Refining exclusion criteria based on pilot trials: Lessons from PROSPECT
CCCF ePoster library. Duan E. Nov 2, 2016; 150991
Disclosure(s): No conflicts of interest to declare.
Dr. Erick Duan
Dr. Erick Duan
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Abstract
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Topic: Clinical Trial

Refining exclusion criteria based on pilot trials: Lessons from PROSPECT


EH Duan1 2
J Johnstone 3 4 8
MO Meade 1, 2,
JC Marshall 5 6
F Lauzier 7
S Mehta 6, 8
PM Dodek 9
L McIntyre 10
R Hall 14
D Ovakim 15 
G Wood  15
G Pagliarello 10
W Henderson 11
E Golan 6, 8
M Herridge 6, 8
T Karachi 1
F Lamontagne 16
E Charbonney 17
R Zarychanski 18
R Taylor 12
R Cartin-Ceba 13
DJ Cook 1, 2
for the PROSPECT Pilot Trial Investigators and the CCCTG

 
Departments of Medicine 1 Clinical Epidemiology & Biostatistics 2, McMaster University, Hamilton, Canada
Public Health Ontario, Toronto, Ontario, Canada 3
St. Joseph’s Health Center, Toronto, Ontario, Canada 4
Department of Surgery 5, Interdepartmental Division of Critical Care 6, Department of Medicine 8, University of Toronto, Toronto, Canada
Research Center of the CHU de Québec - Population Health and Optimal Health Practices Research Unit, Department of Medicine, and Department of Anesthesiology & Critical Care, Université Laval, Québec, Canada 7
Division of Critical Care Medicine and Center for Health Evaluation and Outcome Sciences, St. Paul’s Hospital and University of British Columbia, Vancouver, Canada 9
Division of Critical Care, University of Ottawa, Ottawa, Canada 10
Division of Critical Care Medicine, Vancouver General Hospital, Vancouver, Canada 11
Department of Critical Care Medicine, Mercy Hospital, St Louis, USA 12
Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Arizona, USA 13
Departments of Critical Care & Anesthesia, Dalhousie University, Halifax, Canada 14
Departments of Anesthesia & Critical Care, Vancouver Island Health Authority, Victoria, Canada 15
Centre de recherché du CHUS and Department of Medicine, Université de Sherbrooke 16
Centre de Recherche de  l'Hôpital du Sacré-Coeur de Montréal 17
Department of Internal Medicine, University of Manitoba 18
 


Grant acknowledgements:
TechValueNet, Canadian Institutes of Health Research, Physicians Services Incorporated, and Hamilton Academy of Health Sciences Organization.

Abstract:

Background
Lactobacillus probiotics are commonly available natural health products which have been studied in many contexts. Serious adverse effects are rare, but concern exists for patients with risk factors for development of Lactobacillus sepsis or bacteremia. The PROSPECT Trial is a randomized controlled trial in mechanically ventilated adults examining the effect of twice daily enteral L. rhamnosus GG vs placebo on the rates of ventilator-associated pneumonia and other nosocomial infections. Feasibility of the PROSPECT Main Trial was assessed by the PROSPECT Pilot Trial. Between the Pilot and Main Trials, we revisited the exclusion criteria to minimize the undesirable risk of sepsis or bacteremia from Lactobacillus probiotics while maximizing patient eligibility.

Objective
To systematically refine the exclusion criteria for participation in the PROSPECT Pilot in anticipation of the Main Trial. 

Methods
We conducted a search of PubMed using the search terms: 'lactobacillus' and 'probiotic', with keywords from the PROSPECT Pilot exclusion criteria. We repeated this search, adding the terms: 'sepsis' and 'bacteremia.' We included studies which enrolled patients with at least one of the Pilot Trial exclusion criteria and who consumed Lactobacillus probiotics, and any reports of patients with at least one exclusion criteria who developed sepsis or bacteremia after Lactobacillus probiotics. One co-author (EHD) screened abstracts, selected relevant publications, and systematically summarized the findings. Using a structured evidence report, each exclusion criterion was discussed at 3 meetings of the PROSPECT Steering Committee and Investigators, composed of experts in critical care, infectious disease, and methodology.  Affirmation or iterative revision of the exclusion criteria ensued. The revised exclusion criteria were presented to the Canadian Critical Care Trials Group members for further input and endorsement.  The PROSPECT Main Trial exclusion criteria were then approved by Health Canada and Research Ethics Boards.

Results
46 published relevant studies were identified (6 systematic reviews, 26 RCTs, 1 prospective cohort study, 2 case series and 11 case reports). Review of the evidence led to changes in exclusion criteria. Some exclusion criteria were omitted when we did not identify any reports of Lactobacillus sepsis (e.g. radiation therapy, corticosteroid exposure, anti-TNF agents and pregnancy). Some exclusion criteria were added when we did identify reports of Lactobacillus sepsis (e.g. hematopoetic cell transplantation, and intracardiac repair with prosthetic material). The exclusion criterion of 'gastrointestinal surgery' was replaced with 'any contraindication to enteral study product.' Common questions about excluded populations arising during the Pilot were addressed and the Main Trial now explicitly allows enrolment of patients with coronary stents, neurovascular coils/stents, C. difficile infection, and inflammatory bowel disease.

Conclusions
We found few studies in the form of case series and case reports citing sepsis or bacteremia with Lactobacillus probiotics. Using the best available evidence, discussion and consensus among clinicians and investigators, and approval from regulators, the exclusion criteria for the PROSPECT Pilot were revised for the PROSPECT Main Trial to balance the objectives of recruitment efficiency, maximum safety, and enhanced generalizability.


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