Assessment of the End Point Adjudication Process on the Results of the Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) Trial: A Secondary Analysis

Abstract

Importance: Debate continues about the value of event adjudication in clinical trials and whether independent centralized assessments improve reliability and validity of study results in masked randomized trials compared with local, investigator-assessed end points.

Objective: To assess the results of the adjudicated end point process in the Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial by comparing end points assessed by local site investigators with centrally adjudicated end points.

Design, setting, and participants: This is an ad hoc secondary analysis of a randomized, double-blind clinical trial comparing safety and effectiveness of clopidogrel bisulphate plus aspirin vs placebo plus aspirin. Patients received either 600 mg of clopidogrel bisulphate on day 1, then 75 mg per day through day 90 plus 50 to 325 mg of aspirin per day, or the same range of dosages of placebo plus aspirin. Investigators reported all potential end points; independent masked adjudicators were randomly assigned to review using definitions specified in the study protocol. This was a multicenter study; 269 international sites in 10 countries enrolled from May 28, 2010, to December 19, 2017. The study enrolled 4881 patients 18 years or older with transient ischemic attack or minor acute ischemic stroke within 12 hours of symptom onset and followed for 90 days from randomization; last follow-up was completed in March 2018.

Main outcomes and measures: Independent adjudicators external to the study and masked to study treatment assignment adjudicated 467 primary and secondary effectiveness outcomes and major and minor bleeding events, including the primary composite end point, which was the risk of a composite of major ischemic events at 90 days, defined as ischemic stroke, myocardial infarction, or death from an ischemic vascular event. The primary safety end point was major hemorrhage. All components of the primary and safety outcomes were adjudicated.

Results: In this secondary analysis of an international randomized clinical trial, a total of 269 sites worldwide randomized 4881 patients (median age, 65.0 years; interquartile range, 55-74 years); 55.0% were male. The primary results have been published previously. The hazard ratios for clopidogrel plus aspirin vs placebo plus aspirin for the primary composite end point were 0.75 (95% CI, 0.59-0.95) for adjudicator-assessed events and 0.76 (95% CI, 0.60-0.95) for investigator-assessed events. Agreement between adjudicator and investigator assessments was 90.7%. The hazard ratios for clopidogrel plus aspirin vs placebo plus aspirin for the primary safety end point were 2.32 (95% CI, 1.10-4.87) for adjudicator-assessed events and 2.58 (95% CI, 1.19-5.58) for investigator-assessed events, with an agreement rate of 77.5%.

Conclusions and relevance: Independent end point adjudication did not substantially alter estimates of the primary treatment effectiveness in the POINT trial.

Trial registration: ClinicalTrials.gov identifier: NCT00991029.

Conflict of interest statement

Conflict of Interest Disclosures: Ms Farrant reported receiving research grant support from the National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS) for the Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial and from AstraZeneca for conducting the SOCRATES trial. Dr Easton reported receiving research grant support from the NIH/NINDS as coprincipal investigator for the POINT trial; receiving support from Boehringer Ingelheim as a consultant for the planning, conduct, and publication of the results of the RE-SPECT ESUS trial; participating in planning and conduct of the SOCRATES trial; that his institution received research grant support from AstraZeneca; receiving nonfinancial support from Sanofi; and serving as a consultant for Sanofi at an advisory board meeting. Dr Adelman reported receiving research grant support from the NIH/NINDS for the POINT trial, receiving funding as an adjudicator for the SOCRATES trial, receiving salary support as the chair of the adjudications committee for the POINT trial, receiving grants from the NIH, and receiving personal fees from the University of California, San Francisco. Dr Cucchiara reported receiving research grant support from the NIH/NINDS for the POINT trial, receiving funding as an adjudicator for the SOCRATES trial, and receiving grants from the NINDS. Dr Barsan reported receiving salary support from the NIH/NINDS for the POINT trial and receiving salary support from the NIH/NINDS as principal investigator for the Neurologic Emergencies Treatment Trials (NETT) network, as coinvestigator for the SHINE trial, and as coinvestigator for the ESETT trial. Ms Tillman reported receiving grants from the Medical University of South Carolina. Dr Elm reported receiving research grant support from the NIH/NINDS for the POINT trial. Dr Kim reported receiving research grant support from the NIH/NINDS as coprincipal investigator for the POINT trial, support from Neuravi as a member of the data and safety monitoring board for the ARISE-2 trial, and grants from SanBio. Dr Lindblad reported serving as president and CEO of The Emmes Corporation (a for-profit contract research organization) and receiving research grant support from the NIH/NINDS for the POINT trial. Dr Palesch reported receiving grant support from the NIH/NINDS for the POINT trial. Dr Zhao reported receiving salary support from the NIH/NINDS for the POINT trial. Mr Pauls reported receiving salary support from the NIH/NINDS for the POINT trial. Dr Walsh reported receiving salary support from the NIH/NINDS for the POINT trial. Dr Martí-Fàbregas reported receiving salary support from the NIH/NINDS for the POINT trial. Dr Bernstein reported receiving salary support from the NIH/NINDS for the POINT trial and receiving grants or personal fees from Boehringer Ingleheim, Bristol-Myers Squibb, Medtronic, Pfizer, Abbott, AbbVie, and Amgen. Dr Johnston reported receiving research grant support from the NIH/NINDS as principal investigator for the POINT trial, serving as a consultant to AstraZeneca during planning of the SOCRATES and THALES trials (his institution received research support for their conduct), and receiving nonfinancial support from Sanofi and AstraZeneca.

Figures

Figure.. Six-Step Outcome Adjudication Module

The web-based clinical trial management system for the Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial automates the coordination of adjudication activities by controlling workflows, in real time, based on data collected. ACC indicates adjudication committee chair; ADJ, adjudicator; CEC, clinician event monitor; CRF, case report form; PM, project manager; Q, question; S, step; and SAE, serious adverse event.