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

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ClinicalTrials.gov Identifier: NCT02290327
Recruitment Status : Completed
First Posted : November 14, 2014
Last Update Posted : February 8, 2016
Sponsor:
Collaborator:
The Physicians' Services Incorporated Foundation
Information provided by (Responsible Party):
McMaster University

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.

Condition or disease Intervention/treatment Phase
Stress Ulcer Prophylaxis Drug: Pantoprazole Drug: Placebo Phase 3

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 91 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Study Start Date : May 2015
Actual Primary Completion Date : January 2016

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Placebo Comparator: Placebo
50 ml of 0.9% Normal Saline Intravenously once daily
Drug: Placebo
50 ml of 0.9% normal saline

Active Comparator: Pantoprazole
Pantoprazole 40 mg in 50 ml 0.9% Normal Saline Intravenously once daily
Drug: Pantoprazole
Proton pump inhibitor




Primary Outcome Measures :
  1. Consent Rate [ Time Frame: 12 months ]

    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.


  2. Recruitment Rate [ Time Frame: 12 months ]
    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.

  3. Protocol Adherence [ Time Frame: 12 months ]

    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.



Secondary Outcome Measures :
  1. Clinically important upper gastrointestinal bleeding [ Time Frame: During ICU stay (expected average is 10 days) ]
  2. Ventilator associated pneumonia [ Time Frame: During ICU stay (expected average is 10 days) ]
  3. Mortality [ Time Frame: During ICU and hospital stay (expected average ICU stay is 10 days, expected average hospital stay is 30 days) ]
  4. Clostridium Difficile infection [ Time Frame: During ICU stay (expected average ICU stay is 10 days) ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02290327


Locations
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Australia
Royal Adelaide
Adelaide, Australia
Canada, Nova Scotia
Queen Elizabeth II
Halifax, Nova Scotia, Canada
Canada, Ontario
St. Joseph's HealthCare Hospital
Hamilton, Ontario, Canada, L9K 1N3
Jurvinski 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, Canada
Saudi Arabia
Dammam University
Dammam, Eastern Province, Saudi Arabia
Sponsors and Collaborators
McMaster University
The Physicians' Services Incorporated Foundation
Investigators
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Principal Investigator: Waleed Alhazzani, MD,FRCPC,MSc McMaster University

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: McMaster University
ClinicalTrials.gov Identifier: NCT02290327     History of Changes
Other Study ID Numbers: REV-06MAR14
First Posted: November 14, 2014    Key Record Dates
Last Update Posted: February 8, 2016
Last Verified: February 2016

Keywords provided by McMaster University:
Stress ulcer bleeding
proton pump inhibitors
pneumonia
clostridium difficile infection

Additional relevant MeSH terms:
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Pantoprazole
Proton Pump Inhibitors
Anti-Ulcer Agents
Gastrointestinal Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action