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

Study Overview
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Brief Summary
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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.

Official Title
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A 2 Year Prospective Multicentre Randomised Controlled Trial Comparing Effectiveness in Daily Practice of Different Treatment Strategies for Early Rheumatoid Arthritis.

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Methotrexate
* Drug: Sulfasalazine
* Drug: Leflunomide
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: CoBRA classic high risk group<br>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<br>* Methotrexate tablet<br>* Other names: Ledertrexate;Drug: Sulfasalazine<br>* Sulfasalazine tablet<br>* Other names: Salazopyrine;Drug: Prednisone<br>* Prednisone tablet<br>|
| Other: CoBRA slim high risk group<br>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<br>* Methotrexate tablet<br>* Other names: Ledertrexate;Drug: Prednisone<br>* Prednisone tablet<br>|
| Other: CoBRA avant-garde high risk group<br>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<br>* Methotrexate tablet<br>* Other names: Ledertrexate;Drug: Leflunomide<br>* Leflunomide tablet<br>* Other names: Arava;Drug: Prednisone<br>* Prednisone tablet<br>|
| Other: CoBRA slim low risk group<br>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<br>* Methotrexate tablet<br>* Other names: Ledertrexate;Drug: Prednisone<br>* Prednisone tablet<br>|
| Other: Tight Step Up low risk group<br>Methotrexate 15mg tablet by mouth, weekly for entire trial No oral steroids allowed during the first year of the trial | Drug: Methotrexate<br>* Methotrexate tablet<br>* Other names: Ledertrexate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Remission According to DAS28-CRP at 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. | week 16 | 
| Remission According to DAS28-CRP at 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. | week 52 | 
| Remission According to DAS28-CRP at 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. | week 104 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Remission According to SDAI (Simple Disease Activity Index) at 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. | week 16 | 
| Remission According to SDAI at 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. | week 52 | 
| Remission According to SDAI at 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. | week 104 | 
| Clinically Significant Change in HAQ Score | 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. | Baseline-week104 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CoBRA