Combination of Baricitinib and Anti-TNF vs. Baricitinib in Patients With Rheumatoid Arthritis: a Randomized Controlled Phase III Trial

Official Summary

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

Eligibility Requirements

• Minimum Age: 18 Years
• Maximum Age: 65 Years

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: TRIPLE
• Enrollment: 160 participants

Study Arms

• Period A : baricitinib + anti-TNF (EXPERIMENTAL)
• Period A : baricitinib + placebo (PLACEBO_COMPARATOR)
• Period B : baricitinib + anti-TNF (EXPERIMENTAL)
• Period B : baricitinib (ACTIVE_COMPARATOR)

Interventions

• DRUG: baricitinib treatment — 4 mg daily during 12 months
• DRUG: anti-TNF therapy — adalimumab at 40 mg every 2 weeks or etanercept 50 mg per week according to treatments history
• DRUG: Placebo — 40 mg every 2 weeks during 6 months only during Period A

Primary Outcomes

• Proportion of patients who achieve an ACR 50 response (At weeks 24 after baseline)
• Quantitative change in DAS28-CRP (At weeks 24 after baseline)

Secondary Outcomes

• Proportion of adverse events (AE) and serious adverse events (SAE) in each treatment group (weeks 52 after baseline (Day 0))
• Proportion of patients who achieve an ACR20 response in each treatment group (At weeks 4, 12 and 24 after baseline (Day 0))
• Proportion of patients who achieve an ACR70 response in each treatment group (At weeks 4, 12 and 24 after baseline (Day 0))
• Proportion of patients who achieve an ACR50 response in each treatment group (At weeks 4 and 12 after baseline (Day 0))
• Proportion of patients who present a EULAR response according to DAS28-ESR, in each treatment group (at weeks 4, 12 and 24 after baseline (Day 0))

Eligibility Criteria

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).

Exclusion Criteria:

* 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 p

Trial Locations

• 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
• AP-HP - Hôpital Kremlin-Bicêtre - service de rhumatologie, Le Kremlin-Bicêtre, France
• ...and 10 more locations

Study Officials

• Christophe RICHEZ, Prof — PRINCIPAL_INVESTIGATOR
  University Hospital, Bordeaux
• Edouard LHOMME, MD — STUDY_CHAIR
  University Hospital, Bordeaux

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