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Randomized Controlled Trial
. 2012 Feb;9(1):113-24.
doi: 10.1177/1740774511432726.

Midcourse correction to a clinical trial when the event rate is underestimated: the Look AHEAD (Action for Health in Diabetes) Study

Frederick L Brancati  1 , Mary Evans, Curt D Furberg, Nancy Geller, Steven Haffner, Steven E Kahn, Peter G Kaufmann, Cora E Lewis, David M Nathan, Bertram Pitt, Monika M Safford; Look AHEAD Study Group
Collaborators, Affiliations
Randomized Controlled Trial

Midcourse correction to a clinical trial when the event rate is underestimated: the Look AHEAD (Action for Health in Diabetes) Study

Frederick L Brancati et al. Clin Trials. 2012 Feb.

Abstract

The Look AHEAD (Action for Health in Diabetes) Study is a long-term clinical trial that aims to determine the cardiovascular disease (CVD) benefits of an intensive lifestyle intervention (ILI) in obese adults with type 2 diabetes. The study was designed to have 90% statistical power to detect an 18% reduction in the CVD event rate in the ILI Group compared to the Diabetes Support and Education (DSE) Group over 10.5 years of follow-up. The original power calculations were based on an expected CVD rate of 3.125% per year in the DSE group; however, a much lower-than-expected rate in the first 2 years of follow-up prompted the Data and Safety Monitoring Board (DSMB) to recommend that the Steering Committee undertake a formal blinded evaluation of these design considerations. The Steering Committee created an Endpoint Working Group (EPWG) that consisted of individuals masked to study data to examine relevant issues. The EPWG considered two primary options: (1) expanding the definition of the primary endpoint and (2) extending follow-up of participants. Ultimately, the EPWG recommended that the Look AHEAD Steering Committee approve both strategies. The DSMB accepted these modifications, rather than recommending that the trial continue with inadequate statistical power. Trialists sometimes need to modify endpoints after launch. This decision should be well justified and should be made by individuals who are fully masked to interim results that could introduce bias. This article describes this process in the Look AHEAD study and places it in the context of recent articles on endpoint modification and recent trials that reported endpoint modification.

Trial registration: ClinicalTrials.gov NCT00017953.

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Figures

Figure 1
Figure 1
Timeline of events and key study dates. The Look AHEAD study. EPWG: Endpoint Working Group; AHA: American Heart Association; DSMB: Data and Safety Monitoring Board; NIDDK: National Institute of Diabetes, Digestive and Kidney Diseases; AHEAD: Action for Health in Diabetes.
Figure 2
Figure 2
Look AHEAD adjudication criteria for hospitalized angina. AHEAD: Action for Health in Diabetes.
See this image and copyright information in PMC

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