A Multiple Testing Procedure for Clinical Trials

O’Brien, Peter C.; Fleming, Thomas R.

doi:10.2307/2530245

Cited by 2,905 publications

(1,649 citation statements)

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“…Three interim analyses, respectively after 15, 30 and 45 months, and one final analysis will be performed. The O'Brien-Fleming rule 25 will be employed and the monitoring boundaries will be set at the 1% significance level. Syst-Eur 2 could be stopped, if the age-and sexadjusted rates for all-cause, cardiovascular or cancer mortality would exceed those observed in the placebo group during the Syst-Eur trial proper.…”

Section: Resultsmentioning

confidence: 99%

Systolic Hypertension in Europe (Syst-Eur) Trial Phase 2: objectives, protocol, and initial progress

Gąsowski¹,

Staessen²,

Celis³

et al. 1999

J Hum Hypertens

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on behalf of the Systolic Hypertension in Europe InvestigatorsThe Systolic Hypertension in Europe (Syst-Eur) trial proved that blood pressure (BP) lowering therapy starting with nitrendipine reduces the risk of cardiovascular complications in older (у60 years) patients with isolated systolic hypertension (systolic BP у160 mm Hg and diastolic BP Ͻ95 mm Hg). After the completion of the Syst-Eur trial on 14 February 1997, 3506 consenting patients (93.0% of those eligible) were enrolled in phase 2 of the Syst-Eur trial. This open follow-up study aims to confirm the safety of long-term antihypertensive therapy based on a dihydropyridine. To lower the sitting systolic BP below 150 mm Hg (target BP), the first-line agent nitrendipine (10-40 mg/day) may be associated with enalapril (5-20 mg/day), hydrochlorothiazide (12.5-25 mg/day), both add-on study drugs, or if required any other antihypertensive agent. On 1 November 1998, 3248 patients were still being followed, 86 patients had proceeded to non-supervised follow-up, and 43 had died. The median follow-up in Syst-Eur 2 was 14.3 months. At Keywords: calcium-channel blockade; elderly; dihydropyridine; isolated systolic hypertension IntroductionIn 1989 the European Working Party on High Blood Pressure in the Elderly started the placebo-controlled double-blind Systolic Hypertension in Europe trial (Syst-Eur). 1 Active treatment was initiated with the dihydropyridine calcium-channel blocker nitrendipine 2 with the possible addition of enalapril, hydrochlorothiazide or both drugs. The Syst-Eur trial stopped on 14 February 1997 according to predefined rules, 3 because the second of four planned interim analyses had shown a significant benefit for stroke, the primary end-point. 1 At the Syst-Eur investigators meeting in March 1997, the decision was taken to keep the Syst-Eur patients in followup. This article summarizes the rationale and protocol of this study, named Systolic Hypertension in Correspondence: Dr Jan A Staessen, Klinisch Laboratorium Hypertensie, Inwendige Geneeskunde-Cardiologie, UZ Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium Received 14 October 1998; accepted 21 October 1998 the last available visit, systolic/diastolic BP in the patients formerly randomised to placebo (n = 1682) or active treatment (n = 1824), had decreased by 13.2/5.2 mm Hg and by 4.6/1.6 mm Hg, respectively, so that the between-group BP difference was 1.7 mm Hg systolic (95% Cl: 0.8 to 2.6 mm Hg; P Ͻ 0.001) and 0.9 mm Hg diastolic (95% Cl: 0.4 to 1.5 mm mm Hg; P Ͻ 0.001). At the beginning of Syst-Eur 2, the goal BP was reached by 25.4% and 50.6% of the former placebo and activetreatment groups; at the last visit these proportions were 55.9% and 63.1%, respectively. At that moment, 45.9% of the patients were on monotherapy with nitrendipine, 29.3% took nitrendipine in combination with other study drugs. Until the end of 2001, BP control of the Syst-Eur 2 patients will be further improved. Cardiovascular complications and adverse events, such as cancer or gastro-intestinal bleeding, wi...

