Probiotics to Prevent Severe Pneumonia and Endotracheal Colonization Trial

NCT02462590 | Completed Phase 4 DMC

• 1 other identifier: 27022015
• Study Type: interventional
• Target: 2,650
• Locations: 3 countries
• Sites: 44

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 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.

Conditions

Ventilator Associated Pneumonia; Infections; C-Difficile; Antibiotic-associated Diarrhea; Diarrhea

Keywords

Probiotics; Ventilator Associated Pneumonia; Infections; C-Difficile; Antibiotic-associated Diarrhea; Diarrhea

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (7)

• Number of patients with infections acquired during the ICU stay

  60 Days

• Number of patients with Clostridium Difficile-associated diarrhea

  60 Days

• Number of patients with antibiotic-associated diarrhea

  60 Days

• Number of patients with diarrhea

  60 Days

• Defined Daily Dose Antibiotic Exposure

  60 Days

Study Arms (2)

Lactobacillus rhamnosus GG

ACTIVE COMPARATOR

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

Placebo

PLACEBO COMPARATOR

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

Interventions

L. rhamnosus GG - Probiotic DRUG

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

Also known as: Culturelle Probiotic

Lactobacillus rhamnosus GG

Placebo - Microcrystalline Cellulose DRUG

Microcrystalline Cellulose

Also known as: Placebo

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• Invasively mechanically ventilated \>72 hours at the time of screening;
• 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;
• 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;
• Patients with percutaneous gastric or jejunal feeding tubes already in situ as per Health Canada guidance;
• Strict contraindication or inability to receive enteral medications;
• Intent to withdraw advanced life support as per the ICU physician;
• Previous enrolment in this or current enrolment in a potentially confounding tria

Sponsors & Collaborators

• McMaster University: lead

Study Sites (44)

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

St. John's Mercy Medical Center

St Louis, Missouri, 63141, United States

Location

Peter Louheed Center

Calgary, Alberta, T1Y 6J4, Canada

Location

Foothills Medical Center

Calgary, Alberta, T2N 2T9, Canada

Location

Univeristy of Alberta

Edmonton, Alberta, T6G 2B7, Canada

Location

Royal Columbia Hospital

New Westminster, British Columbia, V3L 3W7, Canada

Location

Vancouver General Hospital

Vancouver, British Columbia, V5Z 1M9, Canada

Location

St. Paul's Hospital

Vancouver, British Columbia, V6Z 1Y6, Canada

Location

Vancouver Island Health Authority

Vancouver, British Columbia, Canada

Location

Health Science - Winnipeg

Winnipeg, Manatoba, R3E 0M1, Canada

Location

St. Boniface

Winnipeg, Manitoba, R2H 2A6, Canada

Location

QEII

Halfax, Nova Scotia, B3H 1V7, Canada

Location

William Osler Brampton - Brampton Civic Hospital

Brampton, Ontario, L6R 3J7, Canada

Location

Brantford General Hospital

Brantford, Ontario, N3R 1G9, Canada

Location

Joseph Brant Hospital

Burlington, Ontario, L7S 1W7, Canada

Location

Royal Alexandra Hospital

Edmonton, Ontario, T5H 3V9, Canada

Location

Hamilton Health Science Centre - Hamilton General Hospital

Hamilton, Ontario, L8N 3Z5, Canada

Location

St Joseph's Healthcare Hamilton

Hamilton, Ontario, L8N 4A6, Canada

Location

Hamilton Health Science Centre - Juravinski Hospital

Hamilton, Ontario, L8V 1C3, Canada

Location

Kingston General Hospital

Kingston, Ontario, K7L 2V7, Canada

Location

Grand River Hospital

Kitchener, Ontario, N2G 1G3, Canada

Location

LHSC - University Hospital

London, Ontario, N6A 5W9, Canada

Location

LHSC - Victoria Hospital

London, Ontario, N6A 5W9, Canada

Location

Ottawa General Hospital

Ottawa, Ontario, K1H 8L6, Canada

Location

Ottawa Civic Hospital

Ottawa, Ontario, K1Y 4E9, Canada

Location

Niagara Health - St. Catharine's Hospital

St. Catharines, Ontario, L2S 0A9, Canada

Location

Sunnybrook Health Sciences Centre

Toronto, Ontario, M4N 3M5, Canada

Location

St. Michael's Hospital

Toronto, Ontario, M5B 1W8, Canada

Location

Mount Sinai Hospital

Toronto, Ontario, M5G 1X5, Canada

Location

Toronto General Hospital

Toronto, Ontario, M5G 2C4, Canada

Location

UHN - Toronto Western Hospital

Toronto, Ontario, M5T 2S8, Canada

Location

St. Joseph's Hospital

Toronto, Ontario, M6R 1B5, Canada

Location

Institut universitaire de cardiologie et de pneumologie de Québec - Université Laval

