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

NCT05502731 | Unknown Phase 4

• 2 other identifiers: NL79681.058.212021-006007-15
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

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.

Conditions

Rheumatoid Arthritis

Keywords

Autoreactive B cells; Immunological Remission; Anti citrullinated protein antibodies

Outcome Measures

Primary Outcomes (1)

• Frequency of ACPA-expressing B cells

  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.

  24 weeks

Secondary Outcomes (8)

• Disease activity

  24 weeks

• Immunological serum/plasma markers

  0, 12, 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

Study Arms (2)

Add-on filgotinib

EXPERIMENTAL

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

Drug: Filgotinib

Add-on adalimumab

ACTIVE COMPARATOR

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

Drug: Adalimumab

Interventions

Filgotinib 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.

Also known as: Jyseleca

Add-on filgotinib

Adalimumab DRUG

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

Also known as: Hyrimoz

Add-on adalimumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Leiden University Medical Center: lead
• Galapagos NV: collaborator

Study Sites (1)

Leiden University Medical Center

Leiden, South Holland, 2300RC, Netherlands

Location

Related Publications (7)

• 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.

  PMID: 33208502 BACKGROUND

• 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.

  PMID: 26034045 BACKGROUND

• Kerkman PF, Rombouts Y, van der Voort EI, Trouw LA, Huizinga TW, Toes RE, Scherer HU. Circulating plasmablasts/plasmacells as a source of anticitrullinated protein antibodies in patients with rheumatoid arthritis. Ann Rheum Dis. 2013 Jul;72(7):1259-63. doi: 10.1136/annrheumdis-2012-202893. Epub 2013 Apr 26.

  PMID: 23625975 BACKGROUND

• Scherer HU, Huizinga TWJ, Kronke G, Schett G, Toes REM. The B cell response to citrullinated antigens in the development of rheumatoid arthritis. Nat Rev Rheumatol. 2018 Mar;14(3):157-169. doi: 10.1038/nrrheum.2018.10. Epub 2018 Feb 8.

  PMID: 29416134 BACKGROUND

• Westhovens R, Taylor PC, Alten R, Pavlova D, Enriquez-Sosa F, Mazur M, Greenwald M, Van der Aa A, Vanhoutte F, Tasset C, Harrison P. Filgotinib (GLPG0634/GS-6034), an oral JAK1 selective inhibitor, is effective in combination with methotrexate (MTX) in patients with active rheumatoid arthritis and insufficient response to MTX: results from a randomised, dose-finding study (DARWIN 1). Ann Rheum Dis. 2017 Jun;76(6):998-1008. doi: 10.1136/annrheumdis-2016-210104. Epub 2016 Dec 19.

  PMID: 27993829 BACKGROUND

• Van Rompaey L, Galien R, van der Aar EM, Clement-Lacroix P, Nelles L, Smets B, Lepescheux L, Christophe T, Conrath K, Vandeghinste N, Vayssiere B, De Vos S, Fletcher S, Brys R, van 't Klooster G, Feyen JH, Menet C. Preclinical characterization of GLPG0634, a selective inhibitor of JAK1, for the treatment of inflammatory diseases. J Immunol. 2013 Oct 1;191(7):3568-77. doi: 10.4049/jimmunol.1201348. Epub 2013 Sep 4.

  PMID: 24006460 BACKGROUND

• 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.

  PMID: 29087507 BACKGROUND

MeSH Terms

Conditions

Arthritis, Rheumatoid

Interventions

GLPG0634; Adalimumab

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Tom WJ Huizinga, MD PhD

  Leiden University Medical Center

  STUDY CHAIR

Central Study Contacts

Hans Ulrich Scherer, MD PhD

CONTACT

+31715298733; h.u.scherer@lumc.nl

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Rheumatology

Model Details: Open-label, randomized, single center, two-arm, investigator-initiated, interventional clinical study

Study Record Dates

• First Submitted: August 9, 2022
• First Posted: August 16, 2022
• Study Start: October 1, 2022
• Primary Completion: March 1, 2025
• Study Completion: October 1, 2025
• Last Updated: August 16, 2022

Record last verified: 2022-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Upon publication of the main study results in a scientific journal.

Locations

NL (1)