Probiotics to Prevent Severe Pneumonia and Endotracheal Colonization Trial

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Diarrhea, Ventilator Associated Pneumonia, Infections, C-Difficile, Antibiotic-associated Diarrhea

Intervention / Treatment
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* Drug: L. rhamnosus GG - Probiotic
* Drug: Placebo - Microcrystalline Cellulose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Lactobacillus rhamnosus GG<br>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<br>* 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<br>* Other names: Culturelle Probiotic;|
| Placebo Comparator: Placebo<br>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<br>* Microcrystalline Cellulose<br>* Other names: Placebo;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ventilator Associated Pneumonia, Infections, C-Difficile, Antibiotic-associated Diarrhea, Diarrhea, Probiotics