Combination of Baricitinib and Anti-TNF in Rheumatoid Arthritis
NCT ID: NCT04870203
Last Updated: 2025-12-19
Study Results
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Basic Information
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RECRUITING
PHASE3
178 participants
INTERVENTIONAL
2021-07-15
2027-03-31
Brief Summary
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* 40 to 50% of patients with early RA, treated with methotrexate (MTX) monotherapy as first-line therapy,
* 20 to 30% of patients treated with a combination of MTX and biologic as second-line therapy.
* Less than 10% of patients treated with a combination of MTX and another targeted DMARD, such as baricitinib, as third-line therapy.
Therefore, new strategies targeted at achieving a higher percentage of remission are needed, that do not require waiting for multiple failed therapies. Combinations of biologics have shown synergistic improvement of symptoms in murine models of RA relative to the improvement observed with either agent alone. However, in RA patients, only five randomised clinical trials (RCTs) have explored the efficacy and safety of combining tumour necrosis factor (TNF) inhibitor with another biologic (anakinra, abatacept, rituximab or bimekizumab).
Baricitinib is a selective, reversible and competitive inhibitor of Janus kinases (Jaki). This treatment is efficient in a number of therapeutic scenarios in RA and showed a clinical superiority over adalimumab in one RCT (RA-BEAM study in MTX inadequate responders). Of note, baricitinib inhibits many of the pro-inflammatory cytokines involved in the pathogenesis of RA but does not block signalling downstream of TNF. Owing to the interest in combining different mechanisms of action, the investigators plan to assess the efficacy and safety of combination therapy with baricitinib and a TNF inhibitor. The investigators are aware that combining targeted therapies is not recommended due to a potential increase in the frequency of serious adverse events. However, several case series on patients treated with a combination of targeted therapies have been published, suggesting a certain efficacy in patients with refractory RA. The first ones focused on inflammatory bowel diseases and psoriasis, but more recently, combination of tofacitinib (which belongs to the same Jaki family as baricitinib) with various biologics has been reported in a sample of RA patients. No serious adverse effects were reported over a mean of approximately 11 months of therapy. The clinical improvement was mild but noticeable in these refractory RA cases.
Recently, data of interest from the RA-BEAM study have been reported. Patients who switched from adalimumab to baricitinib showed improvements in disease control. Because the switch from adalimumab to baricitinib occurred without a washout period, and because adalimumab has a mean circulating half-life of approximately 14 days, patients would have received several weeks of dual TNF and Jak1/Jak2 inhibition in the course of the change of treatment. The observation of increased efficacy, with no apparent acute safety issues during the weeks when patients were exposed to both adalimumab and baricitinib, is of interest, and supports our strategy to combine the two treatments for patients with refractory RA.
The investigators consider that there is a need for investigation into the addition of anti-TNF to baricitinib in patients suffering of refractory RA (inadequate response to TNF inhibitors). The investigators hypothesize that in this population, based on ACR50 score, this combination therapy will decrease disease activity more efficiently than a switch to another targeted DMARD, such as baricitinib.
Detailed Description
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Conditions
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Keywords
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
TRIPLE
Study Groups
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Period B : baricitinib + anti-TNF
baricitinib treatment
4 mg daily during 12 months
anti-TNF therapy
adalimumab at 40 mg every 2 weeks or etanercept 50 mg per week according to treatments history
Period B : baricitinib
baricitinib treatment
4 mg daily during 12 months
Period A : baricitinib + anti-TNF
baricitinib treatment
4 mg daily during 12 months
anti-TNF therapy
adalimumab at 40 mg every 2 weeks or etanercept 50 mg per week according to treatments history
Period A : baricitinib + placebo
baricitinib treatment
4 mg daily during 12 months
Placebo
40 mg every 2 weeks during 6 months only during Period A
Interventions
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baricitinib treatment
4 mg daily during 12 months
anti-TNF therapy
adalimumab at 40 mg every 2 weeks or etanercept 50 mg per week according to treatments history
Placebo
40 mg every 2 weeks during 6 months only during Period A
Eligibility Criteria
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Inclusion Criteria
* Age between 18 and 65 years-old;
* Adult patient with a diagnosis of RA as defined by the ACR/EULAR 2010 criteria for the classification of RA;
* Patient who presents an inadequate response to at least one bDMARD or tsDMARD for at least 12 weeks prior to study entry at a dose that is considered acceptable to assess clinical response adequately;
* Patient affected by active RA (DAS28-ESR \> 3.2 or sDAI \> 11 or cDAI \> 10) eligible to receive a bDMARD or tsDMARD according to the French Society of Rheumatology guidelines;
* Patient treated by prednisone dosage ≤ 10mg per day. The corticosteroids dosage will be decreased to 7,5 mg/day at the beginning of the study (W0);
* Person affiliated with or beneficiary of the French social security scheme;
* Free, informed and written consent signed by the participant and the investigator (on the day of inclusion at the latest and before any examination required by the research project).
