Probiotics to Prevent Severe Pneumonia and Endotracheal Colonization Trial (PROSPECT)

Probiotics to Prevent Severe Pneumonia and Endotracheal Colonization Trial (PROSPECT)

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 was needed. The Investigators completed a multicenter pilot RCT for which the primary outcomes relate to feasibility. Feasibility goals were met. 1) Recruitment for the Pilot was achieved in 1 year; 2) Adherence to the protocol was 96%; 3) There were no cases of contamination; 4) The VAP rate was 15%. 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.

Study Overview

• Status: Completed
• Conditions: Infections; Diarrhea; Ventilator Associated Pneumonia; Antibiotic-associated Diarrhea; C-Difficile
• Intervention / Treatment: Drug: L. rhamnosus GG - Probiotic; Drug: Placebo - Microcrystalline Cellulose

Detailed Description

Background:Probiotics are live microorganisms thought to have health benefits when ingested. Randomized controlled trials (RCTs) have documented favourable impact on a range of clinical problems, including prevention of upper respiratory tract infections, antibiotic-associated diarrhea, Clostridium difficile-associated diarrhea, and irritable bowel syndrome. Our recent meta-analysis of probiotic RCTs in the intensive care unit (ICU) also suggests 25% lower rates of ventilator-associated pneumonia (VAP) and 18% lower infection rates overall when administered to critically ill mechanically ventilated patients. However, these estimates arise from small, modest quality single-center RCTs yielding imprecise estimates of effect and uncertain generalizability, and require confirmation in a large methodologically rigourous RCT. Before launching a complex costly RCT testing whether probiotics confer benefit, harm, or have no impact on infectious and non-infectious outcomes, a pilot trial was needed. The investigators completed a multicenter pilot RCT for which the primary outcomes relate to feasibility: 1) recruitment success in 1 year; 2) >90% adherence to the probiotic protocol; 3) <5% contamination; 4) an estimated VAP rate. Patients have been randomized in 14 centers in Canada and the US, with an informed consent rate of 84%. Feasibility goals were met. 1) Recruitment for the Pilot was achieved in 1 year; 2) Adherence to the protocol was 96%; 3) There were no cases of contamination; 4) The VAP rate was 15%. This will be an internal Pilot which will be incorporated into the main trial.

Setting: 13 ICUs in Canada, 2 ICUs in United States

Methods: Patients age 18 years or older, admitted to the ICU, with an anticipated duration of ventilation of ≥72 hours are included. Patients are excluded if they have increased risk of iatrogenic probiotic infection or endovascular infection, primary diagnosis of severe acute pancreatitis, percutaneous gastric or jejunal feeding tubes already in situe, strict contraindication or inability to receive enteral medications, have hopeless prognosis, withholding or withdrawal of advanced life support is planned, or if previous enrolment in this or a related trial. Following informed consent, patients are randomized in variable unspecified block sizes in a fixed allocation ratio of 1:1, stratified by ICU and medical/surgical/trauma status. Twice daily, patients receive either 1x1010 colony forming units (CFU) of L. rhamnosus GG (Culturelle, Locin Industries Ltd) in 1 capsule or an identical placebo capsule. Both are suspended in water administered via nasogastric tube or by capsule. Research Nurses notify local Study Pharmacists after obtaining informed consent. Study Pharmacists obtain the allocation from the PROSPECT website. Only the Database Manager and Study Pharmacists will have access to the randomization schedule; everyone else remains blinded. Patients receive the intervention until:1) ICU discharge; 2) death; or 3) isolation of Lactobacillus spp. in a sterile site, or if cultured as the sole or predominant organism from a non-sterile site.

RCT Trial Outcomes: The primary outcome is VAP; secondary outcomes include ICU-acquired infections, diarrhea (total, antibiotic-associated and CDAD), antibiotic use, length of stay and mortality in the ICU and hospital, and acquired L. rhamnosus GG infections.

Relevance: Despite clinical uptake of some existing VAP prevention strategies, the morbidity, mortality and cost of VAP underscore the need for further cost-effective interventions to reduce its impact. Whether probiotics impact on VAP, other infections such as CDAD, antibiotic-associated diarrhea or antibiotic use is unclear. When rigorously evaluated, probiotics may have salutary effects decreasing nosocomial infections as prior RCTs suggest; alternatively, probiotics may have no demonstrable effect, or actually cause infections in critically ill patients with impaired immune function.

