Rheumatoid ArthritisPhase 3SEQUENS-RANCT05428488
Efficacy of a Sequential Treatment Strategy in Rheumatoid Arthritis
A Phase 3 study testing Abatacept (W12-W48), TNF Inhibitor (W12-W48) and TNF Inhibitor (W0-W12) in people with Rheumatoid Arthritis, run by University Hospital, Montpellier at 17 sites in 2 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Rheumatoid Arthritis
- What is being tested?
- Abatacept (W12-W48), TNF Inhibitor (W12-W48) and TNF Inhibitor (W0-W12)
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 220 participants
- Where
- 17 sitesin 2 countries
- Study dates
- 28 Nov 2022to Nov 2027
- Phase
- Phase 3
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 25Show fewer
- 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)
Trial locations and contacts
17 sites in 2 countries. Contact the study team or a site near you to ask about taking part.
17 sites in 2 countries
France16 sites, 16 recruiting
- Recruiting
CHU Bordeaux groupe Pellegrin
Bordeaux
Christophe RICHEZ, MD, christophe.richez@chu-bordeaux.fr
- Recruiting
CHU de Brest La Cavale Blanche
Brest
Alain SARAUX, MD, alain.saraux@chu-brest.fr
- Not yet recruiting
Centre Hospitalier de Cahors
Cahors
Slim LASSOUED, MD, slim.lassoued@ch-cahors.fr
- Recruiting
CHD Vendée
La Roche-sur-Yon
Grégoire CORMIER, MD, gregoire.cormier@ght85.fr
- Recruiting
CH du Mans
Le Mans
Emmanuelle DERNIS, MD, edernis@ch-lemans.fr
- Recruiting
Centre Hospitalier Universitaire de Montpellier
Montpellier, France, 34295
Jacques MOREL, MD-PhD, 467338710 ext. +33, j-morel@chu-montpellier.fr
- Recruiting
CHU de Nantes
Nantes
Jean Marie BERTHELOT, MD, jeanmarie.berthelot@chu-nantes.fr
- Recruiting
CHU de Nice
Nice
Christian ROUX, MD, roux.c2@chu-nice.fr
- Not yet recruiting
CHU de Nîmes Carémeau
Nîmes
Cécile GAUJOUX VIALA, MD, cecile.gaujoux.viala@chu-nimes.fr
- Recruiting
CHR Orléans Nouvel hôpital d'Orléans
Orléans
Carine SALLIOT, MD, carine.salliot@chr-orleans.fr
- Not yet recruiting
APHP Bicêtre
Paris
Xavier MARIETTE, MD, xavier.mariette@aphp.fr
- Recruiting
APHP Cochin
Paris
Jérôme AVOUAC, MD, jerome.avouac@aphp.fr
- Recruiting
APHP La Pitié Salpetrière
Paris
Bruno FAUTREL, MD, bruno.fautrel@aphp.fr
- Not yet recruiting
CHU de Strasbourg Hautepierre
Strasbourg
Jacques Eric GOTTENBERG, MD, jacques-eric.gottenberg@chru-strasbourg.fr
- Not yet recruiting
Chu Purpan
Toulouse
Arnaud CONSTANTIN, MD, constantin.a@chu-toulouse.fr
- Recruiting
CHU de Tours - Hopital Trousseau
Tours
Denis MULLEMAN, MD, denis.mulleman@univ-tours.fr
Monaco1 site, 1 recruiting
- Recruiting
Centre hospitalier Princesse Grace
Monaco
Olivier BROCQ, MD, olivier.brocq@chpg.mc
About this study
Official title: Efficacy of a Sequential Treatment Strategy in Rheumatoid Arthritis. A Randomized Controlled Trial With an Independent Efficacy Assessor.
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).
Read more
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.
Read the 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
- Being tested
- Abatacept (W12-W48), TNF Inhibitor (W12-W48), TNF Inhibitor (W0-W12)
- Keywords
- Rheumatoid arthritis, sequential therapeutic strategy, immunological remission, anti-TNF, abatacept
- Medical subject headings
- Arthritis, Rheumatoid
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
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.
