Clinical trial NCT01782755: Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial (PROSPECT): A Feasibility Clinical Trial
Official title: Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial (PROSPECT): A Feasibility Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Ventilator Associated Pneumonia (VAP)
Other Infections
Antibiotic-Associated Diarrhea
C-Difficile
Duration of Mechanical Ventilation
Length of ICU Stay
Length of Hospital Stay
ICU and Hospital Mortality
Keywords: Probiotics
Ventilator Associated Pneumonia (VAP)
Infection
Antibiotic-Associated Diarrhea
C-Difficile
Lead sponsor: McMaster University
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
name: Technology Evaluation in the Elderly Network (TVN)
name: Physician's Services Incorporated (PSI)
name: Hamilton Academy of Health Science Research Organization (HAHSO)
First posted: 2013-02-04
Enrollment: 150
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: Probiotics are commercially available live bacteria thought to have health benefits when ingested. A literature review of probiotic studies in the intensive care unit (ICU) found that in patients who receive probiotics, there is a 25% reduction in lung infection, known as ventilator-associated pneumonia (VAP). There is also an 18% reduction in the chance of developing any infection in the ICU. However, the studies reviewed were small and not well done. Therefore, whether probiotics are really helpful or not is unclear. Before a large carefully performed study is done to evaluate the effects of probiotics in critically ill patients, a pilot trial is needed. The investigators plan to study the feasibility of such a trial in mechanically ventilated ICU patients in 11 ICUs in Ontario, investigating whether orally ingested L. rhamnosus GG (a common probiotic) prevents VAP and other infections. The 4 goals of the pilot study will be to ensure that we can successfully enrol patients; follow the protocol faithfully; make sure patients don't receive additional probiotics, and estimate how much pneumonia exists in these patients. In a separate substudy, the investigators will evaluate the effects of probiotics on lower lung infiltration with potential harmful bacteria, stool bacteria, markers of immunity called cytokines, and markers of infection called endotoxin levels. The investigators plan to enroll 150 adults admitted to ICU and receiving mechanical ventilation. Following informed consent, patients will be randomized to either L. rhamnosus GG group or an identical placebo. Twice daily, patients will receive probiotics or placebo in a feeding tube. The investigators will record all infections and other important outcomes in the ICU. This study is very important in the ongoing search for more effective strategies to prevent serious infection during critical illness. Probiotics may be an easy-to-use, readily available, inexpensive approach to help future critically ill patients around the world.

Detailed description: Background: Probiotics are defined as live microorganisms that may confer health benefits when ingested. Meta-analysis of probiotic trials suggests a 25 % lower ventilator-associated pneumonia (VAP) and 18 % lower infection rates overall when administered to patients in the intensive care unit (ICU). However, prior trials are small, largely single center, and at high risk of bias. Before a large rigorous trial is launched, testing whether probiotics confer benefit, harm, or have no impact, a pilot trial is needed. The aim of the PROSPECT Pilot Trial is to determine the feasibility of performing a larger trial in mechanically ventilated critically ill patients investigating Lactobacillus rhamnosus GG. A priori, we determined that the feasibility of the larger trial would be based on timely recruitment, high protocol adherence, minimal contamination, and an acceptable VAP rate.

Methods/design: Patients ≥18 years old in the ICU who are anticipated to receive mechanical ventilation for ≥72 hours will be included. Patients are excluded if they are at increased risk of probiotic-associated infection, have strict enteral medication contraindications, are pregnant, previously enrolled in a related trial, or are receiving palliative care. Following informed consent, patients are randomized in variable unspecified block sizes in a fixed 1:1 ratio, stratified by ICU, and medical, surgical, or trauma admitting diagnosis. Patients receive 1 × 1010 colony forming units of L. rhamnosus GG (Culturelle, Locin Industries Ltd) or an identical placebo suspended in tap water administered twice daily via nasogastric tube in the ICU. Clinical and research staff, patients, and families are blinded.

Discussion: The primary outcomes for this pilot trial are the following: (1) recruitment success, (2) ≥90 % protocol adherence, (3) ≤5 % contamination, and (4) \~10 % VAP rate. Additional clinical outcomes are VAP, other infections, diarrhea (total, antibiotic associated, and Clostridium difficile), ICU and hospital length of stay, and mortality. The morbidity, mortality, and cost of VAP underscore the need for cost-effective prophylactic interventions. The PROSPECT Pilot Trial is the initial step toward rigorously evaluating whether probiotics decrease nosocomial infections, have no effect, or actually cause infections in critically ill patients.

