Effects of the Endpoint Adjudication Process on the Results of a Randomised Controlled Trial: The ADVANCE Trial

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.

[1]  R. Califf,et al.  Disagreements between central clinical events committee and site investigator assessments of myocardial infarction endpoints in an international clinical trial: review of the PURSUIT study , 2001, Current controlled trials in cardiovascular medicine.

[2]  ToshiharuNinomiya,et al.  Effects of the End Point Adjudication Process on the Results of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) , 2009 .

[3]  C. Wilson.  A study in progress. , 2008, Canadian family physician Medecin de famille canadien.

[4]  S. Lehto,et al.  The impact of an end-point committee in a large multicentre, randomized, placebo-controlled clinical trial: results with and without the end-point committee's final decision on end-points. , 1999, European heart journal.

[5]  Advance Management Committee.  Study Rationale and Design of ADVANCE: Action in Diabetes and Vascular disease – preterax and diamicron MR controlled evaluation , 2001, Diabetologia.

[6]  M. Woodward,et al.  Effects of the End Point Adjudication Process on the Results of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) , 2009, Stroke.

[7]  S. Schinner,et al.  Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes , 2009 .

[8]  Anushka Patel,et al.  Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial , 2007, The Lancet.

[9]  S. Yusuf,et al.  Evaluating the benefit of event adjudication of cardiovascular outcomes in large simple RCTs , 2009, Clinical trials.

[10]  A. Hall,et al.  Validation of primary and secondary outcomes and classification of mode of death among patients with clinical evidence of heart failure after a myocardial infarction: a report from the Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. , 1993, Journal of cardiovascular pharmacology.

[11]  G. Lamas,et al.  Comparing classifications of death in the Mode Selection Trial: agreement and disagreement among site investigators and a clinical events committee. , 2006, Contemporary clinical trials.

[12]  Diederick Grobbee,et al.  Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. , 2008, The New England journal of medicine.

[13]  R. Califf,et al.  Misreporting of myocardial infarction end points: results of adjudication by a central clinical events committee in the PARAGON-B trial. Second Platelet IIb/IIIa Antagonist for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network Trial. , 2002, American heart journal.

[14]  C. Granger,et al.  Do we need to adjudicate major clinical events? , 2008, Clinical trials.

[15]  R. Califf,et al.  Systematic adjudication of myocardial infarction end-points in an international clinical trial , 2001, Current controlled trials in cardiovascular medicine.

[16]  D. Cook,et al.  Outcome assessment for clinical trials: how many adjudicators do we need? Canadian Lung Oncology Group. , 1997, Controlled clinical trials.