• Study Type: Interventional
• Enrollment (Anticipated): 2650
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 2T9
      • Foothills Medical Center
    • Calgary, Alberta, Canada, T1Y 6J4
      • Peter Louheed Center
    • Edmonton, Alberta, Canada, T6G 2B7
      • Univeristy of Alberta
  • British Columbia
    • New Westminster, British Columbia, Canada, V3L 3W7
      • Royal Columbia Hospital
    • Vancouver, British Columbia, Canada, V6Z 1Y6
      • St. Paul's Hospital
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • Vancouver General Hospital
    • Vancouver, British Columbia, Canada
      • Vancouver Island Health Authority
  • Manatoba
    • Winnipeg, Manatoba, Canada, R3E 0M1
      • Health Science - Winnipeg
  • Manitoba
    • Winnipeg, Manitoba, Canada, R2H 2A6
      • St. Boniface
  • Nova Scotia
    • Halfax, Nova Scotia, Canada, B3H 1V7
      • QEII
  • Ontario
    • Brampton, Ontario, Canada, L6R 3J7
      • William Osler Brampton - Brampton Civic Hospital
    • Brantford, Ontario, Canada, N3R 1G9
      • Brantford General Hospital
    • Burlington, Ontario, Canada, L7S 1W7
      • Joseph Brant Hospital
    • Edmonton, Ontario, Canada, T5H 3V9
      • Royal Alexandra Hospital
    • Hamilton, Ontario, Canada, L8N 4A6
      • St Joseph's Healthcare Hamilton
    • Hamilton, Ontario, Canada, L8N 3Z5
      • Hamilton Health Science Centre - Hamilton General Hospital
    • Hamilton, Ontario, Canada, L8V 1C3
      • Hamilton Health Science Centre - Juravinski Hospital
    • Kingston, Ontario, Canada, K7L 2V7
      • Kingston General Hospital
    • Kitchener, Ontario, Canada, N2G 1G3
      • Grand River Hospital
    • London, Ontario, Canada, N6A 5W9
      • LHSC - Victoria Hospital
    • London, Ontario, Canada, N6A 5W9
      • LHSC - University Hospital
    • Ottawa, Ontario, Canada, K1H 8L6
      • Ottawa General Hospital
    • Ottawa, Ontario, Canada, K1Y 4E9
      • Ottawa Civic Hospital
    • St. Catharines, Ontario, Canada, L2S 0A9
      • Niagara Health - St. Catharine's Hospital
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Health Sciences Centre
    • Toronto, Ontario, Canada, M5B 1W8
      • St. Michael's Hospital
    • Toronto, Ontario, Canada, M5G 2C4
      • Toronto General Hospital
    • Toronto, Ontario, Canada, M5G 1X5
      • Mount Sinai Hospital
    • Toronto, Ontario, Canada, M5T 2S8
      • UHN - Toronto Western Hospital
    • Toronto, Ontario, Canada, M6R 1B5
      • St. Joseph's Hospital
  • Quebec
    • Laval, Quebec, Canada, G1V 4G5
      • Institut Universitaire de Cardiologie et de Pneumologie de Quebec - Université Laval
    • Lévis, Quebec, Canada, G6V 3Z1
      • Hotel-Dieu de Levis
    • Montreal, Quebec, Canada, H3G 1A4
      • Montreal General Hospital
    • Montreal, Quebec, Canada, H4A 3J1
      • Royal Victoria Hospital
    • Montreal, Quebec, Canada, H2L 4M1
      • Center Hospital University Montreal (NCHUM)
    • Montreal, Quebec, Canada, H4J 1C5
      • Sacre Coeur Hospital
    • Montréal, Quebec, Canada, H1T 2M4
      • Hôpital Maisonneuve-Rosemont
    • Montréal, Quebec, Canada, H2L M1
      • Center Hospital University Montreal (CHUM) - Notre Dame
    • Montréal, Quebec, Canada, H2X 1R9
      • Center Hospital University (CHUM) - Saint Luc
    • Quebec City, Quebec, Canada, G1J 1Z4
      • Hôpital de l'Enfant-Jesus, CHU de Quebec
    • Sherbrooke, Quebec, Canada, J1G 2E8
      • Sherbrooke Hospital
• Saudi Arabia
  • Riyadh, Saudi Arabia, 11426
    • King Adulaziz Medical Center
• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Saint Louis, Missouri, United States, 63141
      • St. John's Mercy Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Adults ≥ 18 years of age
2. Admitted to any ICU and receiving invasive mechanical ventilation
3. Anticipated ventilation of ≥72 hours at the time of screening, as per the ICU physician.

