Abatacept vs Tocilizumab for the Treatment of RA in TNF Alpha Inhibitor Inadequate Responders
NCT ID: NCT03227419
Last Updated: 2023-09-13
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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UNKNOWN
PHASE4
224 participants
INTERVENTIONAL
2018-01-22
2024-11-30
Brief Summary
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Biological agents have been proposed for patients with RA who have the most severe form of the disease and that are inadequate responder patients to conventional synthetic Disease-modifying antirheumatic drugs (csDMARDs). TNF inhibitors (TNFi) are historically proposed as the first biological DAMRD for inadequate responder patients to csDMARDs. A diverse therapeutic arsenal has become available in recent years with the development of non-anti-TNFα drugs whose mechanisms of action are different from the classical TNFi. This new biotherapy class includes tocilizumab and abatacept, two drugs recently available for subcutaneous administration that enables ambulatory care for patients who would otherwise require repeated in-hospital care.
The role of these new treatments in the therapeutic strategy has been emphasized by studies that demonstrated their efficacy as first-line treatments. However, in clinical practice, TNFi remain the most common first-line treatment for the majority of patients, non-anti-TNFα biological agents being reserved for inadequate responder patients.
In second line, several studies have investigated therapeutic strategies for inadequate responder patients to TNFi. Current data suggest that it could be wise to change the therapeutic target after failure of a first-line treatment with TNFi.
Data about the comparative efficacy of different biologics proposed after failure of a first-line treatment with TNFi are in progress. Meta-analyses from registries and academic trials conducted in France and The Netherlands suggest that non-anti-TNFα agents would have equivalent or superior efficacy compared with a second TNFi. This finding suggests clinicians to switch for an alternate therapeutic target after failure of a first-line TNFi.
Data comparing different non-anti-TNFα biologics in inadequate responder patients to TNFi are scare. Industrial trials have demonstrated sustained biological efficacy of non-anti-TNFα biologics after failure of a TNFi. However, there is very little solid data on the direct comparison between them.
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Detailed Description
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Biologic agents are taking on an increasingly important role in the management of patients with an inadequate response to conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs).
Biological DMARD (bDMARD) therapy consists in the use of monoclonal antibodies or fusion proteins, administered intravenously or subcutaneously. The earliest developed biologic agents have been available for more than 15 years. Tumor necrosis factor alpha (TNFα), a pro-inflammatory cytokine, was the first cytokine successfully targeted by a biologic agent for RA treatment. TNF inhibitors (TNFi) are historically proposed as the first bDAMRD for inadequate responder patients to csDMARDs. More recently non-anti-TNFα drugs have emerged, with other biological targets such as interleukin-6 receptor (tocilizumab) or B- (rituximab) and T-lymphocytes (abatacept) that are implicated in the inflammatory response. Initially administered strictly intravenously, these drugs are now available in formulations adapted to subcutaneous administration, which allows ambulatory care for patients who otherwise would require repeated in-hospital care.
National and international guidelines, especially those issued in 2013 by the European League Against Rheumatism (EULAR) and also in 2013 by the French Society of Rheumatology now recommend first-line treatment not only with TNFi but also with non-anti-TNFα biologic agents. However, in routine practice, most clinicians preferably prescribe TNFi for the first-line regimen, reserving non-anti-TNFα drugs to TNFi inadequate responder patients.
There is a growing body of research focusing on first-line biologic agents but there is very little solid data on the direct randomized comparison between them. Actually, all three of the published studies have systematically compared a non-anti-TNFα biomedication versus TNFi (one study with a blinded design and two open studies).
The therapeutic strategy that should be adapted after failure of a TNFi regimen has also been investigated. Those studies favor non-anti-TNF drugs over an alternate TNFi.
There is adequate evidence of the efficacy of the different non-anti-TNFα biologic agents versus placebo after TNFi failure. In other hands, industrial trials have not provided any comparative data between drugs. An academic trial from The Netherlands using medico-economic performance as the primary outcome found no difference in efficacy between abatacept and rituximab (a non-anti-TNFα drug administered exclusively intravenously) after failure of a TNFi. Meta-analyses using data from care networks have not reported any difference between different non-anti-TNFα drugs after failure of a TNFi.
