Efficacy of a Sequential Treatment Strategy in Rheumatoid Arthritis

NCT ID: NCT05428488

Last Updated: 2025-10-03

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 220 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-11-28
• Study Completion Date: 2027-11-30

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.

Detailed Description

In rheumatoid arthritis (RA), the consensual 1st line conventional synthetic disease modifying antirheumatic drugs (csDMARD) of RA is methotrexate (MTX) (1). 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 (b) DMARD (TNF inhibitors, anti-IL6, abatacept, or rituximab) or a targeted synthetic (ts) DMARD (JAK inhibitors) is considered.

Current practice is to start a bDMARD 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.

This is the first study to propose a therapeutic sequential strategy with an induction therapy using a TNF inhibitor for 12 weeks to control inflammation followed by a cell-targeted biological DMARD targeting T cells (abatacept) in order to decrease auto-antibodies (rheumatoid factor and/or ACPA).

Presence of auto-antibodies (ACPA/RF) are predictive of better response to cell- targeted DMARDs.

In early AMPLE trial, RA patients ACPA+ with insufficient response to MTX were treated with abatacept or adalimumab. DAS28-CRP remission rates were 55% in abatacept group and 30% in adalimumab group.

Patients carrying the shared epitope (HLA-DR (Human Leucocyte Antigen-DR) alleles associated with RA), were also more likely to reach remission (DAS28-CRP<2.6) with abatacept (50%) than adalimumab (23%) at 24 weeks.

The clinical trial offered by investigateors here could change the paradigm in the strategy used in RA supporting the importance to first control inflammation environment in order to allow the cell-targeted bDMARDs to control immunological process which has been recently associated with a higher percentage of clinical remission.

To compare the percentage of remission (DAS28-CRP<2.6) obtained during the 36 weeks following randomization, with a sequential therapeutic strategy using abatacept versus a routine strategy continuing TNF inhibitors (TNFi), in ACPA positive RA patients responding to a first TNFi, initiated 12 weeks before randomization.

The primary endpoint will be analyzed with a generalized estimating equations (GEE) model for repeated data.

It is a multicentric, open label, randomized controlled trial comparing two different strategies of treatment with an independent efficacy assessor. For this clinical trial, to limit response bias, bDMARDs with a similar mode of administration (subcutaneous) are proposed.

In the experimental arm, a therapeutic sequential strategy will be proposed and in the control arm TNF inhibitors will be proposed for 48 weeks. All included patients will receive TNF inhibitors subcutaneous for 12 weeks. 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 arm, the 88 randomized RA patients will be switched to abatacept subcutaneous for 36 weeks. Patients who will withdraw abatacept during the follow-up will be considered as a failure.

In the control group, the 88 randomized RA patients will be treated with TNF inhibitor subcutaneous for another 36 weeks. In case of insufficient response to a first TNF inhibitor at 24 or 36 weeks, a second TNF inhibitor will be proposed. Anti-TNF drugs withdrawal will be considered as a failure. Steroids 0.1mg/kg/ day will be allowed but at stable dose 2 weeks before and with guided step-down strategy targeting withdrawal before 24 weeks following randomization. Clinical evaluation of disease activity using different scores (DAS28-ESR, CDAI, SDAI, Boolean criteria) and tolerance will be performed at all visits.

Conditions

Rheumatoid Arthritis

Study Design

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

Study Groups

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.

Group Type: EXPERIMENTAL

Abatacept (W12-W48)

Intervention Type: 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.

TNF Inhibitor (W0-W12)

Intervention Type: DRUG

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

Control

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.

Group Type: ACTIVE_COMPARATOR

TNF Inhibitor (W12-W48)

Intervention Type: 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.

TNF Inhibitor (W0-W12)

Intervention Type: DRUG

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

Interventions

Abatacept (W12-W48)

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.

Intervention Type: DRUG

TNF Inhibitor (W12-W48)

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.

