Re-EValuating the Inhibition of Stress Erosions (REVISE) Trial

NCT03374800 | Completed Phase 3 DMC FDA Drug

• 1 other identifier: CCT38473
• Study Type: interventional
• Target: 4,800
• Locations: 8 countries
• Sites: 67

Brief Summary

Patients who are critically ill in the in the Intensive Care Unit (ICU), especially those who need a breathing machine, can develop ulcers in the stomach that bleed. To prevent bleeding, many such patients around the world receive a drug called pantoprazole that decreases acid production. However, today, compared to decades ago, critically ill patients rarely develop upper gastrointestinal bleeding. This decrease is likely due to modern medicine, better resuscitation and earlier feeding. There may also be harms associated with pantoprazole and other drugs that reduce acid levels in the stomach including lung infections (pneumonia) and bowel infections (Clostridioides difficile). Studies in this area are old and of modest quality. Therefore, it is difficult to know whether pantoprazole does decrease stomach bleeding these days, or whether the possible harms of lung and bowel infections are actually more common and more serious problems. The goal of this international study is to determine if, in critically ill patients using breathing machines, the use of pantoprazole is effective in preventing bleeding from stomach ulcers or whether it causes more problems such as lung infection (pneumonia) and bowel infection (Clostridioides difficile), or whether pantoprazole has no effect at all. Whether the harms are worth the benefits, and whether the benefits are worth the costs, will be determined by an economic analysis to inform patients, families, clinicians, and healthcare systems globally.

Conditions

Gastrointestinal Hemorrhage (Clinically Important, Upper)

Outcome Measures

Primary Outcomes (2)

• Rate of clinically important upper gastro-intestinal bleeding

  Clinically important upper GI bleeding requires the presence of overt GI bleeding which is defined as one of the following; * Hematemesis * Overt nasogastric bleeding * Melena * Hematochezia PLUS (in the absence of another cause), at least one of the following in the 24 hours following overt GI bleeding: * Haemodynamic change defined as a spontaneous decrease in invasively monitored mean arterial pressure or non-invasive systolic or diastolic blood pressure of 20 mmHg or more or an orthostatic increase in pulse rate of 20 beats/minute and a decrease in systolic blood pressure of 10 mmHg, with or without vasopressor initiation, or increase * Vasopressor initiation * A decrease in haemoglobin of ≥ 20 g/l in a 24-hour period or less, * Transfusion of ≥2 units of packed red blood cells within 24 hours of bleeding to maintain stable haemoglobin or haemodynamics, or * Need for therapeutic intervention (e.g. angiography, surgery or endoscopic treatment of bleeding).

  90 days (In ICU or resulting in ICU readmission, censored at 90 days after randomization)

• Primary Safety Outcome: 90 Day Mortality

  Mortality status at day 90 post randomization

  90 days post randomization

Secondary Outcomes (6)

• Rate of ventilator associated pneumonia (VAP) in ICU

  90 Days (while in ICU,censored at 90 days after randomization)

• Rate of Clostridioides difficile associated infection

  90 days (during the index hospital admission, censored at 90 days)

• New initiation of treatment with renal replacement therapy in ICU

  90 Days (In the ICU, censored at 90 days)

• Rate of all-cause-in-hospital mortality

  While in hospital, censored at 90 days after randomization

• Rate of ICU mortality

  While in the ICU, censored at 90 days after randomization

Other Outcomes (5)

• Total units of red blood cells transfused in the first 14 days of ICU stay

  Censored at 14 days after randomization

• Peak serum creatinine concentration in ICU

  Censored at 90 days after randomisation

• Duration of mechanical ventilation (days)

  Censored at 90 days after randomisation

Study Arms (2)

Placebo (0.9% saline)

PLACEBO COMPARATOR

Withholding Stress ulcer prophylaxis (intravenous 0.9% saline as placebo)

Drug: Placebo (0.9% saline)

Stress Ulcer Prophylaxis (Pantoprazole)

