Effects of the Endpoint Adjudication Process on the Results of a Randomised Controlled Trial: The ADVANCE Trial
Author(s)
Type
Journal Article
Abstract
Background: Endpoint adjudication committees (EPAC) are widely used in clinical trials. The aim of the present analysis is to
assess the effects of the endpoint adjudication process on the main findings of the ADVANCE trial (Trial registration:
ClinicalTrials.gov NCT00145925).
Methods and Findings: The ADVANCE trial was a multicentre, 262 factorial randomised controlled trial of blood pressure
lowering and intensive blood glucose control in 11140 patients with type 2 diabetes. Primary outcomes were major
macrovascular (nonfatal myocardial infarction, nonfatal stroke and cardiovascular death) and microvascular (new or
worsening nephropathy and retinopathy) events. Suspected primary outcomes were initially reported by the investigators
at the 215 sites with subsequent adjudication by the EPAC. The EPAC also adjudicated upon potential events identified
directly by ongoing screening of all reported events. Over a median follow-up of 5 years, the site investigators reported one
or more primary outcomes among 2443 participants. After adjudication these events were confirmed for 2077 (85%) with 48
further events added through the EPAC-led database screening process. The estimated relative risk reductions (95%
confidence intervals) in the primary outcome for the blood pressure lowering comparison were 8% (21 to 15%) based on
the investigator-reported events and 9% (0 to 17%) based on the EPAC-based events (P for homogeneity = 0.70). The
corresponding findings for the glucose comparison were 8% (1 to 15%) and 10% (2% to 18%) (P for homogeneity = 0.60).
The effect estimates were also highly comparable when studied separately for macrovascular events and microvascular
events for both comparisons (all P for homogeneity.0.6).
Conclusions: The endpoint adjudication process had no discernible impact on the main findings in ADVANCE. These data
highlight the need for careful consideration of the likely impact of an EPAC on the findings and conclusions of clinical trials
prior to their establishment.
assess the effects of the endpoint adjudication process on the main findings of the ADVANCE trial (Trial registration:
ClinicalTrials.gov NCT00145925).
Methods and Findings: The ADVANCE trial was a multicentre, 262 factorial randomised controlled trial of blood pressure
lowering and intensive blood glucose control in 11140 patients with type 2 diabetes. Primary outcomes were major
macrovascular (nonfatal myocardial infarction, nonfatal stroke and cardiovascular death) and microvascular (new or
worsening nephropathy and retinopathy) events. Suspected primary outcomes were initially reported by the investigators
at the 215 sites with subsequent adjudication by the EPAC. The EPAC also adjudicated upon potential events identified
directly by ongoing screening of all reported events. Over a median follow-up of 5 years, the site investigators reported one
or more primary outcomes among 2443 participants. After adjudication these events were confirmed for 2077 (85%) with 48
further events added through the EPAC-led database screening process. The estimated relative risk reductions (95%
confidence intervals) in the primary outcome for the blood pressure lowering comparison were 8% (21 to 15%) based on
the investigator-reported events and 9% (0 to 17%) based on the EPAC-based events (P for homogeneity = 0.70). The
corresponding findings for the glucose comparison were 8% (1 to 15%) and 10% (2% to 18%) (P for homogeneity = 0.60).
The effect estimates were also highly comparable when studied separately for macrovascular events and microvascular
events for both comparisons (all P for homogeneity.0.6).
Conclusions: The endpoint adjudication process had no discernible impact on the main findings in ADVANCE. These data
highlight the need for careful consideration of the likely impact of an EPAC on the findings and conclusions of clinical trials
prior to their establishment.
Date Issued
2013-02-04
Date Acceptance
2013-01-02
Citation
PLOS One, 2013, 8 (2)
ISSN
1932-6203
Publisher
Public Library of Science
Journal / Book Title
PLOS One
Volume
8
Issue
2
Copyright Statement
© 2013 Hata et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
use, distribution, and reproduction in any medium, provided the original author and source are credited.
License URL
Sponsor
Imperial College Healthcare NHS Trust- BRC Funding
National Institute for Health Research
Grant Number
RDC02 79560
n/a
Subjects
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
MULTIDISCIPLINARY SCIENCES
CLINICAL EVENTS COMMITTEE
MYOCARDIAL-INFARCTION
OUTCOMES
INVESTIGATORS
PERINDOPRIL
DEATH
MODE
NEED
Publication Status
Published
Article Number
e55807