Efficacy of a Sequential Treatment Strategy in Rheumatoid Arthritis

NCT05428488 | Recruiting Phase 3

• 1 other identifier: RECHMPL21_0568
• Study Type: interventional
• Target: 220
• Locations: 2 countries
• Sites: 17

Brief Summary

In rheumatoid arthritis (RA), the consensual 1st line conventional synthetic disease modifying antirheumatic drugs (csDMARD) of RA is methotrexate (MTX). In case of contra-indication or intolerance to MTX, leflunomide is an alternative. If the treatment target is not achieved with csDMARD strategy, addition of a biological DMARD (TNF inhibitors, anti-Interleukin 6 (anti-IL6)), abatacept, or rituximab) or a targeted synthetic (ts) DMARD (JAK inhibitors) is considered. Current practice is to start a bDMARD (biologic Disease Modifying Antirheumatic Drugs) and especially TNF inhibitors (etanercept or monoclonal anti-TNF antibodies) with the benefit of hindsight. However, abatacept and TNF inhibitors have demonstrated similar efficacy in patients with insufficient response to csDMARD (AMPLE trial). Although abatacept has shown a very good tolerance profile that might be superior to other bDMARDs rheumatologists might be reluctant to use it as a first line bDMARD as there is a belief of a slower efficacy compared to other bDMARDs or JAK inhibitors. Indeed, in real world study, compared to TNF inhibitors it seems that discontinuation of abatacept is more related to lack of effectiveness than safety issues. Investigators have hypothesized that first rapidly controlling the inflammation phase, using TNF inhibitors followed by abatacept to induce an immunological remission would optimize response and tolerance of ACPA positive patients with RA. To demonstrate our hypothesis, the investigaors propose a randomized controlled trial with one arm receiving an induction therapy for 12 weeks with a TNF inhibitor followed by a cell-targeted bDMARD (abatacept) and the other arm, receiving TNF inhibitors.

Conditions

Rheumatoid Arthritis

Keywords

Rheumatoid arthritis; sequential therapeutic strategy; immunological remission; anti-TNF; abatacept

Outcome Measures

Primary Outcomes (1)

• Percentage of patients in remission

  Percentage of patients in remission defined by DAS28-CRP\<2.6 score during the 36 weeks following randomization. Disease Activity Score-28 with C-Reactive Protein (DAS28-CRP) describes severity of rheumatoid arthritis using clinical and laboratory data, specifically CRP. It includes 4 variables (number of painful joints out of 28 joints, number of swollen joints out of 28 joints, global assessment of the disease by the patient on a Visual Analogue Scale (VAS), markers of inflammation : CRP) A DAS28-CRP score \> 5.1 means high disease activity, DAS28-CRP \< or = 3.2 indicates low disease activity, a DAS28-CRP \< 2.6 indicates disease remission.

  36 weeks following randomization

Secondary Outcomes (38)

• percentage of patients in remission at 12 weeks after randomization (DAS28-ESR)

  At 24 weeks visit (corresponding to 12 weeks after randomization)

• percentage of patients in remission at 12 weeks after randomization (CDAI)

  At 24 weeks visit (corresponding to 12 weeks after randomization)

• percentage of patients in remission at 12 weeks after randomization (SDAI)

  At 24 weeks visit (corresponding to 12 weeks after randomization)

• percentage of patients in remission at 12 weeks after randomization (Boolean)

  At 24 weeks visit (corresponding to 12 weeks after randomization)

• Percentage of patients in remission at 24 weeks after randomization (DAS28-ESR)

  At 36 weeks visit (corresponding to 24 weeks after randomization)

Study Arms (2)

Experimental

EXPERIMENTAL

All included patients will receive TNF inhibitors subcutaneous for 12 weeks. In the experimental arm, a therapeutic sequential strategy will be proposed from W12 visit. At 12 weeks (W12), patients who have at least a moderate EULAR response (delta DAS28-CRP between W0 and W12\>0.6 and DAS28-CRP≤5.1 at W12) will be randomized with a 1:1 ratio in the sequential strategy arm or the control arm. In the sequential strategy (experimental) arm, the 88 randomized RA patients will be switched to abatacept subcutaneous for 36 weeks.

Drug: Abatacept (W12-W48); Drug: TNF Inhibitor (W0-W12)

Control

ACTIVE COMPARATOR

All included patients will receive TNF inhibitors subcutaneous for 12 weeks. In the control group, the 88 randomized RA patients will be treated with TNF inhibitor subcutaneous for another 36 weeks (from W12 visit). In case of insufficient response to a first TNF inhibitor at 24 or 36 weeks, a second TNF inhibitor will be proposed.

Drug: TNF Inhibitor (W12-W48); Drug: TNF Inhibitor (W0-W12)

Interventions

Abatacept (W12-W48) DRUG

The experimental strategy will evaluate abatacept 125 mg/week following 12 weeks of anti-TNF prescribed in usual care. Concomitant treatment with stable doses of csDMARD, non-steroidal anti-inflammatory drugs, analgesic agents, glucocorticoids (≤10 mg of prednisone or the equivalent per day), or a combination of these drugs will be permitted. Patients will continue to take methotrexate or leflunomide for the duration of the study.

