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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)

Primary Purpose

Rheumatoid Arthritis, Insufficient Response to Methotrexate or Leflunomide

Status

Recruiting

Phase

Phase 4

Locations

France

Study Type

Interventional

Intervention

Methotrexate + targeted therapy administration

methotrexate or leflunomide + sulfasalazine + hydroxychloroquine administration

About this trial

This is an interventional treatment trial for Rheumatoid Arthritis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

Hôpitaux Universitaires de StrasbourgRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

methotrexate + targeted therapy group

Triple therapy

Arm Description

Methotrexate or leflunomide + targeted therapy chosen by investigator

Triple therapy using 3 conventional disease modifying drugs (DMARDs)

Outcomes

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

Secondary Outcome Measures

Serious adverse events rate

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.

Clinical disease activity index (CDAI).

DAS 28 CRP score.

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

Modified Sharp Van der Heijde score.

Change in comedications (dose)

Change in comedications (route of administration)

Change in comedications (drug)

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

Medico-economic costs.

Treatment compliance

A questionnaire will be filled by patient

Full Information

NCT ID

NCT02714634

First Posted

February 1, 2016

Last Updated

July 8, 2022

Sponsor

University Hospital, Strasbourg, France

1. Study Identification

Unique Protocol Identification Number

NCT02714634

Brief Title

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

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

Study Type

Interventional

2. Study Status

Record Verification Date

July 2022

Overall Recruitment Status

Recruiting

Study Start Date

March 30, 2016 (Actual)

Primary Completion Date

March 2025 (Anticipated)

Study Completion Date

March 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University Hospital, Strasbourg, France

4. Oversight

Data Monitoring Committee

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Rheumatoid Arthritis, Insufficient Response to Methotrexate or Leflunomide

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

286 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

methotrexate + targeted therapy group

Arm Type

Experimental

Arm Description

Methotrexate or leflunomide + targeted therapy chosen by investigator

Arm Title

Triple therapy

Arm Type

Active Comparator

Arm Description

Triple therapy using 3 conventional disease modifying drugs (DMARDs)

Intervention Type

Drug

Intervention Name(s)

Methotrexate + targeted therapy administration

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

methotrexate or leflunomide + sulfasalazine + hydroxychloroquine administration

Primary Outcome Measure Information:

Title

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 Outcome Measure Information:

Title

Serious adverse events rate

Time Frame

At 3, 6, 9 and at 12 months

Title

Time Frame

at 6, and 12 months

Title

Clinical disease activity index (CDAI).

Time Frame

At inclusion, 3, 6, 9 and 12 months

Title

DAS 28 CRP score.

Time Frame

at inclusion, 3, 6, 9 and 12 months.

Title

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.

Title

Modified Sharp Van der Heijde score.

Time Frame

at inclusion and at 12 months

Title

Change in comedications (dose)

Time Frame

at 3, 6, 9 and 12 months

Title

Change in comedications (route of administration)

Time Frame

at 3, 6, 9 and 12 months

Title

Change in comedications (drug)

Time Frame

at 3, 6, 9 and 12 months

Title

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

Time Frame

at inclusion, 6 months and at 12 months.

Title

Medico-economic costs.

Time Frame

at inclusion, 3, 6, 9 and at 12 months.

Title

Treatment compliance

Description

A questionnaire will be filled by patient

Time Frame

at 3, 6, 9 and 12 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Jacques-Eric GOTTENBERG, Professor

Phone

3 88 12 79 53

Ext

+33

jacques-eric.gottenberg@chru-strasbourg.fr

Facility Information:

Facility Name

Hôpitaux Universitaires de Strasbourg

City

Strasbourg

ZIP/Postal Code

67098

Country

France

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Jacques-Eric Gottenberg

Phone

3 88 12 81 89

Ext

0033

jacques-eric.gottenberg@chru-strasbourg.fr

First Name & Middle Initial & Last Name & Degree

Jacques-Eric Gottenberg

12. IPD Sharing Statement

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