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Effectiveness in Daily Practice of Different Treatment Strategies for Early Rheumatoid Arthritis.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01172639
Recruitment Status : Completed
First Posted : July 30, 2010
Results First Posted : December 10, 2018
Last Update Posted : January 22, 2019
Sponsor:
Collaborator:
Agentschap voor Innovatie door Wetenschap en Technologie
Information provided by (Responsible Party):
P. Verschueren, Universitaire Ziekenhuizen KU Leuven

Study Description
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Brief Summary:

The Combinatietherapie Bij Reumatoide Artritis (CoBRA) trial was a milestone in the development of the present treatment paradigm for Rheumatoid Arthritis (RA). This study introduced the principle of fast remission induction by means of a combination of standard Disease Modifying AntiRheumatic Drugs (DMARDs) and a step down bridge therapy with high dose glucocorticoids in early Rheumatoid Arthritis.

The purpose of the present study is to compare different combinations of traditional DMARDs and glucocorticoids, based on the original CoBRA protocol, for treatment of early Rheumatoid Arthritis.

Besides the efficacy and effectiveness of these strategies, patient centered outcomes and potential implementation problems of such treatment strategies are evaluated.


Condition or disease Intervention/treatment Phase
Rheumatoid Arthritis Drug: Methotrexate Drug: Sulfasalazine Drug: Leflunomide Drug: Prednisone Phase 4

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 400 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Before randomisation patients were stratified to a high-risk or low-risk group according to the presence of risk factors at screening (having erosions, rheumatoid factor and/or anticitrullinated protein antibody and a high disease activity score calculated with C-reactive protein (DAS28-CRP)). Randomisation to treatment arms was performed via a digitally generated sequence. Patients in the high-risk group were randomised into CoBRA Classic, Clim or Avant-Garde arm. Patients in the low-risk group were randomised into CoBRA Slim or Tight Step Up arm.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A 2 Year Prospective Multicentre Randomised Controlled Trial Comparing Effectiveness in Daily Practice of Different Treatment Strategies for Early Rheumatoid Arthritis.
Study Start Date : February 2009
Actual Primary Completion Date : June 2015
Actual Study Completion Date : June 2015

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
CoBRA classic high risk group
  • Methotrexate 15mg tablet by mouth, weekly for entire trial
  • Sulfasalazine 2g tablet by mouth, daily for 40 weeks
  • Prednisone tablet by mouth, weekly step down scheme 60 - 40 - 25 - 20 - 15 - 10 mg daily for 6 weeks, followed by 7.5mg daily till week 28, then further tapered down to stop at week 32
 Drug: Methotrexate
Methotrexate tablet
Other Name: Ledertrexate

Drug: Sulfasalazine
Sulfasalazine tablet
Other Name: Salazopyrine

Drug: Prednisone
Prednisone tablet
CoBRA slim high risk group
  • Methotrexate 15mg tablet by mouth, weekly for entire trial
  • Prednisone tablet by mouth, weekly step down scheme 30 - 20 - 12.5 - 10 - 7.5 mg daily for 5 weeks, followed by 5mg daily till week 28, then further tapered down to stop at week 32
 Drug: Methotrexate
Methotrexate tablet
Other Name: Ledertrexate

Drug: Prednisone
Prednisone tablet
CoBRA avant-garde high risk group
  • Methotrexate 15mg tablet by mouth, weekly for 40 weeks (continued for entire trial if randomized to Methotrexate monotherapy at week 40)
  • Leflunomide 10mg tablet by mouth, daily for 40 weeks (continued for entire trial if randomized to Leflunomide monotherapy at week 40)
  • Prednisone tablet by mouth, weekly step down scheme 30 - 20 - 12.5 - 10 - 7.5 mg daily for 5 weeks, followed by 5mg daily till week 28, then further tapered down to stop at week 32
 Drug: Methotrexate
Methotrexate tablet
Other Name: Ledertrexate

Drug: Leflunomide
Leflunomide tablet
Other Name: Arava

Drug: Prednisone
Prednisone tablet
CoBRA slim low risk group
  • Methotrexate 15mg tablet by mouth, weekly for entire trial
  • Prednisone tablet by mouth, weekly step down scheme 30 - 20 - 12.5 - 10 - 7.5 mg daily for 5 weeks, followed by 5mg daily till week 28, then further tapered down to stop at week 32
 Drug: Methotrexate
Methotrexate tablet
Other Name: Ledertrexate

Drug: Prednisone
Prednisone tablet
Tight Step Up low risk group
  • Methotrexate 15mg tablet by mouth, weekly for entire trial
  • No oral steroids allowed during the first year of the trial
 Drug: Methotrexate
Methotrexate tablet
Other Name: Ledertrexate


Outcome Measures
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Primary Outcome Measures :
  1. Remission According to DAS28-CRP at Week 16 [ Time Frame: week 16 ]

    Number of patients in remission according to DAS28-CRP (Disease Activity Score based on 28 joint count and C-reactive Protein) at week 16.

    DAS28-CRP is calculated with the following formula : 0.56*SQRT TJC28+0.28*SQRT SJC28+0.36*ln (CRP+1)+0.014*GH+0.96 in which TJC is the tender joint count, SJC the Swollen Joint Count and GH the general health estimated by the patient on a Visual Analogue Scale (VAS).

    A value below 2.6 is indicating remission, below or equal to 3.2 low disease activity, between 3.2 and 5.1 moderate disease activity and above 5.1 high disease activity.


