Januse Kinase Inhibition With Filgotinib to Silence Autoreactive B Cells in Rheumatoid Arthritis (JAKAR)

Leiden University Medical Center (LUMC)

Status and phase: Not yet enrolling; Phase 4

Conditions: Rheumatoid Arthritis

Treatments: Drug: Filgotinib; Drug: Adalimumab

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT05502731

2021-006007-15 (EudraCT Number)

NL79681.058.21

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 40 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

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 > 11.
• 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

Exclusion criteria

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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40 participants in 2 patient groups

Add-on filgotinib

Experimental group

Description:

Treatment with a combination therapy of MTX (7.5 - 15 mg once weekly) and filgotinib p.o. (200 mg once daily) for 24 weeks

Treatment:

Drug: Filgotinib

Add-on adalimumab

Active Comparator group

Description:

Treatment with a combination therapy of MTX (7.5 - 15 mg once weekly) and adalimumab s.c. (40 mg biweekly) for 24 weeks

Treatment:

Drug: Adalimumab