ACTIVE COMPARATOR

pantoprazole 40mg powder for injection reconstituted with 0.9% saline

Drug: Pantoprazole

Interventions

Placebo (0.9% saline) DRUG

normal saline

Also known as: normal saline; NaCl 0.9%

Placebo (0.9% saline)

Pantoprazole DRUG

40 mg powder for injection reconstituted with 0.9% saline

Also known as: Protonix

Stress Ulcer Prophylaxis (Pantoprazole)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18 years or more.
• Receiving invasive mechanical ventilation in an ICU and in the opinion of the treating ICU physician mechanical ventilation will not be discontinued before the end of the day after tomorrow.

You may not qualify if:

• The treating clinician considers either Pantoprazole or placebo are indicated or contraindicated for this patient.
• Pantoprazole contraindicated for patient due to local product information;
• Australia/New Zealand;
• being treated with HIV protease inhibitors atazanavir or nelfinavir
• being treated with high dose methotrexate (i.e., greater than 300 mg as part of a chemotherapy regimen).
• documented cirrhosis or severe liver disease (for example as indicated by an INR greater than 5.0 due to underlying liver disease).
• Canada;
• being treated with rilpivirine or atazanavir
• patients who are hypersensitive to pantoprazole, substituted benzimidazoles, or to any ingredient in the formulation
• Patients in whom a PPI or histamine 2 receptor antagonist (H2RA) is indicated due to active bleeding or increased bleeding risk, defined as patients with acute GI bleeding, severe oesophagitis or peptic ulcer disease within the previous 8 weeks, Zollinger Ellison syndrome, Barrett's oesophagus or any previous admission to hospital because of upper GI bleeding (patients receiving PPIs for mild dyspepsia or mild gastroesophageal reflux disease or an uncertain indication are not excluded).
• Received invasive mechanical ventilation during this ICU admission for 72 hours or more.
• Patients who have received more than 24 hours treatment (i.e., more than one daily dose equivalent) with a PPI or H2RA during this ICU admission.
• Being treated with or need for dual anti-platelet therapy.
• Admitted for palliative care or the ICU physician is not committed to continuing life-sustaining therapies at the time of enrolment.
• Known or suspected pregnancy.

Sponsors & Collaborators

• McMaster University: lead
• Canadian Institutes of Health Research (CIHR): collaborator
• Canadian Critical Care Trials Group: collaborator
• Australian and New Zealand Intensive Care Society Clinical Trials Group: collaborator
• National Health and Medical Research Council, Australia: collaborator

Study Sites (67)