Experimental

TNF Inhibitor (W12-W48) DRUG

In the control group, the 88 randomized RA patients will be treated with TNF inhibitor subcutaneous for 36 weeks. In case of insufficient response to a first TNF inhibitor at 24 or 36 weeks, a second TNF inhibitor will be proposed.

Control

TNF Inhibitor (W0-W12) DRUG

All included patients will receive TNF inhibitors subcutaneous for 12 weeks.

Control; Experimental

Eligibility Criteria

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

You may qualify if:

• Aged between 18 or above
• Rheumatoid arthritis according to ACR-EULAR 2010 (American College of Rheumatology-European League Against Rheumatism)
• ACPA positive
• Under methotrexate or leflunomide treatment for at least 3 months
• DAS28-CRP\>3.2 under methotrexate or leflunomide calculated with CRP dated less than 7 days from baseline
• Escape under synthetic background treatment defined by an elevation of C-reactive protein (CRP) (CRP\> 5mg/L ) or Erythrocyte sedimentation rate (ESR) (for men: \> age in years/2 ; for women: \> age (+10) /2)) within the last 6 months before baseline
• Targeted DMARDs (biological and targeted synthetic DMARDs) naïve
• Indication for a TNF inhibitor

You may not qualify if:

• Subject unable to read or/and write
• Planned longer stay outside the region that prevents compliance with the visit plan
• Subject unable to sign informed consent form
• Subject not covered by public health insurance
• Dementia
• Fibromyalgia
• Contra-indications to TNF inhibitor and/or Abatacept
• Absence of tuberculosis screening in the previous 3 months before baseline
• Patient with untreated active tuberculosis
• Patient who cannot be followed during 48 weeks
• Drug addiction, addiction to alcohol
• Protected populations according to the French Public Health Code Articles L1121-5,6,8 (For example, pregnant, parturient or lactating women, prisoners, adults under guardianship or otherwise unable to consent).
• Women of child bearing potential, unless they are using an effective method of birth control
• Patient under law protection
• Prisoners

Sponsors & Collaborators

• University Hospital, Montpellier: lead

Study Sites (17)

Centre Hospitalier Universitaire de Montpellier

Montpellier, France, 34295, France

RECRUITING

CHU Bordeaux groupe Pellegrin

Bordeaux, France

RECRUITING

CHU de Brest La Cavale Blanche

Brest, France

RECRUITING

Centre Hospitalier de Cahors

Cahors, France

NOT YET RECRUITING

CHD Vendée

La Roche-sur-Yon, France

RECRUITING

CH du Mans

Le Mans, France

RECRUITING

CHU de Nantes

Nantes, France

RECRUITING

CHU de Nice

Nice, France

RECRUITING

CHU de Nîmes Carémeau

Nîmes, France

NOT YET RECRUITING

CHR Orléans Nouvel hôpital d'Orléans

Orléans, France

RECRUITING

APHP Bicêtre

Paris, France

NOT YET RECRUITING

APHP Cochin

Paris, France

RECRUITING

APHP La Pitié Salpetrière

Paris, France

RECRUITING

CHU de Strasbourg Hautepierre

Strasbourg, France

NOT YET RECRUITING

Chu Purpan

Toulouse, France

NOT YET RECRUITING

CHU de Tours - Hopital Trousseau

Tours, France

RECRUITING

Centre hospitalier Princesse Grace

Monaco, Monaco

RECRUITING

MeSH Terms

Conditions

Arthritis, Rheumatoid

Interventions

Abatacept; Tumor Necrosis Factor Inhibitors

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)

Immunoconjugates; Antibodies; Immunoglobulins; Serum Globulins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Globulins; Anti-Inflammatory Agents; Therapeutic Uses; Pharmacologic Actions; Chemical Actions and Uses

Study Officials

• Jacques MOREL, MD-PhD

  UF of Montpellier

  STUDY DIRECTOR

Central Study Contacts

Jacques MOREL, MD-PhD

CONTACT

467338710; j-morel@chu-montpellier.fr

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This study will include a 12 weeks non-randomized phase. This phase will include RA patients ACPA+ with insufficient response to cs DMARDs and eligible for TNF inhibitors. All included patients will receive TNF inhibitors subcutaneous for 12 weeks. At 12 weeks visit (W12), patients who have at least a moderate EULAR response (delta DAS28-CRP between and W0 and W12\>0.6 and DAS28-CRP≤5.1 at W12) will be randomized with a 1:1 ratio in the sequential strategy arm or the control arm. Then, the randomized phase will be 36 weeks long.

Study Record Dates

• First Submitted: June 16, 2022
• First Posted: June 23, 2022
• Study Start: November 28, 2022
• Primary Completion (Estimated): November 1, 2026
• Study Completion (Estimated): November 1, 2027
• Last Updated: October 3, 2025

Record last verified: 2025-03

Locations

MO (1); FR (16)