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

• ClinicalTrials.gov Identifier: NCT02462590
• Recruitment Status: Completed
• First Posted: June 4, 2015
• Last Update Posted: December 17, 2020
• Sponsor: McMaster University
• Information provided by (Responsible Party): McMaster University

Tracking Information

• First Submitted Date: June 2, 2015
• First Posted Date: June 4, 2015
• Last Update Posted Date: December 17, 2020
• Study Start Date: June 2015
• Actual Primary Completion Date: March 13, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 4, 2015)

Number of patients with Ventilator Associated Pneumonia (VAP) [ Time Frame: 60 Days ]

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.

Original Primary Outcome Measures (submitted: June 2, 2015)

Ventilator Associated Pneumonia (VAP) [ Time Frame: 60 Days ]

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.

Current Secondary Outcome Measures (submitted: June 4, 2015)

• Number of patients with infections acquired during the ICU stay [ Time Frame: 60 Days ]
  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.
• Number of patients with Clostridium Difficile-associated diarrhea [ Time Frame: 60 Days ]
  3 or more episodes of unformed stools in ≤24 hours and C. difficile toxin positive stool or colonoscopic or histopathologic findings demonstrating pseudomembranous colitis
• Number of patients with antibiotic-associated diarrhea [ Time Frame: 60 Days ]
  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
• Number of patients with diarrhea [ Time Frame: 60 Days ]
  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
• Defined Daily Dose Antibiotic Exposure [ Time Frame: 60 Days ]
  Defined daily dose (DDD), daily doses of therapy (DOT), and antibiotic-free days in ICU
• Duration of mechanical ventilation [ Time Frame: 60 Days ]
  Endotracheal tube or tracheostomy, length of ICU stay and length of hospital stay: recorded as number of days
• ICU mortality and in-hospital mortality: [ Time Frame: 60 Days ]
  ICU mortality and in-hospital mortality recorded at ICU discharge and hospital discharge.

Original Secondary Outcome Measures (submitted: June 2, 2015)

• Infections acquired during the ICU stay [ Time Frame: 60 Days ]
  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.
• Clostridium difficile-associated diarrhea [ Time Frame: 60 Days ]
  3 or more episodes of unformed stools in ≤24 hours and C. difficile toxin positive stool or colonoscopic or histopathologic findings demonstrating pseudomembranous colitis
• Antibiotic-associated diarrhea [ Time Frame: 60 Days ]
  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
• Diarrhea [ Time Frame: 60 Days ]
  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
• Antibiotic use [ Time Frame: 60 Days ]
  Defined daily dose (DDD), daily doses of therapy (DOT), and antibiotic-free days in ICU
• Duration of mechanical ventilation [ Time Frame: 60 Days ]
  Endotracheal tube or tracheostomy, length of ICU stay and length of hospital stay: recorded as number of days
• ICU mortality and in-hospital mortality: [ Time Frame: 60 Days ]
  ICU mortality and in-hospital mortality recorded at ICU discharge and hospital discharge.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Probiotics to Prevent Severe Pneumonia and Endotracheal Colonization Trial
• Official Title: Probiotics to Prevent Severe Pneumonia and Endotracheal Colonization Trial (PROSPECT)
• 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.

• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Prevention

Condition

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

Intervention

• Drug: 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
  Other Name: Culturelle Probiotic
• Drug: Placebo - Microcrystalline Cellulose
  Microcrystalline Cellulose
  Other Name: Placebo

Study Arms

• Active Comparator: 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.
  Intervention: Drug: L. rhamnosus GG - Probiotic
• Placebo Comparator: 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.
  Intervention: Drug: Placebo - Microcrystalline Cellulose

Publications *

• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Estimated Enrollment (submitted: June 2, 2015): 2650
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: November 17, 2020
• Actual Primary Completion Date: March 13, 2019 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, Saudi Arabia, United States

Administrative Information

• NCT Number: NCT02462590
• Other Study ID Numbers: 27022015
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: McMaster University
• Original Responsible Party: Same as current
• Current Study Sponsor: McMaster University
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Deborah J Cook, MD; McMaster University

• PRS Account: McMaster University
• Verification Date: January 2019