  2. Remission According to DAS28-CRP at Week 52 [ Time Frame: week 52 ]

    Number of patients in remission according to DAS28-CRP (Disease Activity Score based on 28 joint count and C-reactive Protein) at week 52. (co-primary end point)

    DAS28-CRP is calculated with the following formula : 0.56*SQRT TJC28+0.28*SQRT SJC28+0.36*ln (CRP+1)+0.014*GH+0.96 in which TJC is the tender joint count, SJC the Swollen Joint Count and GH the general health estimated by the patient on a Visual Analogue Scale (VAS).

    A value below 2.6 is indicating remission, below or equal to 3.2 low disease activity, between 3.2 and 5.1 moderate disease activity and above 5.1 high disease activity.


  3. Remission According to DAS28-CRP at Week 104 [ Time Frame: week 104 ]

    Number of patients in remission according to DAS28-CRP (Disease Activity Score based on 28 joint count and C-reactive Protein) at week 104. (co-primary endpoints)

    DAS28-CRP is calculated with the following formula : 0.56*SQRT TJC28+0.28*SQRT SJC28+0.36*ln (CRP+1)+0.014*GH+0.96 in which TJC is the tender joint count, SJC the Swollen Joint Count and GH the general health estimated by the patient on a Visual Analogue Scale (VAS).

    A value below 2.6 is indicating remission, below or equal to 3.2 low disease activity, between 3.2 and 5.1 moderate disease activity and above 5.1 high disease activity.



Secondary Outcome Measures :
  1. Remission According to SDAI (Simple Disease Activity Index) at Week 16 [ Time Frame: week 16 ]

    Number of patients in remission according to SDAI (Simplified Disease Activity Index) at week 16.

    SDAI is calculated with the following formula : TJC28+SJC28+GH+GA ph in which TJC is the number of tender joints, SJC the number of Swollen Joint and GH the general health assessed by the patient on a Visual Analogue Scale (VAS) and GA ph the general assessment of the physician on a VAS.

    A value below 3.3 is indicating remission, between 3.4 and 11.0 low disease activity, between 11.1 and 26.0 moderate disease activity and above 26.0 high disease activity.


  2. Remission According to SDAI at Week 52 [ Time Frame: week 52 ]

    Number of patients in remission according to SDAI (Simplified Disease Activity Index) at week 52.

    SDAI is calculated with the following formula : TJC28+SJC28+GH+GA ph in which TJC is the number of tender joints, SJC the number of Swollen Joint and GH the general health assessed by the patient on a Visual Analogue Scale (VAS) and GA ph the general assessment of the physician on a VAS.

    A value below 3.3 is indicating remission, between 3.4 and 11.0 low disease activity, between 11.1 and 26.0 moderate disease activity and above 26.0 high disease activity.


  3. Remission According to SDAI at Week 104 [ Time Frame: week 104 ]

    Number of patients in remission according to SDAI (Simplified Disease Activity Index) at week 104.

    SDAI is calculated with the following formula : TJC28+SJC28+GH+GA ph in which TJC is the number of tender joints, SJC the number of Swollen Joint and GH the general health assessed by the patient on a Visual Analogue Scale (VAS) and GA ph the general assessment of the physician on a VAS.

    A value below 3.3 is indicating remission, between 3.4 and 11.0 low disease activity, between 11.1 and 26.0 moderate disease activity and above 26.0 high disease activity.


  4. Clinically Significant Change in HAQ Score [ Time Frame: Baseline-week104 ]

    Number of patients with a change of > 0.22 in the Health Assessment Questionnaire (HAQ) score over the period between baseline and week 104.

    A change of > 0.22 in this score is considered as clinical relevant for rheumatoid arthritis patients.



Eligibility Criteria
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Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of RA as defined by the 1987 or 2010 revised American College of Rheumatology (ACR) criteria
  • Early RA (less than 1 year)
  • Use a reliable method of contraception for women of childbearing potential
  • Able and willing to give written informed consent and participate in the study

Exclusion Criteria:

  • Previous treatment with DMARDs
  • Previous treatment with oral corticosteroids at a dosage of more than 10 milligrams (mg) prednisone within 4 weeks before baseline
  • Previous treatment with oral corticosteroids at a dosage equal to or less than 10 mg prednisone within 2 weeks before baseline
  • Previous treatment with oral corticosteroids for more than 4 weeks
  • Previous treatment with Intra Articular corticosteroids within 4 weeks before baseline
  • Previous treatment with an investigational drug for the treatment or prevention of RA
  • Contraindications for corticosteroids
  • Contraindications for DMARDs
  • 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
  • Alcohol or drug abuse
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01172639


Locations
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Sponsors and Collaborators
P. Verschueren
Agentschap voor Innovatie door Wetenschap en Technologie
Investigators
Layout table for investigator information
Principal Investigator: Patrick Verschueren, MD, PhD Universitaire Ziekenhuizen KU Leuven
More Information
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Publications of Results:

Other Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Layout table for additonal information
Responsible Party: P. Verschueren, Prof. Dr., Universitaire Ziekenhuizen KU Leuven
ClinicalTrials.gov Identifier: NCT01172639    
Other Study ID Numbers: CareRA
2008-007225-39 ( EudraCT Number )
First Posted: July 30, 2010    Key Record Dates
Results First Posted: December 10, 2018
Last Update Posted: January 22, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Keywords provided by P. Verschueren, Universitaire Ziekenhuizen KU Leuven:
CoBRA
Additional relevant MeSH terms:
Layout table for MeSH terms
Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Sulfasalazine
Prednisone
Methotrexate
Leflunomide
Anti-Inflammatory Agents
Glucocorticoids
Hormones
 Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors