BIO3: 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

Sponsor

University Hospital, Strasbourg, France (Other)

Overall Status

Recruiting

CT.gov ID

NCT02714634

Collaborator

(none)

286

Enrollment

Location

Arms

107

Anticipated Duration (Months)

2.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Rheumatoid Arthritis Insufficient Response to Methotrexate or Leflunomide	Drug: Methotrexate + targeted therapy administration Drug: methotrexate or leflunomide + sulfasalazine + hydroxychloroquine administration	Phase 4

Study Design

Study Type:

Interventional

Anticipated Enrollment :

286 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official 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

Actual Study Start Date :

Mar 30, 2016

Anticipated Primary Completion Date :

Mar 1, 2025

Anticipated Study Completion Date :

Mar 1, 2025

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

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

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 [at 3, 6, 9 and 12 months]
A questionnaire will be filled by patient

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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