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

Overview

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.

Full Title of Study: “A 2 Year Prospective Multicentre Randomised Controlled Trial Comparing Effectiveness in Daily Practice of Different Treatment Strategies for Early Rheumatoid Arthritis.”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: June 2015

Interventions

  • Drug: Methotrexate
    • Methotrexate tablet
  • Drug: Sulfasalazine
    • Sulfasalazine tablet
  • Drug: Leflunomide
    • Leflunomide tablet
  • Drug: Prednisone
    • Prednisone tablet

Arms, Groups and Cohorts

  • Other: 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
  • Other: 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
  • Other: 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
  • Other: 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
  • Other: 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

Clinical Trial Outcome Measures

Primary Measures

  • 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.
  • 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.
  • 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 Measures

  • 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.
  • 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.
  • 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.
  • 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.

Participating in This Clinical Trial

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

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • P. Verschueren
  • Collaborator
    • Agentschap voor Innovatie door Wetenschap en Technologie
  • Provider of Information About this Clinical Study
    • Sponsor-Investigator: P. Verschueren, Prof. Dr. – Universitaire Ziekenhuizen KU Leuven
  • Overall Official(s)
    • Patrick Verschueren, MD, PhD, Principal Investigator, Universitaire Ziekenhuizen KU Leuven

References

Verschueren P, Esselens G, Westhovens R. Predictors of remission, normalized physical function, and changes in the working situation during follow-up of patients with early rheumatoid arthritis: an observational study. Scand J Rheumatol. 2009 May-Jun;38(3):166-72. doi: 10.1080/03009740802484846.

Verschueren P, Esselens G, Westhovens R. Daily practice effectiveness of a step-down treatment in comparison with a tight step-up for early rheumatoid arthritis. Rheumatology (Oxford). 2008 Jan;47(1):59-64. doi: 10.1093/rheumatology/kem288. Epub 2007 Nov 26.

Durez P, Malghem J, Nzeusseu Toukap A, Depresseux G, Lauwerys BR, Westhovens R, Luyten FP, Corluy L, Houssiau FA, Verschueren P. Treatment of early rheumatoid arthritis: a randomized magnetic resonance imaging study comparing the effects of methotrexate alone, methotrexate in combination with infliximab, and methotrexate in combination with intravenous pulse methylprednisolone. Arthritis Rheum. 2007 Dec;56(12):3919-27. doi: 10.1002/art.23055.

Esselens G, Westhovens R, Verschueren P. Effectiveness of an integrated outpatient care programme compared with present-day standard care in early rheumatoid arthritis. Musculoskeletal Care. 2009 Mar;7(1):1-16. doi: 10.1002/msc.136.

Boers M, Verhoeven AC, Markusse HM, van de Laar MA, Westhovens R, van Denderen JC, van Zeben D, Dijkmans BA, Peeters AJ, Jacobs P, van den Brink HR, Schouten HJ, van der Heijde DM, Boonen A, van der Linden S. Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet. 1997 Aug 2;350(9074):309-18. doi: 10.1016/S0140-6736(97)01300-7. Erratum In: Lancet 1998 Jan 17;351(9097):220.

De Cock D, Van der Elst K, Meyfroidt S, Verschueren P, Westhovens R. The optimal combination therapy for the treatment of early rheumatoid arthritis. Expert Opin Pharmacother. 2015;16(11):1615-25. doi: 10.1517/14656566.2015.1056735. Epub 2015 Jun 10.

Citations Reporting on Results

Verschueren P, De Cock D, Corluy L, Joos R, Langenaken C, Taelman V, Raeman F, Ravelingien I, Vandevyvere K, Lenaerts J, Geens E, Geusens P, Vanhoof J, Durnez A, Remans J, Vander Cruyssen B, Van Essche E, Sileghem A, De Brabanter G, Joly J, Meyfroidt S, Van der Elst K, Westhovens R. Methotrexate in combination with other DMARDs is not superior to methotrexate alone for remission induction with moderate-to-high-dose glucocorticoid bridging in early rheumatoid arthritis after 16 weeks of treatment: the CareRA trial. Ann Rheum Dis. 2015 Jan;74(1):27-34. doi: 10.1136/annrheumdis-2014-205489. Epub 2014 Oct 30.

Verschueren P, De Cock D, Corluy L, Joos R, Langenaken C, Taelman V, Raeman F, Ravelingien I, Vandevyvere K, Lenaerts J, Geens E, Geusens P, Vanhoof J, Durnez A, Remans J, Vander Cruyssen B, Van Essche E, Sileghem A, De Brabanter G, Joly J, Van der Elst K, Meyfroidt S, Westhovens R; CareRA study group. Patients lacking classical poor prognostic markers might also benefit from a step-down glucocorticoid bridging scheme in early rheumatoid arthritis: week 16 results from the randomized multicenter CareRA trial. Arthritis Res Ther. 2015 Apr 9;17(1):97. doi: 10.1186/s13075-015-0611-8.

Verschueren P, De Cock D, Corluy L, Joos R, Langenaken C, Taelman V, Raeman F, Ravelingien I, Vandevyvere K, Lenaerts J, Geens E, Geusens P, Vanhoof J, Durnez A, Remans J, Vander Cruyssen B, Van Essche E, Sileghem A, De Brabanter G, Joly J, Meyfroidt S, Van der Elst K, Westhovens R. Effectiveness of methotrexate with step-down glucocorticoid remission induction (COBRA Slim) versus other intensive treatment strategies for early rheumatoid arthritis in a treat-to-target approach: 1-year results of CareRA, a randomised pragmatic open-label superiority trial. Ann Rheum Dis. 2017 Mar;76(3):511-520. doi: 10.1136/annrheumdis-2016-209212. Epub 2016 Jul 18.

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