Exclusion Criteria:

1. Invasively mechanically ventilated >72 hours at the time of screening;
2. Patients at potential increased risk of iatrogenic probiotic infection (see Section 2.6 for detailed explanation) including specific immunocompromised populations (HIV <200 CD4 cells/μL, those receiving chronic immunosuppressive medications (e.g., azathioprine, cyclosporine, cyclophosphamide, tacrolimus, methotrexate, mycofenolate, Anti-IL2), previous transplantation (including stem cell) at any time, malignancy requiring chemotherapy in the last 3 months, neutropenia [absolute neutrophil count < 500]). However, patients receiving corticosteroids previously or presently or projected to receive corticosteroids are not excluded;
3. Patients at risk for endovascular infection (previously documented rheumatic heart disease, congenital valve disease, surgically repaired congenital heart disease, unrepaired cyanotic congenital heart disease, any intracardiac repair with prosthetic material [mechanical or bio-prosthetic cardiac valves], previous or current endocarditis, permanent endovascular devices (e.g., endovascular grafts [e.g., aortic aneurysm repair, stents involving large arteries such as aorta, femorals and carotids], inferior vena cava filters, dialysis vascular grafts), tunnelled (not short-term) hemodialysis catheters, pacemakers or defibrillators. Patients with temporary central venous catheters, central venous dialysis catheters or peripherally inserted central catheters (PICCs) are not excluded and patients with coronary artery stents, coronary artery bypass grafts (CABG) or neurovascular coils are not excluded; patients with mitral valve prolapse or bicuspid aortic valve are not excluded providing they have no other exclusion criteria;
4. Patients with a primary diagnosis of severe acute pancreatitis, without reference to a Ranson score [Ranson 1974]). However, patients with mild or moderate pancreatitis are not excluded;
5. Patients with percutaneous gastric or jejunal feeding tubes already in situ as per Health Canada guidance;
6. Strict contraindication or inability to receive enteral medications;
7. Intent to withdraw advanced life support as per the ICU physician;
8. Previous enrolment in this or current enrolment in a potentially confounding tria

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Lactobacillus rhamnosus GG; Patients allocated to the intervention group will receive 1x1010 colony forming units (CFU) of L. rhamnosus GG (Culturelle, Locin Industries Ltd) in 1 capsule suspended in tap water, administered through a nasogastric (or orogastric) or nasoduodenal (or oroduodenal) tube twice daily while patients are in the ICU. The first dose will be within 72 hours of intubation. Patients in the ICU who await discharge and can swallow pills will take the capsules orally.	Drug: L. rhamnosus GG - Probiotic; Twice daily, patients will receive either 1x1010 colony forming units (CFU) of L. rhamnosus GG (Culturelle, Locin Industries Ltd) in 1 capsule or an identical placebo capsule; Other Names: Culturelle Probiotic
Placebo Comparator: Placebo; Patients allocated to the placebo group will receive a capsule identical in appearance to the L. rhamnosus GG capsule, but containing microcrystalline cellulose. The placebo will also be suspended in tap water and similarly administered twice a day. When suspended in water, the placebo has identical appearance and consistency as the probiotic. The placebo will be prepared by the manufacturer of L. rhamnosus GG, Culturelle, and has been used successfully in a recent RCT in the ICU population [Morrow 2010]. This has also been used successfully in the PROSPECT Pilot Trial.	Drug: Placebo - Microcrystalline Cellulose; Microcrystalline Cellulose; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with Ventilator Associated Pneumonia (VAP)	VAP will be diagnosed clinically at each site in patients who are receiving invasive mechanical ventilation for at least 48 hours, when there is a new, progressive or persistent radiographic infiltrate with no other obvious cause and the presence of any 2 of the following symptoms or signs: 1) fever (temperature >38°C) or hypothermia (temperature <36°C as measured by core body temperature); 2) relative neutropenia (<3.0 x 106/L) or leukocytosis (>10 x 106/L) and 3) purulent sputum.	60 Days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with infections acquired during the ICU stay	Any infection acquired during the ICU stay, defined as respiratory or other infections including bloodstream infections, intravascular catheter-related sepsis, intra-abdominal infections, urosepsis and surgical wound infections.	60 Days
Number of patients with Clostridium Difficile-associated diarrhea	3 or more episodes of unformed stools in ≤24 hours and C. difficile toxin positive stool or colonoscopic or histopathologic findings demonstrating pseudomembranous colitis	60 Days
Number of patients with antibiotic-associated diarrhea	Antibiotic-associated diarrhea and defined as more than 2 liquid stools a day for 3 or more days in quantities in excess of normal for each patient	60 Days
Number of patients with diarrhea	Diarrhea defined as 3 or more loose or watery bowel movements, according to the Bristol Stool Chart (type 6 or 7) and use of a fecal management device	60 Days
Defined Daily Dose Antibiotic Exposure	Defined daily dose (DDD), daily doses of therapy (DOT), and antibiotic-free days in ICU	60 Days
Duration of mechanical ventilation	Endotracheal tube or tracheostomy, length of ICU stay and length of hospital stay: recorded as number of days	60 Days
ICU mortality and in-hospital mortality:	ICU mortality and in-hospital mortality recorded at ICU discharge and hospital discharge.	60 Days

