Table 1

Summary of key features of LTE studies

DesignLTE durationAnalysis populationPrimary outcomeAnalysisSafety reportingImputation of missing data in initial DB-RCT/subsequent LTERescue arm in initial DB-RCT
Synthetic DMARD
Leflunomide 200317Inclusion from two phase III studies; ≥2 years leflunomide exposureOpen-label, LTEUpon leflunomide availability (last observation)Intent to treatNot stated(Long-term safety and efficacy outcomes (ACR response, HAQ))Descriptive% Responders of all patients on continued leflunomideAE and SAE: (frequency)LOCF/not statedNo
Biological DMARD
Anakinra 200212Blinded extensionOriginal placebo group randomly assigned to three doses in LTE231 YearIntent to treatACR20, 12 months (6 months LTE)Completers onlySeparate RCT placebo analysis18 Months (12 months into LTE)No (%)LOCF/non-responder imputation; LOCFNo
Etanercept 200313Open-label extensionWeek 12: methotrexate±steroid dose reductionObservational, on-going studyMedian 44 months drug exposurePer protocolNot statedMax. 3 year efficacy/safety evaluationCompleters for each annual time point (ACR)SAE/patient-yearNon-responder imputation24/not statedNo
ARMADA (adalimumab) 200625Open-labelPI determined co-medication change after 6 months extensionUp to 4 years of adalimumab exposure (with methotrexate)Per protocolEfficacy:2–4 year exposure4 year exposureNot stated6-monthly efficacy (ACR response)AE/100 patient-yearsObserved-expected malignancy SIR (95% CI)LOCF5/not statedEscape open-label option in DB-RCT study
Etanercept 200614Previous seven trials (phase I–III, open-label)Original etanercept dose year 1; licensed dose post year 1Additional DMARD/steroid post year 1To data cut-off time (ongoing study)Intent to treat year 1Only completers subsequent yearsSafetyPhysical functionQuality of lifeEfficacy: Completers for each LTE year onlySafety: AE and SAE per 100 patient-yearsSafety from phase I–III, open-label±LTENon-serious AE year 1SAE throughout LTE (no/100 patient-years)Malignancy (event/100 patient-years)Deaths/100 patient-yearsNone usedNo
Rituximab 200711Open-labelInclusion from three previous phase IIa, IIb, III (DB-RCT/open-label)Data from specified clinical programmePer protocolSafety and efficacyACR 20 week 24 after each rituximab courseDescriptive; on observed data for efficacy analysisAE & SAEAll exposure populationNot statedNo
AIM 2008 (abatacept)9Blinding maintained in extension (original placebo arm unknown)2 YearsIntent to treatPrespecified analysisAs-observed data (inc post hoc)Not statedEfficacy outcomes:ACR responseACR70 for >6 and >9 monthsResponder analysisNon-completers included within non-responder analysisIncidence rate AE, SAE, infection/100 patient-yearsFrequencies for rarer events/malignancyNon-responder imputation/Not statedNo
STREAM 2009 (tocilizumab)26Open-label5 YearsPer protocolNot statedEfficacy: parameters/exposure yearsEfficacy: of completersContinuation rateSAE/infection/malignancy/100 patient-yearsHaemoglobin/lipid: descriptive statisticsNone usedNo
Toclilzumab 3.5 year data (abstract)15Open-label (patients from four phase III DB-RCT)8 2729DMARD±TNF inhibitor inadequate responder3.5 Years‘As observed’Efficacy outcomes:ACR 20, 50, 70 responseHAQ=0LDADAS28 remissionBaseline=first active dose of tocilizumab (ie, initial RCT baseline for active randomised group; rescue time point or LTE baseline for initial RCT placebo group)Proportion of patients achieving ACR response, HAQ=0Absolute numbers and proportion of patients LDA and DAS28 remissionSafety data reported (separately); median 3.1 years30AE/100 patient-yearsNone usedNo imputation of assessments (patient excluded if missing measurement)LOCF for missing TJC and SJCYes (all four DB-RCT)
  • A summary of several recently reported long-term extension studies illustrates the variation in content, analysis and method of reporting.

    ACR, American College of Rheumatology; AE, adverse event; DAS28, disease activity score; DB, double-blind; DMARD, disease modifying antirheumatic drug; HAQ, health assessment questionnaire; LDA, low disease activity; LOCF, last observation carried forward; LTE, long-term extension; PI, principal investigator; RCT, randomised controlled trial; SIR, standardised incidence ratio; SAE, serious adverse event; SJC, swollen joint count; TJC, tender joint count; TNF, tumour necrosis factor.