Biomarker Signature-Supported Antibiotic Treatment Decisions in Intensive Care Units
Phase: NA
Conditions: Intensive Care Unit (ICU) Admission
Sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre

BAST ICU 
 
 
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Clinical Study Protocol 
 
 
Biomarker-signature Supported 
Antibiotic Treatment Decisions in 
ICU  
(BAST-ICU) 
 
Version 1.6 
Date: 03-Sep-2025 
 
 
 
This document contains confidential information and should not be disclosed to anyone 
other than the study investigators, study team, members of REB or regulatory 
authorities. No part of this document may be retrieved, reproduced or transmitted in any 
form without consent from the study PI. 
 

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GCP Statement 
This clinical study will be conducted in accordance with applicable Health Canada regulations, International 
Conference on Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human 
Use ICH guidelines on current Good Clinical Practice (GCP), and the Declaration of Helsinki. 
 
Confidentiality Statement 
This clinical study protocol contains information which is of a confidential, trade-secret or proprietary nature. The 
protocol is for the use of Dr. Makeda Semret and her designated representatives participating in the investigational 
trial. It is not to be disclosed to any other person or party without the prior written approval of Dr. Makeda Semret. 
 
 
 
Full Title: 
Biomarker-signature Supported Antibiotic Treatment 
Decisions in ICU (BAST-ICU) 
 
 
Principal-Investigator: 
Makeda Semret, MD FRCP(C) 
 
 
Study Support/Funding: 
Canadian Institutes of Health Research (CIHR) 
 
 
 
 
Study Management Group: 
Mi4 Clinical Research Platform (Mi4-CRP) 
 
 
Central Research Laboratory: Research Institute of McGill University Health Centre 
 
Glen site 
1001 Decarie Blvd. Bloc E 
Montreal, QC, H4A 3J1, Canada 
 
 
Date: 
03-Sep-2025 
 
 

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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................. 3 
INVESTIGATOR AGREEMENT ..................................................................................... 7 
STUDY CONTACT DETAILS ......................................................................................... 8 
PROTOCOL SYNOPSIS ............................................................................................... 12 
1. INTRODUCTION, BACKGROUND, AND STUDY RATIONALE ........................... 14 
1.1 
The need for a trial ......................................................................................... 14 
1.2 
Study Rationale .............................................................................................. 15 
1.3 
Potential impact ............................................................................................. 16 
2. MEDICAL DEVICE ................................................................................................. 16 
2.1 
Description ..................................................................................................... 16 
3. STUDY OBJECTIVES AND DESIGN .................................................................... 16 
3.1 
Overall Study Design ..................................................................................... 16 
3.2 
Objectives ....................................................................................................... 17 
3.2.1 
Primary Objective(s) ................................................................................... 17 
3.2.2 
Secondary Objective(s) .............................................................................. 17 
3.2.3 
Exploratory Objectives(s) .......................................................................... 17 
4. SELECTION AND ENROLLMENT OF PARTICIPANTS ....................................... 17 
4.1 
Number of Participants .................................................................................. 18 
4.2 
Inclusion Criteria ............................................................................................ 18 
4.3 
Exclusion Criteria ........................................................................................... 18 
4.4 
Strategies for Recruitment ............................................................................ 19 
4.5 
Enrollment Procedures .................................................................................. 19 
4.6 
Co-enrollment Guidelines.............................................................................. 20 
4.7 Pregnancy and/or breastfeeding. ......................................................................... 20 
5. PILOT Testing of Enrollment Processes and BV Score Validation .................. 20 
5.1 
Number of Pilot Participants ............................................................................ 20 
5.2 
Pilot Participant Eligibility Criteria ................................................................... 20 
5.3 
Pilot Procedures ................................................................................................ 20 
5.4 
Pilot Data Collection and Analysis................................................................... 21 
6. WITHDRAWAL OF PARTICIPANTS ..................................................................... 21 

