Clinical trial NCT02462590: Probiotics to Prevent Severe Pneumonia and Endotracheal Colonization Trial
Official title: Probiotics to Prevent Severe Pneumonia and Endotracheal Colonization Trial (PROSPECT)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Ventilator Associated Pneumonia
Infections
C-Difficile
Antibiotic-associated Diarrhea
Diarrhea
Keywords: Probiotics
Ventilator Associated Pneumonia
Infections
C-Difficile
Antibiotic-associated Diarrhea
Diarrhea
Lead sponsor: McMaster University
Sponsor class: OTHER
First posted: 2015-06-04
Enrollment: 2650
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 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.

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;
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

Primary outcomes:
measure: Number of patients with Ventilator Associated Pneumonia (VAP)
timeFrame: 60 Days
Secondary outcomes:
measure: Number of patients with infections acquired during the ICU stay
timeFrame: 60 Days
measure: Number of patients with Clostridium Difficile-associated diarrhea
timeFrame: 60 Days
measure: Number of patients with antibiotic-associated diarrhea
timeFrame: 60 Days
measure: Number of patients with diarrhea
timeFrame: 60 Days
measure: Defined Daily Dose Antibiotic Exposure
timeFrame: 60 Days
measure: Duration of mechanical ventilation
timeFrame: 60 Days
measure: ICU mortality and in-hospital mortality:
timeFrame: 60 Days
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: Calgary
country: Canada
facility: Peter Louheed Center
state: Alberta
city: Calgary
country: Canada
facility: Foothills Medical Center
state: Alberta
city: Edmonton
country: Canada
facility: Univeristy of Alberta
state: Alberta
city: New Westminster
country: Canada
facility: Royal Columbia Hospital
state: British Columbia
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: Vancouver
country: Canada
facility: St. Paul's Hospital
state: British Columbia
city: Vancouver
country: Canada
facility: Vancouver Island Health Authority
state: British Columbia
city: Winnipeg
country: Canada
facility: Health Science - Winnipeg
state: Manatoba
city: Winnipeg
country: Canada
facility: St. Boniface
state: Manitoba
city: Halfax
country: Canada
facility: QEII
state: Nova Scotia
city: Brampton
country: Canada
facility: William Osler Brampton - Brampton Civic Hospital
state: Ontario
city: Brantford
country: Canada
facility: Brantford General Hospital
state: Ontario
city: Burlington
country: Canada
facility: Joseph Brant Hospital
state: Ontario
city: Edmonton
country: Canada
facility: Royal Alexandra Hospital
state: Ontario
city: Hamilton
country: Canada
facility: Hamilton Health Science Centre - 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 Centre - Juravinski Hospital
state: Ontario
city: Kingston
country: Canada
facility: Kingston General Hospital
state: Ontario
city: Kitchener
country: Canada
facility: Grand River Hospital
state: Ontario
city: London
country: Canada
facility: LHSC - University Hospital
state: Ontario
city: London
country: Canada
facility: LHSC - Victoria Hospital
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa General Hospital
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Civic Hospital
state: Ontario
city: St. Catharines
country: Canada
facility: Niagara Health - St. Catharine's Hospital
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
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: Toronto General Hospital
state: Ontario
city: Toronto
country: Canada
facility: UHN - Toronto Western Hospital
state: Ontario
city: Toronto
country: Canada
facility: St. Joseph's Hospital
state: Ontario
city: Laval
country: Canada
facility: Institut universitaire de cardiologie et de pneumologie de Québec - Université Laval
state: Quebec
city: Lévis
country: Canada
facility: Hôtel-Dieu de Lévis
state: Quebec
city: Montreal
country: Canada
facility: Center Hospital University Montreal (NCHUM)
state: Quebec
city: Montreal
country: Canada
facility: Montreal General Hospital
state: Quebec
city: Montreal
country: Canada
facility: Royal Victoria Hospital
state: Quebec
city: Montreal
country: Canada
facility: Sacre Coeur Hospital
state: Quebec
city: Montréal
country: Canada
facility: Hôpital Maisonneuve-Rosemont
state: Quebec
city: Montréal
country: Canada
facility: Center Hospital University Montreal (CHUM) - Notre Dame
state: Quebec
city: Montréal
country: Canada
facility: Center Hospital University (CHUM) - Saint Luc
state: Quebec
city: Quebec City
country: Canada
facility: Hôpital de l'Enfant-Jesus, CHU de Quebec
state: Quebec
city: Sherbrooke
country: Canada
facility: Sherbrooke Hospital
state: Quebec
city: Riyadh
country: Saudi Arabia
facility: King Adulaziz Medical Center
Study officials:
affiliation: McMaster University
name: Deborah J Cook, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.