Effects of the endpoint adjudication process on the results of a randomised controlled trial: the ADVANCE trial

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, 2 × 2 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% (-1 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.

Conflict of interest statement

Competing Interests: The authors have read the journal's policy and have the following conflicts: SZ reports being an advisory board member for MSD, Novo Nordisk, Sanofi Aventis, Boehringer Ingelheim, Astra Zeneca, and BMS, and receiving lecture fees from Servier, MSD, Novartis, Novo Nordisk, Boheringer Ingelheim, Sanofi Aventis, Astra Zeneca and BMS. CP reports being an advisory board member for Amgen, Boehringer Ingelheim, MSD, Janssen Cilag, Reata and Abbott, and receiving lecture fees from MSD, Boehringer Ingelheim and BMS. MW reports receiving consulting fees from Roche and lecture fees from Servier and Sonofi Aventis. NP reports receiving grant support from Pfizer, Julius Clinical Research, and Novartis, and lecture fees from Gilead, Daiichi-Sankyo, Servier, Takeda, Pfizer, Novo-Nordisk, Roche, Boehringer Ingelheim, Medtronic, and Jannsen. SM reports being an advisory board member for Servier, Pfizer, and Novartis, and receiving lecture fees from Servier and Pfizer and grant support from Servier, Pfizer, and Novartis. JC reports being a member of an advisory board for Servier and receiving lecture fees and grant support from Servier. BN reports being a board member of Roche, Takeda, and Pepsico and receiving lecture fees from Amgen, AstraZeneca, GlaxoSmithKline, Novartis, Pepsico, Pfizer, Pharmacy Guild of Australia, Sanofi Aventis, Servier, and Tanabe. This study was partly funded by Servier. There are no patents, products in development, or marketed products products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Figures

Figure 1. Enrolment, randomisation, and follow-up of study participants.

A total of 11140 patients were randomly assigned, in a 2x2 factorial design, to active blood pressure lowering treatment with perindopril-indapamide or matching placebo, and to a gliclazide-based intensive glucose control strategy or a standard glucose control strategy.

Figure 2. Effects of endpoint adjudication on the results of ADVANCE blood pressure lowering arm.

Effects of blood pressure lowering treatment on the risks of clinical outcomes were examined based on diagnoses reported by the site investigators (SI) and those assigned by the endpoint adjudication committee (EPAC). Centers of the boxes are placed at the estimates of effect; areas of the boxes are proportional to the reciprocal of the variance of the estimates. Horizontal lines represent 95% confidence intervals (CI).

Figure 3. Effects of endpoint adjudication on the results of ADVANCE blood glucose control arm.

Effects of intensive glucose control on the risks of clinical outcomes were examined based on diagnoses reported by the site investigators (SI) and those assigned by the endpoint adjudication committee (EPAC). Centers of the boxes are placed at the estimates of effect; areas of the boxes are proportional to the reciprocal of the variance of the estimates. Horizontal lines represent 95% confidence intervals (CI).