title: Experience collecting interim data on mortality: an example from the RALES study.
abstract: INTRODUCTION: The Randomized Aldactone Evaluation Study (RALES) randomized 822 patients to receive 25 mg spironolactone daily and 841 to receive placebo. The primary endpoint was death from all causes. Randomization began on March 24, 1995; recruitment was completed on December 31, 1996; follow-up was scheduled to continue through December 31, 1999. Evidence of a sizeable benefit on mortality emerged early in the RALES. The RALES data safety monitoring board (DSMB), which met semiannually throughout the trial, used a prespecified statistical guideline to recommend stopping for efficacy. At the DSMB's request, its meetings were preceded by an 'endpoint sweep', that is, a census of all participants to confirm their vital status. METHODS: We used computer simulation to evaluate the effect of the sweeps. RESULTS: The sweeps led to an estimated 5 to 8% increase in the number of reported deaths at the fourth and fifth interim analyses. The data crossed the statistical boundary at the fifth interim analysis. If investigators had reported all deaths within the protocol-required 24-h window, the DSMB might have recommended stopping after the fourth interim analysis. DISCUSSION: Although endpoint sweeps can cause practical problems at the clinical centers, sweeps are very useful if the intervals between patient visits or contact are long or if endpoints require adjudication by committee, reading center, or central laboratory. CONCLUSION: We recommend that trials with interim analyses institute active reporting of the primary endpoints and endpoint sweeps.
authors.affiliation: Statistics Collaborative, Inc, Washington, DC, USA. janet@statcollab.com
authors.forename: Janet
authors.initials: J
authors.lastname: Wittes
authors.forename: Jolie
authors.initials: J
authors.lastname: Palensky
authors.forename: Debra
authors.initials: D
authors.lastname: Asner
authors.forename: Desmond
authors.initials: D
authors.lastname: Julian
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Boissel
authors.forename: Curt D
authors.initials: CD
authors.lastname: Furberg
authors.forename: Henri
authors.initials: H
authors.lastname: Kulbertus
authors.forename: Stuart
authors.initials: S
authors.lastname: Pocock
authors.forename: Barbara
authors.initials: B
authors.lastname: Roniker