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.
TNF Inhibitor (W0-W12)Drug
All included patients will receive TNF inhibitors subcutaneous for 12 weeks.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: TNF Inhibitor (W12-W48); Drug: TNF Inhibitor (W0-W12) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 36 weeks following randomization
Secondary outcomes (38)
percentage of patients in remission at 12 weeks after randomization (DAS28-ESR)
Percentage of patients in remission using definition : DAS28-ESR<2.6, at 12 weeks after randomization
Disease Activity Score-28 with Erythrocyte Sedimentation Rate (DAS28-ESR) describes severity of rheumatoid arthritis using clinical and laboratory data, specifically ESR.
Measured: At 24 weeks visit (corresponding to 12 weeks after randomization)
percentage of patients in remission at 12 weeks after randomization (CDAI)
Percentage of patients in remission using definition : CDAI≤2.8, at 12 weeks after randomization
Clinical Disease Activity Index (CDAI) is a useful clinical composite score. It's the sum of 4 parameters : Swollen 28-Joint + Tender 28-Joint Count + Patient Global disease Activity + Evaluator's Global disease Activity.
Remission is defined as an CDAI of ≤2.8, low disease activity as >2.8 and ≤10, moderate disease activity as >10 and ≤22 and high disease activity as >22.
Measured: At 24 weeks visit (corresponding to 12 weeks after randomization)
percentage of patients in remission at 12 weeks after randomization (SDAI)
Percentage of patients in remission using definition : SDAI≤3.3, at 12 weeks after randomization
Score Disease Activity Index (SDAI) is the sum of 5 parameters: the number of painful joints and synovitis (28 joints are tested) the global assessment of the patient and the therapist on a visual
Measured: At 24 weeks visit (corresponding to 12 weeks after randomization)
percentage of patients in remission at 12 weeks after randomization (Boolean)
Percentage of patients in remission using definition: Boolean criteria, at 12 weeks after randomization Boolean criteria of remission are : number of tender and swollen joint, visual analogue scale for global health and CRP all ≤1
Measured: At 24 weeks visit (corresponding to 12 weeks after randomization)
Percentage of patients in remission at 24 weeks after randomization (DAS28-ESR)
Percentage of patients in remission using definition : DAS28-ESR<2.6, at 24 weeks after randomization
Measured: At 36 weeks visit (corresponding to 24 weeks after randomization)
Percentage of patients in remission at24 weeks after randomization (CDAI)
Percentage of patients in remission using definition : CDAI≤2.8, at 24 weeks after randomization
Measured: At 36 weeks visit (corresponding to 24 weeks after randomization)
Percentage of patients in remission at 24 weeks after randomization (SDAI)
Percentage of patients in remission using definition : SDAI≤3.3, at 24 weeks after randomization
Measured: At 36 weeks visit (corresponding to 24 weeks after randomization)
Percentage of patients in remission at 24 weeks after randomization (Boolean)
Percentage of patients in remission using definitions : Boolean criteria, at 24 weeks after randomization
Measured: At 36 weeks visit (corresponding to 24 weeks after randomization)
Percentage of patients in remission at 36 weeks after randomization (DAS28-ESR)
Percentage of patients in remission using definition : DAS28-ESR<2.6, at 36 weeks after randomization
Measured: At 48 weeks visit (corresponding to 36 weeks after randomization)
Percentage of patients in remission at 36 weeks after randomization (CDAI)
Percentage of patients in remission using definition : CDAI≤2.8, at 36 weeks after randomization
Measured: At 48 weeks visit (corresponding to 36 weeks after randomization)
Percentage of patients in remission at 36 weeks after randomization (SDAI)
Percentage of patients in remission using definition : SDAI≤3.3, at 36 weeks after randomization
Measured: At 48 weeks visit (corresponding to 36 weeks after randomization)
Percentage of patients in remission at 36 weeks after randomization (Boolean)
