COBRA-Slim With or Without Fast Access to TNF Blockade for Remission Induction in Early RA (CareRA2020)

June 4, 2025 updated by: P. Verschueren

Effectiveness of a Combination of Methotrexate and a Step Down Glucocorticoid Regimen (COBRA-Slim) for Remission Induction in Patients With Early Rheumatoid Arthritis (RA), With or Without Fast Access to 24 Weeks of Tumor Necrosis Factor (TNF) Blockade in Insufficient Responders, a Randomized, Multicenter, Pragmatic Trial

In the Care in Rheumatoid Arthritis (CareRA) trial (NCT01172639) about 70% of early RA patients are in remission at the 2 year evaluation point independent of the combination scheme used.

Interesting to see is that the 30% of insufficient responders can be identified in an early stage of the treatment course.

The purpose of the present study is to investigate if, for patients with an insufficient response to a COBRA-Slim regimen, accelerated access to a short course of anti-TNF therapy already early after treatment initiation (from w8 until w32) could improve outcomes compared to a more traditional treat to target sequence.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

276

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Belgium
      • Brussel, Belgium, 1000
        • CHU Saint Pierre
      • Brussel, Belgium, 1000
        • Cliniques Universitaire Saint Luc (UCL)
      • Brussel, Belgium, 1070
        • Hôpital Erasme-ULB
      • Brussels, Belgium, 1090
        • UZ Brussel
      • Liège, Belgium, 4000
        • Chu Liege
    • Antwerpen
      • Bonheiden, Antwerpen, Belgium, 2820
        • Imelda Ziekenhuis Bonheiden
      • Herentals, Antwerpen, Belgium, 2200
        • AZ Herentals
      • Merksem, Antwerpen, Belgium, 2170
        • ZNA Jan Palfijn
    • Henegouwen
      • Gilly, Henegouwen, Belgium, 6060
        • GHdC Saint Joseph
    • Limburg
      • Genk, Limburg, Belgium, 3600
        • Reuma centrum Genk
      • Genk, Limburg, Belgium, 3600
        • Reuma Clinic Genk
      • Hasselt, Limburg, Belgium, 3500
        • Reuma Instituut Hasselt
    • Namur
      • Yvoir, Namur, Belgium, 5530
        • CHU UCL Namur asbl Site Godinne
    • Oost Vlaanderen
      • Aalst, Oost Vlaanderen, Belgium, 9300
        • OLV Ziekenhuis Aalst
    • Vlaams Brabant
      • Leuven, Vlaams Brabant, Belgium, 3000
        • UZ Leuven
      • Leuven, Vlaams Brabant, Belgium, 3000
        • Regionaal Ziekenhuis Heilig Hart Leuven
      • Vilvoorde, Vlaams Brabant, Belgium, 1800
        • AZ Jan Portaels
    • West Vlaanderen
      • Brugge, West Vlaanderen, Belgium, 8310
        • AZ St Lucas Brugge
    • West-Vlaanderen
      • Brugge, West-Vlaanderen, Belgium, 8000
        • AZ Sint Jan Brugge

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Age 18 years and older
  • Diagnosis of RA as defined by the American College of Rheumatology (ACR)/ European League Against Rheumatism (EULAR) 2010 criteria for early RA
  • Early RA defined by a diagnosis made ≤ 1 year ago.
  • Use a reliable method of contraception for women of childbearing potential to be evaluated as in daily clinical practice
  • Able and willing to give written informed consent and to participate in the study
  • Understanding and able to write Dutch or French

Exclusion Criteria:

  • Previous treatment with:

