TNF and IL23 Blocking Agents Gene Expression Ratios in the Psoriatic Arthritis Synovium_(TIGERS) Study

NCT04261010 | Completed

• 3 other identifiers: P1200_32 (TIGERS)2017-003249-18FAGG/R&D/SEJ/sej
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 2

Brief Summary

This study compare the genomics profiles in synovial biopsies obtained prior to, and 24 weeks after a biologic disease modifying anti-rheumatic drugs (DMARDs)(Adalimumab, Ustekinumab, Guselkumab) in patients with active psoriatic arthritis despite a treatment with a conventional synthetic DMARDs (such as methotrexate).

Conditions

Psoriatic Arthritis

Keywords

Synovium, Biologics, Genomics

Outcome Measures

Primary Outcomes (1)

• Quantitative measurement of the molecular changes in relation to the up-regulated or down-regulated genes in the synovium.

  The primary endpoint of the study is not the comparative efficacy of the 3 drugs, but the comparative molecular changes they induce in the synovium. In a first set of analyses, the magnitude of fold-changes in (global and single cell) gene expression profiles between baseline and W24 will be analysed in each group. The higher values correspond to the high intensity in the up-regulation or down-regulation of the gene expression.

  24 weeks

Secondary Outcomes (3)

• Comparison between the magnitude of molecular changes (up-regulation or down-regulation of the genes) and clinical changes (improvement or worsening of the swollen joints count).

  24 weeks

• Comparison between the magnitude of molecular changes (up-regulation or down-regulation of the genes) and imaging changes on ultrasound (US).

  24 weeks

• Comparison between the magnitude of molecular changes (up-regulation or down-regulation of the genes) and imaging changes on Magnetic Resonance Imaging (MRI).

  24 weeks

Study Arms (3)

Ustekinumab

EXPERIMENTAL

Group 1 (n=12): ustekinumab 45 mg (or 90 mg for patients \> 100 kg) subcutaneously at baseline (W0), 4 weeks later (W4), and every 12 weeks until week 24 (i.e. W0, W4, and W16).

Procedure: Global/single cell gene expression profiles obtained from Synovial biopsies

Guselkumab

EXPERIMENTAL

Group 2 (n=12): guselkumab 100 mg subcutaneously (regardless of the weight of the patient) at weeks 0 and 4, followed by a maintenance dose every 8 weeks through week 24 (i.e. W0, W4, W12 and W20).

Procedure: Global/single cell gene expression profiles obtained from Synovial biopsies

ADALIMUMAB

ACTIVE COMPARATOR

Group 3 (n=12): adalimumab 40 mg (regardless of the weight of the patient), subcutaneously every other week, starting from the baseline until week 24 (i.e.W0, W2, W4, W6, W8, W10, W12, W14, W16, W18, W20 and W22).

Procedure: Global/single cell gene expression profiles obtained from Synovial biopsies

Interventions

Global/single cell gene expression profiles obtained from Synovial biopsies PROCEDURE

Global/single cell gene expression profiles obtained from synovial biopsies before and after 24 weeks of treatment with the drug.

ADALIMUMAB; Guselkumab; Ustekinumab

Eligibility Criteria

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

You may qualify if:

• Patient must be able to understand and communicate with the investigator and comply with the requirements of the study and must give a written, signed and dated informed consent before any study assessment is performed.
• Male or non-pregnant, non-nursing female patients at least 18 years of age. Before randomization, a woman of childbearing potential must be on a highly effective method of birth control consistent with local regulations regarding the use of birth control methods for subjects participating in clinical studies: eg, established use of oral, injected or implanted hormonal methods of contraception associated with inhibition of ovulation; placement of an intrauterine device (IUD) or intrauterine system (IUS); male partner sterilization (the vasectomized partner should be the sole partner for that subject); true abstinence (when this is in line with the preferred and usual lifestyle of the subject).
• A woman of childbearing potential must have a negative serum (β-human chorionic gonadotropin \[β-hCG\]) at baseline before randomization. A woman must agree not to donate ovocytes for the purposes of assisted reproduction during the study and for 3 months after receiving the last dose of study agent.
• Note: If the childbearing potential changes after start of the study (eg, woman who is not heterosexually active becomes active, premenarchal woman experiences menarche) that woman must begin a highly effective method of birth control, as described above.
• A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a barrier method of birth control eg, either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository, and all men must also not donate sperm during the study and for 3 months after receiving the last dose of study agent
• The method of birth control will be clearly documented in patient file.
• Patients with active PsA according to CASPAR criteria for ≥6 months, despite ≥3 months of csDMARD therapy, and ≥4 weeks of non-steroidal anti- inflammatory drugs (NSAIDs) therapy.
• At least 1 swollen joint at screening or baseline (despite csDMARD therapy) with ability to perform a synovial biopsy at W0.
• Patients with newly documented latent TB are eligible provided initiation of appropriate treatment.
• Concomitant MTX or SSZ is permitted if started ≥3 months prior to study start and at a stable dose (≤25 mg/week for MTX and ≤ 3 g/day for SSZ) for ≥4 weeks.
• Patients on MTX must be on stable folic acid supplementation before randomization.
• Concomitant NSAIDs and oral corticosteroids (≤10 mg prednisone/day) are permitted if stable for at least 2 weeks.
• Allowed concomitant medications are to remain stable through week 24.
• Patients cannot have previously received any biologic agent
• DMARDs other than MTX or sulfasalazine (SSZ) must be interrupted. DMARDs other than MTX are not allowed within 4 weeks prior to or during trial participation. A washout period needs to be considered. (8 weeks for leflunomide).

