Re-Evaluating the Inhibition of Stress Erosions: Gastrointestinal Bleeding Prophylaxis In ICU

Stress Ulcer Prophylaxis Clinical Trial

— REVISE  

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02290327
• Other study ID #: REV-06MAR14
• Status: Completed
• Phase: Phase 3
• First received: October 31, 2014
• Last updated: February 5, 2016
• Start date: May 2015

Study information

• Verified date: February 2016
• Source: McMaster University
• Contact: n/a
• Is FDA regulated: No
• Health authority: Canada: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

The purpose of the this Pilot Trial is to determine the feasibility of conducting a large randomized controlled trial (RCT), that aims to examine the efficacy and safety of using pantoprazole compared to placebo for stress ulcer prophylaxis in critically ill mechanically ventilated patients in the ICU.

Description:

Background For almost 4 decades, stress ulcer prophylaxis to prevent upper gastrointestinal (GI) bleeding has been standard of care in the ICU. The 1999 American Society of Health-System Pharmacists guidelines recommend stress ulcer prophylaxis for the critically ill. The 2013 Surviving Sepsis Campaign guidelines recommend stress ulcer prophylaxis for patients mechanically ventilated for > 48 hours or with coagulopathy. However, GI bleeding rates are significantly lower today than in the past, potentially reduced by optimal resuscitation and early enteral nutrition. Additional concerns include whether acid suppression has any impact on bleeding at all, and whether acid suppression does more harm than good, given the apparent increased risk of more common, serious problems of pneumonia and Clostridium difficile infection. Further, prophylaxis has become almost universal rather than targetted at patients at risk of GI bleeding. Thus, clinicians and investigators globally are calling for a re-evaluation of acid suppression with a large Randomized controlled trial (RCT) comparing proton pump inhibitor against placebo.

Objectives To determine the feasibility of performing a large RCT to investigate whether intravenously administered pantoprazole, compared to placebo prevents clinically important gastrointestinal bleeding in mechanically ventilated patients in the intensive care unit (ICU), based on 3 outcomes: the informed consent rate; recruitment rate, and protocol adherence

Design Prospective, concealed, stratified, randomized, blinded, multicentre trial.

Setting Canadian and Saudi medical-surgical university-affiliated ICUs.

Methods Patients will be stratified by center, and medical/surgical/trauma status, then will be randomized to intervention or placebo using an allocation ratio of 1:1 and undisclosed variable block sizes. Research pharmacists will prepare identical 100ml mini-bags of the pantoprazole 40mg or placebo with blinded research labels for once daily dosing.

Followup Research Coordinators in the ICU will review all patients daily, where most of the trial data will be collected. This will involve baseline data (e.g., demographics, illness severity, advanced life support), and daily data (e.g., study medication administered and reasons why not administered), other relevant medications and co-interventions that might influence bleeding, ventilator associated pneumonia (VAP) or Clostridium difficile outcomes (e.g., enteral nutrition, antibiotics, anticoagulants, possible VAP prevention strategies including probiotics), laboratory, microbiology, transfusion or radiology documentation to help adjudicate the outcomes of clinically important and overt bleeding, VAP, and Clostridium difficile infection, and mortality. We do not anticipate any loss to follow up; we expect to have complete follow up of patients in the ICU.

Patients will be followed for primary and secondary outcomes during their ICU stay on daily basis. Once patients are discharged from the ICU, they will no longer be followed daily; only duration of hospital stay and vital status at hospital discharge will be obtained.

A secure web-based central randomization method will ensure site-specific stratified allocation tables. When the patient is identified as eligible and consent is obtained by Research Coordinator, the Research Pharmacist will take the assignment and dispense study drug accordingly.

Relevance Results of the REVISE Pilot Trial will provide key feasibility and safety data which will serve to plan a larger multicentre trial of pantoprazole versus placebo for stress ulcer prophylaxis in mechanically ventilated critically ill patients.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 91
• Est. primary completion date: January 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Adults = 18 years

2. Anticipated invasive mechanical ventilation of =48 hours, determined by the intensivist

Exclusion Criteria:

1. Invasive mechanical ventilation >72 hours before randomization.

2. Patients who must receive PPI due to active bleeding or increased bleeding risk (e.g., patients with acute GI bleeding, recent severe esophagitis, Zollinger Ellison syndrome, Barrett's esophagus, peptic ulcer bleeding within 8 weeks [mild dyspepsia or mild gastroesophageal reflex disease will not be excluded])

3. Receiving dual antiplatelet therapy aspirin and clopidogrel prior to randomization

4. Palliative care or decision to withdraw advanced life support (patients with a decision to forgo cardiopulmonary resuscitation will not be excluded)

5. Previous enrolment in this or a related trial

6. Pregnancy

7. Physician, patient, or substitute decision maker (SDM) declines

8. Two or more 'daily doses' of prophylaxis with H2RA or PPI (one day of a single PPI dose is not an exclusion criterion if once daily dosing of PPI prophylaxis was administered; one day of bid [twice daily] dosing of an H2RA is not an exclusion criterion if twice daily H2RA prophylaxis was administered; one day of tid [thrice daily] dosing of an H2RA is not an exclusion criterion if thrice daily H2RA prophylaxis was administered).

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Stress Ulcer Prophylaxis

Intervention

Drug:
• Pantoprazole
Proton pump inhibitor
• Placebo
50 ml of 0.9% normal saline

Locations

Country	Name	City	State
Australia	Royal Adelaide	Adelaide
Canada	Queen Elizabeth II	Halifax	Nova Scotia
Canada	Jurvinski Hospital	Hamilton	Ontario
Canada	St. Joseph's HealthCare Hospital	Hamilton	Ontario
Canada	Kingston General Hospital	Kingston	Ontario
Canada	Ottawa Civic Hospital	Ottawa	Ontario
Canada	Ottawa General Hospital	Ottawa	Ontario
Canada	Mount Sinai Hospital	Toronto	Ontario
Canada	St Michael's Hospital	Toronto	Ontario
Saudi Arabia	Dammam University	Dammam	Eastern Province

Sponsors (2)

Lead Sponsor	Collaborator
McMaster University	The Physicians' Services Incorporated Foundation

Countries where clinical trial is conducted

Australia,  Canada,  Saudi Arabia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Consent Rate	This will be calculated as the overall proportion of consented patients of those substitute decision makers (SDMs) approached (with 95% CI).; A successful consent rate will be defined as =70% of SDMs approached to consent.	12 months	No
Primary	Recruitment Rate	A successful recruitment rate will be defined as achieving enrolment of 90 patients, conventionally expressed as 2 patients per center per month over 12 months.	12 months	No
Primary	Protocol Adherence	This will be calculated as doses of study drug administered as a proportion of doses prescribed and associated 95% confidence intervals.; A successful adherence will be defined as =80% of prescribed drugs being administered.	12 months	No
Secondary	Clinically important upper gastrointestinal bleeding		During ICU stay (expected average is 10 days)	No
Secondary	Ventilator associated pneumonia		During ICU stay (expected average is 10 days)	Yes
Secondary	Mortality		During ICU and hospital stay (expected average ICU stay is 10 days, expected average hospital stay is 30 days)	No
Secondary	Clostridium Difficile infection		During ICU stay (expected average ICU stay is 10 days)	Yes