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

Phase 4

Completed

Conditions: Rheumatoid Arthritis

Interventions: Drug: Methotrexate
Drug: Sulfasalazine
Drug: Prednisone
Drug: Leflunomide

Registration Number: NCT01172639

Lead Sponsor: P. Verschueren

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 400

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
CoBRA classic high risk group	Sulfasalazine	* 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
CoBRA slim high risk group	Prednisone	* 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
CoBRA classic high risk group	Methotrexate	* 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
CoBRA classic high risk group	Prednisone	* 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
CoBRA slim high risk group	Methotrexate	* 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
CoBRA avant-garde high risk group	Methotrexate	* 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
CoBRA avant-garde high risk group	Prednisone	* 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
CoBRA avant-garde high risk group	Leflunomide	* 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
CoBRA slim low risk group	Methotrexate	* 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
CoBRA slim low risk group	Prednisone	* 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
Tight Step Up low risk group	Methotrexate	* Methotrexate 15mg tablet by mouth, weekly for entire trial * No oral steroids allowed during the first year of the trial

Primary Outcome Measures

Name	Time	Method
Remission According to DAS28-CRP at Week 52	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.
Remission According to DAS28-CRP at Week 104	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.
Remission According to DAS28-CRP at Week 16	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.

Secondary Outcome Measures

Name	Time	Method
Clinically Significant Change in HAQ Score	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.
Remission According to SDAI at Week 104	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.
Remission According to SDAI (Simple Disease Activity Index) at Week 16	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.
Remission According to SDAI at Week 52	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.

Trial Locations

Locations (17): Reuma instituut Hasselt
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Hasselt, Belgium
ZNA Jan Palfijn
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Merksem, Belgium
Henri Serruys ziekenhuis
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Oostende, Belgium
ASZ
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Aalst, Belgium
OLV Ziekenhuis
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Aalst, Belgium
AZ St Lucas
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Brugge, Belgium
Reumacentrum
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Genk, Belgium
Imelda Ziekenhuis
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Bonheiden, Belgium
Reuma praktijk
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Genk, Belgium
Reumapraktijk
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Hasselt, Belgium
UZ Gent, dept. of Rheumatology
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Gent, Belgium
Universitaire Ziekenhuizen Leuven
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Leuven, Belgium
AZ St maarten
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Mechelen, Belgium
HHart Ziekenhuis
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Leuven, Belgium
MCH
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Leuven, Belgium
Jan Yperman Ziekenhuis
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Ieper, Belgium
AZ groeninge
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Kortrijk, Belgium