Clinical trial NCT05502731: Januse Kinase Inhibition With Filgotinib to Silence Autoreactive B Cells in Rheumatoid Arthritis
Official title: Januse Kinase Inhibition With Filgotinib to Silence Autoreactive B Cells in Rheumatoid Arthritis
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE4
Conditions: Rheumatoid Arthritis
Keywords: Autoreactive B cells
Immunological Remission
Anti citrullinated protein antibodies
Lead sponsor: Leiden University Medical Center
Sponsor class: OTHER
Collaborators: name: Galapagos NV
First posted: 2022-08-16
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Open-label, randomized, single center, two-arm, investigator-initiated, interventional clinical study
Primary purpose: TREATMENT

Brief summary: 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Frequency of ACPA-expressing B cells
timeFrame: 24 weeks
Secondary outcomes:
measure: Disease activity
timeFrame: 24 weeks
measure: Immunological serum/plasma markers
timeFrame: 0, 12, 24 weeks
measure: B cell receptor (BCR) repertoire
timeFrame: 0, 12, 24 weeks
measure: Secreted ACPA serum repertoire
timeFrame: 0, 12, 24 weeks
measure: Patient reported outcome parameter: BRAF-MDQ
timeFrame: 0, 12, 24 weeks
measure: Phenotypic cellular markers on circulating lymphocytes
timeFrame: 0, 12, 24 weeks
measure: Patient reported outcome parameter: Netherlands RAID
timeFrame: 0, 12, 24 weeks
measure: Patient reported outcome parameter: BRAF-NRS
timeFrame: 0, 12, 24 weeks
Other outcomes:
Locations:
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
state: Zuid-Holland
Study officials:
affiliation: Leiden University Medical Center
name: Tom WJ Huizinga, MD PhD
role: STUDY_CHAIR
References:
citation: Kristyanto H, Blomberg NJ, Slot LM, van der Voort EIH, Kerkman PF, Bakker A, Burgers LE, Ten Brinck RM, van der Helm-van Mil AHM, Spits H, Baeten DL, Huizinga TWJ, Toes REM, Scherer HU. Persistently activated, proliferative memory autoreactive B cells promote inflammation in rheumatoid arthritis. Sci Transl Med. 2020 Nov 18;12(570):eaaz5327. doi: 10.1126/scitranslmed.aaz5327.
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