Laval, Quebec, G1V 4G5, Canada

Location

Hôtel-Dieu de Lévis

Lévis, Quebec, G6V 3Z1, Canada

Location

Hôpital Maisonneuve-Rosemont

Montreal, Quebec, H1T 2M4, Canada

Location

Center Hospital University Montreal (NCHUM)

Montreal, Quebec, H2L 4M1, Canada

Location

Center Hospital University Montreal (CHUM) - Notre Dame

Montreal, Quebec, H2L M1, Canada

Location

Center Hospital University (CHUM) - Saint Luc

Montreal, Quebec, H2X 1R9, Canada

Location

Montreal General Hospital

Montreal, Quebec, H3G 1A4, Canada

Location

Royal Victoria Hospital

Montreal, Quebec, H4A 3J1, Canada

Location

Sacre Coeur Hospital

Montreal, Quebec, H4J 1C5, Canada

Location

Hôpital de l'Enfant-Jesus, CHU de Quebec

Québec, Quebec, G1J 1Z4, Canada

Location

Sherbrooke Hospital

Sherbrooke, Quebec, J1G 2E8, Canada

Location

King Adulaziz Medical Center

Riyadh, 11426, Saudi Arabia

Location

Related Publications (7)

• Fernando SM, Muscedere J, Rochwerg B, Johnstone J, Daneman N, Marshall JC, Lauzier F, Rudkowski JC, Arabi YM, Heels-Ansdell D, Sligl W, Kristof AS, Duan E, Dionne JC, St-Arnaud C, Reynolds S, Khwaja K, Cook DJ; PROSPECT Investigators and the Canadian Critical Care Trials Group. Frailty and the risk of ICU-acquired infections in a randomised trial: a protocol and statistical analysis plan. BMJ Open. 2025 Nov 13;15(11):e105227. doi: 10.1136/bmjopen-2025-105227.

  PMID: 41248372 DERIVED

• Thabane A, Heels-Ansdell D, Zytaruk N, Johnstone J, Lauzier F, Arabi YM, Muscedere J, Clarke F, Hand L, Watpool I, Porteous R, Sandu G, Santos M, Tassy D, Marshall J, McIntyre L, Ball I, Rochwerg B, Karachi T, Zarychanski R, Marquis F, Friedrich JO, Lysecki P, Cook D; PROSPECT Investigators and the Canadian Critical Care Trials Group. Coenrollment of critically ill patients in PROSPECT: characteristics and association with treatment efficacy and safety. Trials. 2025 Sep 26;26(1):370. doi: 10.1186/s13063-025-09028-w.

  PMID: 41013603 DERIVED

• Takaoka A, Johnstone J, Lauzier F, Heels-Ansdell D, Davis M, Zytaruk N, Duan E, Dionne J, Saunders L, Arabi YM, Marshall J, Thabane L, Clarke F, Hand L, Masse MH, Rochwerg B, McIntyre L, Girard M, Freitag A, Karachi T, Cook DJ; PROSPECT Investigators; Canadian Critical Care Trials Group. Enrolment patterns in a randomized controlled trial of probiotics in critically ill patients: a retrospective analysis of the PROSPECT trial. Trials. 2024 Dec 27;25(1):851. doi: 10.1186/s13063-024-08701-w.

  PMID: 39731129 DERIVED

• Dionne JC, Johnstone J, Heels-Ansdell D, Duan E, Lauzier F, Arabi YM, Adhikari NKJ, Sligl W, Dodek P, Rochwerg B, Marshall JC, Niven DJ, Williamson DR, Reynolds S, Zytaruk N, Cook D. Clostridioides difficile infection in mechanically ventilated critically ill patients: A nested cohort study. J Crit Care. 2023 Jun;75:154254. doi: 10.1016/j.jcrc.2023.154254. Epub 2023 Jan 20.

  PMID: 36682909 DERIVED

• 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.

  PMID: 35724443 DERIVED

• 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.

  PMID: 34546300 DERIVED

• 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.

  PMID: 31227528 DERIVED

MeSH Terms

Conditions

Pneumonia, Ventilator-Associated; Infections; Diarrhea

Condition Hierarchy (Ancestors)

Healthcare-Associated Pneumonia; Cross Infection; Pneumonia; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases; Iatrogenic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Signs and Symptoms, Digestive; Signs and Symptoms

Study Officials

• Deborah J Cook, MD

  McMaster University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 2, 2015
• First Posted: June 4, 2015
• Study Start: June 1, 2015
• Primary Completion: March 13, 2019
• Study Completion: November 17, 2020
• Last Updated: December 17, 2020

Record last verified: 2019-01

Locations

SA (1); CA (41); US (2)