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6.1 
Withdrawal criteria ......................................................................................... 21 
7. RANDOMIZATION AND BLINDING PROCEDURES ............................................ 21 
7.1 
Randomization ............................................................................................... 21 
7.2 
Blinding during Enrollment and Clinical Assessments .............................. 21 
7.3 
Unblinding at the Intervention Stage ............................................................ 22 
8. STUDY PROCEDURES ......................................................................................... 22 
8.1 
Study Flow Chart ............................................................................................ 22 
8.2 
Schedule of Events ........................................................................................ 23 
8.3 
Screening Period (-3 days to 0 days) ........................................................... 24 
8.4 
Baseline Visit (Day 0) ..................................................................................... 24 
8.5 
Randomization and Intervention (Day 1) ...................................................... 25 
8.6 
Follow-Up (Days 3, 7, & 14 ± 1 day) .............................................................. 25 
8.7 
End of Study Visit EOSV (Day 28 + 2 days) ................................................. 25 
8.8 
Study Procedures common to both groups: Assessment of antibiotic 
prescription .............................................................................................................. 26 
8.9 
Antibiotic treatment decision procedure specific to the control group .... 26 
8.10 
Antibiotic treatment decision procedure specific to the experimental 
group 27 
8.11 
Table 1 Data Collection .............................................................................. 27 
9. CLINICAL AND LABORATORY EVALUATIONS ................................................. 28 
9.1 
Clinical Evaluations ....................................................................................... 28 
9.2 
Schedule of Clinical Evaluations and Data Collection ................................ 29 
9.3 
Specimen Collection and Laboratory Evaluations ...................................... 29 
9.3.1 
Research Blood Collection Serum Specimen .......................................... 30 
10. 
RISK MANAGEMENT ......................................................................................... 30 
10.1 
Risk Management ....................................................................................... 30 
11. 
EVALUATION, RECORDING, AND REPORTING OF ADVERSE EVENTS ...... 31 
11.1 
Definitions ................................................................................................... 31 
11.1.1 
Adverse Event (AE) ................................................................................. 31 
11.1.2 
Serious Adverse Events (SAEs) ............................................................. 31 
11.2 
Event Reporting .......................................................................................... 31 

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11.3 
Criteria for Adverse Events related to antibiotics .................................... 32 
11.3.1 
AE Descriptions and Reporting .............................................................. 33 
11.3.2 
Intensity .................................................................................................... 33 
11.4 
Reporting and Evaluation of SAEs ............................................................ 33 
11.4.1 
SAEs ......................................................................................................... 33 
12. 
STATISTICAL CONSIDERATIONS .................................................................... 33 
12.1 
Rationale ......................................................................................................... 33 
12.2 
Definitions for clinical outcomes and ranking of outcome categories 
(DOOR)34 
12.3 
RADAR Score ................................................................................................. 34 
12.4 
Sample Size and Justification ....................................................................... 35 
12.5 
Expected Study Recruitment Flow Chart ..................................................... 35 
12.6 
Estimations of Adverse Outcomes in ICU.................................................... 36 
12.7 
Primary Analysis ............................................................................................ 36 
12.8 
Frequency of Analyses .................................................................................. 36 
12.9 
Final Analysis ................................................................................................. 37 
12.10 
Sub-Group Analyses: .................................................................................... 37 
13. 
DATA MANAGEMENT ....................................................................................... 37 
13.1 
Data Monitoring and Auditing .................................................................... 38 
13.2 
Data Safety and Monitoring Committee (DSMC) ...................................... 38 
13.3 
Record Keeping .......................................................................................... 38 
13.3.1 
Source Documents .................................................................................. 38 
13.3.2 
Record Retention ..................................................................................... 39 
14. 
GENERAL TRIAL CONDUCT CONSIDERATIONS ........................................... 39 
14.1 
Trial Oversight ................................................................................................ 39 
14.2 
Trial Coordination .......................................................................................... 39 
14.3 
Participating MUHC Sites .............................................................................. 40 
14.4 
Protocol Deviations ....................................................................................... 40 
14.5 
Intervention Adherence ................................................................................. 40 
15. 
STUDY ETHICAL CONSIDERATIONS .............................................................. 41 
15.1 
Informed Consent .......................................................................................... 41 

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15.2 
Institutional Review Board, Ethics Committee, or Research Ethics Board
 
