Abatacept to Silence Anti-citrullinated Protein Antibody-expressing B Cells in Rheumatoid Arthritis (ASCARA).
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 发起方
- 入组人数
- 46
- 试验地点
- 1
- 主要终点
- Percentage of ACPA-expressing B cells that express the marker Ki-67
研究概览
简要总结
To investigate the effect of CTLA4-Ig (abatacept) on phenotype, transcriptional profile, B cell receptor usage and functional parameters of circulating B cells expressing anticitrullinated protein antibodies (ACPA) in patients with early, methotrexate-naïve, ACPA positive rheumatoid arthritis.
详细描述
B cells expressing anti citrullinated protein antibodies (ACPA) in patients with rheumatoid arthritis (RA) display an activated, proliferative phenotype. Experimental data indicate that ACPA and ACPA-expressing B cells are actively involved in driving the disease process in RA. The present study is based on the hypothesis that targeted intervention with CTLA4-Ig (abatacept) as a means to interfere with T cell help for B cells in early, active, ACPA-positive rheumatoid arthritis can reverse the activated, proliferative phenotype of citrullinated antigen-specific B cells.
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
- 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
- •Each patient must:
- •have a diagnosis of rheumatoid arthritis according to the revised 2010 EULAR/ACR criteria for classification of RA
- •have a positive test for the presence of anti-citrullinated protein antibodies (ACPA) in serum as determined by routine clinical assay.
- •have adequate hematologic function (ANC ≥ 4000 cells/μL, platelet count ≥ 150000/μL, and hemoglobin ≥ 10 g/dL (corresponding to 6.2 mmol/L)
- •have serum creatinine concentrations < 1.5 mg/dl and/or a normal creatinine clearance
- •if a female patient is of childbearing potential, agree to: comply with effective contraceptive measures, use adequate contraception since the last menses, use adequate contraception during the study, have a negative pregnancy test within one week of study entry
- •be willing to receive a booster vaccination against tetanus toxoid three to four weeks prior to randomization
- •be able and willing to give written informed consent prior to entry in the study
排除标准
- •Any patient who has:
- •been previously treated with either abatacept and/or methotrexate or another csDMARD
- •been previously treated with a kinase inhibitor
- •been previously treated with rituximab or another B-cell depleting agent
- •been previously treated with a biological DMARD
- •received intra-articular or systemic glucocorticoid injections or has required treatment for acute RA flare (not being part of a regular therapeutic regimen) within four weeks prior to randomization or requires narcotic analgesics other than those accepted by the investigator for analgesia (e.g. paracetamol, codeine, tramadol)
- •been tested negative for anti citrullinated protein antibodies
- •contraindications for a booster vaccination against tetanus toxoid prior to randomization to the treatment arms; if a patient refuses booster vaccination but has detectable numbers of tetanus toxoid-specific B cells circulating in peripheral blood prior to the baseline visit, the patient can still be allowed to participate in the study at the judgement of the investigator.
- •evidence of any other major chronic inflammatory disease (i.e. psoriasis, psoriatic arthritis, spondyloarthritis or inflammatory bowel disease)
- •evidence of poorly controlled diabetes, history of clinically significant pulmonary disease including interstitial lung disease or methotrexate-induced lung disease, poorly controlled asthma or a history of severe life-threatening asthma attacks, history of active tuberculosis, history of latent tuberculosis without adequate medical treatment, liver cirrhosis or fibrosis, significant active infection or any underlying diseases that could predispose the subject to infections
- •liver function abnormality (total bilirubin ≥ 1.5x the upper limit of normal range, AST, ALT ≥ 3x upper limit of normal range)
- •concurrent treatment with an experimental drug or who has participated in another clinical trial with an investigational drug within 30 days prior to study entry
- •pre-existing sensory or motor polyneuropathy ≥ Grade 2 according to NCI CTC
- •past or current history of neoplasms, except for curatively treated non-melanoma skin cancer, adequately treated in situ carcinoma of the cervix or another cancer curatively treated and with no evidence of disease for at least 10 years
- •significant cardiac disease, cardiac arrhythmia (Lown Grade ≥ III), uncontrolled hypertension or recent history of myocardial ischemia
- •pregnant or nursing women
研究组 & 干预措施
Combination therapy (MTX/abatacept)
Treatment with a combination of methotrexate (10 - 25 mg once weekly) and abatacept (125 mg subcutaneously once weekly) for 6 months, followed by methotrexate monotherapy (10 - 25 mg once weekly) for another 6 months.
干预措施: Abatacept (Drug)
Combination therapy (MTX/abatacept)
Treatment with a combination of methotrexate (10 - 25 mg once weekly) and abatacept (125 mg subcutaneously once weekly) for 6 months, followed by methotrexate monotherapy (10 - 25 mg once weekly) for another 6 months.
干预措施: Methotrexate (Drug)
Methotrexate (MTX) monotherapy
Treatment with methotrexate monotherapy (10 - 25 mg once weekly) for 12 months.
干预措施: Methotrexate (Drug)
结局指标
主要结局
Percentage of ACPA-expressing B cells that express the marker Ki-67
时间窗: 24 weeks
Flow cytometry-based determination of the percentage of ACPA-expressing B cells that stain positive for Ki-67, circulating in peripheral blood of patients with early, ACPA-positive rheumatoid arthritis.
次要结局
- Change in disease activity(24 weeks)
研究者
Hans Ulrich Scherer
Principal Investigator
Leiden University Medical Center