Exclusion Criteria
* Patient previously treated by both adalimumab and etanercept. If the patient received previously only one of these two treatments, he/she can be included in the study with the treatment he/she has not yet received (if he/she is randomized in the experimental COMBI group);
* Patient affected by another form of inflammatory arthritis with the exception of secondary Sjögren syndrome;
* Patient who presents contraindications to the study treatments;
* Patients who is an active smoker or former smokers with a maximum exposure of 10 years;
* Patient who is currently receiving glucocorticosteroids at doses \>10 mg of prednisone per day (or equivalent) or has been receiving an unstable dosing regimen of corticosteroids within 4 weeks of study entry;
* Patient who is currently receiving more than 1 concomitant csDMARD (MTX, leflunomide, hydroxychloroquine or sulfasalazine) at the time of study entry;
* Patient who is currently receiving or has received csDMARDs (eg, gold salts, cyclosporine, azathioprine, or any other immunosuppressives) other than MTX (up to 25 mg/week), leflunomide (up to 20 mg/day), hydroxychloroquine (up to 400 mg/day), or sulfasalazine (up to 3000 mg/day) within 4 weeks prior to study entry.
* Doses of hydroxychloroquine or sulfasalazine should be stable for at least 4 weeks prior to study entry; if either has been recently discontinued, the patient must not have taken any dose within 4 weeks prior to study entry.
* Immunosuppression related to organ transplantation is not permitted;
* Patient who has received any parenteral corticosteroid administered by intramuscular or intravenous injection within 4 weeks prior to study entry, or is anticipated to require parenteral injection of corticosteroids during the study;
* Patient who had 3 or more joints injected with intraarticular corticosteroids or hyaluronic acid within 4 weeks prior to study entry. Joints injected with intraarticular corticosteroids or hyaluronic acid within 2 weeks prior to study entry or within 6 weeks prior to planned randomization cannot be counted in the TJC and SJC for entry or enrollment purposes;
* Patient with haemoglobin less than 80 g/L, absolute lymphocyte count lower than 0.5×109/L, absolute neutrophil count less than 1×109/L, or platelet count less than 100×109/L; clearance creatinine less than 60 mL/min; total bilirubin more than 1.5 times the upper limit of normal (ULN) at screening, aspartate aminotransferase, or alanine amino-transferase more than 2 times the upper limit of normal (ULN) at screening.
* Patient with co-administration with OAT3 inhibitors (such as probenecid);
* Patient who has a history or presence of cardiovascular, respiratory, hepatic, gastrointestinal, endocrine, hematological, neurological, or neuropsychiatric diseases or any other serious and/or unstable illness that, in the opinion of the investigator, could constitute a risk when taking investigational product or could interfere with the interpretation of data;
* Patient with an history of Moderate to severe heart failure (NYHA classes III/IV);
* Patient with an history of Major Adverse Cardiovascular Events (non-fatal myocardial infarction or non-fatal stroke);
* Patient who has a history of Venous Thromboembolic Event (VTE) (DVT/PE) within 12 weeks prior to randomization or have a history of recurrent (\>1) VTE (DVT/PE). Prior DVT with PE where events overlapped in time (i.e., with PE considered resulting from DVT) is not considered recurrent DVT/PE for the purpose of this criterion.
* Patient who has been exposed to a live vaccine within 12 weeks prior to planned randomization or are expected to need/receive a live vaccine during the course of the study (with the exception of herpes zoster vaccination). Investigators should review the vaccination status of their patients and follow the local guidelines for adult vaccination with nonlive vaccines intended to prevent infectious disease prior to entering patients into the study;
* Patient with an active cancer;
* Patient with malignancy or history of malignancy;
* Patient who has a current or recent (\<30 days prior to study entry) clinically serious viral, bacterial, fungal, or parasitic infection;
* Patient who is immunocompromised and, in the opinion of the investigator, is at an unacceptable risk for participating in the study;
* Patient with a history of active hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV);
* Patient who had household contact with a person with active tuberculosis (TB) and did not receive appropriate and documented prophylaxis for TB;
* Patient who has evidence of active TB or has previously had evidence of active TB and did not receive appropriate and documented treatment;
* Patient who has evidence of latent TB (as documented by a positive Purified Protein Derivative (PPD), no clinical symptoms consistent with active TB, and a normal chest x-ray at screening) unless patient completes at least 3 weeks of appropriate treatment prior to study entry and agrees to complete the remainder of treatment while in the trial
* Patient who had any major surgery within 8 weeks prior to study entry or will require major surgery during the study that, in the opinion of the investigator, would pose an unacceptable risk to the patient;
* Pregnant or breastfeeding woman, or woman who refuses to use an effective contraception during the study course;
* Patient governed by articles L 1121-5 to L 1121-8 (persons deprived of their liberty by a judicial or administrative decision, minors, persons of legal age who are the object of a legal protection measure or unable to express their consent).