41 
15.3 
Confidentiality ................................................................................................ 41 
16. 
DISCLOSURE AND PUBLICATION POLICY .................................................... 42 
17. 
REFERENCES .................................................................................................... 42 
18. 
Appendix I: Sample Size Calculations ............................................................. 49 
 
 
 

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INVESTIGATOR AGREEMENT 
Protocol Title: 
Biomarker-signature Supported Antibiotic Treatment Decisions in ICU 
(BAST-ICU) 
Date: 
03-Sep--2025 
 
This clinical study will be conducted in accordance with applicable Health Canada 
regulations, ICH guidelines on current GCP ISO 14155:2011 (E), Clinical investigation 
of medical devices for human subject - Good Clinical Practice, 2011-02-01 and ISO 
14971:2007, and the Declaration of Helsinki. 
I confirm that I have read and understand this protocol and I agree to conduct this 
clinical study in accordance with the design and specific provisions of the protocol, with 
the exception of a change intended to eliminate an immediate hazard to participants. 
Any deviation from the study protocol will be documented in the case report form. 
I agree to promptly report to the applicable ethics boards any changes in the research 
activity and all unanticipated problems involving risks to human participants or others. 
Additionally, I will not make any changes in the research without prior ethics and 
sponsor approval, except where necessary to ensure the safety of study participants. 
 
 
 
 
 
 
 
 
Name 
 
Signature 
 
Date (dd-mmm-yyyy) 
 
 

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STUDY CONTACT DETAILS 
Name 
Role 
Responsibility 
Email 
Makeda Semret 
NPA 
Responsible for the study design and oversight;  
Will lead study procedures and activities; steering 
committee, knowledge mobilization and translation 
activities. Will supervise clinical fellow in 
antimicrobial stewardship (PDF).  
10 hours/week 
Makeda.semr
et@mcgill.ca 
Nandini Dendukuri 
Co-A 
Statistical analysis (interim and final); supervision of 
trainee in biostatistics 
2 hours/week 
Nandini,dend
ukuri@mcgill.
ca 
Dao Nguyen 
Co-A 
Knowledge mobilization and translation activities; 
linkage between commercial partner (Diasorin) and 
study team. 
1 hour/week 
Dao,nguyen
@mcgill.ca 
Arnold Kristoff 
Co-A 
Study procedures; linkage between ICU treating 
team and study team including responsibility for in-
training sessions for ICU translation and knowledge 
mobilization. Member of Data Safety and Monitoring 
Committee  
2 hours/week 
arnold.kristof
@mcgill.ca 
Patrick Ryan 
Lawler 
Co-A 
Study design and study analysis (interim and final). 
Member of the steering committee 
2 hours/week 
patrick.lawler
@mcgill.ca 
Alexander 
Lawandi 
Co-A 
(Early career 
researcher) 
Study design, study procedures; linkage between 
study team and treating team; site PI; participant 
recruitment 
2 hours/week  
alexander.law
andi@mcgill.c
a 
Francois 
Bourdeau 
Co-A; 
Principal 
Knowledge 
user (KU; 
pharmacist) 
Study procedures including prescription quality 
assessments and treatment recommendations; 
linkages between pharmacists and study team; 
knowledge translation and mobilization strategies; 
member of the Data Safety and Monitoring 
Committee  
8 hours/week 
Francois.bour
deau@muhc.
mcgill.ca 
Don Vinh 
Co-A 
Laboratory testing for BV signature, biobanking of 
specimens and post-hoc analysis for potential 
additional biomarker signatures 
Member of the steering committee 
2 hours/week 
donald.vinh@
mcgill.ca 
Daniel Thirion 
KU - 
pharmacist 
Study procedures including prescription quality 
assessments and treatment recommendations; 
assessment of adverse events related to antibiotics; 
supervision of MSc pharmacy trainee 
2 hours/week 
daniel.thirion
@umontreal.c
a 
Gerasimos (Jerry) 
Zaharatos 
KU - 
decision-
maker 
Knowledge translation; will serve as a conduit 
between research team and health system; policy 
implications of research findings for Health systems  
1 hour/week 
jerry.zaharato
s@mcgill.ca 

