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

NCT ID: NCT05502731

Last Updated: 2022-08-16

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-10-31
• Study Completion Date: 2025-10-31

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.

Conditions

Rheumatoid Arthritis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: EXPERIMENTAL

Filgotinib

Intervention Type: DRUG

Filgotinib is a small molecule that reversibly inhibits Janus kinases (JAK, selectively JAK 1), thereby inhibiting downstream signalling events induced by various pro-inflammatory and regulatory cytokines.

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

Group Type: ACTIVE_COMPARATOR

Adalimumab

Intervention Type: DRUG

Adalimumab is a monoclonal antibody selectively inhibiting the pro-inflammatory cytokine TNF-alpha.

Interventions

Filgotinib

Filgotinib is a small molecule that reversibly inhibits Janus kinases (JAK, selectively JAK 1), thereby inhibiting downstream signalling events induced by various pro-inflammatory and regulatory cytokines.

Intervention Type: DRUG

Adalimumab

Adalimumab is a monoclonal antibody selectively inhibiting the pro-inflammatory cytokine TNF-alpha.

Intervention Type: DRUG

Other Intervention Names

Jyseleca; Hyrimoz

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Galapagos NV

INDUSTRY

Sponsor Role: collaborator

Leiden University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Hans Ulrich Scherer

Associate Professor of Rheumatology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Tom WJ Huizinga, MD PhD

Role: STUDY_CHAIR

Leiden University Medical Center

Locations

Leiden University Medical Center

Leiden, South Holland, Netherlands

Countries

Netherlands

Central Contacts

Hans Ulrich Scherer, MD PhD

Role: CONTACT

h.u.scherer@lumc.nl

+31715298733

Facility Contacts

Hans Ulrich Scherer, MD PhD

Role: primary

h.u.scherer@lumc.nl

+31715298733

References

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Reference Type: BACKGROUND

PMID: 33208502 (View on PubMed)

Kerkman PF, Fabre E, van der Voort EI, Zaldumbide A, Rombouts Y, Rispens T, Wolbink G, Hoeben RC, Spits H, Baeten DL, Huizinga TW, Toes RE, Scherer HU. Identification and characterisation of citrullinated antigen-specific B cells in peripheral blood of patients with rheumatoid arthritis. Ann Rheum Dis. 2016 Jun;75(6):1170-6. doi: 10.1136/annrheumdis-2014-207182. Epub 2015 Jun 1.

Reference Type: BACKGROUND

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Reference Type: BACKGROUND

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Reference Type: BACKGROUND

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Hewlett S, Kirwan J, Bode C, Cramp F, Carmona L, Dures E, Englbrecht M, Fransen J, Greenwood R, Hagel S, van de Laar M, Molto A, Nicklin J, Petersson IF, Redondo M, Schett G, Gossec L. The revised Bristol Rheumatoid Arthritis Fatigue measures and the Rheumatoid Arthritis Impact of Disease scale: validation in six countries. Rheumatology (Oxford). 2018 Feb 1;57(2):300-308. doi: 10.1093/rheumatology/kex370.

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Other Identifiers

2021-006007-15

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

NL79681.058.21

Identifier Type: -

Identifier Source: org_study_id