Percentage of patients in remission using definition : Boolean criteria at 36 weeks after randomization
Measured: At 48 weeks visit (corresponding to 36 weeks after randomization)
Percentage of patients with low disease activity at 12 weeks after randomization (DAS28-ESR)
Percentage of patients in low disease activity using definition : 2.6≤DAS28-ESR≤3.2, at 12 weeks after randomization:
Measured: At 24 weeks visit (corresponding to 12 weeks after randomization)
Percentage of patients with low disease activity at 12 weeks after randomization (DAS28-CRP)
Percentage of patients in low disease activity using definition : 2.6≤DAS28-CRP≤3.2, at 12 weeks after randomization
Measured: At 24 weeks visit (corresponding to 12 weeks after randomization)
Percentage of patients with low disease activity at 12 weeks after randomization (CDAI)
Percentage of patients in low disease activity using definition : 2.8<CDAI≤10, at 12 weeks after randomization
Measured: At 24 weeks visit (corresponding to 12 weeks after randomization)
Percentage of patients with low disease activity at 12 weeks after randomization (SDAI)
Percentage of patients in low disease activity using definition : 3.3<SDAI≤11, at 12 weeks after randomization
Measured: At 24 weeks visit (corresponding to 12 weeks after randomization)
Percentage of patients with low disease activity at 24 weeks after randomization (DAS28-ESR)
Percentage of patients in low disease activity using definition: 2.6≤DAS28-ESR≤3.2, at 24 weeks after randomization
Measured: At 36 weeks visit (corresponding to 24 weeks after randomization)
Percentage of patients with low disease activity at 24 weeks after randomization (DAS28-CRP)
Percentage of patients in low disease activity using definition : 2.6≤DAS28-CRP≤3.2, at 24 weeks after randomization
Measured: At 36 weeks visit (corresponding to 24 weeks after randomization)
Percentage of patients with low disease activity at 24 weeks after randomization (CDAI)
Percentage of patients in low disease activity using definition : 2.8<CDAI≤10, at 24 weeks after randomization
Measured: At 36 weeks visit (corresponding to 24 weeks after randomization)
Percentage of patients with low disease activity at 24 weeks after randomization (SDAI)
Percentage of patients in low disease activity using definition : 3.3<SDAI≤11, at 24 weeks after randomization
Measured: At 36 weeks visit (corresponding to 24 weeks after randomization)
Percentage of patients with low disease activity at 36 weeks after randomization (DAS28-ESR)
Percentage of patients in low disease activity using definition : 2.6≤DAS28-ESR≤3.2, at 36 weeks after randomization
Measured: At 48 weeks visit (corresponding to 36 weeks after randomization)
Percentage of patients with low disease activity at 36 weeks after randomization (DAS28-CRP)
Percentage of patients in low disease activity using definition : 2.6≤DAS28-CRP≤3.2, at 36 weeks after randomization
Measured: At 48 weeks visit (corresponding to 36 weeks after randomization)
Percentage of patients with low disease activity at 36 weeks after randomization (CDAI)
Percentage of patients in low disease activity using definition : 2.8<CDAI≤10, at 36 weeks after randomization
Measured: At 48 weeks visit (corresponding to 36 weeks after randomization)
Percentage of patients with low disease activity at 36 weeks after randomization (SDAI)
Percentage of patients in low disease activity using definition : 3.3<SDAI≤11, at 36 weeks after randomization
Measured: At 48 weeks visit (corresponding to 36 weeks after randomization)
Proportion of responder patients at 12 weeks after randomization
Proportion of responders using EULAR (European Alliance of Associations for Rheumatology) definition (variations of DAS28-CRP from baseline >0.6 and DAS28-CRP≤5.1) at 12 weeks after randomization.
Measured: At 24 weeks visit (corresponding to 12 weeks after randomization)
Proportion of responder patients at 24 weeks after randomization
Proportion of responders using EULAR definition (variations of DAS28-CRP from baseline >0.6 and DAS28-CRP≤5.1) at 24 weeks after randomization.
Measured: At 36 weeks visit (corresponding to 24 weeks after randomization)
Proportion of responder patients at 36 weeks after randomization
Proportion of responders using EULAR definition (variations of DAS28-CRP from baseline >0.6 and DAS28-CRP≤5.1) at 36 weeks after randomization.
Measured: At 48 weeks visit (corresponding to 36 weeks after randomization)
Variations in the results of health assessment questionnaires administered to patients - HAQ-DI
Values and variations from baseline of patient-reported outcomes including health assessment questionnaire (HAQ-DI)
The Health Assessment Questionnaire Disability Index (HAQ-DI) is an assessment of functional impairment. There are 8 sections: dressing, arising, eating, walking, hygiene, reach, grip, and activities. Scoring within each section is from 0 (without any difficulty) to 3 (unable to do).
Measured: Between baseline and 48 weeks
Variations in the results of health assessment questionnaires administered to patients - EQ5D
Values and variations from baseline of patient-reported outcomes including health assessment questionnaire EQ5D
The EuroQol 5-dimensional descriptive system (EQ5D) is a Health Assessment Scale quality of life questionnaire evaluating: mobility, washing and dressing, daily activities, pain and anxiety. Each question has 3 levels of answers: No problem, some problems and important problems.
Measured: Between baseline and 48 weeks
Variations in the results of health assessment questionnaires administered to patients - SF-36
Values and variations from baseline of patient-reported outcomes including health assessment questionnaire SF-36
The Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) is a patient-operated, self-administered measure created to assess health-related quality of life
Measured: Between baseline and 48 weeks
Variation in autoantibody titers (RF)
Variation of auto-antibodies titles (RF (rheumatoid factor)) and correlation of these variations with remission rate defined by DAS28-CRP<2.6.
Measured: between baseline and 48 weeks
Variation in autoantibody titers (ACPA)
Variation of auto-antibodies titles (ACPA (Anti Citrullinated Peptides Antibodies)) and correlation of these variations with remission rate defined by DAS28-CRP<2.6.
Measured: between baseline and 48 weeks
Frequency of flares
Frequency of flares assessed using the FLARE questionnaire completed by the patient between visits
The self-administered Flare Assessment in Rheumatoid Arthritis (FLARE) is a self-administered questionnaire that was developed to help identify patients who had flare in the interval between 2 rheumatology consultations.
Measured: between baseline and 48 weeks
Cumulative doses of steroids consumed
Cumulative doses of steroids collected with a booklet between baseline and 48 weeks
Measured: between baseline and 48 weeks
Percentage of Serious Adverse Events Occurring
Safety: rates of serious adverse events including severe infections between baseline and 48 weeks
Measured: between baseline and 48 weeks
Variation of medical costs on Quality Adjusted Life Year
Cost efficacy analysis based on direct and indirect costs and QALY (Quality Adjusted Life Year) between baseline and 48 weeks.
Measured: between baseline and 48 weeks
Variation of Sharp's score
Variations Sharp's score between baseline and 48 weeks
The Sharp method for scoring radiographs of hands and feet in rheumatoid arthritis.
The method includes, in each hand, 16 areas for erosions and 15 areas for joint space narrowing, and, in each foot, 6 areas for erosions and 6 areas for joint space narrowing.
The maximal erosion score for each hand is thus 80, considering the 16 areas for erosions per hand.
Maximal total narrowing/(sub)luxation score in the hands is 120. Maximal total erosion score (hands and feet) is 280. Maximal total narrowing/(sub)luxation score in the feet is 48. Maximal total narrowing/(sub)luxation score (hands and feet) is 168.
Maximal total Sharp score is 448.
Sharp score will be calculated at W0 (baseline) and W48 (last visit). Variation of Shard score= score at W48- score at W0.
Measured: between baseline and 48 weeks
Percentage of patients remaining on abatacept
Percentage of patients remaining on abatacept in the sequential arm and on the 1st TNF inhibitor in the control arm at 48 weeks
Measured: At 48 weeks visit (corresponding to 36 weeks after randomization)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Jun 2022
- Study start28 Nov 2022
- Primary completionNov 2026 (estimated)
- Study completionNov 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Rheumatoid ArthritisStudies of the same condition, open and under way.
