cobra-light vs croba
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A non-inferiority trial of an attenuated combinationstrategy (COBRA-light) compared to the originalCOBRA strategy: clinical results after 26 weeksDebby den Uyl,1 Marieke ter Wee,1 Maarten Boers,1,2 Pit Kerstens,2,3
Alexandre Voskuyl,1 Mike Nurmohamed,1,2 Hennie Raterman,1
Dirkjan van Schaardenburg,1,2 Nancy van Dillen,2 Ben Dijkmans,1,2 Willem Lems1,2
Handling editor Tore K Kvien1Department of Rheumatology,VU University Medical Center,Amsterdam, The Netherlands2Department of Rheumatology,Jan van Breemen ResearchInstitute /Reade, Amsterdam,Noord Holland, TheNetherlands3Westfriesgasthuis, Hoorn,The Netherlands
Correspondence toDebby den Uyl, Department ofRheumatology, VU UniversityMedical Center, Room 3A52,De Boelelaan 1117,Amsterdam 1081 HV,The Netherlands;email@example.com
DdU and MtW contributedequally to this paper.
Accepted 19 March 2013Published Online First19 April 2013
To cite: den Uyl D, terWee M, Boers M, et al. AnnRheum Dis 2014;73:10711078.
ABSTRACTBackground Early, intensive treatment of rheumatoidarthritis (RA) with the combination of (initially high dose)prednisolone, methotrexate and sulfasalazine (COBRAtherapy) considerably lowers disease activity andsuppresses radiological progression, but is infrequentlyprescribed in daily practice. Attenuating the COBRAregimen might lessen concerns about side effects, butthe efcacy of such strategies is unknown.Objective To compare the COBRA-light strategy withonly two drugs, comprising a lower dose of prednisolone(starting at 30 mg/day, tapered to 7.5 mg/day in 9 weeks)and methotrexate (escalated to 25 mg/week in 9 weeks)to COBRA therapy (prednisolone 60 mg/day, tapered to7.5 mg/day in 6 weeks, methotrexate 7.5 mg/week andsulfasalazine 2 g/day).Method An open, randomised controlled, non-inferiority trial in 164 patients with early active RA, alltreated according to a treat to target strategy.Results At baseline patients had moderately activedisease: mean (SD) 44-joint disease activity score (DAS44)4.13 (0.81) for COBRA and 3.95 (0.9) for COBRA-light.After 6 months, DAS44 signicantly decreased in bothgroups (2.50 (1.21) for COBRA and 2.18 (1.10) forCOBRA-light). The adjusted difference in DAS44improvement between the groups, 0.21 (95% CI 0.11to 0.53), was smaller than the predened clinicallyrelevant difference of 0.5. Minimal disease activity(DAS44
score of 20 mm or greater on a 0100 mm visual analoguescale. Exclusion criteria included: previous treatment with glu-cocorticoids or DMARD other than antimalarial agents, uncon-trolled diabetes mellitus, heart failure (New York HeartAssociation class 34), uncontrolled hypertension, ALT or ASTlevel more than three times the upper limit of normal, reducedrenal function (serum creatinine level >150 mmoles/l), contrain-dications for glucocorticoids and a positive tuberculin skin test.The eligibility criteria strongly resemble earlier trials establishingthe efcacy of COBRA.6 9 The medical ethics committee at eachparticipating centre approved the protocol and the study wasconducted in accordance with the Declaration of Helsinki/goodclinical practice. All patients gave written informed consentbefore inclusion.