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Alexandre Cherton 
 PWLE (non-
academic) 
Review of informed consent form and strategies for 
participant recruitment; input on additional outcomes 
of interest; knowledge translation strategies and 
policy translation 
2 hours/month 
alexandrecher
ton@hotmail.
com 
Lorne Schweitzer  
Co-A 
(PWLE) 
Review of study procedures and patient recruitment 
strategies. Input on outcomes of interest. Knowledge 
mobilization and dissemination strategies.  
1 hour/week 
lorne.schweitz
er@mail.mcgi
ll.ca 
Salman Qureshi 
Collaborator 
Linkages between ICU treating teams and study 
team; participant recruitment 
1 hour/week 
salman.qures
hi@mcgill.ca 
Jean Bourbeau 
Collaborator 
Training of students (MSc and PDF) in clinical trials, 
core component of HQP development plan; 
assistance with studentship awards  
 
Guy Rouleau  
Collaborator 
ACT/AEC 
Trial promotion and awareness raising through the 
network communication program; help in identifying 
potential additional study sites for future 
 
 
 
 

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ABBREVIATIONS AND DEFINITIONS 
Acronym / 
Abbreviation 
Definition 
AEs 
Adverse Events 
AMR 
Antimicrobial Resistance 
AMU 
Antimicrobial Use 
AMS 
Antimicrobial Stewardship 
AWare 
Antibiotic Watch and Reserve Classification 
BAST- ICU 
Biomarker-Supported Antibiotic Stewardship Trial in ICU  
BV 
MeMed BV® (Diagnostic Assay) 
CIHR 
Canadian Institute of Health Research 
Co-I 
Co-investigators  
CTCAE 
Common Terminology Criteria for Adverse Events  
CRP 
C-Reactive Protein 
DOOR 
Desirability of Outcome Ranking 
ICU 
Intensive Care Unit 
IP-10 
Interferon Gamma-Induced Protein 10 
MGH 
Montreal General Hospital 
MUHC 
McGill University Health Centre 
NIH 
National Institutes of Health 
PCT 
Procalcitonin 
RADAR 
Response Adjusted for Antibiotic Risk  
RCT 
Randomized Controlled Trial 
REB 
Research Ethics Board 
REDCap 
Research Electronic Data Capture 
RVH 
Royal Victoria Hospital 
TRAIL 
Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand 
WHO 
World Health Organization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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SUMMARY 
Reducing excessive or inappropriate antibiotics is critical for Canada’s National Action 
Plan to contain Antimicrobial Resistance (AMR), which has been declared a global threat 
by the World Health Organization (WHO). A major limitation of that objective is that 
diagnostic uncertainty and fear of under-treating patients, particularly in critical care 
settings, drive a large proportion of antibiotic overuse and misuse in human healthcare. 
We propose to accelerate improved clinical decision-making for antibiotic therapy in the 
ICU setting, using a novel biomarker, MeMedBV which exploits a targeted host-protein 
signature to distinguish between infections that require antibiotics versus those that do 
not. The BV test is a promising assay to evaluate in an antibiotic cessation decision matrix, 
given its performance characteristics (high negative predictive value for bacterial 
infections), rapid results (1 hour), and the fact it does not seem to be affected by the 
presence of colonizing bacteria. 
The central question of this study is whether a biomarker-signature supported antibiotic 
treatment decision matrix can have a beneficial impact on antibiotic use and patient 
outcomes in an ICU population.  
 
We propose to pragmatically combine the evaluation of the diagnostic test with an 
antibiotic treatment decision matrix, in a manner that mimics real-life but is as close as 
possible to a “best-case” scenario. The study will be a Randomized clinical trial to 
determine the effect of implementing a BV-supported antibiotic treatment decision matrix 
(efficacy) on antibiotic use and on a combined clinical endpoint among study participants 
(safety). As secondary outcomes, individual endpoints of Antibiotic use (days of treatment, 
daily defined doses), antibiotic-free days in ICU, use of reserve/restricted antibiotics, 
adherence to recommendations; incidence of clinically significant (grade IV) adverse 
events, recurrent infections, infectious complications, length of stay in ICU, death, 
colonization with multi-drug-resistant organisms will be analyzed.  
 
