Percentage of Visits With RA Flares(Randomization to 24 weeks)
- Time to First Administration of Flare Rescue Medication(Randomization to 24 weeks)
- Change From Baseline in Clinical Disease Activity Index (CDAI) at Week 24(Baseline and Week 24)
- Number of Administrations of Flare Rescue Medication(Randomization to 24 weeks)
- Changes From Baseline in American College of Rheumatology (ACR) Core Set Components at Week 24: Swollen 66 Joint Counts(Baseline to Week 24)
- Percentage of Participants With >=1 Flare(24 weeks)
- Changes From Baseline in American College of Rheumatology (ACR) Core Set Components at Week 24: Tender 68 Joint Counts(Baseline to Week 24)
- Percentage of Participants Who Permanently Discontinue Study Treatment Due to Insufficient Flare Control(24 weeks)
- Cumulative Prednisone Exposure (Dose)(Randomization to 24 weeks)
- Percentage of Participants Who Maintain LDA (DAS28 ESR Score <=3.2) or Remission (DAS28 ESR Score <2.6) and the Percentage of Participants Who Maintain the Baseline Disease Activity Level(Randomization to Week 24)
- Percentage of Participants With >=1 Administration of Flare Rescue Medication(Randomization to 24 weeks)
- Changes From Baseline in American College of Rheumatology (ACR) Core Set Components at Week 24: Physician's Global Assessment of Disease Activity(Baseline to Week 24)
- Changes From Baseline in American College of Rheumatology (ACR) Core Set Components at Week 24: Patient's Global Assessment of Disease Activity(Baseline to Week 24)
- Changes From Baseline in American College of Rheumatology (ACR) Core Set Components at Week 24: High Sensitivity C-Reactive Protein (hsCRP)(Baseline to Week 24)
- Changes From Baseline in American College of Rheumatology (ACR) Core Set Components at Week 24: Patient's Assessment of Pain(Baseline to Week 24)
- Changes From Baseline in American College of Rheumatology (ACR) Core Set Components at Week 24: Health Assessment Questionnaire-Disability Index (HAQ-DI)(Baseline to Week 24)
- Changes From Baseline in American College of Rheumatology (ACR) Core Set Components at Week 24: Erythrocyte Sedimentation Rate (ESR)(Baseline to Week 24)
- Changes From Baseline in Rheumatoid Arthritis Impact of Disease (RAID) Final Score(Baseline and Week 24)
- Changes From Baseline in Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI:SHP) Score(Baseline and Week 24)
- Change From Baseline in Simplified Disease Activity Index (SDAI) at Week 24(Randomization to Week 24)