Treatment allocation and interventionThe COBRA-light study was a randomised, open, multicentretrial comparing two treatment schedules for the treatment ofearly RA (http://www.controlled-trials.com; ISRCTN55552928).Patients were randomly assigned to either COBRA therapy orCOBRA-light therapy using sequentially numbered envelopescontaining the allocated treatment group. Online randomisationsoftware was used to obtain variable blocks of six, stratied percentre. After checking eligibility and informed consent, thestudy physician entered each patient into the study. For somepatients the assigned treatment was started after 1 week to allowbaseline measurements of insulin resistance (results reportedseparately).17
This study included a strict treatment regime during 1 yearand a second year of follow-up.Patients assigned to COBRA therapy started with prednisolone
60 mg/day, tapered to 7.5 mg/day in 6 weeks, methotrexate7.5 mg/week and sulfasalazine 1 g/day, increased to 2 g/day after1 week (gure 1) according to the COBRA study.6 The decisionto adjust medication was based on the disease activity score in 44joints (DAS44), including the Ritchie articular index, assessedevery 3 months. The primary treatment goal was minimal diseaseactivity, at that time dened as DAS44 less than 1.6. The protocolrequired an increase of the methotrexate dose to 25 mg/weekafter 13 weeks of treatment if the DAS44 was 1.6 or over.Patients receiving COBRA-light therapy started with prednisol-one 30 mg/day, tapered to 7.5 mg/day in 9 weeks and methotrex-ate 10 mg/week with stepwise increments in all patients to25 mg/week in 9 weeks; the protocol required the treating phys-ician to consider parenteral methotrexate after 13 weeks if theDAS44 was 1.6 or greater (gure 1). All patients received folicacid 5 mg/week and daily calcium/vitamin supplementation.Bisphosphonates were prescribed according to the guidelines forglucocorticoid-induced osteoporosis.18 Concomitant treatmentwith non-steroidal anti-inammatory drugs and intra-articularinjections with glucocorticoids during the study were permitted.For analyses, it was assumed that all intra-articular glucocorticoidinjections given less than 3 months before the next visit inu-enced the disease activity calculations. Therefore, the injectedjoint was scored as being tender and swollen. If an intramuscularglucocorticoid injection was given within 4 weeks before a nextvisit, the disease activity calculation was recorded as missing.In general, in the case of an adverse event, the responsible
drug(s) were reduced to the lowest tolerable dose. Additionaloptions for methotrexate included subcutaneous injections ifpatients experienced gastrointestinal side effects and nallypatients could switch to leunomide if they remained intolerantto methotrexate.
Assessment of endpointsEvery 3 months independent research nurses and (for VUMedical Center) study physicians performed the assessments.The primary outcome was the change in DAS44 after 26 weeksof treatment compared with baseline (DAS44). Secondary out-comes included the proportions of patients achieving minimaldisease activity according to DAS44 criterion (DAS44 1.6) andthe new ACR/European League Against Rheumatism (EULAR)criteria (Boolean approach).19 20 Other secondary outcomeswere changes in core set variables, the EULAR and ACRresponse criteria and physical function as measured by theDutch version of the health assessment questionnaire(HAQ).21 22 All protocol violations were recorded. Protocolisedtreatment deviations were recorded separately. Major protocolviolations were dened as any unapproved changes in the treat-ment protocol or procedures that could affect the completeness,accuracy, reliability and integrity of the study data; this was adju-dicated by an independent committee of two rheumatologistsnot involved in the execution of the study.
SafetyDuring follow-up safety was monitored at each study visit byactive solicitation: patients were interviewed on the presence ofadverse effects following a detailed list. In addition, laboratorymonitoring comprised a complete blood cell count, serum levelsof ALT, alkaline phosphatase, creatinine, electrolytes, glucoseand lipids. All adverse events and subsequent treatment adjust-ments were recorded. A serious adverse event was dened asany untoward medical occurrence that resulted in death, waslife-threatening, (planned) inpatient hospitalisation or prolonga-tion of existing hospitalisation, resulted in persistent or signi-cant disability/incapacity, or (planned) intervention to preventpermanent impairment or damage. An independent committeeidentied all serious events and assessed their potential relation-ship with treatment.
Statistical analysisThe primary outcome of this trial was the mean DAS44 after26 weeks. The limit for non-inferiority was set at a difference inchange of 0.5 points. Sample size calculations showed that 142patients would be needed to obtain 80% power, with a two-sided signicance level of 5%, to detect this difference. Thetarget inclusion was set at 160 to compensate for loss tofollow-up. Data are presented as mean valuesSD or as median(IQR) in the case of skewed distribution. Analyses were per-formed by a modied intention to treat (ITT) protocol, includ-ing all patients who received at least one dose of the allocatedtreatment schedule. Two patients (one in each group) were lostto follow-up at weeks 13 and 16, respectively, and their missingdata were imputed as follows: the mean change in DAS44between week 13 and week 26 of all patients was used to calcu-late the missing DAS44 scores at week 26 for the individualpatient. Post hoc, after checking results, DAS44 calculationswith C-reactive protein (CRP) were performed to investigate theeffect of different acute phase proteins.All outcome variables with Gaussian distribution were ana-
lysed by linear regression. The primary outcome was analysedwith DAS44 as outcome and treatment group and baselineDAS44 as explanatory variables. Non-normally distributed para-meters were rst log-transformed and also analysed by linearregression. Categorical variables were tested by the 2 test.Subgroup analyses were performed to explore the effect ofprotocol deviations on the primary outcome. All statistical
1072 den Uyl D, et al. Ann Rheum Dis 2014;73:10711078. doi:10.1136/annrheumdis-2012-202818
Clinical and epidemiological research
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- analyses were run on SPSS for Windows V.15.0. A two-sidedp
a difference in DAS44 of 0.044 (95% CI 0.29 to 0.38), andadjusted for baseline DAS44 CRP: 0.06 (95% CI 0.36 to 0.23).There