Evaluating probiotics for the prevention of ventilator-associated pneumonia: a randomised placebo-controlled multicentre trial protocol and statistical analysis plan for PROSPECT

Abstract

Introduction: Ventilator-associated pneumonia (VAP) is the most common healthcare-associated infection in critically ill patients. Prior studies suggest that probiotics may reduce VAP and other infections in critically ill patients; however, most previous randomised trials were small, single centre studies. The Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial (PROSPECT) aims to determine the impact of the probiotic Lactobacillus rhamnosus GG on VAP and other clinically important outcomes in critically ill adults.

Methods: PROSPECT is a multicentre, concealed, randomised, stratified, blinded, controlled trial in patients ≥18 years old, anticipated to be mechanically ventilated ≥72 hours, in intensive care units (ICUs) in Canada, the USA and Saudi Arabia. Patients receive either 1×1010 colony forming units of L. rhamnosus GG twice daily or an identical appearing placebo. Those at increased risk of probiotic infection are excluded. The primary outcome is VAP. Secondary outcomes are other ICU-acquired infections including Clostridioides difficile infection, diarrhoea (including antibiotic-associated diarrhoea), antimicrobial use, ICU and hospital length of stay and mortality. The planned sample size of 2650 patients is based on an estimated 15% VAP rate and will provide 80% power to detect a 25% relative risk reduction.

Ethics and dissemination: This protocol and statistical analysis plan outlines the methodology, primary and secondary analyses, sensitivity analyses and subgroup analyses. PROSPECT is approved by Health Canada (#9427-M1133-45C), the research ethics boards of all participating hospitals and Public Health Ontario. Results will be disseminated via academic channels (peer reviewed journal publications, professional healthcare fora including international conferences) and conventional and social media. The results of PROSPECT will inform practice guidelines worldwide.

Trialregistration number: NCT02462590; Pre-results.

Keywords: critically ill; infection; intensive care; probiotics; ventilator-associated pneumonia.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Pneumonia classifications that could arise in patients who require ICU admission and invasive mechanical ventilation at the time of presentation to the emergency room, and are randomised into PROSPECT that day. The primary outcome is adjudicated VAP (any, including early or late), arising on study day 3 or later. Secondary outcomes illustrated include early VAP, late VAP and post-extubation pneumonia. These figures illustrate the pneumonia classification that we are using, according to when the lung infection develops in a patient’s hospital trajectory. The different classifications over time in each example relate to the day of hospital admission, day of ICU admission, day of initiation of mechanical ventilation (via endotracheal intubation or tracheostomy), day of randomisation in the trial and day of discontinuation of mechanical ventilation. Note that the pneumonia classifications over time do not reflect persistent or progressive lung infections, but rather the pneumonia classification that would be ascribed if a new infection develops on each day shown. CAP, community-acquired pneumonia; ER, emergency room; Extub, Extubation; HAP, hospital-acquired pneumonia; ICU, intensive care unit; ICUAP, intensive care unit associated pneumonia; IMV, invasive mechanical ventilation; PROSPECT, Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial; Rand, randomisation; VAP, ventilator-associated pneumonia.

Figure 2

Pneumonia classifications that could arise in patients who require ICU admission and invasive mechanical ventilation after an initial hospital stay, and are randomised into PROSPECT the day following ICU admission. The primary outcome is adjudicated VAP (any, including early or late), arising on study day 3 or later. These figures illustrate the pneumonia classification that we are using, according to when the lung infection develops in a patient’s hospital trajectory. The different classifications over time in each example relate to the day of hospital admission, day of ICU admission, day of initiation of mechanical ventilation (via endotracheal intubation or tracheostomy), day of randomisation in the trial and day of discontinuation of mechanical ventilation. Note that the pneumonia classifications over time do not reflect persistent or progressive lung infections, but rather the pneumonia classification that would be ascribed if a new infection develops on each day shown. CAP, community-acquired pneumonia; ER, emergency room; HAP, hospital-acquired pneumonia; ICU, intensive care unit; IMV, invasive mechanical ventilation; PROSPECT, Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial; Rand, randomisation; VAP, ventilator-associated pneumonia.