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NCT Number: NCT02714634

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.

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Key information

Conditions

Rheumatoid Arthritis Arthritis Arthritis, Rheumatoid Autoimmune Diseases Connective Tissue Diseases Immune System Diseases Insufficient Response to Methotrexate or Leflunomide Joint Diseases Musculoskeletal Diseases Rheumatic Diseases Skin and Connective Tissue Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Primary location

Hôpitaux Universitaires de Strasbourg

Strasbourg, 67098, France

Location status: Recruiting

Location contact

Jacques-Eric Gottenberg

CONTACT

[email protected]

3 88 12 81 89 ext. 0033

Jacques-Eric Gottenberg

PRINCIPAL_INVESTIGATOR

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Methotrexate + targeted therapy administration

Drug
  • 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

methotrexate or leflunomide + sulfasalazine + hydroxychloroquine administration

Drug

Primary outcomes

  1. Numbers of participant with low disease activity (DAS28-CRP<3.2) and a daily dose ≤ 7.5 mg/day of equivalent prednisone

    Time frame: At 12 months

Secondary outcomes

  1. Serious adverse events rate

    Time frame: At 3, 6, 9 and at 12 months

  2. 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.

    Time frame: at 6, and 12 months

  3. Clinical disease activity index (CDAI).

    Time frame: At inclusion, 3, 6, 9 and 12 months

  4. DAS 28 CRP score.

    Time frame: at inclusion, 3, 6, 9 and 12 months.

  5. 2010 ACR (American College of Rheumatology)/EULAR classification Criteria for RA, ACR 20, 50, 70 and boolean remission.

    Time frame: at 3, 6, 9 and 12 months.

  6. Modified Sharp Van der Heijde score.

    Time frame: at inclusion and at 12 months

  7. Change in comedications (dose)

    Time frame: at 3, 6, 9 and 12 months

  8. Change in comedications (route of administration)

    Time frame: at 3, 6, 9 and 12 months

  9. Change in comedications (drug)

    Time frame: at 3, 6, 9 and 12 months

  10. QUALISEX score at inclusion, 6 months and at 12 months.

    Time frame: at inclusion, 6 months and at 12 months.

  11. Medico-economic costs.

    Time frame: at inclusion, 3, 6, 9 and at 12 months.

  12. Treatment compliance

    Time frame: at 3, 6, 9 and 12 months

    A questionnaire will be filled by patient

Study contacts

Contact information is provided by the study sponsor or research team.

Jacques-Eric GOTTENBERG, Professor

CONTACT

[email protected]

3 88 12 79 53 ext. +33

Sponsors and collaborators

Lead sponsor

University Hospital, Strasbourg, France

Other

Registry information

Official study title

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

Acronym: BIO3

Important dates

Study start
2016
Primary completion
2029
Study completion
2029
First posted
Mar 21, 2016
Registry last updated
Mar 12, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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