- More trials run by University Hospital, MontpellierThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Model description
- 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.
- Masking
- None (open label)
- Enrolment
- 220 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University Hospital, Montpellier
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Jacques MOREL, MD-PhD, Study director, UF of Montpellier
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05428488
- Sponsor's protocol ID
- RECHMPL21_0568
- Acronym
- SEQUENS-RA
- Status last verified
- Mar 2025
- First submitted
- 16 Jun 2022
- Last updated
- 3 Oct 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 3 Oct 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Efficacy of a Sequential Treatment Strategy in Rheumatoid Arthritis. A Randomized Controlled Trial With an Independent Efficacy Assessor.
- ClinicalTrials.gov ID
- NCT05428488
- Acronym / sponsor ID
- SEQUENS-RA / RECHMPL21_0568
- Conditions
- Rheumatoid Arthritis
- Keywords
- Rheumatoid arthritis, sequential therapeutic strategy, immunological remission, anti-TNF, abatacept
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 220 participants (estimated)
- Lead sponsor
- University Hospital, MontpellierUniversity, hospital or other
- Study start
- 28 Nov 2022 (actual)
- Primary completion
- Nov 2026 (estimated)
- Study completion
- Nov 2027 (estimated)
- First posted
- 23 Jun 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- 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.
| Arm | Type | Receives |
|---|---|---|
| Experimental | Experimental | Drug: Abatacept (W12-W48), Drug: TNF Inhibitor (W0-W12)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. |
| Control | Active comparator | Drug: TNF Inhibitor (W12-W48), Drug: TNF Inhibitor (W0-W12)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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- 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
Key exclusion criteria (25 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| 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. | Drug | Experimental |
| 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. | Drug | Control |
| TNF Inhibitor (W0-W12)All included patients will receive TNF inhibitors subcutaneous for 12 weeks. | Drug | Control, Experimental |
Primary outcome
Percentage of patients in remission
Time frame: 36 weeks following randomization
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.
38 secondary outcomes
percentage of patients in remission at 12 weeks after randomization (DAS28-ESR)
Time frame: At 24 weeks visit (corresponding to 12 weeks after randomization)
percentage of patients in remission at 12 weeks after randomization (CDAI)
Time frame: At 24 weeks visit (corresponding to 12 weeks after randomization)
percentage of patients in remission at 12 weeks after randomization (SDAI)
Time frame: At 24 weeks visit (corresponding to 12 weeks after randomization)
percentage of patients in remission at 12 weeks after randomization (Boolean)
Time frame: At 24 weeks visit (corresponding to 12 weeks after randomization)
Percentage of patients in remission at 24 weeks after randomization (DAS28-ESR)
Time frame: At 36 weeks visit (corresponding to 24 weeks after randomization)
Percentage of patients in remission at24 weeks after randomization (CDAI)
Time frame: At 36 weeks visit (corresponding to 24 weeks after randomization)
Percentage of patients in remission at 24 weeks after randomization (SDAI)
Time frame: At 36 weeks visit (corresponding to 24 weeks after randomization)
Percentage of patients in remission at 24 weeks after randomization (Boolean)
Time frame: At 36 weeks visit (corresponding to 24 weeks after randomization)
Percentage of patients in remission at 36 weeks after randomization (DAS28-ESR)
Time frame: At 48 weeks visit (corresponding to 36 weeks after randomization)
Percentage of patients in remission at 36 weeks after randomization (CDAI)
Time frame: At 48 weeks visit (corresponding to 36 weeks after randomization)
Percentage of patients in remission at 36 weeks after randomization (SDAI)
Time frame: At 48 weeks visit (corresponding to 36 weeks after randomization)
Percentage of patients in remission at 36 weeks after randomization (Boolean)
Time frame: At 48 weeks visit (corresponding to 36 weeks after randomization)
