Clinical trial NCT02290327: Re-Evaluating the Inhibition of Stress Erosions: Gastrointestinal Bleeding Prophylaxis In ICU
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Stress Ulcer Prophylaxis
Keywords: Stress ulcer bleeding
proton pump inhibitors
pneumonia
clostridium difficile infection
Lead sponsor: McMaster University
Sponsor class: OTHER
Collaborators: name: The Physicians' Services Incorporated Foundation
First posted: 2014-11-14
Enrollment: 91
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief 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.

Detailed 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.

Eligibility criteria: 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).

Primary outcomes:
measure: Consent Rate
timeFrame: 12 months
measure: Recruitment Rate
timeFrame: 12 months
measure: Protocol Adherence
timeFrame: 12 months
Secondary outcomes:
measure: Clinically important upper gastrointestinal bleeding
timeFrame: During ICU stay (expected average is 10 days)
measure: Ventilator associated pneumonia
timeFrame: During ICU stay (expected average is 10 days)
measure: Mortality
timeFrame: During ICU and hospital stay (expected average ICU stay is 10 days, expected average hospital stay is 30 days)
measure: Clostridium Difficile infection
timeFrame: During ICU stay (expected average ICU stay is 10 days)
Other outcomes:
Locations:
city: Adelaide
country: Australia
facility: Royal Adelaide
city: Halifax
country: Canada
facility: Queen Elizabeth II
state: Nova Scotia
city: Hamilton
country: Canada
facility: St. Joseph's HealthCare Hospital
state: Ontario
city: Hamilton
country: Canada
facility: Jurvinski Hospital
state: Ontario
city: Kingston
country: Canada
facility: Kingston General Hospital
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Civic Hospital
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa General Hospital
state: Ontario
city: Toronto
country: Canada
facility: Mount Sinai Hospital
state: Ontario
city: Toronto
country: Canada
facility: St Michael's Hospital
state: Ontario
city: Dammam
country: Saudi Arabia
facility: Dammam University
state: Eastern Province
Study officials:
affiliation: McMaster University
name: Waleed Alhazzani, MD,FRCPC,MSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: Alhazzani W, Guyatt G, Marshall JC, Hall R, Muscedere J, Lauzier F, Thabane L, Alshahrani M, English SW, Arabi YM, Deane AM, Karachi T, Rochwerg B, Finfer S, Daneman N, Zytaruk N, Heel-Ansdell D, Cook D, Of OB. Re-evaluating the Inhibition of Stress Erosions (REVISE): a protocol for pilot randomized controlled trial. Ann Saudi Med. 2016 Nov-Dec;36(6):427-433. doi: 10.5144/0256-4947.2016.427.