Collaborators and Investigators

• Sponsor: McMaster University

Publications and helpful links

General Publications

• Takaoka A, Zytaruk N, Davis M, Matte A, Johnstone J, Lauzier F, Marshall J, Adhikari N, Clarke FJ, Rochwerg B, Lamontagne F, Hand L, Watpool I, Porteous RK, Masse MH, D'Aragon F, Niven D, Heels-Ansdell D, Duan E, Dionne J, English S, St-Arnaud C, Millen T, Cook DJ; PROSPECT Investigators and the Canadian Critical Care Trials Group. Monitoring and auditing protocol adherence, data integrity and ethical conduct of a randomized clinical trial: A case study. J Crit Care. 2022 Oct;71:154094. doi: 10.1016/j.jcrc.2022.154094. Epub 2022 Jun 17.
• Johnstone J, Meade M, Lauzier F, Marshall J, Duan E, Dionne J, Arabi YM, Heels-Ansdell D, Thabane L, Lamarche D, Surette M, Zytaruk N, Mehta S, Dodek P, McIntyre L, English S, Rochwerg B, Karachi T, Henderson W, Wood G, Ovakim D, Herridge M, Granton J, Wilcox ME, Goffi A, Stelfox HT, Niven D, Muscedere J, Lamontagne F, D'Aragon F, St-Arnaud C, Ball I, Nagpal D, Girard M, Aslanian P, Charbonney E, Williamson D, Sligl W, Friedrich J, Adhikari NK, Marquis F, Archambault P, Khwaja K, Kristof A, Kutsogiannis J, Zarychanski R, Paunovic B, Reeve B, Lellouche F, Hosek P, Tsang J, Binnie A, Trop S, Loubani O, Hall R, Cirone R, Reynolds S, Lysecki P, Golan E, Cartin-Ceba R, Taylor R, Cook D; Prevention of Severe Pneumonia and Endotracheal Colonization Trial (PROSPECT) Investigators and the Canadian Critical Care Trials Group. Effect of Probiotics on Incident Ventilator-Associated Pneumonia in Critically Ill Patients: A Randomized Clinical Trial. JAMA. 2021 Sep 21;326(11):1024-1033. doi: 10.1001/jama.2021.13355.
• Johnstone J, Heels-Ansdell D, Thabane L, Meade M, Marshall J, Lauzier F, Duan EH, Zytaruk N, Lamarche D, Surette M, Cook DJ; PROSPECT Investigators and the Canadian Critical Care Trials Group. Evaluating probiotics for the prevention of ventilator-associated pneumonia: a randomised placebo-controlled multicentre trial protocol and statistical analysis plan for PROSPECT. BMJ Open. 2019 Jun 20;9(6):e025228. doi: 10.1136/bmjopen-2018-025228.

Study record dates

Study Major Dates

• Study Start: June 1, 2015
• Primary Completion (Actual): March 13, 2019
• Study Completion (Actual): November 17, 2020

Study Registration Dates

• First Submitted: June 2, 2015
• First Submitted That Met QC Criteria: June 2, 2015
• First Posted (Estimate): June 4, 2015

Study Record Updates

• Last Update Posted (Actual): December 17, 2020
• Last Update Submitted That Met QC Criteria: December 15, 2020
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: Diarrhea; Probiotics; Ventilator Associated Pneumonia; Infections; Antibiotic-associated Diarrhea; C-Difficile
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Disease Attributes; Signs and Symptoms, Digestive; Cross Infection; Iatrogenic Disease; Healthcare-Associated Pneumonia; Pneumonia; Diarrhea; Pneumonia, Ventilator-Associated
• Other Study ID Numbers: 27022015