Percentage of patients with low disease activity at 12 weeks after randomization (DAS28-ESR)
Time frame: At 24 weeks visit (corresponding to 12 weeks after randomization)
Percentage of patients with low disease activity at 12 weeks after randomization (DAS28-CRP)
Time frame: At 24 weeks visit (corresponding to 12 weeks after randomization)
Percentage of patients with low disease activity at 12 weeks after randomization (CDAI)
Time frame: At 24 weeks visit (corresponding to 12 weeks after randomization)
Percentage of patients with low disease activity at 12 weeks after randomization (SDAI)
Time frame: At 24 weeks visit (corresponding to 12 weeks after randomization)
Percentage of patients with low disease activity at 24 weeks after randomization (DAS28-ESR)
Time frame: At 36 weeks visit (corresponding to 24 weeks after randomization)
Percentage of patients with low disease activity at 24 weeks after randomization (DAS28-CRP)
Time frame: At 36 weeks visit (corresponding to 24 weeks after randomization)
Percentage of patients with low disease activity at 24 weeks after randomization (CDAI)
Time frame: At 36 weeks visit (corresponding to 24 weeks after randomization)
Percentage of patients with low disease activity at 24 weeks after randomization (SDAI)
Time frame: At 36 weeks visit (corresponding to 24 weeks after randomization)
Percentage of patients with low disease activity at 36 weeks after randomization (DAS28-ESR)
Time frame: At 48 weeks visit (corresponding to 36 weeks after randomization)
Percentage of patients with low disease activity at 36 weeks after randomization (DAS28-CRP)
Time frame: At 48 weeks visit (corresponding to 36 weeks after randomization)
Percentage of patients with low disease activity at 36 weeks after randomization (CDAI)
Time frame: At 48 weeks visit (corresponding to 36 weeks after randomization)
Percentage of patients with low disease activity at 36 weeks after randomization (SDAI)
Time frame: At 48 weeks visit (corresponding to 36 weeks after randomization)
Proportion of responder patients at 12 weeks after randomization
Time frame: At 24 weeks visit (corresponding to 12 weeks after randomization)
Proportion of responder patients at 24 weeks after randomization
Time frame: At 36 weeks visit (corresponding to 24 weeks after randomization)
Proportion of responder patients at 36 weeks after randomization
Time frame: At 48 weeks visit (corresponding to 36 weeks after randomization)
Variations in the results of health assessment questionnaires administered to patients - HAQ-DI
Time frame: Between baseline and 48 weeks
Variations in the results of health assessment questionnaires administered to patients - EQ5D
Time frame: Between baseline and 48 weeks
Variations in the results of health assessment questionnaires administered to patients - SF-36
Time frame: Between baseline and 48 weeks
Variation in autoantibody titers (RF)
Time frame: between baseline and 48 weeks
Variation in autoantibody titers (ACPA)
Time frame: between baseline and 48 weeks
Frequency of flares
Time frame: between baseline and 48 weeks
Cumulative doses of steroids consumed
Time frame: between baseline and 48 weeks
Percentage of Serious Adverse Events Occurring
Time frame: between baseline and 48 weeks
Variation of medical costs on Quality Adjusted Life Year
Time frame: between baseline and 48 weeks
Variation of Sharp's score
Time frame: between baseline and 48 weeks
Percentage of patients remaining on abatacept
Time frame: At 48 weeks visit (corresponding to 36 weeks after randomization)
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Oct 2025.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Jacques MOREL, MD-PhD study director
UF of Montpellier
17 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Abatacept (W12-W48), TNF Inhibitor (W12-W48) and TNF Inhibitor (W0-W12) in people with Rheumatoid Arthritis, run by University Hospital, Montpellier at 17 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 3 Oct 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 17 sites in France, Monaco. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Jacques MOREL, MD-PhD (467338710 ext. +33, j-morel@chu-montpellier.fr), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percentage of patients in remission (time frame: 36 weeks following randomization). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Oct 2025.