University of Nebraska - Nebraska Medical Center

Omaha, Nebraska, 987400, United States

Location

Bankstown-Lidcombe Hospital

Bankstown, New South Wales, 2200, Australia

Location

Blacktown Hospital

Blacktown, New South Wales, 2148, Australia

Location

Sutherland Hospital

Caringbah, New South Wales, 2050, Australia

Location

Gosford Hospital

Gosford, New South Wales, 2250, Australia

Location

Nepean Hospital

Kingswood, New South Wales, 2747, Australia

Location

St George Hospital

Kogarah, New South Wales, 2217, Australia

Location

Royal North Shore Hospital

Saint Leonards, New South Wales, 2050, Australia

Location

Wollongong Hospital

Wollongong, New South Wales, 2500, Australia

Location

Royal Brisbane Womens Hospital

Brisbane, Queensland, 4029, Australia

Location

Ipswich Hospital

Ipswich, Queensland, 4305, Australia

Location

Mater Hospital

South Brisbane, Queensland, 4101, Australia

Location

Princess Alexandra Hospital

Woolloongabba, Queensland, 4102, Australia

Location

Royal Adelaide Hospital

Adelaide, South Australia, 5000, Australia

Location

Bendigo Health

Bendigo, Victoria, 3550, Australia

Location

Geelong University Hospital

Geelong, Victoria, 3220, Australia

Location

Austin Hospital

Heidelberg, Victoria, 3084, Australia

Location

Alfred Hospital

Melbourne, Victoria, 3004, Australia

Location

Royal Melbourne Hospital

Melbourne, Victoria, 3050, Australia

Location

Epworth Hospital

Melbourne, Victoria, 3121, Australia

Location

Sociedade Hospitalar Angelina Caron

Campina Grande do Sul, Brazil

Location

Beneficência Social Bom Samaritano

Governador Valadares, 35044-220, Brazil

Location

Foothills Hospital

Calgary, Alberta, Canada

Location

Peter Lougheed Hospital

Calgary, Alberta, Canada

Location

University of Alberta Hospital

Edmonton, Alberta, T6G 2B7, Canada

Location

Nanaimo Regional General Hospital

Nanaimo, British Columbia, V9S 2B7, Canada

Location

Royal Columbian Hospital

New Westminster, British Columbia, V3L 3W7, Canada

Location

Vancouver General Hospital

Vancouver, British Columbia, Canada

Location

Vancouver Island Health Authority

Victoria, British Columbia, Canada

Location

St. Boniface Hospital

Winnipeg, Manitoba, R2H 2A6, Canada

Location

Health Science Center Winnipeg

Winnipeg, Manitoba, R3A 1R9, Canada

Location

Grace Hospital

Winnipeg, Manitoba, R3J 3M7, Canada

Location

Saint John Regional Hospital

Saint John, New Brunswick, E2L 4L2, Canada

Location

QEII Health Sciences Centre

Halifax, Nova Scotia, B3H 2Y9, Canada

Location

William Osler Hospital, McKenzie Health, Brampton Civic Hospital

Brampton, Ontario, L6R 3J7, Canada

Location

Brantford General Hospital

Brantford, Ontario, Canada

Location

Cambridge Memorial Hospital

Cambridge, Ontario, N1R 3G2, Canada

Location

St. Joseph's Healthcare Hamilton

Hamilton, Ontario, L9N 4A6, Canada

Location

Hamilton Health Science Center - General Hospital

Hamilton, Ontario, Canada

Location

Hamilton Health Science Center - Juravinski Hospital

Hamilton, Ontario, Canada

Location

Kingston General Hospital

Kingston, Ontario, Canada

Location

Grand River Hospital

Kitchener, Ontario, N2G 1G3, Canada

Location

London Health Science Center (LHSC) - University Hospital

London, Ontario, Canada

Location

London Health Science Center (LHSC) - Victoria Hospital

London, Ontario, Canada

Location

North York General Hospital

North York, Ontario, M2K 1E1, Canada

Location

Ottawa Health Research Institute - OHRI (General and Civic Hospital)

Ottawa, Ontario, Canada

Location

Niagara Health Services - St. Catharine's Hospital

St. Catharines, Ontario, Canada

Location

Sunnybrook Health Science Center

Toronto, Ontario, M4N 3M5, Canada

Location

Mount Sinai Hospital

Toronto, Ontario, M5G 1X5, Canada

Location

University Health Network - Toronto Western Hospital

Toronto, Ontario, M5T 2S8, Canada

Location

St. Joseph's Health Centre, Toronto

Toronto, Ontario, M6R 1B5, Canada

Location

St. Michael's Hospital

Toronto, Ontario, Canada

Location

Windsor Regional Hospital

Windsor, Ontario, N8W 1L9, Canada

Location

Centre de recherche de l'Hôtel-Dieu de Lévis

Lévis, Quebec, Canada

Location

Hôpital Maisonneuve Rosemont

Montreal, Quebec, H1T 2M4, Canada

Location

Center Hospital University Montreal (CHUM)

