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

NCT01172639 | Completed Phase 4 Results DMC

• 2 other identifiers: CareRA2008-007225-39
• Study Type: interventional
• Target: 400
• Locations: 1 country
• Sites: 17

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.

Conditions

Rheumatoid Arthritis

Keywords

CoBRA

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (4)

• Remission According to SDAI (Simple Disease Activity Index) at Week 16

  week 16

• Remission According to SDAI at Week 52

  week 52

• Remission According to SDAI at Week 104

  week 104

• Clinically Significant Change in HAQ Score

  Baseline-week104

Study Arms (5)

CoBRA classic high risk group

OTHER

* 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; Drug: Sulfasalazine; Drug: Prednisone

CoBRA slim high risk group

OTHER

* 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; Drug: Prednisone

CoBRA avant-garde high risk group

OTHER

* 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; Drug: Leflunomide; Drug: Prednisone

CoBRA slim low risk group

OTHER

* 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; Drug: Prednisone

Tight Step Up low risk group

OTHER

* Methotrexate 15mg tablet by mouth, weekly for entire trial * No oral steroids allowed during the first year of the trial

Drug: Methotrexate

Interventions

Methotrexate DRUG

Methotrexate tablet

Also known as: Ledertrexate

CoBRA avant-garde high risk group; CoBRA classic high risk group; CoBRA slim high risk group; CoBRA slim low risk group; Tight Step Up low risk group

Sulfasalazine DRUG

Sulfasalazine tablet

Also known as: Salazopyrine

CoBRA classic high risk group

Leflunomide DRUG

Leflunomide tablet

Also known as: Arava

CoBRA avant-garde high risk group

Prednisone DRUG

Prednisone tablet

CoBRA avant-garde high risk group; CoBRA classic high risk group; CoBRA slim high risk group; CoBRA slim low risk group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• P. Verschueren: lead
• Agentschap voor Innovatie door Wetenschap en Technologie: collaborator

Study Sites (17)

ASZ

Aalst, 9300, Belgium

Location

OLV Ziekenhuis

Aalst, 9300, Belgium

Location

Imelda Ziekenhuis

Bonheiden, 2820, Belgium

Location

AZ St Lucas

Bruges, 8310, Belgium

Location

Reuma praktijk

Genk, 3600, Belgium

Location

Reumacentrum

Genk, 3600, Belgium

Location

UZ Gent, dept. of Rheumatology

Ghent, 9000, Belgium

Location

Reuma instituut Hasselt

Hasselt, 3500, Belgium

Location

Reumapraktijk

Hasselt, 3500, Belgium

Location

Jan Yperman Ziekenhuis

Ieper, 8900, Belgium

Location

AZ groeninge

Kortrijk, 8500, Belgium

Location

HHart Ziekenhuis

Leuven, 3000, Belgium

Location

MCH

Leuven, 3000, Belgium

Location

Universitaire Ziekenhuizen Leuven

Leuven, 3000, Belgium

Location

AZ St maarten

Mechelen, 2800, Belgium

Location

ZNA Jan Palfijn

Merksem, 2170, Belgium

Location

Henri Serruys ziekenhuis

Ostend, 8400, Belgium

Location

Related Publications (15)

• 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.

  PMID: 19169906 BACKGROUND

• 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.

  PMID: 18039681 BACKGROUND

• 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.

  PMID: 18050189 BACKGROUND

• 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.

  PMID: 18618520 BACKGROUND

• 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.

  PMID: 9251634 BACKGROUND

• 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.

  PMID: 26058860 BACKGROUND

• 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.

  PMID: 25359382 RESULT

• 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.

  PMID: 25889222 RESULT

• 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.

  PMID: 27432356 RESULT

• Pazmino S, Boonen A, De Cock D, Stouten V, Joly J, Bertrand D, Westhovens R, Verschueren P. Short-term glucocorticoids reduce risk of chronic NSAID and analgesic use in early methotrexate-treated rheumatoid arthritis patients with favourable prognosis: subanalysis of the CareRA randomised controlled trial. RMD Open. 2021 May;7(2):e001615. doi: 10.1136/rmdopen-2021-001615.

  PMID: 34031262 DERIVED

• Stouten V, Westhovens R, De Cock D, Van der Elst K, Pazmino S, Bertrand D, Joly J, Verschueren P. Having a co-morbidity predicts worse outcome in early rheumatoid arthritis despite intensive treatment: a post hoc evaluation of the pragmatic randomized controlled CareRA trial. Rheumatology (Oxford). 2021 Aug 2;60(8):3699-3708. doi: 10.1093/rheumatology/keaa841.

  PMID: 33434277 DERIVED

• Pazmino S, Lovik A, Boonen A, De Cock D, Stouten V, Joly J, Bertrand D, Van der Elst K, Westhovens R, Verschueren P. Does Including Pain, Fatigue, and Physical Function When Assessing Patients with Early Rheumatoid Arthritis Provide a Comprehensive Picture of Disease Burden? J Rheumatol. 2021 Feb;48(2):174-178. doi: 10.3899/jrheum.200758. Epub 2020 Nov 15.

  PMID: 33191282 DERIVED

• Pazmino S, Boonen A, Stouten V, De Cock D, Joly J, Van der Elst K, Westhovens R, Verschueren P. Two-year cost-effectiveness of different COBRA-like intensive remission induction schemes in early rheumatoid arthritis: a piggyback study on the pragmatic randomised controlled CareRA trial. Ann Rheum Dis. 2020 May;79(5):556-565. doi: 10.1136/annrheumdis-2019-216874. Epub 2020 Apr 2.

  PMID: 32241795 DERIVED

• Stouten V, Michiels S, Westhovens R, De Cock D, Belba A, Pazmino S, Van der Elst K, Joly J, Verschueren P. Effectiveness of maintenance therapy with methotrexate compared with leflunomide for patients with RA having achieved disease control with both these drugs: results of a predefined sub-analysis of CareRA, a pragmatic RCT. Clin Rheumatol. 2020 Sep;39(9):2593-2601. doi: 10.1007/s10067-020-05008-4. Epub 2020 Mar 12.

  PMID: 32166429 DERIVED

• Stouten V, Westhovens R, Pazmino S, De Cock D, Van der Elst K, Joly J, Verschueren P; CareRA study group. Effectiveness of different combinations of DMARDs and glucocorticoid bridging in early rheumatoid arthritis: two-year results of CareRA. Rheumatology (Oxford). 2019 Dec 1;58(12):2284-2294. doi: 10.1093/rheumatology/kez213.

  PMID: 31236568 DERIVED

MeSH Terms

Conditions

Arthritis, Rheumatoid

Interventions

Methotrexate; Sulfasalazine; Salazopyrine; Leflunomide; Prednisone

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Isoxazoles; Azoles; Heterocyclic Compounds, 1-Ring; Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Results Point of Contact

• Title: Prof. Dr. Patrick Verschueren
• Organization: University Hospitals Leuven

patrick.verschueren@uzleuven.be

+32 16 34 25 41

Study Officials

• Patrick Verschueren, MD, PhD

  Universitaire Ziekenhuizen KU Leuven

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Prof. Dr.

Model Details: 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.

Study Record Dates

• First Submitted: July 28, 2010
• First Posted: July 30, 2010
• Study Start: February 1, 2009
• Primary Completion: June 1, 2015
• Study Completion: June 1, 2015
• Last Updated: January 22, 2019
• Results First Posted: December 10, 2018

Record last verified: 2019-01

Locations

BE (17)