Data from national registries have provided interesting complementary information since in everyday practice these agents are generally used after failure of at least one TNFi. The Danish registry thus suggests that the therapeutic response would be better with tocilizumab than with abatacept. This observation was confirmed by an analysis of French registries data presented at the American College of Rheumatology (ACR) congress in November 2016 showing that tocilizumab exhibits superiority for treatment persistence over 2 years. These results were fully in agreement with the findings of the French ROC trial comparing intravenous administration of a second anti-TNFα drug versus a non-anti-TNFα agent after failure of an anti-TNFα drug that suggested a superiority of tocilizumab over abatacept in the subgroup of patients given a non-anti-TNFα agent. A recent Bayesian network meta-analysis showed better efficacy in the non-anti-TNFα groups for ACR20 in patients who responded insufficiently to an anti-TNFα.
Subcutaneous formulations have been recently developed for both tocilizumab and abatacept. Subcutaneous administration is important because it enables ambulatory care for a substantial number of patients who to date are recurrently hospitalized in day-care units for their intravenous infusions. Excepting specific situations, the subcutaneous formulation will be favored for a large majority of patients because of economic as well as practical considerations. Phase III trials have demonstrated the equivalence of the intravenous versus subcutaneous routes of administration focusing on efficacy and tolerance. The subcutaneous formulation is now also available for routine administration of both tocilizumab and abatacept. Nevertheless, despite large-scale industrial trials on drug equivalence, data issuing from clinical practice suggest a potential difference in the behavior of these two formulations which needs to be explored. Rituximab is apart in the treatment strategy because of its exclusive intravenous administration at spaced intervals and because it is used for specific patient profiles (extra-articular involvement, history of neoplasia, rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) positivity). There is no perspective for the development of a subcutaneous formulation of rituximab for RA patients. Furthermore, the routine treatment schedule for rituximab (one-time injections at a mean interval of 9 months) would compromise comparison, especially short-term comparison, with other subcutaneous treatments.
These findings illustrate the need for a new multicentric, prospective, randomized trial designed to demonstrate the superiority of tocilizumab over abatacept in patients exhibiting inadequate response to a first anti-TNFα. A direct comparison of subcutaneous formulation is the need for the promising route of administration for future ambulatory care.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Tocilizumab Prefilled Syringe
Market approval recommendations will be respected. Treatment should be started within 7 days of randomization.
The treatment protocol has no specific provision for treatment adaptation. Treatment will be managed in compliance with the marketing approval recommendations and drug labeling described below.
Tocilizumab Prefilled Syringe
Treatment arm: tocilizumab (RoActemra®):
162 mg weekly a schema for therapeutic adaptation with injection intervals determined according to transaminase levels or blood cell counts (neutropenia, thrombopenia) as recommended by Roche-Chugaï (see table below).
Abatacept Prefilled Syringe
Market approval recommendations will be respected. Treatment should be started within 7 days of randomization.
The treatment protocol has no specific provision for treatment adaptation. Treatment will be managed in compliance with the marketing approval recommendations and drug labeling described below.
Abatacept Prefilled Syringe
Treatment arm: abatacept (Orencia®)
125 mg weekly after an initial dose of 500 mg (body weight \<60kg), 750 mg (body weight between 60 and 100 kg), or 1000 mg (body weight \>100 mg) 24 hours before the first subcutaneous injection.
Interventions
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Tocilizumab Prefilled Syringe
Treatment arm: tocilizumab (RoActemra®):
162 mg weekly a schema for therapeutic adaptation with injection intervals determined according to transaminase levels or blood cell counts (neutropenia, thrombopenia) as recommended by Roche-Chugaï (see table below).
