Clinical Trial Evaluating Methotrexate or Leflunomide + Targeted Therapy Versus Methotrexate or Leflunomide + Sulfasalazine + Hydroxychloroquine in Patients with Rheumatoid Arthritis and Insufficient Response to Methotrexate or Leflunomide (BIO3)

Randomized Controlled Clinical Trial Evaluating Methotrexate or Leflunomide + Targeted Therapy Versus Methotrexate or Leflunomide + Sulfasalazine + Hydroxychloroquine in Patients with Rheumatoid Arthritis and Insufficient Response to Methotrexate or Leflunomide

Approximately, 40 to 50% of patients with rheumatoid arthritis (RA), the most frequent inflammatory arthritide, are non responders to the consensual 1st line of treatment : methotrexate. In these patients, it is well demonstrated that the addition of other immunomodulatory drug(s) often results in a significant improvement. However, the best option regarding the drug(s) to add remains unclear. Rheumatologists are currently used to adding a targeted therapy, such as anti-TNFα, and more recently abatacept or tocilizumab. Triple therapy using 3 conventional disease-modifying drugs (DMARDs), methotrexate or leflunomide+salazopyrine+hydroxychloroquine could be an alternative option to targeted therapies, all the more as they have a more favorable safety profile and a much lower cost. Uncertainty remains regarding the superiority of targeted therapies on triple therapy in methotrexate or leflunomide insufficient responders (IR). Investigators decided to address this issue by performing a randomized controlled pragmatic trial.

Study Overview

• Status: Recruiting
• Conditions: Rheumatoid Arthritis; Insufficient Response to Methotrexate or Leflunomide
• Intervention / Treatment: Drug: Methotrexate + targeted therapy administration; Drug: methotrexate or leflunomide + sulfasalazine + hydroxychloroquine administration

• Study Type: Interventional
• Enrollment (Estimated): 286
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Jacques-Eric GOTTENBERG, Professor; Phone Number: +33 3 88 12 79 53; Email: jacques-eric.gottenberg@chru-strasbourg.fr

Study Locations

• France
  • Strasbourg, France, 67098
    • Recruiting
    • Hôpitaux Universitaires de Strasbourg
    • Contact: Jacques-Eric Gottenberg
    • Contact: Jacques-Eric Gottenberg; Phone Number: 0033 3 88 12 81 89; Email: jacques-eric.gottenberg@chru-strasbourg.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patient with rheumatoid arthritis according to EULAR/ACR 2010 criteria
• DAS28-CRP>3.2
• Insufficient response to methotrexate at a weekly dose≥15mg after at least 3 months or to leflunomide at a dose of 10 (in case 20 mg are not well tolerated) to 20 mg per day after 3 months of treatment
• RA radiographic erosions and/or serum rheumatoid factor associated to anti-Cyclic Citrullinated Peptide (Anti-CCP)
• Age greater or equal to 18 years
• Written informed consent, dated and signed before initiating any trial-related procedure
• Affiliation to a social insurance system
• Women of child bearing potential, negative β-HCG assay (Human chorionic gonadotropin)
• Effective method of birth control during the study and continuing after the discontinuation of the investigational drug or study. The duration will depend on the drug used (referred to the summary product characteristic).

Exclusion Criteria:

• Previous treatment with or contraindication to targeted therapies (biologic or JAK/STAT inhibitor)
• Previous treatment with triple therapy
• Other inflammatory arthritis except RA associated with Sjögren's syndrome
• Contraindication to all biologics/ JAK/STAT inhibitors or to methotrexate, leflunomide, sulfasalazine and hydroxychloroquine
• Corticosteroids at a dose >15 mg/d of equivalent prednisone for at least 4 weeks before the inclusion
• Absence of tuberculosis screening
• Patient who cannot be followed during 12 months
• Pregnancy, breastfeeding, desire of pregnancy in the 12 months
• Drug addiction, addiction to alcohol
• Participation in a clinical study with an investigational product within 4 weeks prior to the start of the study treatment
• Women of child bearing potential, unless they are using an effective method of birth control
• Patient under law protection
• Prisoners

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: methotrexate + targeted therapy group; Methotrexate or leflunomide + targeted therapy chosen by investigator	Drug: Methotrexate + targeted therapy administration; Methotrexate or leflunomide + adalimumab or; Methotrexate or leflunomide + certolizumab or; Methotrexate or leflunomide + etanercept or; Methotrexate or leflunomide + golimumab or; Methotrexate or leflunomide + infliximab or; Methotrexate or leflunomide + abatacept or; Methotrexate or leflunomide + rituximab or; Methotrexate or leflunomide + tocilizumab or; Methotrexate or leflunomide + sarilumab or; Methotrexate or leflunomide + filgotinib or; Methotrexate or leflunomide + upadacitinib or; Methotrexate or leflunomide + Tofacitinib or; Methotrexate or leflunomide + baricitinib
Active Comparator: Triple therapy; Triple therapy using 3 conventional disease modifying drugs (DMARDs)	Drug: methotrexate or leflunomide + sulfasalazine + hydroxychloroquine administration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Numbers of participant with low disease activity (DAS28-CRP<3.2) and a daily dose ≤ 7.5 mg/day of equivalent prednisone	At 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serious adverse events rate		At 3, 6, 9 and at 12 months
Blood concentrations of hydroxychloroquine, leflunomide, sulfasalazine and methotrexate in the triple therapy group and methotrexate, leflunomide, biologic / JAK/STAT inhibitor and anti-drug antibody in the other group.		at 6, and 12 months
Clinical disease activity index (CDAI).		At inclusion, 3, 6, 9 and 12 months
DAS 28 CRP score.		at inclusion, 3, 6, 9 and 12 months.
2010 ACR (American College of Rheumatology)/EULAR classification Criteria for RA, ACR 20, 50, 70 and boolean remission.		at 3, 6, 9 and 12 months.
Modified Sharp Van der Heijde score.		at inclusion and at 12 months
Change in comedications (dose)		at 3, 6, 9 and 12 months
Change in comedications (route of administration)		at 3, 6, 9 and 12 months
Change in comedications (drug)		at 3, 6, 9 and 12 months
QUALISEX score at inclusion, 6 months and at 12 months.		at inclusion, 6 months and at 12 months.
Medico-economic costs.		at inclusion, 3, 6, 9 and at 12 months.
Treatment compliance	A questionnaire will be filled by patient	at 3, 6, 9 and 12 months

Collaborators and Investigators

• Sponsor: University Hospital, Strasbourg, France

Study record dates

Study Major Dates

• Study Start (Actual): March 30, 2016
• Primary Completion (Estimated): March 1, 2029
• Study Completion (Estimated): March 1, 2029

Study Registration Dates

• First Submitted: February 1, 2016
• First Submitted That Met QC Criteria: March 15, 2016
• First Posted (Estimated): March 21, 2016

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 10, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Joint Diseases; Rheumatic Diseases; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Arthritis; Arthritis, Rheumatoid; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Inflammatory Agents; Peripheral Nervous System Agents; Gastrointestinal Agents; Enzyme Inhibitors; Antirheumatic Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Reproductive Control Agents; Antimetabolites, Antineoplastic; Antimetabolites; Dermatologic Agents; Folic Acid Antagonists; Nucleic Acid Synthesis Inhibitors; Sensory System Agents; Analgesics, Non-Narcotic; Analgesics; Anti-Inflammatory Agents, Non-Steroidal; Antimalarials; Antiprotozoal Agents; Antiparasitic Agents; Leflunomide; Methotrexate; Hydroxychloroquine; Sulfasalazine
• Other Study ID Numbers: 6020

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO