Introduction Economic evaluations in healthcare can guide practice and inform policy. The objective of this paper is to present the protocol for a health economic evaluation comparing the cost-effectiveness of prophylactic treatment using pantoprazole 40 mg IV daily compared to no pantoprazole to prevent upper gastrointestinal (GI) bleed among invasively ventilated patients.

Methods and analysis This is an economic evaluation conducted alongside the Re-Evaluating the Inhibition of Stress Erosions trial. The primary outcome is the incremental cost per clinically-important upper GI bleed prevented. Secondary outcomes include the incremental cost of a patient-important upper GI bleed prevented. We will explore the incremental cost per secondary trial outcome (e.g., ventilator-associated pneumonia, Clostridioides difficile infection, and patient-important GI bleeding); and incremental cost per life gained. The analysis will be conducted from a Canadian public healthcare payer’s perspective over a time horizon of ICU admission to hospital discharge or death. The study protocol was developed following good practice guidelines of Canada’s Drug Agency (CDA) and the Professional Society for Health Economics and Outcomes Research (ISPOR).

Ethics and dissemination The trial was approved by the Hamilton Integrated Research Ethics Board and at each participating institution; this economic evaluation is currently under review for ethics approval. Given widespread daily use of proton pump inhibitors for critically ill patients, the results of this economic evaluation will be of high relevance to patients, family members, physicians, pharmacists, policymakers and guideline developers. Integrated knowledge translation will involve periodic progress reports to collaborators. End-of-study knowledge translation will include rounds, videoconferences, abstracts and slide-decks for ICU quality councils and healthcare organizations, and open-access publications. Patient and Family Partners will co-create lay language summaries for traditional and social media to help inform all stakeholders.

The authors have no conflicts of interest to declare. However, DC, VL, DHA, BR, RF, NZ, and FX were involved in the REVISE trial in some capacity.

NCT03374800

E-REVISE is funded by a grant from Hamilton Academic Health Sciences Organization (HAH-24-003). The REVISE trial was funded by peer-reviewed grants (Canadian Institutes of Health Research 201610PJT-378226-PJT-CEBA-18373, Canadian Institutes of Health Research 202207CL3-492565-CTP-CEBA-19215), and the Canadian Institutes of Health Research Accelerating Clinical Trials Fund (ACT Consortium RFA-1 Application), as well as the Hamilton Academy of Health Sciences Organization (HAH-22-009), and funds from St. Joseph's Healthcare Hamilton and McMaster University. The National Health and Medical Research Council of Australia grant (GNT1124675) funded enrolment in Australia. REVISE was approved by the National Institute for Health Research (NIHR) in the UK as a Portfolio Study (CPMS ID 45782), eligible for support from the NIHR Clinical Research Network (https://www.nihr. ac.uk/researchers/collaborations-services-and-support-for-your-research/run- your-study/crn-portfolio.htm). Neither the trial nor the economic evaluation received funds from the commercial or private sector. The funders/sponsors had no role in the conception, design, conduct, oversight, analysis, interpretation, write-up, review or approval of the manuscript, or decision to submit the manuscript for publication.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

All participating centres received research ethics approval before initiation by hospital, region or country, including, but not limited to Australia: Northern Sydney Local Health District Human Research Ethics Committee and Mater Misericordiae Ltd Human Research Ethics Committee; Brazil: Comissao Nacional de Etica em Pesquisa; Canada: Hamilton Integrated Research Ethics Board; Kuwait: Ministry of Health Standing Committee for Coordination of Health and Medical Research; Pakistan: Maroof Institutional Review Board; Saudi Arabia: Ministry of National Guard Health Affairs Institutional Review Board: United Kingdom: Hampshire B Research Ethics Committee; United States: Institutional Review Board of the Nebraska Medical Centre. This economic evaluation is under review at the lead Research Ethics Board: Hamilton Integrated Research Ethics Board.

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