This clinical trial will establish the efficacy and safety of a new diagnostic assay on a real-
world ICU patient population, an important step in the translational pathway to establish 
this platform for diagnostic testing in the critically ill.  By improving antimicrobial 
stewardship interventions in the ICU, the study will help curtail the emergence of AMR 
and potentially improve the outcomes of critically ill patients.    
 
 
 
 

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PROTOCOL SYNOPSIS 
Full Title 
Biomarker signature-supported Antibiotic Treatment Decisions in 
ICU 
Short Title 
BAST-ICU 
Protocol and Version 
No. 
V1.5 02-Apr-2025 
Study Duration 
Enrollment period: October 1, 2024 – March 31, 2027 
Study period: August 1, 2024 – July 31, 2027 
Sponsor-Investigator  
RI-MUHC, Dr. Makeda Semret  
Number of Centers 
MUHC; Royal Victoria Hospital and Montreal General Hospital  
Diagnostic Test 
Description 
Diagnostic test: MeMed BV  
Medical Device Licence Number: 104240 
Test result combined with clinical assessment to facilitate decision 
on antibiotic treatment. 
Pilot Study Design 
Standard procedures for the Validation of the BV Score in 
Differentiating Bacterial and Non-Bacterial Infections 
Pilot Sample Size 
N = 40 
Pilot Study Population 
Participants who are admitted to Intensive Care Unit (ICU) and: 
non-infected, confirmed bacterial infection, presumed or 
confirmed viral pneumonia.   
Pilot Objective 
To evaluate the feasibility of the study procedures and the 
performance of the BV Score before the full-scale study begins 
Pilot Eligibility Criteria 
18 years old, admitted to ICU 
Study Design 
Pivotal Study, Observer-Blind, Randomized Controlled Clinical 
Trial  
Sample Size 
N = 1200 
Study Population 
Inpatients admitted to ICU and started on antibiotic treatment 
within the preceding 72 hours (approximately 3 days). 
Control 
Results of BV test masked 
Randomization 
Randomly assigned 1:1 ratio to either the control group or the 
intervention group. 
Primary Objective 
To evaluate the combined endpoint of efficacy and safety at 28 
days (approximately 4 weeks). This will include: 
1. Efficacy: Assessed by the use of antibiotics. 
2. Safety: Assessed by clinical outcomes. 
The assessment at 28 days will determine the overall 
effectiveness and safety of the intervention. 
Secondary Objectives 
To evaluate antibiotic-free days in ICU, use of reserve/restricted 
antibiotics, adherence to recommendations; incidence of clinically 
significant (grade IV) adverse events, recurrent infections, 
infectious complications, length of stay in ICU, death, colonization 
with multi-drug-resistant organisms. 
Primary Outcome 
To evaluate the combined endpoint of efficacy and safety at 28 
days (approximately 4 weeks) using Desirability of Outcome 

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Ranking (DOOR) and Response Adjusted for Antibiotic Risk 
(RADAR). 
Secondary Outcomes 
To evaluate the following parameters; antibiotic-free days in ICU, 
adverse events, adherence to treatment recommendations, death, 
and length of stay in ICU. 
Exploratory Outcomes 
To assess the incidence of colonization or infection with drug-
resistant organisms. 
Interventional arms  
Treatment decision matrix (intervention) plus standard of care 
compared to standard of care alone (control). 
Duration of 
Intervention 
1 Day (BV testing) 
Statistical Analysis 
Wilcoxon-Mann-Whitney statistic with a 2-sided 95% CI to 
compare differences between groups, specific to each component 
and comparison of DOOR distribution between groups.  
Descriptive analyses for secondary outcomes, and modeling to 
examine impact of confounding factors.  
Chi-Square tests will be used for categorical measures and t-tests 
or Wilcoxon tests for continuous measures. 
 
