Evaluation of Baricitinib Combined with Anti-TNF Agents Adalimumab or Etanercept Versus Baricitinib Monotherapy in Refractory Rheumatoid Arthritis Patients

Trial ID: 2024-511442-39-00
Protocol: CHUBX 2019/56
Sponsor: Centre Hospitalier Universitaire De Bordeaux

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Diseases & Conditions

Rheumatoid arthritis

Objectives

The primary objective of this study is to evaluate the **clinical efficacy** at 24 weeks of a combination strategy involving anti-TNF therapy (adalimumab or etanercept) with baricitinib versus baricitinib alone in patients with refractory **rheumatoid arthritis**. This assessment is clinically relevant as it aims to determine whether the combination therapy offers superior efficacy in managing symptoms and disease progression compared to monotherapy, potentially informing treatment strategies for patients with inadequate response to existing therapies.

Secondary objectives include:

Assessing the safety of the combination therapy versus baricitinib alone by comparing clinical and biological safety profiles over 24 weeks.
Evaluating drug retention rates at weeks 4, 12, and 24 in each treatment group.
Determining the proportion of patients who reduce glucocorticosteroid doses to ≤ 5 mg per day, sustained from week 12 to week 24, among those with a baseline dose > 5 mg per day.
Assessing patient-reported outcomes (HAQ, FACIT, RAID) at week 24.
Evaluating the maintenance of clinical efficacy at week 52.
Comparing changes in DAS28-CRP scores between baseline and week 24.
Comparing the proportion of patients achieving ACR20 and ACR70 responses at weeks 4, 12, and 24.
Comparing the proportion of patients achieving an ACR50 response at weeks 4 and 12.
Comparing the proportion of patients with a EULAR response at weeks 4, 12, and 24, according to DAS28-ESR.
Comparing the proportion of patients achieving remission or low disease activity at weeks 4, 12, and 24, according to DAS28-ESR.
Comparing changes in DAS28-ESR, DAS28-CRP, sDAI, and cDAI scores between baseline and each visit up to week 24.

Participants

The clinical trial involves a total of **9 participants** diagnosed with **rheumatoid arthritis (RA)**, as defined by the ACR/EULAR 2010 criteria. The study population includes both male and female adults aged between **18 and 65 years**. Participants are required to have an inadequate response to at least one biologic or targeted synthetic disease-modifying antirheumatic drug (bDMARD or tsDMARD) for a minimum of 12 weeks prior to study entry. The trial includes individuals with active RA, indicated by a DAS28-ESR score greater than 3.2, sDAI greater than 11, or cDAI greater than 10, who are eligible to receive a bDMARD or tsDMARD according to the French Society of Rheumatology guidelines. Participants are also required to be treated with a prednisone dosage of 10 mg per day or less, which will be reduced to 7.5 mg per day at the start of the study. All participants must be affiliated with or beneficiaries of the French social security scheme and have provided free, informed, and written consent. The trial population was selected based on these criteria to ensure the inclusion of individuals who are representative of the target demographic for the study's objectives.

Plans and Procedures

The clinical trial is designed to evaluate the **clinical efficacy** of combining anti-TNF therapy with **baricitinib** in patients with **rheumatoid arthritis**. This is a randomized, placebo-controlled, phase-III trial. The study will compare the combination of **adalimumab** or **etanercept** with baricitinib against baricitinib alone. The trial is expected to last until December 31, 2026, with recruitment having started on July 15, 2021. Participants will be involved for a maximum of 52 weeks, with the primary endpoint being the proportion of patients achieving an ACR 50 response at week 24.

Study visits are structured to ensure comprehensive data collection and participant safety. The inclusion visit, or screening, will confirm eligibility based on criteria such as age, diagnosis of rheumatoid arthritis, and previous treatment responses. Follow-up visits will occur at weeks 4, 12, and 24, with assessments including ACR responses, EULAR responses, and changes in disease activity scores. The end-of-study visit will occur at week 52, evaluating long-term outcomes such as drug retention rates and sustained responses.

Participants are expected to adhere to the study protocol, with conditions for early termination including non-compliance, adverse events, or withdrawal of consent. The trial employs a double-blind design to minimize bias, ensuring neither participants nor investigators know the treatment allocation. This methodology is critical for maintaining the integrity of the trial results and ensuring reliable data on the efficacy and safety of the treatment strategies being tested.

Treatment

The clinical trial involves several treatments, including both experimental and non-experimental medications. **Imraldi**, a solution for injection in a pre-filled pen, contains the active substance **adalimumab**. It is administered via injection with a maximum daily dose of 40 mg, and the treatment period is up to 24 weeks. The pharmaceutical form is a solution for injection, and the product is manufactured by Samsung Bioepis NL B.V. The administration involves removal from the primary packaging and repacking.