18 Years
65 Years
ALL
No
Sponsors
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Eli Lilly and Company
INDUSTRY
Biogen
INDUSTRY
Ministry for Health and Solidarity, France
OTHER_GOV
University Hospital, Bordeaux
OTHER
Responsible Party
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Principal Investigators
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Christophe RICHEZ, Prof
Role: PRINCIPAL_INVESTIGATOR
University Hospital, Bordeaux
Edouard LHOMME, MD
Role: STUDY_CHAIR
University Hospital, Bordeaux
Locations
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Polyclinique de Limoges - service de rhumatologie
Limoges, , France
Groupement des Hôpitaux de l'Institut Catholique de Lille - service de rhumatologie
Lomme, , France
AP-HM - service de rhumatologie
Marseille, , France
Hôpital Saint-Joseph - service de rhumatologie
Marseille, , France
CHU de Montpellier - service de rhumatologie
Montpellier, , France
CHU de Nice - service de rhumatologie
Nice, , France
CH de Niort - service de rhumatologie
Niort, , France
CHU de Nîmes - service de rhumatologie
Nîmes, , France
Nouvel Hôpital Orléans La Source - service de rhumatologie
Orléans, , France
AP-HP - Hôpital Bichat - service de rhumatologie
Paris, , France
AP-HP - Hôpital Cochin - service de rhumatologie
Paris, , France
AP-HP - Hôpital La Pitié-Salpetrière - service de rhumatologie
Paris, , France
AP-HP - Hôpital Saint-Antoine - service de rhumatologie
Paris, , France
CH de Pau - service de rhumatologie
Pau, , France
Hospices Civils de Lyon - service de rhumatologie
Pierre-Bénite, , France
Hopital NOVO - service de rhumatologie
Pontoise, , France
CH de Reims - service de rhumatologie
Reims, , France
CHU de Saint-Etienne- service de rhumatologie
Saint-Etienne, , France
CH de la Côte Basque - service de rhumatologie
Bayonne, , France
CH de Belfort - service de rhumatologie
Belfort, , France
AP-HP - Hopital Avicenne - service de rhumatologie
Bobigny, , France
CHU de Bordeaux - service de rhumatologie
Bordeaux, , France
CHU de Brest - Service de rhumatologie
Brest, , France
Clinique de l'Infirmerie - service de rhumatologie
Caluire-et-Cuire, , France
CHU de Clermont-Ferrand - service de rhumatologie
Clermont-Ferrand, , France
CH de Dax - service de rhumatologie
Dax, , France
CHD VENDEE - service de rhumatologie
La Roche-sur-Yon, , France
CH de Saint-Malo - service de rhumatologie
St-Malo, , France
CHRU de Strasbourg - service de rhumatologie
Strasbourg, , France
CHU de Toulouse - service de rhumatologie
Toulouse, , France
CHRU du Tours - service de rhumtologie
Tours, , France
CHRU de Nancy - service de rhumatologie
Vandœuvre-lès-Nancy, , France
AP-HP - Hôpital Kremlin-Bicêtre - service de rhumatologie
Le Kremlin-Bicêtre, , France
CH du Mans - service de rhumatologie
Le Mans, , France
CH Emile Roux - service rhumatologie
Le Puy-en-Velay, , France
service de Rhumatologie - CH Princesse Grace
Monaco, , Monaco
Countries
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Central Contacts
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Facility Contacts
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Alexia HOURDILLE, MD
Role: primary
Anne LOHSE, MD
Role: primary
Luca SEMERANO, Prof
Role: primary
Christophe RICHEZ, Prof
Role: primary
Thomas BARNETCHE, PhD
Role: backup
Divi CORNEC, Prof
Role: primary
André BASCH, MD
Role: primary
Anne TOURNADRE, Prof
Role: primary
Emilie SHIPLEY, MD
Role: primary
Grégoire CORMIER, MD
Role: primary
Raphaele SEROR, Prof
Role: primary
Guillaume DIREZ, MD
Role: primary
Benjamin CASTAGNE, MD
Role: primary
Damien COYRAL, MD
Role: primary
Tristan PASCART, Prof
Role: primary
Thao PHAM, Prof
Role: primary
Damien ROCHE, MD
Role: primary
Jacques MOREL, Prof
Role: primary
Christian ROUX, Prof
Role: primary
Christian LORMEAU, MD
Role: primary
Cécile GAUJOUX-VIALA, Prof
Role: primary
Carine SAILLOT, MD
Role: primary
Philippe DIEUDE, Prof
Role: primary
Jérôme AVOUAC, MD
Role: primary
Bruno FAUTREL, Prof
Role: primary
Jéremie SELLAM, Prof
Role: primary
Vincent GERMAIN, MD
Role: primary
Cyrille CONFAVREUX, Prof
Role: primary
Omar AL TABAA, MD
Role: primary
Jean-Hugues SALMON, Prof
Role: primary
Hubert MAROTTE, Prof
Role: primary
Guillaume COIFFIER, MD
Role: primary
Jacques-Eric GOTTENBERG, Prof
Role: primary
Adeline RUYSSEN-WITRAND, Prof
Role: primary
Denis MULLEMAN, MD
Role: primary
Damien LOEUILLE, Prof
Role: primary
Olivier BROCQ, MD
Role: primary
Role: backup
Other Identifiers
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CHUBX 2019/56
Identifier Type: -
Identifier Source: org_study_id