Intervention Type: DRUG

TNF Inhibitor (W0-W12)

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

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• 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

Exclusion Criteria

• 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
• Subject who are in a dependency or employment with the sponsor or the investigator
• Participation in another interventional clinical trial or administration of an investigational product within the last 4 weeks before the screening date
• Subject with moderate to severe heart failure (class 3 or class 4 cardiac disease as defined by the New York Heart Association Functional Classification)
• Patients had a history of chronic obstructive pulmonary disease (COPD) and heavy smoking
• Patients had a planned surgical procedure at least 30 days before the screening day
• Known allergy or intolerance to an anti-TNF therapy
• Hypersensitivity to the Abatacept or to any of its excipients
• Patient with untreated active hepatitis B
• Patient vaccinated with a live vaccine within 30 days prior to screening
• Patients with an Inflammatory Bowel Disease (IBD) (loss of chance if switching from an anti-TNF to abatacept)

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

Sponsors

University Hospital, Montpellier

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jacques MOREL, MD-PhD

Role: STUDY_DIRECTOR

UF of Montpellier

Locations

Centre Hospitalier Universitaire de Montpellier

Montpellier, France, France

Site Status: RECRUITING

CHU Bordeaux groupe Pellegrin

Bordeaux, , France

Site Status: RECRUITING

CHU de Brest La Cavale Blanche

Brest, , France

Site Status: RECRUITING

Centre Hospitalier de Cahors

Cahors, , France

Site Status: NOT_YET_RECRUITING

CHD Vendée

La Roche-sur-Yon, , France

Site Status: RECRUITING

CH du Mans

Le Mans, , France

Site Status: RECRUITING

CHU de Nantes

Nantes, , France

Site Status: RECRUITING

CHU de Nice

Nice, , France

Site Status: RECRUITING

CHU de Nîmes Carémeau

Nîmes, , France

Site Status: NOT_YET_RECRUITING

CHR Orléans Nouvel hôpital d'Orléans

Orléans, , France

Site Status: RECRUITING

APHP Bicêtre

Paris, , France

Site Status: NOT_YET_RECRUITING

APHP Cochin

Paris, , France

Site Status: RECRUITING

APHP La Pitié Salpetrière

Paris, , France

Site Status: RECRUITING

CHU de Strasbourg Hautepierre

Strasbourg, , France

Site Status: NOT_YET_RECRUITING

Chu Purpan

Toulouse, , France

Site Status: NOT_YET_RECRUITING

CHU de Tours - Hopital Trousseau

Tours, , France

Site Status: RECRUITING

Centre hospitalier Princesse Grace

Monaco, , Monaco

Site Status: RECRUITING

Countries

France; Monaco

Central Contacts

Jacques MOREL, MD-PhD

Role: CONTACT

j-morel@chu-montpellier.fr

467338710 ext. +33

Facility Contacts

Jacques MOREL, MD-PhD

Role: primary

j-morel@chu-montpellier.fr

467338710 ext. +33

Christophe RICHEZ, MD

Role: primary

christophe.richez@chu-bordeaux.fr

Alain SARAUX, MD

Role: primary

alain.saraux@chu-brest.fr

Slim LASSOUED, MD

Role: primary

slim.lassoued@ch-cahors.fr

Grégoire CORMIER, MD

Role: primary

gregoire.cormier@ght85.fr

Emmanuelle DERNIS, MD

Role: primary

edernis@ch-lemans.fr

Jean Marie BERTHELOT, MD

Role: primary

jeanmarie.berthelot@chu-nantes.fr

Christian ROUX, MD

Role: primary

roux.c2@chu-nice.fr

Cécile GAUJOUX VIALA, MD

Role: primary

cecile.gaujoux.viala@chu-nimes.fr

Carine SALLIOT, MD

Role: primary

carine.salliot@chr-orleans.fr

Xavier MARIETTE, MD

Role: primary

xavier.mariette@aphp.fr

Jérôme AVOUAC, MD

Role: primary

jerome.avouac@aphp.fr

Bruno FAUTREL, MD

Role: primary

bruno.fautrel@aphp.fr

Jacques Eric GOTTENBERG, MD

Role: primary

jacques-eric.gottenberg@chru-strasbourg.fr

Arnaud CONSTANTIN, MD

Role: primary

constantin.a@chu-toulouse.fr

Denis MULLEMAN, MD

Role: primary

denis.mulleman@univ-tours.fr

Olivier BROCQ, MD

Role: primary

olivier.brocq@chpg.mc

Other Identifiers

RECHMPL21_0568

Identifier Type: -

Identifier Source: org_study_id