Combination of Baricitinib and Anti-TNF in Rheumatoid Arthritis

NCT04870203 | Active Not Recruiting Phase 3 DMC

• 1 other identifier: CHUBX 2019/56
• Study Type: interventional
• Target: 160
• Locations: 2 countries
• Sites: 36

Brief 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 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.

Conditions

Rheumatoid Arthritis

Keywords

baricitinib; adalimumab; etanercept; placebo

Outcome Measures

Primary Outcomes (2)

• Proportion of patients who achieve an ACR 50 response

  in each treatment group (COMBI group (anti-TNF therapy + baricitinib) vs. MONO group (baricitinib conventional therapy)).

  At weeks 24 after baseline

• Quantitative change in DAS28-CRP

  in each treatment group (COMBI group (anti-TNF therapy + baricitinib) vs. MONO group (baricitinib conventional therapy)).

  At weeks 24 after baseline

Secondary Outcomes (20)

• 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)

Study Arms (4)

Period A : baricitinib + anti-TNF

EXPERIMENTAL

Drug: baricitinib treatment; Drug: anti-TNF therapy

Period A : baricitinib + placebo

PLACEBO COMPARATOR

Drug: baricitinib treatment; Drug: Placebo

Period B : baricitinib + anti-TNF

EXPERIMENTAL

Drug: baricitinib treatment; Drug: anti-TNF therapy

Period B : baricitinib

ACTIVE COMPARATOR

Drug: baricitinib treatment

Interventions

baricitinib treatment DRUG

4 mg daily during 12 months

Period A : baricitinib + anti-TNF; Period A : baricitinib + placebo; Period B : baricitinib; Period B : baricitinib + anti-TNF

anti-TNF therapy DRUG

adalimumab at 40 mg every 2 weeks or etanercept 50 mg per week according to treatments history

Period A : baricitinib + anti-TNF; Period B : baricitinib + anti-TNF

Placebo DRUG

40 mg every 2 weeks during 6 months only during Period A

Period A : baricitinib + placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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;

You may not qualify if:

• 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;

Sponsors & Collaborators

• University Hospital, Bordeaux: lead
• Eli Lilly and Company: collaborator
• Biogen: collaborator
• Ministry for Health and Solidarity, France: collaborator

Study Sites (36)

CH de la Côte Basque - service de rhumatologie

Bayonne, France

Location

CH de Belfort - service de rhumatologie

Belfort, France

Location

AP-HP - Hopital Avicenne - service de rhumatologie

Bobigny, France

Location

CHU de Bordeaux - service de rhumatologie

Bordeaux, France

Location

CHU de Brest - Service de rhumatologie

Brest, France

Location

Clinique de l'Infirmerie - service de rhumatologie

Caluire-et-Cuire, France

Location

CHU de Clermont-Ferrand - service de rhumatologie

Clermont-Ferrand, France

Location

CH de Dax - service de rhumatologie

Dax, France

Location

CHD VENDEE - service de rhumatologie

La Roche-sur-Yon, France

Location

AP-HP - Hôpital Kremlin-Bicêtre - service de rhumatologie

Le Kremlin-Bicêtre, France

Location

CH du Mans - service de rhumatologie

Le Mans, France

Location

CH Emile Roux - service rhumatologie

Le Puy-en-Velay, France

Location

Polyclinique de Limoges - service de rhumatologie

Limoges, France

Location

Groupement des Hôpitaux de l'Institut Catholique de Lille - service de rhumatologie

Lomme, France

Location

AP-HM - service de rhumatologie

Marseille, France

Location

Hôpital Saint-Joseph - service de rhumatologie

Marseille, France

Location

CHU de Montpellier - service de rhumatologie

Montpellier, France

Location

CHU de Nice - service de rhumatologie

Nice, France

Location

CH de Niort - service de rhumatologie

Niort, France

Location

CHU de Nîmes - service de rhumatologie

Nîmes, France

Location

Nouvel Hôpital Orléans La Source - service de rhumatologie

Orléans, France

Location

AP-HP - Hôpital Bichat - service de rhumatologie

Paris, France

Location

AP-HP - Hôpital Cochin - service de rhumatologie

Paris, France

Location

AP-HP - Hôpital La Pitié-Salpetrière - service de rhumatologie

Paris, France

Location

AP-HP - Hôpital Saint-Antoine - service de rhumatologie

Paris, France

Location

CH de Pau - service de rhumatologie

Pau, France

Location

Hospices Civils de Lyon - service de rhumatologie

Pierre-Bénite, France

Location

Hopital NOVO - service de rhumatologie

Pontoise, France

Location

CH de Reims - service de rhumatologie

Reims, France

Location

CHU de Saint-Etienne- service de rhumatologie

Saint-Etienne, France

Location

CH de Saint-Malo - service de rhumatologie

St-Malo, France

Location

CHRU de Strasbourg - service de rhumatologie

Strasbourg, France

Location

CHU de Toulouse - service de rhumatologie

Toulouse, France

Location

CHRU du Tours - service de rhumtologie

Tours, France

Location

CHRU de Nancy - service de rhumatologie

Vandœuvre-lès-Nancy, France

Location

service de Rhumatologie - CH Princesse Grace

Monaco, Monaco

Location

MeSH Terms

Conditions

Arthritis, Rheumatoid

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Study Officials

• Christophe RICHEZ, Prof

  University Hospital, Bordeaux

  PRINCIPAL INVESTIGATOR

• Edouard LHOMME, MD

  University Hospital, Bordeaux

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Period A : Participant / Care provider / Investigator \*\*\* Period B : An independent efficacy assessor will perform the joint evaluation, whereas the investigator will evaluate safety.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Period A : placebo-controlled trial \*\*\* Period B : controlled trial - study switch to an open-label design from the 17th August 2024

Study Record Dates

• First Submitted: April 26, 2021
• First Posted: May 3, 2021
• Study Start: July 15, 2021
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): March 1, 2027
• Last Updated: March 17, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

FR (35); MO (1)