    • Methotrexate (MTX) or leflunomide
    • cyclophosphamide, azathioprine or cyclosporine
    • sulphasalazine (SSZ) for more than 3 weeks
    • hydroxychloroquine for more than 6 weeks
    • oral Glucocorticoids (GC) for more than 4 weeks within 4 months before screening
    • oral GC at a daily dosage of more than 10 mg prednisone equivalent within 4 weeks before baseline
    • oral GC at a daily dosage equal to or less than 10 mg prednisone equivalent within 2 weeks before baseline
    • intra-articular GC within 4 weeks before BL
    • an investigational drug for the treatment/prevention of RA
  • History of chronic heart failure
  • History of severe infections or chronic infection
  • History of malignant neoplasm within 5 years
  • Contra indications for GC
  • Contra indications for TNF blocking agents
  • Contra indications for MTX or leflunomide
  • Psoriatic Arthritis
  • Underlying cardiac, pulmonary, metabolic, renal or gastrointestinal conditions, chronic or latent infectious diseases or immune deficiency which in the opinion of the investigator places the patient at an unacceptable risk for participation in the study
  • Pregnancy, breastfeeding or no use of a reliable method of contraception for woman of childbearing potential (as in daily clinical practice)
  • Alcohol or drug abuse
  • Active tuberculosis (TB)
  • Latent TB unless adequate prophylactic treatment is given according to local guidelines
  • No access to the Belgian Health Insurance system-

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: standard COBRA-Slim induction
Leflunomide 10mg PO daily added to the COBRA-Slim scheme (Methotrexate 15 mg PO weekly, Step down scheme of GC: 30-20-12,5-10-7,5-5 mg prednisone PO daily, each for 7 days except for the lowest dose of 5 mg, this will be maintained until w28 and then tapered to 2.5 mg daily for two weeks before stopping completely.)
Drug: Leflunomide 10 milligram (MG)
Leflunomide 10mg PO daily added to the COBRA-Slim scheme
Experimental: COBRA-Slim Bio-induction
Etanercept 50mg subcutaneous (SC) weekly added for 24 weeks to COBRA-Slim scheme (Methotrexate 15 mg PO weekly, Step down scheme of GC: 30-20-12,5-10-7,5-5 mg prednisone PO daily, each for 7 days except for the lowest dose of 5 mg, this will be maintained until w28 and then tapered to 2.5 mg daily for two weeks before stopping completely.)
Drug: Etanercept 50 MG/ML
Etanercept 50mg subcutaneous (SC) weekly added for 24 weeks to COBRA-Slim scheme

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Area Under Curve (AUC) of Disease Activity Score Based on a 28 Jointcount and C-reactive Protein (DAS28CRP)
Time Frame: baseline, w4, w8, w16, w24, w32, w40, w52, w64, w78, w92 and w104

Analysis was based on an intention to treat population, which focused on all patients randomized into the study, irrespective if they actually received the randomized treatment. Fifty-five patients were allocated to Standard COBRA-Slim and 55 to COBRA-Slim Bio-induction.

This measure is an indication of the total disease-activity over time or long-term effectiveness, a higher area under the curve indicates a higher disease activity over time and so a lower effectiveness over the time frame of the trial.

The scale range for the duration of the trial (104 weeks) is 0.0 to 977.6

  • remission: value below 270.4
  • low disease activity: from 270.4 till 332.8 (included)
  • moderate disease activity: above 332.8 till 530.4
  • high disease activity: above 530.4
baseline, w4, w8, w16, w24, w32, w40, w52, w64, w78, w92 and w104

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Proportion of Insufficient Responders Achieving Remission (DAS28CRP<2.6) 28 Weeks After Randomization (Short Term Efficacy) to Either COBRA-Slim Bio-Induction or Standard COBRA-Slim Induction
Time Frame: From randomization till 28 weeks after randomization.
Short-time efficacy of disease activity based on a swollen and tender joint count of 28 joints and C-reactive proteine (scale range 0.0 to 9.4; remission: value below 2.6; low disease activity: from 2.6 till 3.2 (included); moderate disease activity: above 3.2 till 5.1; high disease activity: above 5.1).
From randomization till 28 weeks after randomization.
Proportion of Patients in Remission Defined as DAS28CRP<2.6
Time Frame: at week 104
Short-time efficacy of disease activity based on a swollen and tender joint count of 28 joints and C-reactive proteine (scale range 0.0 to 9.4; remission: value below 2.6; low disease activity: from 2.6 till 3.2 (included); moderate disease activity: above 3.2 till 5.1; high disease activity: above 5.1).
at week 104
Proportion of Patients Achieving a EULAR Response
Time Frame: at 28 weeks after randomization

proportion of patients achieving a EULAR response, based on actual disease activity on a tender/swollen joint count and C-reactive proteine (DAS28-CRP) 28 weeks after randomization and improvement in DAS28-CRP from baseline.

