Informations générales (source: ClinicalTrials.gov)
Combination of Baricitinib and Anti-TNF vs. Baricitinib in Patients With Rheumatoid Arthritis: a Randomized Placebo-controlled Phase III Trial (CRI-RA)
Interventional
Phase 3
University Hospital, Bordeaux (Voir sur ClinicalTrials)
juillet 2021
décembre 2025
29 juin 2024
As stated by the European League Against Rheumatism (EULAR) and the Société Française
de Rhumatologie (SFR), treatment of patients with rheumatoid arthritis (RA) should target
sustained remission or at least low disease activity. However, despite significant
advances based on various combinations of conventional synthetic disease-modifying
antirheumatic drugs (DMARDs) and biologic DMARDs, RA therapies meet treatment goals only
in some patients:
- 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.
Etablissements
| Les établissements d'Île-de-France dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
|---|---|---|---|---|---|
| AP-HP - Hôpital Bichat | Philippe DIEUDE, Prof | Contact (sur clinicalTrials) | |||
| AP-HP - Hôpital Saint Antoine | Jéremie SELLAM, Prof | Contact (sur clinicalTrials) | |||
| IFSI COCHIN-LA ROCHEFOUCAULT (AP-HP) | Jérôme AVOUAC, MD | Contact (sur clinicalTrials) | |||
| Les établissements hors Île-de-France dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| CH de Belfort - service de rhumatologie - Belfort - France | Anne LOHSE, MD | Contact (sur clinicalTrials) | |||
| CH de Dax - service de rhumatologie - Dax - France | Emilie SHIPLEY, MD | Contact (sur clinicalTrials) | |||
| CH de Reims - service de rhumatologie - Reims - France | Jean-Hugues SALMON, Prof | Contact (sur clinicalTrials) | |||
| CH de Saint-Malo - service de rhumatologie - Saint-Malo - France | Guillaume COIFFIER, MD | Contact (sur clinicalTrials) | |||
| CHU de Clermont-Ferrand - service de rhumatologie - Clermont-Ferrand - France | Anne TOURNADRE, Prof | Contact (sur clinicalTrials) | |||
| CHU de Saint-Etienne- service de rhumatologie - Saint-Étienne - France | Hubert MAROTTE, Prof | Contact (sur clinicalTrials) | |||
| Les établissements sans correspondance certaine dans le répertoire FINESS dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| AP-HM - service de rhumatologie - Marseille - France | Thao PHAM, Prof | Contact (sur clinicalTrials) | |||
| AP-HP - Hôpital Kremlin-Bicêtre - service de rhumatologie - Le Kremlin-Bicêtre - France | Raphaele SEROR, Prof | Contact (sur clinicalTrials) | |||
| AP-HP - Hôpital La Pitié-Salpetrière - service de rhumatologie - Paris - France | Bruno FAUTREL, Prof | Contact (sur clinicalTrials) | |||
| CH de la Côte Basque - service de rhumatologie - Bayonne - France | Alexia HOURDILLE, MD | Contact (sur clinicalTrials) | |||
| CH de Niort - service de rhumatologie - Niort - France | Christian LORMEAU, MD | Contact (sur clinicalTrials) | |||
| CH de Pau - service de rhumatologie - Pau - France | Vincent GERMAIN, MD | Contact (sur clinicalTrials) | |||
| CH du Mans - service de rhumatologie - Le Mans - France | Guillaume DIREZ, MD | Contact (sur clinicalTrials) | |||
| CH Emile Roux - service rhumatologie - Le Puy-en-Velay - France | Benjamin CASTAGNE, MD | Contact (sur clinicalTrials) | |||
| CHD VENDEE - service de rhumatologie - La Roche-sur-Yon - France | Grégoire CORMIER, MD | Contact (sur clinicalTrials) | |||
| CHRU de Nancy - service de rhumatologie - Vandœuvre-lès-Nancy - France | Damien LOEUILLE, Prof | Contact (sur clinicalTrials) | |||
| CHRU de Strasbourg - service de rhumatologie - Strasbourg - France | Jacques-Eric GOTTENBERG, Prof | Contact (sur clinicalTrials) | |||
| CHRU du Tours - service de rhumtologie - Tours - France | Denis MULLEMAN, MD | Contact (sur clinicalTrials) | |||
| CHU de Bordeaux - service de rhumatologie - Bordeaux - France | Christophe RICHEZ, Prof | Contact (sur clinicalTrials) | |||
| CHU de Brest - Service de rhumatologie - Brest - France | Divi CORNEC, Prof | Contact (sur clinicalTrials) | |||
| CHU de Montpellier - service de rhumatologie - Montpellier - France | Jacques MOREL, Prof | Contact (sur clinicalTrials) | |||
| CHU de Nice - service de rhumatologie - Nice - France | Christian ROUX, Prof | Contact (sur clinicalTrials) | |||
| CHU de Nîmes - service de rhumatologie - Nîmes - France | Cécile GAUJOUX-VIALA, Prof | Contact (sur clinicalTrials) | |||
| CHU de Toulouse - service de rhumatologie - Toulouse - France | Adeline RUYSSEN-WITRAND, Prof | Contact (sur clinicalTrials) | |||
| Clinique de l'Infirmerie - service de rhumatologie - Caluire-et-Cuire - France | André BASCH, MD | Contact (sur clinicalTrials) | |||
| Groupement des Hôpitaux de l'Institut Catholique de Lille - service de rhumatologie - Lomme - France | Tristan PASCART, Prof | Contact (sur clinicalTrials) | |||
| Hôpital Saint-Joseph - service de rhumatologie - Marseille - France | Damien ROCHE, MD | Contact (sur clinicalTrials) | |||
| Hospices Civils de Lyon - service de rhumatologie - Pierre-Bénite - France | Cyrille CONFAVREUX, Prof | Contact (sur clinicalTrials) | |||
| Nouvel Hôpital Orléans La Source - service de rhumatologie - Orléans - France | Carine SAILLOT, MD | Contact (sur clinicalTrials) | |||
| Polyclinique de Limoges - service de rhumatologie - Limoges - France | Damien COYRAL, MD | Contact (sur clinicalTrials) | |||
Critères
Tous
Inclusion Criteria:
- Male or female;
- 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).
- Male or female;
- 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).
- Patient previously treated with baricitinib;
- 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).