**Benepali** is another solution for injection in a pre-filled pen, containing the active substance **etanercept**. It is administered via injection with a maximum daily dose of 50 mg, and the treatment period is up to 24 weeks. The pharmaceutical form is a solution for injection, and it is also manufactured by Samsung Bioepis NL B.V.

**Olumiant** is provided as 4 mg film-coated tablets containing the active substance **baricitinib**. It is administered orally with a maximum daily dose of 4 mg, and the treatment period extends up to 52 weeks. The pharmaceutical form is a film-coated tablet, and the product is manufactured by Eli Lilly Nederland B.V.

**Prednisone** is included as a non-experimental treatment, provided in tablet form. It is administered orally with a maximum daily dose of 7.5 mg, and the treatment period is up to 52 weeks. Prednisone is classified as a corticoid and serves as an auxiliary medication in the trial.

The trial also includes a placebo, referred to as PL1, which is strictly identical to Imraldi and not strictly identical to Benepali. The placebo is used to maintain the study's integrity by providing a control for comparison against the active treatments.

Efficacy

The clinical trial aims to assess the efficacy of a combination therapy involving anti-TNF agents (adalimumab or etanercept) with baricitinib compared to baricitinib alone in patients with refractory **rheumatoid arthritis** (RA). The primary endpoint for evaluating efficacy is the proportion of patients achieving an ACR 50 response at week 24 in each treatment group. Secondary endpoints include the proportion of patients achieving ACR20 and ACR70 responses at weeks 4, 12, and 24, as well as the proportion of patients achieving remission or low disease activity according to DAS28-ESR at the same time points. Additional secondary endpoints involve quantitative changes in DAS28-ESR, DAS28-CRP, sDAI, and cDAI scores, drug retention rates, and changes in patient-reported outcomes such as HAQ, FACIT, and RAID.

Efficacy parameters will be measured and collected at baseline and at weeks 4, 12, 24, and 52. The ACR response criteria and DAS28-ESR scores will be used as validated scales for assessing clinical response. Patient-reported outcomes will be evaluated using standardized instruments like HAQ, FACIT, and RAID. The analysis will focus on comparing the combination therapy group with the monotherapy group to determine the relative efficacy of the treatment strategies. The trial is designed to provide comprehensive data on the clinical benefits of combining anti-TNF therapy with baricitinib in managing refractory RA.

Inclusion and Exclusion 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)

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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, she/he can be included in the study but with the treatment she/he has not yet received (if she/he 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
Patient with a history of hypersensitivity to etanercept/baricitinib/adalimumab and any of the excipients
Patient who smokes or has done so for a long time in the past
Patient who is currently receiving corticosteroids 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.
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 purpose
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 with a strong inhibition potential (such as probenecid).
Patient who has a history or presence of cardiovascular, respiratory, hepatic, gastrointestinal, endocrine, hematological, neurological, or neuropsychiatric disorders 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 Stevens-Johnson syndrome and/or cutaneous vasculitis.
Patient with an history of CNS demyelinating disorders and peripheral demyelinating polyneuropathies.
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 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 an history of sepsis or risk of sepsis.
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 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 of childbearing potential who refuses to use an effective contraception during the study course, and who does not take an effective contraception at least one week after baricitinib treatment, five months after adalimumab treatment and three weeks after etanercept treatment.
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).

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
France	Recruiting	15 Jul 2021	169

Sites & Investigators

Research sites

Clinique De L'infirmerie Protestante De Lyon Institut de Cancérologie Hématologie Universitaire de Saint Etienne (iCHUSE)Centre Hospitalier Departemental Vendee Polyclinique De Limoges

Investigators

Gaelle V.Omar A. T.Jacques M.Carine S.

Investigational Products

Details about the medicinal products being studied in this clinical trial.

Product Name	Role in Trial	Formulation	Administration	Max Daily Dose	Treatment Duration	EU MP Number
Imraldi 40 mg solution for injection in pre-filled pen	Test	SOLUTION FOR INJECTION IN PRE-FILLED PEN	INJECTION	40	24	PRD5895486
Benepali 50 mg solution for injection in pre-filled pen.	Test	SOLUTION FOR INJECTION IN PRE-FILLED PEN	INJECTION	50	24	PRD3616091
PL1 : placebo - Imraldi (strictly identical) AND Benepalinot strictly identical	Placebo	N/A	—	—	—	N/A
PREDNISONE	Other	—	ORAL USE	7.5	52	SUB10020MIG
Olumiant 4 mg film-coated tablets	Test	FILM-COATED TABLETS	ORAL USE	4	52	PRD4765061