The EULAR response criteria classify patients as good, moderate or non-responders, using the individual amount of change in the DAS28-CRP and the DAS28-CRP value (low, moderate, or high) reached according to the following tabel:

DAS28-CRP at endpoint improvement in DAS28-CRP from baseline <=1,2 >0,6 and <= 1,2 <=0,6 <= 3,2 good moderate none >3,2 and <= 5,1 moderate moderate none >5,1 moderate none none Additionally all patients with a good response were also included in the number of participants with at least a moderate response.
at 28 weeks after randomization
Proportion of Patients Achieving a EULAR Response
Time Frame: at week 104

proportion of patients achieving a EULAR response, based on actual disease activity on a tender/swollen joint count and C-reactive proteine (DAS28-CRP) at week 104 and improvement in DAS28-CRP from baseline.

The EULAR response criteria classify patients as good, moderate or non-responders, using the individual amount of change in the DAS28-CRP and the DAS28-CRP value (low, moderate, or high) reached according to the following tabel:

DAS28-CRP at endpoint improvement in DAS28-CRP from baseline <=1,2 >0,6 and <= 1,2 <=0,6 <= 3,2 good moderate none >3,2 and <= 5,1 moderate moderate none >5,1 moderate none none Additionally all patients with a good response were also included in the number of participants with at least a moderate response.
at week 104
Health Assessment Questionnaire (HAQ) Response
Time Frame: at 28 weeks after randomization
HAQ measures physical function as reported by the patient, total score range from 0-3 of which higher scores represent worse physical function.
at 28 weeks after randomization
Health Assessment Questionnaire (HAQ) Response
Time Frame: at week 104
HAQ measures physical function as reported by the patient, total score range from 0-3 of which higher scores represent worse physical function.
at week 104
Radiographic Progression
Time Frame: at week 52

Radiographic progression at week 52 is scored according to the Sharp-Van der Heijde score (SvdH).

The SvdH method scores the presence of erosions in 16 joints of hands and wrists (graded from 0 to 5), and in 6 joints of the feet (graded from 0 to 10), and the presence of joint space narrowing in 15 joints of the hands and wrists (graded from 0 to 4) and in 6 joints of the feet (graded from 0 to 4). The maximal range is 280 units for erosion and 168 units for joint space narrowing, summing up to 448 units for the total score.

The progression is calculated by subtracting the total score at week 52 minus the total score at baseline (ranging from 0 to 448) Higher values in each (sub) scale represents a worse outcome.
at week 52
Radiographic Progression
Time Frame: at week 104

Radiographic progression at week 104 is scored according to the Sharp-Van der Heijde score (SvdH).

The SvdH method scores the presence of erosions in 16 joints of hands and wrists (graded from 0 to 5), and in 6 joints of the feet (graded from 0 to 10), and the presence of joint space narrowing in 15 joints of the hands and wrists (graded from 0 to 4) and in 6 joints of the feet (graded from 0 to 4). The maximal range is 280 units for erosion and 168 units for joint space narrowing, summing up to 448 units for the total score.

The progression is calculated by subtracting the total score at week 104 minus the total score at baseline (ranging from 0 to 448) Higher values in each (sub) scale represents a worse outcome.
at week 104

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

P. Verschueren

Collaborators

Belgium Health Care Knowledge Centre

Investigators

  • Principal Investigator: Patrick Verschueren, MD, PhD, UZ Leuven

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 8, 2018

Primary Completion (Actual)

July 1, 2022

Study Completion (Actual)

July 1, 2022

Study Registration Dates

First Submitted

July 30, 2018

First Submitted That Met QC Criteria

August 23, 2018

First Posted (Actual)

August 28, 2018

Study Record Updates

Last Update Posted (Actual)

June 19, 2025

Last Update Submitted That Met QC Criteria

June 4, 2025

Last Verified

June 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • KCE-16002
  • 2017-004054-41 (EudraCT Number)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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