You may not qualify if:

• Contraindications for needle-arthroscopy such as joint replacement (in the affected knee or ankle joint) or anticoagulation.
• Use of any investigational drug and/or devices within 4 weeks of baseline, or a period of 5 half-lives of the investigational drug, whichever is longer.
• Conditions/situations such as:
• Patients with conditions/concomitant diseases making them non evaluable for the primary endpoint
• Impossibility to meet specific protocol requirements (e.g. blood sampling)
• Patient is the Investigator or any sub-investigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the protocol
• Uncooperative or any condition that could make the patient potentially noncompliant to the study procedures
• Any therapy by intra-articular injections (e.g. corticosteroid) within 4 weeks before baseline.
• Any intramuscular corticosteroid injection within 2 weeks before baseline.
• Prior treatment with a biologic agent.
• A history of active tuberculosis (TB).

Sponsors & Collaborators

• Cliniques universitaires Saint-Luc- Université Catholique de Louvain: lead
• Janssen-Cilag International NV: collaborator
• University Hospital, Ghent: collaborator

Study Sites (2)

Dirk ELEWAUT

Ghent, East Flanders, Belgium

Location

Adrien NZEUSSEU TOUKAP

Brussels, 1200, Belgium

Location

Related Publications (16)

• Ritchlin CT, Colbert RA, Gladman DD. Psoriatic Arthritis. N Engl J Med. 2017 Mar 9;376(10):957-970. doi: 10.1056/NEJMra1505557. No abstract available.

  PMID: 28273019 BACKGROUND

• Nzeusseu Toukap A, Galant C, Theate I, Maudoux AL, Lories RJ, Houssiau FA, Lauwerys BR. Identification of distinct gene expression profiles in the synovium of patients with systemic lupus erythematosus. Arthritis Rheum. 2007 May;56(5):1579-88. doi: 10.1002/art.22578.

  PMID: 17469140 BACKGROUND

• Lauwerys BR, Hernandez-Lobato D, Gramme P, Ducreux J, Dessy A, Focant I, Ambroise J, Bearzatto B, Nzeusseu Toukap A, Van den Eynde BJ, Elewaut D, Gala JL, Durez P, Houssiau FA, Helleputte T, Dupont P. Heterogeneity of synovial molecular patterns in patients with arthritis. PLoS One. 2015 Apr 30;10(4):e0122104. doi: 10.1371/journal.pone.0122104. eCollection 2015.

  PMID: 25927832 BACKGROUND

• De Groof A, Ducreux J, Humby F, Nzeusseu Toukap A, Badot V, Pitzalis C, Houssiau FA, Durez P, Lauwerys BR. Higher expression of TNFalpha-induced genes in the synovium of patients with early rheumatoid arthritis correlates with disease activity, and predicts absence of response to first line therapy. Arthritis Res Ther. 2016 Jan 20;18:19. doi: 10.1186/s13075-016-0919-z.

  PMID: 26792343 BACKGROUND

• Badot V, Galant C, Nzeusseu Toukap A, Theate I, Maudoux AL, Van den Eynde BJ, Durez P, Houssiau FA, Lauwerys BR. Gene expression profiling in the synovium identifies a predictive signature of absence of response to adalimumab therapy in rheumatoid arthritis. Arthritis Res Ther. 2009;11(2):R57. doi: 10.1186/ar2678. Epub 2009 Apr 23.

  PMID: 19389237 BACKGROUND

• Badot V, Durez P, Van den Eynde BJ, Nzeusseu-Toukap A, Houssiau FA, Lauwerys BR. Rheumatoid arthritis synovial fibroblasts produce a soluble form of the interleukin-7 receptor in response to pro-inflammatory cytokines. J Cell Mol Med. 2011 Nov;15(11):2335-42. doi: 10.1111/j.1582-4934.2010.01228.x.

  PMID: 21129157 BACKGROUND

• Gutierrez-Roelens I, Galant C, Theate I, Lories RJ, Durez P, Nzeusseu-Toukap A, Van den Eynde B, Houssiau FA, Lauwerys BR. Rituximab treatment induces the expression of genes involved in healing processes in the rheumatoid arthritis synovium. Arthritis Rheum. 2011 May;63(5):1246-54. doi: 10.1002/art.30292.

  PMID: 21337318 BACKGROUND

• Ducreux J, Durez P, Galant C, Nzeusseu Toukap A, Van den Eynde B, Houssiau FA, Lauwerys BR. Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23. doi: 10.1002/art.38202.

