Rheumatoid ArthritisPhase 4NCT01172639
Effectiveness in Daily Practice of Different Treatment Strategies for Early Rheumatoid Arthritis.
A Phase 4 study testing Methotrexate, Sulfasalazine and Leflunomide in people with Rheumatoid Arthritis, run by P. Verschueren at 17 sites in Belgium.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Rheumatoid Arthritis
- What is being tested?
- Methotrexate, Sulfasalazine and Leflunomide
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 400 participants
- Where
- 17 sitesBelgium
- Study dates
- Feb 2009to Jun 2015
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 12Show fewer
- 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
Trial locations and contacts
17 sites in 1 country.
17 sites in 1 country
Belgium17 sites
ASZ
Aalst, 9300
OLV Ziekenhuis
Aalst, 9300
Imelda Ziekenhuis
Bonheiden, 2820
AZ St Lucas
Bruges, 8310
Reuma praktijk
Genk, 3600
Reumacentrum
Genk, 3600
UZ Gent, dept. of Rheumatology
Ghent, 9000
Reuma instituut Hasselt
Hasselt, 3500
Reumapraktijk
Hasselt, 3500
Jan Yperman Ziekenhuis
Ieper, 8900
AZ groeninge
Kortrijk, 8500
HHart Ziekenhuis
Leuven, 3000
MCH
Leuven, 3000
Universitaire Ziekenhuizen Leuven
Leuven, 3000
AZ St maarten
Mechelen, 2800
ZNA Jan Palfijn
Merksem, 2170
Henri Serruys ziekenhuis
Ostend, 8400
About this study
Official title: A 2 Year Prospective Multicentre Randomised Controlled Trial Comparing Effectiveness in Daily Practice of Different Treatment Strategies for Early Rheumatoid Arthritis.
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
- Being tested
- Methotrexate, Sulfasalazine, Leflunomide, Prednisone
- Keywords
- CoBRA
- Medical subject headings
- Arthritis, Rheumatoid
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MethotrexateDrug
Also called Ledertrexate
Methotrexate tablet
SulfasalazineDrug
Also called Salazopyrine
Sulfasalazine tablet
LeflunomideDrug
Also called Arava
Leflunomide tablet
PrednisoneDrug
Prednisone tablet
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: 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 Receives: 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 Receives: 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 Receives: 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 Receives: Drug: Methotrexate |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: week 104
Secondary outcomes (4)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Baseline-week104
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Jul 2010 (estimated)
- Study startFeb 2009
- Primary completionJun 2015
- Study completionJun 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (15)Papers the sponsor has linked to this study.
- Other trials for Rheumatoid ArthritisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- 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)
- Enrolment
- 400 participants (actual)
Sponsor and investigators
- Lead sponsor
- P. Verschueren
- Sponsor type
- University, hospital or other
- Collaborators
- Agentschap voor Innovatie door Wetenschap en Technologie
- Responsible party
- Sponsor-investigator, P. Verschueren, Universitaire Ziekenhuizen KU Leuven
- Investigators
- Patrick Verschueren, MD, PhD, Principal investigator, Universitaire Ziekenhuizen KU Leuven
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01172639
- Sponsor's protocol ID
- CareRA
- Other IDs
- 2008-007225-39, 2008
- Status last verified
- Jan 2019
- First submitted
- 28 Jul 2010
- Last updated
- 22 Jan 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- Undecided
Publications
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.
PubMed 19169906Verschueren 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.
PubMed 18039681Durez 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.
PubMed 18050189Esselens 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.
PubMed 18618520Boers 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.
PubMed 9251634De 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.
PubMed 26058860Verschueren 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.
PubMed 25359382Verschueren 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.
PubMed 25889222Verschueren 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.
PubMed 27432356Pazmino 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.
PubMed 34031262Stouten 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.
PubMed 33434277Pazmino 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.
PubMed 33191282Pazmino 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.
PubMed 32241795Stouten 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.
PubMed 32166429Stouten 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.
PubMed 31236568
Study at a glance
From the registry record, last updated by the sponsor on 22 Jan 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A 2 Year Prospective Multicentre Randomised Controlled Trial Comparing Effectiveness in Daily Practice of Different Treatment Strategies for Early Rheumatoid Arthritis.
- ClinicalTrials.gov ID
- NCT01172639
- Acronym / sponsor ID
- CareRA
- Conditions
- Rheumatoid Arthritis
- Keywords
- CoBRA
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 400 participants (actual)
- Lead sponsor
- P. VerschuerenUniversity, hospital or other
- Collaborators
- Agentschap voor Innovatie door Wetenschap en Technologie
- Study start
- Feb 2009
- Primary completion
- Jun 2015 (actual)
- Study completion
- Jun 2015 (actual)
- First posted
- 30 Jul 2010 (estimated)
- Results
- Posted 10 Dec 2018
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 5
- 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.
| Arm | Type | Receives |
|---|---|---|
| CoBRA classic high risk group | Other | Drug: Methotrexate, Drug: Sulfasalazine, Drug: 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 | Other | Drug: Methotrexate, Drug: 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 avant-garde high risk group | Other | Drug: Methotrexate, Drug: Leflunomide, Drug: 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 slim low risk group | Other | Drug: Methotrexate, Drug: 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 | Other | Drug: Methotrexate* Methotrexate 15mg tablet by mouth, weekly for entire trial * No oral steroids allowed during the first year of the trial |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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
Key exclusion criteria (12 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MethotrexateAlso: LedertrexateMethotrexate tablet | Drug | 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 |
| SulfasalazineAlso: SalazopyrineSulfasalazine tablet | Drug | CoBRA classic high risk group |
| LeflunomideAlso: AravaLeflunomide tablet | Drug | CoBRA avant-garde high risk group |
| PrednisonePrednisone tablet | Drug | CoBRA avant-garde high risk group, CoBRA classic high risk group, CoBRA slim high risk group, CoBRA slim low risk group |
Primary outcome
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.
4 secondary outcomes
Remission According to SDAI (Simple Disease Activity Index) at Week 16
Time frame: week 16
Remission According to SDAI at Week 52
Time frame: week 52
Remission According to SDAI at Week 104
Time frame: week 104
Clinically Significant Change in HAQ Score
Time frame: Baseline-week104
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Jan 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 19169906Verschueren 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.
- Background: PubMed 18039681Verschueren 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.
- Background: PubMed 18050189Durez 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.
- Background: PubMed 18618520Esselens 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.
- Background: PubMed 9251634Boers 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.
- Background: PubMed 26058860De 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.
- Results publication: PubMed 25359382Verschueren 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.
- Results publication: PubMed 25889222Verschueren 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.
- Results publication: PubMed 27432356Verschueren 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.
- Derived from this study: PubMed 34031262Pazmino 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.
- Derived from this study: PubMed 33434277Stouten 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.
- Derived from this study: PubMed 33191282Pazmino 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.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Patrick Verschueren, MD, PhD principal investigator
Universitaire Ziekenhuizen KU Leuven
17 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Methotrexate, Sulfasalazine and Leflunomide in people with Rheumatoid Arthritis, run by P. Verschueren at 17 sites in Belgium.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 22 Jan 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 17 sites in Belgium. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 10 Dec 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Remission According to DAS28-CRP at Week 16 (time frame: week 16). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01172639, which also lists 15 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Jan 2019.