Abatacept Prefilled Syringe
Treatment arm: abatacept (Orencia®)
125 mg weekly after an initial dose of 500 mg (body weight \<60kg), 750 mg (body weight between 60 and 100 kg), or 1000 mg (body weight \>100 mg) 24 hours before the first subcutaneous injection.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* RA according to the ACR/EULAR 2010 criteria
* inadequate response to a subcutaneously administered first-line TNFi defined as moderate to high disease activity (DAS28-ESR\>3.2 and CDAI\>10) after at least 3 months of treatment with a TNFi
* beneficiary of the French National Health Insurance Fund
* signed informed consent form
* for women of childbearing age: effective contraception during treatment period with engagement to continue such contraception for 14 weeks after last administration
Exclusion Criteria
* prior failure of the TNFi due to intolerance
* receiving ≥15 mg/day prednisone for more than 4 weeks
* pregnant or nursing women
18 Years
ALL
No
Sponsors
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Lille Catholic University
OTHER
Responsible Party
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Principal Investigators
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Pascart Tristan, MD
Role: PRINCIPAL_INVESTIGATOR
GHICL
Locations
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Hôpital Saint-Philibert
Lomme, Hauts-de-France, France
Hôpital Avicenne
Bobigny, , France
CHU de Bordeaux
Bordeaux, , France
CH de Boulogne-sur-Mer
Boulogne-sur-Mer, , France
Ch Cahors
Cahors, , France
CHU de Clermont-Ferrand
Clermont-Ferrand, , France
CHU de Grenoble Hôpital Sud
Grenoble, , France
CHD Vendée
La Roche-sur-Yon, , France
Hôpital Bicêtre
Le Kremlin-Bicêtre, , France
CHRU de Lille
Lille, , France
Clinique Infirmerie Protestante de Lyon
Lyon, , France
CHU de Montpellier
Montpellier, , France
CHU Nice
Nice, , France
CHU Bichat
Paris, , France
Hôpital Cochin
Paris, , France
Hôpital de la Pitié-Salpêtrière
Paris, , France
Hôpital Lariboisière
Paris, , France
CHU de Poitiers
Poitiers, , France
CH René-Dubos
Pontoise, , France
CHU de Reims
Reims, , France
CHU Rouen
Rouen, , France
CHU de Saint-Etienne
Saint-Etienne, , France
CHU Saint-Etienne
Saint-Etienne, , France
CHRU de Strasbourg
Strasbourg, , France
CHU de Tours
Tours, , France
CH de Valenciennes
Valenciennes, , France
Countries
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Central Contacts
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Facility Contacts
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Tristan Pascart, MD, PhD
Role: primary
Luca SEMERANO, MD
Role: primary
Marie-Elise TRUCHETET, MD
Role: primary
Christophe RICHEZ, MD
Role: backup
Renaud DESBARBIEUX, MD
Role: primary
Slim LASSOUED, MD
Role: primary
Martin SOUBRIER, MD, Pr
Role: primary
Anne TOURNADRE, MD, Pr
Role: backup
Athan BAILLET, MD, Pr
Role: primary
Grégoire CORMIER, MD
Role: primary
Stéphane VARIN, MD
Role: backup
Xavier MARIETTE, MD, Pr
Role: primary
Frédéric DESMOULINS, MD
Role: backup
René-Marc FLIPO, MD, Pr
Role: primary
André BASCH, MD
Role: primary
Jacques MOREL, MD, Pr
Role: primary
Véronique BREUIL, MD, Pr
Role: primary
Sébastien OTTAVIANI, MD
Role: primary
Jérôme AVOUAC, MD, Pr
Role: primary
Bruno FAUTREL, MD, Pr
Role: primary
Pascal RICHETTE, MD, Pr
Role: primary
Elisabeth GERVAIS, MD, Pr
Role: primary
Edouard PERTUISET, MD
Role: primary
Jean-Hugues SALMON, MD
Role: primary
Olivier VITTECOQ, MD, Pr
Role: primary
Hubert MAROTTE, MD
Role: primary
Hubert MAROTTE, MD
Role: primary
Jacques-Eric GOTTENBERG, MD, Pr
Role: primary
Isabelle GRIFFOUL, MD
Role: primary
Jessica RENE, MD
Role: backup
Xavier DEPREZ, MD
Role: primary
References
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Pascart T, Fautrel B, Gottenberg JE, Ducoulombier V, Richez C, Truchetet ME, Avouac J, Morel J, Basch A, Cormier G; SUNSTAR Study Group; CRI-IMIDIATE Network; Houvenagel E, Mariette X, Norberciak L. Abatacept versus tocilizumab for the treatment of rheumatoid arthritis in TNF inhibitor inadequate responders: study protocol of the SUNSTAR randomised controlled open-label superiority trial. BMJ Open. 2025 Jun 17;15(6):e098298. doi: 10.1136/bmjopen-2024-098298.
Other Identifiers
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RC-P0055
Identifier Type: -
Identifier Source: org_study_id
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