Montreal, Quebec, H2X 0A9, Canada

Location

Centre Universitaire de Santé McGill / McGill University Health Centre

Montreal, Quebec, Canada

Location

CIUSS du Nord de l'île de Montréal - Hôpital du Sacré-Cœur de Montréal

Montreal, Quebec, Canada

Location

McGill University Health Centre - Montreal General Hospital

Montreal, Quebec, Canada

Location

CHU de Québec-Université Laval - Hôpital Enfant-Jésus

Québec, Quebec, Canada

Location

Institut Universitaire de cardiologie et de pneumologie de Québec Laval, Quebec

Québec, Quebec, Canada

Location

Centre Hospitalier Universitaire de Sherbrooke

Sherbrooke, Quebec, J1H 5N4, Canada

Location

Regina General Hospital

Regina, Saskatchewan, S4P 0W5, Canada

Location

AL-Amiri Hospital

Kuwait City, Kuwait

Location

Maroof International Hospital

Islamabad, Pakistan

Location

King Abdulaziz Medical Center

Riyadh, 11426, Saudi Arabia

Location

Guys & St. Thomas Hospital

London, New Westminster, SE1 7EH, United Kingdom

Location

Related Publications (6)

• Humphries B, Zytaruk N, Heels-Ansdell D, Lau V, Rochwerg B, Fowler R, Yao Y, Cook DJ, Xie F. Protocol for an economic evaluation alongside the Re-Evaluating the Inhibition of Stress Erosions (E-REVISE) trial. BMJ Open. 2025 Nov 9;15(11):e106841. doi: 10.1136/bmjopen-2025-106841.

  PMID: 41213683 DERIVED

• Clarke F, Hand L, Deane A, Zytaruk N, Hardie M, Arabi Y, Al-Fares A, Heels-Ansdell D, Dechert W, Ostermann M, Watpool I, Millen T, Muscedere J, English S, Boyd G, Sibley S, Peck L, Eastwood G, Duan E, Soth M, Freitag A, Vazquez-Grande G, Slessarev M, Ball I, Geagea A, Burns K, Binnie A, Mehta S, Tsang J, Burry L, D'Aragon F, Cook D. Coenrollment in a critical care trial: Characteristics and consequences. Contemp Clin Trials. 2025 Jul;154:107938. doi: 10.1016/j.cct.2025.107938. Epub 2025 May 14.

  PMID: 40379131 DERIVED

• Cook D, Deane A, Lauzier F, Zytaruk N, Guyatt G, Saunders L, Hardie M, Heels-Ansdell D, Alhazzani W, Marshall J, Muscedere J, Myburgh J, English S, Arabi YM, Ostermann M, Knowles S, Hammond N, Byrne KM, Chapman M, Venkatesh B, Young P, Rajbhandari D, Poole A, Al-Fares A, Reis G, Johnson D, Iqbal M, Hall R, Meade M, Hand L, Duan E, Clarke F, Dionne JC, Tsang JLY, Rochwerg B, Karachi T, Lamontagne F, D'Aragon F, St Arnaud C, Reeve B, Geagea A, Niven D, Vazquez-Grande G, Zarychanski R, Ovakim D, Wood G, Burns KEA, Goffi A, Wilcox ME, Henderson W, Forrest D, Fowler R, Adhikari NKJ, Ball I, Mele T, Binnie A, Trop S, Mehta S, Morgan I, Loubani O, Vanstone M, Fiest K, Charbonney E, Cavayas YA, Archambault P, Rewa OG, Lau V, Kristof AS, Khwaja K, Williamson D, Kanji S, Sy E, Dennis B, Reynolds S, Marquis F, Lellouche F, Rahman A, Hosek P, Barletta JF, Cirrone R, Tutschka M, Xie F, Billot L, Thabane L, Finfer S; REVISE Investigators. Stress Ulcer Prophylaxis during Invasive Mechanical Ventilation. N Engl J Med. 2024 Jul 4;391(1):9-20. doi: 10.1056/NEJMoa2404245. Epub 2024 Jun 14.