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Section: Resultsmentioning

confidence: 99%

Systolic Hypertension in Europe (Syst-Eur) Trial Phase 2: objectives, protocol, and initial progress

Gąsowski¹,

Staessen²,

Celis³

et al. 1999

J Hum Hypertens

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“…The three interim analyses will follow a symmetric group sequential design using the alpha‐spending methodology of Lan and DeMets30 with O'Brien–Fleming‐type boundaries,31 after 275, 550, and 825 patients have experienced a primary endpoint event, respectively. The DMC will review interim analysis results and will advise on continuation of enrolment and patient follow‐up.…”

Section: Methodsmentioning

confidence: 99%

Rationale and design of the AdaptResponse trial: a prospective randomized study of cardiac resynchronization therapy with preferential adaptive left ventricular‐only pacing

Filippatos

Birnie

Gold

et al. 2017

European J of Heart Fail

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The AdaptResponse trial is designed to test the hypothesis that preferential adaptive left ventricular‐only pacing with the AdaptivCRT® algorithm reduces the incidence of the combined endpoint of all‐cause mortality and intervention for heart failure (HF) decompensation, compared with conventional cardiac resynchronization therapy (CRT), among patients with a CRT indication, left bundle branch block (LBBB) and normal atrioventricular (AV) conduction. The AdaptResponse study is a prospective, randomized, controlled, single‐blinded, multicentre, clinical trial (ClinicalTrials.gov Identifier: NCT02205359), conducted at up to 200 centres worldwide. Following enrolment and baseline assessment, eligible subjects will be implanted with a CRT system containing the AdaptivCRT algorithm, and randomized in a 1:1 fashion to either a treatment (‘AdaptivCRT’) or control (‘Conventional CRT’) group. The study is designed to observe a primary endpoint in 1100 patients (‘event‐driven’) and approximately 3000 patients will be randomized. The primary endpoint is the composite of all‐cause mortality and intervention for HF decompensation; secondary endpoints include all‐cause mortality, intervention for HF decompensation, clinical composite score (CCS) at 6 months, atrial fibrillation, quality of life measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ), health outcome measured by the EQ‐5D instrument, all‐cause readmission after a HF admission, and cost‐effectiveness. The AdaptResponse clinical trial is powered to assess clinical endpoints and is expected to provide definitive evidence on the incremental utility of AdaptivCRT‐enhanced CRT systems.

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“…The method enables the effect of conducting interim analyses without adjusting for multiple testing to be demonstrated and allows the construction of critical values to maintain an overall type I error rate of . This methodology was used by both Pocock [7] and O'Brien and Fleming [8]. Their results were tabulated to allow easy implementation without the need for additional computation.…”

Section: Designmentioning

confidence: 99%

“…However now, the rate at which it is spent is controlled by a specified function, known as the -spending function, * (t). The method introduces flexibility in the choice of the shape of the stopping boundaries and also, in contrast to the tests of Pocock [7], O'Brien and Fleming [8] and Slud and Wei [53], allows construction of a test that maintains the type I error rate when inspections deviate from their planned course.…”

Section: Designmentioning

confidence: 99%

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A 25‐year review of sequential methodology in clinical studies

Todd

2006

Statistics in Medicine

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SUMMARYThis paper explores the theoretical developments and subsequent uptake of sequential methodology in clinical studies in the 25 years since Statistics in Medicine was launched. The review examines the contributions which have been made to all four phases into which clinical trials are traditionally classified and highlights major statistical advancements, together with assessing application of the techniques. The vast majority of work has been in the setting of phase III clinical trials and so emphasis will be placed here. Finally, comments are given indicating how the subject area may develop in the future.

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A Multiple Testing Procedure for Clinical Trials

Cited by 2,905 publications

References 3 publications

Systolic Hypertension in Europe (Syst-Eur) Trial Phase 2: objectives, protocol, and initial progress

Systolic Hypertension in Europe (Syst-Eur) Trial Phase 2: objectives, protocol, and initial progress

Rationale and design of the AdaptResponse trial: a prospective randomized study of cardiac resynchronization therapy with preferential adaptive left ventricular‐only pacing

A 25‐year review of sequential methodology in clinical studies

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