  PMID: 24449571 BACKGROUND

• Burmester GR, Panaccione R, Gordon KB, McIlraith MJ, Lacerda AP. Adalimumab: long-term safety in 23 458 patients from global clinical trials in rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis and Crohn's disease. Ann Rheum Dis. 2013 Apr;72(4):517-24. doi: 10.1136/annrheumdis-2011-201244. Epub 2012 May 5.

  PMID: 22562972 BACKGROUND

• McInnes IB, Mease PJ, Ritchlin CT, Rahman P, Gottlieb AB, Kirkham B, Kajekar R, Delicha EM, Pricop L, Mpofu S. Secukinumab sustains improvement in signs and symptoms of psoriatic arthritis: 2 year results from the phase 3 FUTURE 2 study. Rheumatology (Oxford). 2017 Nov 1;56(11):1993-2003. doi: 10.1093/rheumatology/kex301.

  PMID: 28968735 BACKGROUND

• Sherlock JP, Joyce-Shaikh B, Turner SP, Chao CC, Sathe M, Grein J, Gorman DM, Bowman EP, McClanahan TK, Yearley JH, Eberl G, Buckley CD, Kastelein RA, Pierce RH, Laface DM, Cua DJ. IL-23 induces spondyloarthropathy by acting on ROR-gammat+ CD3+CD4-CD8- entheseal resident T cells. Nat Med. 2012 Jul 1;18(7):1069-76. doi: 10.1038/nm.2817.

  PMID: 22772566 BACKGROUND

• Lories RJ, McInnes IB. Primed for inflammation: enthesis-resident T cells. Nat Med. 2012 Jul 6;18(7):1018-9. doi: 10.1038/nm.2854. No abstract available.

  PMID: 22772553 BACKGROUND

• McInnes IB, Kavanaugh A, Gottlieb AB, Puig L, Rahman P, Ritchlin C, Brodmerkel C, Li S, Wang Y, Mendelsohn AM, Doyle MK; PSUMMIT 1 Study Group. Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial. Lancet. 2013 Aug 31;382(9894):780-9. doi: 10.1016/S0140-6736(13)60594-2. Epub 2013 Jun 13.

  PMID: 23769296 BACKGROUND

• Kavanaugh A, Ritchlin C, Rahman P, Puig L, Gottlieb AB, Li S, Wang Y, Noonan L, Brodmerkel C, Song M, Mendelsohn AM, McInnes IB; PSUMMIT-1 and 2 Study Groups. Ustekinumab, an anti-IL-12/23 p40 monoclonal antibody, inhibits radiographic progression in patients with active psoriatic arthritis: results of an integrated analysis of radiographic data from the phase 3, multicentre, randomised, double-blind, placebo-controlled PSUMMIT-1 and PSUMMIT-2 trials. Ann Rheum Dis. 2014 Jun;73(6):1000-6. doi: 10.1136/annrheumdis-2013-204741. Epub 2014 Feb 19.

  PMID: 24553909 BACKGROUND

• Deodhar A, Gottlieb AB, Boehncke WH, Dong B, Wang Y, Zhuang Y, Barchuk W, Xu XL, Hsia EC; CNTO1959PSA2001 Study Group. Efficacy and safety of guselkumab in patients with active psoriatic arthritis: a randomised, double-blind, placebo-controlled, phase 2 study. Lancet. 2018 Jun 2;391(10136):2213-2224. doi: 10.1016/S0140-6736(18)30952-8. Epub 2018 Jun 1.

  PMID: 29893222 BACKGROUND

• Ritchlin C, Rahman P, Kavanaugh A, McInnes IB, Puig L, Li S, Wang Y, Shen YK, Doyle MK, Mendelsohn AM, Gottlieb AB; PSUMMIT 2 Study Group. Efficacy and safety of the anti-IL-12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional non-biological and biological anti-tumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo-controlled, randomised PSUMMIT 2 trial. Ann Rheum Dis. 2014 Jun;73(6):990-9. doi: 10.1136/annrheumdis-2013-204655. Epub 2014 Jan 30.

  PMID: 24482301 BACKGROUND

MeSH Terms

Conditions

Arthritis, Psoriatic

Condition Hierarchy (Ancestors)

Spondylarthropathies; Spondylarthritis; Spondylitis; Spinal Diseases; Bone Diseases; Musculoskeletal Diseases; Arthritis; Joint Diseases; Psoriasis; Skin Diseases, Papulosquamous; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Adrien NZEUSSEU TOUKAP, MD

  Cliniques universitaires Saint-Luc- Université Catholique de Louvain

  PRINCIPAL INVESTIGATOR

• Dirk ELEWAUT, MD, PhD

  University Hospital, Ghent

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Randomization 1:1:1

Study Record Dates

• First Submitted: January 21, 2020
• First Posted: February 7, 2020
• Study Start: January 14, 2020
• Primary Completion: September 12, 2023
• Study Completion: September 12, 2023
• Last Updated: September 18, 2023

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will not share

Locations

BE (2)