  PMID: 38875111 DERIVED

• Heels-Ansdell D, Billot L, Thabane L, Alhazzani W, Deane A, Guyatt G, Finfer S, Lauzier F, Myburgh J, Young P, Arabi Y, Marshall J, English S, Muscedere J, Ostermann M, Venkatesh B, Zytaruk N, Hardie M, Hammond N, Knowles S, Saunders L, Poole A, Al-Fares A, Xie F, Hall R, Cook D. REVISE: re-evaluating the inhibition of stress erosions in the ICU-statistical analysis plan for a randomized trial. Trials. 2023 Dec 6;24(1):796. doi: 10.1186/s13063-023-07794-z.

  PMID: 38057875 DERIVED

• Deane AM, Alhazzani W, Guyatt G, Finfer S, Marshall JC, Myburgh J, Zytaruk N, Hardie M, Saunders L, Knowles S, Lauzier F, Chapman MJ, English S, Muscedere J, Arabi Y, Ostermann M, Venkatesh B, Young P, Thabane L, Billot L, Heels-Ansdell D, Al-Fares AA, Hammond NE, Hall R, Rajbhandari D, Poole A, Johnson D, Iqbal M, Reis G, Xie F, Cook DJ; Canadian Critical Care Trials Group and the Australian and New Zealand Intensive Care Society Clinical Trials Group. REVISE: Re-Evaluating the Inhibition of Stress Erosions in the ICU: a randomised trial protocol. BMJ Open. 2023 Nov 15;13(11):e075588. doi: 10.1136/bmjopen-2023-075588.

  PMID: 37968012 DERIVED

• Dennis BB, Thabane L, Heels-Ansdell D, Dionne JC, Binnie A, Tsang J, Guyatt G, Ahmed A, Lauzier F, Deane A, Arabi Y, Marshall J, Zytaruk N, Saunders L, Finfer S, Myburgh J, Muscedere J, English S, Ostermann M, Hardie M, Knowles S, Cook D; REVISE Investigators the Canadian Critical Care Trials Group. Proton pump inhibitors in critically ill mechanically ventilated patients with COVID-19: protocol for a substudy of the Re-EValuating the Inhibition of Stress Erosions (REVISE) Trial. Trials. 2023 Aug 30;24(1):561. doi: 10.1186/s13063-023-07589-2.

  PMID: 37644556 DERIVED

MeSH Terms

Conditions

Gastrointestinal Hemorrhage

Interventions

Sodium Chloride; Saline Solution; Pantoprazole

Condition Hierarchy (Ancestors)

Gastrointestinal Diseases; Digestive System Diseases; Hemorrhage; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations; 2-Pyridinylmethylsulfinylbenzimidazoles; Sulfoxides; Sulfur Compounds; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Deborah Cook, MD

  McMaster University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: blinded study drug and placebo
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: A prospective, international, multicentre, parallel group, concealed, blinded, randomized trial in critically ill invasively mechanically ventilated adults

Study Record Dates

• First Submitted: November 21, 2017
• First Posted: December 15, 2017
• Study Start: July 9, 2018
• Primary Completion: October 31, 2023
• Study Completion: January 31, 2024
• Last Updated: September 20, 2024

Record last verified: 2024-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: Anticipated availability 2025 for up to 15 years.
• Access Criteria: Following the publication of REVISE, the dataset will be used for secondary observational studies addressing additional hypothesis-driven questions (e.g., predictors of gastrointestinal bleeding). Access by REVISE investigators will follow a submitted rationale, analysis plan and approval by the Management Committee. Requests for access to the dataset by external academic investigators will be considered following a submitted rationale, analysis plan and approval by the Management Committee and research ethics boards as relevant. Only de-identified data will be provided and will be transferred via a secure web portal. Requirements will be stipulated in a pre-specified data sharing agreement with investigators which aligns with each institution including the data sharing policy of The George Institute (https://www.georgeinstitute.org.au/data-sharing-policy.)

Locations

SA (1); KU (1); BR (2); AU (19); GB (1); US (1); PA (1); CA (41)