Combination of Baricitinib and Anti-TNF in Rheumatoid Arthritis

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 forthe classification of RA;

• Patient who presents an inadequate response to at least one bDMARD or tsDMARD for atleast 12 weeks prior to study entry at a dose that is considered acceptable toassess clinical response adequately;

• Patient affected by active RA (DAS28-ESR > 3.2 or sDAI > 11 or cDAI > 10) eligibleto receive a bDMARD or tsDMARD according to the French Society of Rheumatologyguidelines;

• Patient treated by prednisone dosage ≤ 10mg per day. The corticosteroids dosage willbe 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 theresearch project).

Exclusion Criteria:

• Patient previously treated with baricitinib;

• Patient previously treated by both adalimumab and etanercept. If the patientreceived previously only one of these two treatments, he/she can be included in thestudy with the treatment he/she has not yet received (if he/she is randomized in theexperimental COMBI group);

• Patient affected by another form of inflammatory arthritis with the exception ofsecondary Sjögren syndrome;

• Patient who presents contraindications to the study treatments;

• Patients who is an active smoker or former smokers with a maximum exposure of 10years;

• Patient who is currently receiving glucocorticosteroids at doses >10 mg ofprednisone per day (or equivalent) or has been receiving an unstable dosing regimenof 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 weeksprior to study entry; if either has been recently discontinued, the patient must nothave 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 intramuscularor intravenous injection within 4 weeks prior to study entry, or is anticipated torequire parenteral injection of corticosteroids during the study;

• Patient who had 3 or more joints injected with intraarticular corticosteroids orhyaluronic acid within 4 weeks prior to study entry. Joints injected withintraarticular corticosteroids or hyaluronic acid within 2 weeks prior to studyentry or within 6 weeks prior to planned randomization cannot be counted in the TJCand 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 1.5times the upper limit of normal (ULN) at screening, aspartate aminotransferase, oralanine amino-transferase more than 2 times the upper limit of normal (ULN) atscreening.

• 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 neuropsychiatricdiseases or any other serious and/or unstable illness that, in the opinion of theinvestigator, could constitute a risk when taking investigational product or couldinterfere 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 myocardialinfarction or non-fatal stroke);

• Patient who has a history of Venous Thromboembolic Event (VTE) (DVT/PE) within 12weeks prior to randomization or have a history of recurrent (>1) VTE (DVT/PE). PriorDVT with PE where events overlapped in time (i.e., with PE considered resulting fromDVT) 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 plannedrandomization or are expected to need/receive a live vaccine during the course ofthe study (with the exception of herpes zoster vaccination). Investigators shouldreview the vaccination status of their patients and follow the local guidelines foradult vaccination with nonlive vaccines intended to prevent infectious disease priorto 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) clinicallyserious viral, bacterial, fungal, or parasitic infection;

• Patient who is immunocompromised and, in the opinion of the investigator, is at anunacceptable 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) anddid not receive appropriate and documented prophylaxis for TB;

• Patient who has evidence of active TB or has previously had evidence of active TBand did not receive appropriate and documented treatment;

• Patient who has evidence of latent TB (as documented by a positive Purified ProteinDerivative (PPD), no clinical symptoms consistent with active TB, and a normal chestx-ray at screening) unless patient completes at least 3 weeks of appropriatetreatment prior to study entry and agrees to complete the remainder of treatmentwhile in the trial

• Patient who had any major surgery within 8 weeks prior to study entry or willrequire 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 effectivecontraception during the study course;

• Patient governed by articles L 1121-5 to L 1121-8 (persons deprived of their libertyby a judicial or administrative decision, minors, persons of legal age who are theobject of a legal protection measure or unable to express their consent).