Probiotics to Prevent Severe Pneumonia and Endotracheal Colonization Trial

NCT ID: NCT02462590

Last Updated: 2020-12-17

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 2650 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-06-30
• Study Completion Date: 2020-11-17

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.

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.

Conditions

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

Keywords

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

L. rhamnosus GG - Probiotic

Intervention Type: 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

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.

Group Type: PLACEBO_COMPARATOR

Placebo - Microcrystalline Cellulose

Intervention Type: DRUG

Microcrystalline Cellulose

Interventions

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

Intervention Type: DRUG

Placebo - Microcrystalline Cellulose

Microcrystalline Cellulose

Intervention Type: DRUG

Other Intervention Names

Culturelle Probiotic; Placebo

Eligibility Criteria

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;

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

McMaster University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Deborah J Cook, MD

Role: PRINCIPAL_INVESTIGATOR

McMaster University

Locations

Mayo Clinic

Rochester, Minnesota, United States

St. John's Mercy Medical Center

St Louis, Missouri, United States

Peter Louheed Center

Calgary, Alberta, Canada

Foothills Medical Center

Calgary, Alberta, Canada

Univeristy of Alberta

Edmonton, Alberta, Canada

Royal Columbia Hospital

New Westminster, British Columbia, Canada

Vancouver General Hospital

Vancouver, British Columbia, Canada

St. Paul's Hospital

Vancouver, British Columbia, Canada

Vancouver Island Health Authority

Vancouver, British Columbia, Canada

Health Science - Winnipeg

Winnipeg, Manatoba, Canada

St. Boniface

Winnipeg, Manitoba, Canada

QEII

Halfax, Nova Scotia, Canada

William Osler Brampton - Brampton Civic Hospital

Brampton, Ontario, Canada

Brantford General Hospital

Brantford, Ontario, Canada

Joseph Brant Hospital

Burlington, Ontario, Canada

Royal Alexandra Hospital

Edmonton, Ontario, Canada

Hamilton Health Science Centre - Hamilton General Hospital

Hamilton, Ontario, Canada

St Joseph's Healthcare Hamilton

Hamilton, Ontario, Canada

Hamilton Health Science Centre - Juravinski Hospital

Hamilton, Ontario, Canada

Kingston General Hospital

Kingston, Ontario, Canada

Grand River Hospital

Kitchener, Ontario, Canada

LHSC - University Hospital

London, Ontario, Canada

LHSC - Victoria Hospital

London, Ontario, Canada

Ottawa General Hospital

Ottawa, Ontario, Canada

Ottawa Civic Hospital

Ottawa, Ontario, Canada

Niagara Health - St. Catharine's Hospital

St. Catharines, Ontario, Canada

Sunnybrook Health Sciences Centre

Toronto, Ontario, Canada

St. Michael's Hospital

Toronto, Ontario, Canada

Mount Sinai Hospital

Toronto, Ontario, Canada

Toronto General Hospital

Toronto, Ontario, Canada

UHN - Toronto Western Hospital

Toronto, Ontario, Canada

St. Joseph's Hospital

Toronto, Ontario, Canada

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

Laval, Quebec, Canada

Hôtel-Dieu de Lévis

Lévis, Quebec, Canada

Hôpital Maisonneuve-Rosemont

Montreal, Quebec, Canada

Center Hospital University Montreal (NCHUM)

Montreal, Quebec, Canada

Center Hospital University Montreal (CHUM) - Notre Dame

Montreal, Quebec, Canada

Center Hospital University (CHUM) - Saint Luc

Montreal, Quebec, Canada

Montreal General Hospital

Montreal, Quebec, Canada

Royal Victoria Hospital

Montreal, Quebec, Canada

Sacre Coeur Hospital

Montreal, Quebec, Canada

Hôpital de l'Enfant-Jesus, CHU de Quebec

Québec, Quebec, Canada

Sherbrooke Hospital

Sherbrooke, Quebec, Canada

King Adulaziz Medical Center

Riyadh, , Saudi Arabia

Countries

United States; Canada; Saudi Arabia

References

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Reference Type: DERIVED

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Other Identifiers

27022015

Identifier Type: -

Identifier Source: org_study_id