Trial registration: ClinicalTrials.gov. NCT01782755

Keywords: Critically ill, Intensive care, Probiotics, Infection, Pneumonia

Eligibility criteria: Inclusion criteria:

1. Adults ≥18 years old in the ICU;
2. Mechanically ventilated with anticipated ventilation of ≥72 hours at enrolment.

Exclusion criteria:

1. Mechanical ventilation exceeding 72 hours at time of screening.
2. Increased risk of iatrogenic probiotic infection including specific immunocompromised populations (HIV \<200 CD4 cells/μL, chronic immunosuppressive medications, prior organ or hematological transplant, neutropenia (absolute neutrophil count \<500).
3. Increased risk for endovascular infection (history of rheumatic heart disease, congenital heart defect, mechanical valves, endocarditis, endovascular grafts, permanent endovascular devices such as permanent (not short-term) hemodialysis catheters, pacemakers or defibrillators).
4. Mucosal gastrointestinal tract defects (gastroesophageal or intestinal injury, including active bleeding), surgery of the esophagus, stomach, small or large bowel, liver, gallbladder, hepatobiliary tree, spleen, or pancreas within 72 hours, suspected or documented ischemic gut and severe acute pancreatitis.
5. Strict contraindication or inability to receive enteral medications.
6. Pregnancy.
7. Intent to withdraw advanced life support.
8. Enrolment in this or an ongoing related trial.

Primary outcomes:
measure: Pilot Trial - Feasibility
timeFrame: 90 days
Secondary outcomes:
Other outcomes:
Locations:
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis
country: United States
facility: St. John's Mercy Medical Center
state: Missouri
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: Vancouver
country: Canada
facility: St. Paul's Hospital
state: British Columbia
city: Victoria
country: Canada
facility: Vancouver Island Health Authority
state: British Columbia
city: Hamilton
country: Canada
facility: Hamilton Health Science - Hamilton General Hospital
state: Ontario
city: Hamilton
country: Canada
facility: St Joseph's Healthcare Hamilton
state: Ontario
city: Hamilton
country: Canada
facility: Hamilton Health Science - Juravinski Hospital
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Hospital Research Institute - Civic Campus
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Research Institute - General Hospital
state: Ontario
city: Toronto
country: Canada
facility: St Michael's Hospital
state: Ontario
city: Toronto
country: Canada
facility: Mount Sinai Hospital
state: Ontario
city: Toronto
country: Canada
facility: University Health Network - Toronto Western Hospital
state: Ontario
city: Quebec City
country: Canada
facility: Hopital de l'Enfant Jesus
state: Quebec
Study officials:
affiliation: McMaster University
name: Deborah J Cook, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lau VI, Xie F, Fowler RA, Rochwerg B, Johnstone J, Lauzier F, Marshall JC, Basmaji J, Henderson W, Khwaja K, Loubani O, Niven DJ, Zarychanski R, Arabi YM, Cartin-Ceba R, Thabane L, Heels-Ansdell D, Cook DJ. Health economic evaluation alongside the Probiotics to Prevent Severe Pneumonia and Endotracheal Colonization Trial (E-PROSPECT): a cost-effectiveness analysis. Can J Anaesth. 2022 Dec;69(12):1515-1526. doi: 10.1007/s12630-022-02335-9. Epub 2022 Oct 26.
citation: Lau VI, Cook DJ, Fowler R, Rochwerg B, Johnstone J, Lauzier F, Marshall JC, Basmaji J, Heels-Ansdell D, Thabane L, Xie F; PROSPECT Collaborators. Economic evaluation alongside the Probiotics to Prevent Severe Pneumonia and Endotracheal Colonization Trial (E-PROSPECT): study protocol. BMJ Open. 2020 Jun 28;10(6):e036047. doi: 10.1136/bmjopen-2019-036047.
citation: Lamarche D, Johnstone J, Zytaruk N, Clarke F, Hand L, Loukov D, Szamosi JC, Rossi L, Schenck LP, Verschoor CP, McDonald E, Meade MO, Marshall JC, Bowdish DME, Karachi T, Heels-Ansdell D, Cook DJ, Surette MG; PROSPECT Investigators; Canadian Critical Care Trials Group; Canadian Critical Care Translational Biology Group. Microbial dysbiosis and mortality during mechanical ventilation: a prospective observational study. Respir Res. 2018 Dec 7;19(1):245. doi: 10.1186/s12931-018-0950-5.
citation: Cook DJ, Johnstone J, Marshall JC, Lauzier F, Thabane L, Mehta S, Dodek PM, McIntyre L, Pagliarello J, Henderson W, Taylor RW, Cartin-Ceba R, Golan E, Herridge M, Wood G, Ovakim D, Karachi T, Surette MG, Bowdish DM, Lamarche D, Verschoor CP, Duan EH, Heels-Ansdell D, Arabi Y, Meade M; PROSPECT Investigators and the Canadian Critical Care Trials Group. Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial-PROSPECT: a pilot trial. Trials. 2016 Aug 2;17:377. doi: 10.1186/s13063-016-1495-x.
citation: Johnstone J, Meade M, Marshall J, Heyland DK, Surette MG, Bowdish DM, Lauzier F, Thebane L, Cook DJ; PROSPECT Investigators and the Canadian Critical Care Trials Group. Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial-PROSPECT: protocol for a feasibility randomized pilot trial. Pilot Feasibility Stud. 2015 May 24;1:19. doi: 10.1186/s40814-015-0013-3. eCollection 2015.