Central adjudication of serious events did not affect trial's safety results: data from the Efficacy of Nitric Acid in Stroke (ENOS trial)

Godolphin, Peter; Montgomery, Alan; Woodhouse, Lisa; Bereczki, Daniel; Berge, Eivind; Collins, Ronan; Diez-Tejedor, Exuperio; Gommans, John; Lees, Kennedy; Ozturk, Serefnur; Phillips, Stephen; Pocock, Stuart; Prasad, Kameshwar; Szatmari, Szabolca; Wang, Yongjun; Bath, Philip; Sprigg, Nikola; ENOS Investigators

Abstract

Background and Purpose: Central adjudication of serious adverse events (SAEs) can be undertaken in clinical trials, especially for open-label studies where outcome assessment may be at risk of bias. This study explored the effect of central adjudication of SAEs on the safety results of the Efficacy of Nitric Oxide in Stroke (ENOS) Trial.

Methods: ENOS assigned patients with acute stroke at random to receive either transdermal glyceryl trinitrate (GTN) or no GTN and to Stop or Continue previous antihypertensive treatment. SAEs were reported by local investigators who were not blinded to treatment allocation. Central adjudicators blinded to treatment allocation, reviewed the investigators reports and used evidence available to confirm or re-categorise the classification of event, likely causality, diagnosis and expectedness of event.

Results: Of 4011 patients enrolled in ENOS, 1473 SAEs were reported by local investigators; this was reduced to 1444 after the review by adjudicators, with 29 re-classified as not an SAE. There was fair agreement between investigators and adjudicators regarding likely causality, with 808 agreements and 644 disagreements (56% crude agreement, weighted kappa, κ = 0.31). Agreement increased upon dichotomisation of the causality categories, with 1432 agreements and 20 disagreements (99% crude agreement, kappa = 0.54). Repeating the main trial safety analysis with investigator reported events showed that adjudication had no effect on the main trial safety conclusions.

Conclusions: In a large trial, with many SAEs reported, central adjudication of these events did not affect trial conclusions. This suggests that adjudication of SAEs in a clinical trial where the intervention already has a well-established safety profile may not be necessary. Potential efficiency savings (financial, logistical) can be made through not adjudicating SAEs.

Citation

Godolphin, P., Montgomery, A., Woodhouse, L., Bereczki, D., Berge, E., Collins, R., …ENOS Investigators. (2018). Central adjudication of serious events did not affect trial's safety results: data from the Efficacy of Nitric Acid in Stroke (ENOS trial). PLoS ONE, 13(11), Article e0208142. https://doi.org/10.1371/journal.pone.0208142

• Journal Article Type: Article
• Acceptance Date: Nov 14, 2018
• Online Publication Date: Nov 26, 2018
• Publication Date: Nov 26, 2018
• Deposit Date: Nov 15, 2018
• Publicly Available Date: Nov 15, 2018
• Journal: PLos One
• Electronic ISSN: 1932-6203
• Publisher: Public Library of Science
• Peer Reviewed: Peer Reviewed
• Volume: 13
• Issue: 11
• Article Number: e0208142
• DOI: https://doi.org/10.1371/journal.pone.0208142
• Public URL: https://nottingham-repository.worktribe.com/output/1268010
• Publisher URL: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0208142
• Contract Date: Nov 15, 2018