Januse Kinase Inhibition With Filgotinib to Silence Autoreactive B Cells in Rheumatoid Arthritis
试验速览
- 阶段
- 4 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 40
- 试验地点
- 1
- 主要终点
- Frequency of ACPA-expressing B cells
研究概览
简要总结
To investigate the effect of filgotinib on phenotype, B cell receptor (BCR) usage and functional parameters of circulating B cells expressing ACPA in patients with ACPA-positive RA that show incomplete response to standard, medium-dose methotrexate (MTX) monotherapy.
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 filgotinib as a means to interfere with the activation of B cells in early, active, ACPA-positive RA 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 RA and must have fulfilled the revised 2010 EULAR/ACR criteria for classification of RA prior to initiation of first-line treatment.
- •have a positive test for the presence of anti-citrullinated protein antibodies (ACPA) in serum with a value of at least 200 U/ml, as determined by routine clinical assay.
- •have moderate to highly active disease defined by a disease activity score evaluating 28 joints (DAS28) ≥ 3.2 or, correspondingly, an sDAI score of >
- •have used methotrexate monotherapy at a stable, maximally tolerated dose once weekly for at least 3 months; concomitant glucocorticoid therapy is allowed if at a stable dose of ≤ 7.5 mg prednisolon equivalent within 30 days prior to entry in the study.
- •have adequate hematologic function (ANC ≥ 4000 cells/μL, platelet count ≥ 150000/μL, and haemoglobin ≥ 10 g/dL (corresponding to 6.2 mmol/L)
- •have a serum creatinine clearance of > 15 ml/min.
- •be at least 18 years of age
- •if female and of childbearing potential, agree to: comply with effective contraceptive measures, use adequate contraception since the last menses and use adequate contraception during the study
- •be willing to undergo pre-treatment screening for latent tuberculosis infection by chest X-ray and Mantoux testing as well as serological screening for chronic viral hepatitis infection. As an alternative for the Mantoux test, a standardized IFN-gamma release assay may be used to assess latent tuberculosis infection.
- •be able and willing to give written informed consent prior to entry in the study
排除标准
- •Any patient who:
- •has ever been treated with rituximab or another B-cell depleting agent
- •has been treated with a biological DMARD (except rituximab) or a targeted synthetic DMARD within 6 months prior to entry in the study
- •has received intra-articular or systemic glucocorticoid injections within 30 days prior to baseline or requires narcotic analgesics other than those accepted by the investigator for analgesia (e.g. paracetamol, NSAIDs, codeine, tramadol)
- •receives concomitant treatment with a csDMARD other than methotrexate
- •has been tested negative for ACPA
- •is in clinical remission as defined by a disease activity score evaluating 28 joints (DAS28) ≤ 2.6 or, correspondingly, an sDAI ≤ 3.3
- •has evidence of a medical condition which represents a contra-indication for initiation of either a TNF-alpha inhibitor or a Janus kinase inhibitor, as outlined in the SPCs of either adalimumab and/or filgotinib.
- •has liver function abnormality (AST and/or ALT ≥ 3 x upper limit of normal range)
- •has 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
- •has past or current history of solid or haematological 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
- •is pregnant or a currently nursing woman
- •is female and of childbearing potential, unwilling to use adequate contraceptive measures during the study.
研究组 & 干预措施
Add-on filgotinib
Treatment with a combination therapy of MTX (7.5 - 15 mg once weekly) and filgotinib p.o. (200 mg once daily) for 24 weeks
干预措施: Filgotinib (Drug)
Add-on adalimumab
Treatment with a combination therapy of MTX (7.5 - 15 mg once weekly) and adalimumab s.c. (40 mg biweekly) for 24 weeks
干预措施: Adalimumab (Drug)
结局指标
主要结局
Frequency of ACPA-expressing B cells
时间窗: 24 weeks
Change from baseline in the frequency of ACPA-expressing B cells secreting ACPA-IgG in ex-vivo PBMC cultures at the 24 week time-point compared between the two treatment arms.
次要结局
- Patient reported outcome parameter: Netherlands RAID(0, 12, 24 weeks)
- Immunological serum/plasma markers(0, 12, 24 weeks)
- Patient reported outcome parameter: BRAF-NRS(0, 12, 24 weeks)
- Disease activity(24 weeks)
- B cell receptor (BCR) repertoire(0, 12, 24 weeks)
- Secreted ACPA serum repertoire(0, 12, 24 weeks)
- Patient reported outcome parameter: BRAF-MDQ(0, 12, 24 weeks)
- Phenotypic cellular markers on circulating lymphocytes(0, 12, 24 weeks)
研究者
Hans Ulrich Scherer
Associate Professor of Rheumatology
Leiden University Medical Center