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Ventilator Associated PneumoniaPhase 4PROSPECTNCT02462590

Probiotics to Prevent Severe Pneumonia and Endotracheal Colonization Trial

A Phase 4 study testing L. rhamnosus GG - Probiotic in people with Ventilator Associated Pneumonia and Infections, run by McMaster University at 44 sites in 3 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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). Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
L. rhamnosus GG - Probiotic
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
2,650 participants
Where
44 sitesin 3 countries
Study dates
Jun 2015to 17 Nov 2020
Phase
Phase 4
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.

Who cannot join

  • 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 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;
  • 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

Trial locations and contacts

44 sites in 3 countries.

44 sites in 3 countries

Canada41 sites

  • William Osler Brampton - Brampton Civic Hospital

    Brampton, Ontario, L6R 3J7

  • Brantford General Hospital

    Brantford, Ontario, N3R 1G9

  • Joseph Brant Hospital

    Burlington, Ontario, L7S 1W7

  • Peter Louheed Center

    Calgary, Alberta, T1Y 6J4

  • Foothills Medical Center

    Calgary, Alberta, T2N 2T9

  • Univeristy of Alberta

    Edmonton, Alberta, T6G 2B7

  • Royal Alexandra Hospital

    Edmonton, Ontario, T5H 3V9

  • QEII

    Halfax, Nova Scotia, B3H 1V7

  • Hamilton Health Science Centre - Hamilton General Hospital

    Hamilton, Ontario, L8N 3Z5

  • St Joseph's Healthcare Hamilton

    Hamilton, Ontario, L8N 4A6

  • Hamilton Health Science Centre - Juravinski Hospital

    Hamilton, Ontario, L8V 1C3

  • Kingston General Hospital

    Kingston, Ontario, K7L 2V7

  • Grand River Hospital

    Kitchener, Ontario, N2G 1G3

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

    Laval, Quebec, G1V 4G5

  • Hôtel-Dieu de Lévis

    Lévis, Quebec, G6V 3Z1

  • LHSC - University Hospital

    London, Ontario, N6A 5W9

  • LHSC - Victoria Hospital

    London, Ontario, N6A 5W9

  • Hôpital Maisonneuve-Rosemont

    Montreal, Quebec, H1T 2M4

  • Center Hospital University Montreal (NCHUM)

    Montreal, Quebec, H2L 4M1

  • Center Hospital University Montreal (CHUM) - Notre Dame

    Montreal, Quebec, H2L M1

  • Center Hospital University (CHUM) - Saint Luc

    Montreal, Quebec, H2X 1R9

  • Montreal General Hospital

    Montreal, Quebec, H3G 1A4

  • Royal Victoria Hospital

    Montreal, Quebec, H4A 3J1

  • Sacre Coeur Hospital

    Montreal, Quebec, H4J 1C5

  • Royal Columbia Hospital

    New Westminster, British Columbia, V3L 3W7

  • Ottawa General Hospital

    Ottawa, Ontario, K1H 8L6

  • Ottawa Civic Hospital

    Ottawa, Ontario, K1Y 4E9

  • Hôpital de l'Enfant-Jesus, CHU de Quebec

    Québec, Quebec, G1J 1Z4

  • Sherbrooke Hospital

    Sherbrooke, Quebec, J1G 2E8

  • Niagara Health - St. Catharine's Hospital

    St. Catharines, Ontario, L2S 0A9

  • Sunnybrook Health Sciences Centre

    Toronto, Ontario, M4N 3M5

  • St. Michael's Hospital

    Toronto, Ontario, M5B 1W8

  • Mount Sinai Hospital

    Toronto, Ontario, M5G 1X5

  • Toronto General Hospital

    Toronto, Ontario, M5G 2C4

  • UHN - Toronto Western Hospital

    Toronto, Ontario, M5T 2S8

  • St. Joseph's Hospital

    Toronto, Ontario, M6R 1B5

  • Vancouver General Hospital

    Vancouver, British Columbia, V5Z 1M9

  • St. Paul's Hospital

    Vancouver, British Columbia, V6Z 1Y6

  • Vancouver Island Health Authority

    Vancouver, British Columbia

  • Health Science - Winnipeg

    Winnipeg, Manatoba, R3E 0M1

  • St. Boniface

    Winnipeg, Manitoba, R2H 2A6

Other trials in Canada

United States2 sites

  • Mayo Clinic

    Rochester, Minnesota, 55905

  • St. John's Mercy Medical Center

    St Louis, Missouri, 63141

Other trials in United States

Saudi Arabia1 site

  • King Adulaziz Medical Center

    Riyadh, 11426

Other trials in Saudi Arabia

About this study

Official title: 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.

Read the 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.

Being tested
L. rhamnosus GG - Probiotic, Placebo - Microcrystalline Cellulose
Keywords
Probiotics, Ventilator Associated Pneumonia, Infections, C-Difficile, Antibiotic-associated Diarrhea, Diarrhea
Medical subject headings
Pneumonia, Ventilator-Associated, Infections, Diarrhea

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • L. rhamnosus GG - ProbioticDrug

    Also called Culturelle 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

  • Placebo - Microcrystalline CelluloseDrug

    Also called Placebo

    Microcrystalline Cellulose

Study groups in NCT02462590
Study groupRoleWhat they receive
Lactobacillus rhamnosus GGActive comparatorPatients 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.
Receives: Drug: L. rhamnosus GG - Probiotic
PlaceboPlacebo comparatorPatients 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.
Receives: Drug: Placebo - Microcrystalline Cellulose

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: 60 Days

Secondary outcomes (7)

  1. 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.

    Measured: 60 Days

  2. 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

    Measured: 60 Days

  3. 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

    Measured: 60 Days

  4. 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

    Measured: 60 Days

  5. Defined Daily Dose Antibiotic Exposure

    Defined daily dose (DDD), daily doses of therapy (DOT), and antibiotic-free days in ICU

    Measured: 60 Days

  6. Duration of mechanical ventilation

    Endotracheal tube or tracheostomy, length of ICU stay and length of hospital stay: recorded as number of days

    Measured: 60 Days

  7. ICU mortality and in-hospital mortality:

    ICU mortality and in-hospital mortality recorded at ICU discharge and hospital discharge.

    Measured: 60 Days

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted4 Jun 2015 (estimated)
  2. Study startJun 2015
  3. Primary completion13 Mar 2019
  4. Study completion17 Nov 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
2,650 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02462590
Sponsor's protocol ID
27022015
Acronym
PROSPECT
Status last verified
Jan 2019
First submitted
2 Jun 2015
Last updated
17 Dec 2020
Results posted
No
Data monitoring committee
Yes

Publications

  • 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.

    PubMed 41248372

  • 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.

    PubMed 41013603

  • 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.

    PubMed 39731129

  • 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.

    PubMed 36682909

  • 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.

    PubMed 35724443

  • 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.

    PubMed 34546300

  • 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.

    PubMed 31227528

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing L. rhamnosus GG - Probiotic in people with Ventilator Associated Pneumonia and Infections, run by McMaster University at 44 sites in 3 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 17 Dec 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 44 sites in Canada, United States, Saudi Arabia. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of patients with Ventilator Associated Pneumonia (VAP) (time frame: 60 Days). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02462590, which also lists 7 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Dec 2020.

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