 
 

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1. 
INTRODUCTION, BACKGROUND, AND STUDY RATIONALE 
 
1.1 
The need for a trial 
 
Antimicrobial resistance (AMR) poses a major challenge for human health and is in 
large part fueled by overuse of antibiotics1,2. During the COVID-19 pandemic, global use 
of antibiotics was positively correlated with COVID-19 cases despite bacterial infection 
rates of less than 10%, resulting in further amplification of antimicrobial use (AMU)3. In 
Canada, overall AMU for human health decreased in community settings between 
2017-2021, but consumption of drugs in the “watch” and “reserve” categories of AWaRe 
(the WHO tiered classification system for antibiotics4) has increased by 25%, with 
concomitant increases in rates of infections caused by priority drug-resistant 
organisms5, including non-susceptibility to some of the newest antibiotics approved for 
use in Canada6. A large proportion of any hospital’s use of broad-spectrum antibiotics 
occurs in the intensive care units (ICUs), where the baseline risk of drug-resistant 
infections is higher7–9. Among a worldwide sample of ICU patients in 2017, 54% had a 
suspected or proven infection but 70% were receiving antibiotics10. In Canadian 
hospitals, ICUs account for at least 49% of all AMU, with > 50% of patients in ICU 
receiving antibiotics on any given day8. Because many patients in ICU have an 
undifferentiated illness, empirical antibiotic treatment is much broader than would 
ultimately be required if the infectious etiology was known11; even once a pathogen has 
been identified, appropriate narrowing of the spectrum of antibiotics occurs in only 30-
40% of cases12. Most recent guidelines clearly differentiate between septic shock and 
infection or sepsis without shock and introduce the possibility of delaying or withholding 
antibiotics if shock is absent18; yet, aggressive antibiotic prescribing remains the norm, 
with broadening of coverage when the clinician perceives lack of improvement (even if 
too early to expect improvement) or worsening (even in the absence of objective 
evidence of deterioration)11–13. 
Antibiotic prescription decisions in the critically ill are primarily driven by fear of under-
treatment, with a general impression that antibiotics “can’t hurt”, and this is further 
compounded by diagnostic uncertainty14,15. The cumulative frequency of adverse events 
associated with antibiotic use and patient level risk (C. difficile infection, nephrotoxicity 
associated with certain drugs or combinations, selection for AMR within the patient or 
within the ICU, breakthrough infections with drug-resistant organisms, drug-drug 
interactions, bystander effect on the microbiome which may detrimentally affect 
response to treatment of the underlying disease16 and other risks) are unknown. Such 
knowledge would more effectively counterbalance the fear of under treatment than 
metrics of antibiotic use or societal arguments on the risks of AMR.  
 
Antimicrobial stewardship (AMS) is a systems wide approach to promote appropriate 
AMU17. Studies have shown the benefit of different AMS strategies on clinical 
outcomes, particularly prospective audit-feedback in which a targeted review of the 
indication and appropriateness of antibiotics on a case-by-case basis (patient-level) 
lead to specific antibiotic treatment recommendations18–20. However, the lack of 
uniformity in methodologies, context, and selection of outcomes limit the generalizability 

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of specific interventions and systematic comparisons between studies21–25. Recently, a 
pragmatic cluster-randomized study of an audit-feedback strategy among patients 
hospitalized with COVID-19 in Alberta demonstrated that a simple intervention, with pre-
specified definitions of appropriateness and graded treatment recommendations, 
designed with minimal bias and prioritizing clinical outcomes rather than only antibiotic 
use, can lead to reduction in antibiotic exposure and serves as a useful template for 
further studies aiming to optimize AMU26.  
Optimization of AMU is dependent on accurate decision-making when appropriate 
diagnostic tests are obtained at the onset of infection. Although microbiologic tests 
(culture or nucleic acid-based amplification tests) are helpful to detect specific 
pathogens, they are not sufficient to lead to significant reductions in AMU or changes in 
clinical outcomes for hospitalized patients27,28. Further, positive bacterial results can 
result from colonization or contamination and are not always indicative of infection, in 
fact can lead to over-treatment10,29,30,31-33. Host response-based diagnostics tests could 
more accurately discriminate between non-infectious etiologies vs. microbial 
colonization vs. infectious disease, in an objective and quantifiable format34. 
Procalcitonin (PCT) is the best studied of such markers, with several trials showing that 
test results folded into antibiotic decision support guidelines curb the use of antibiotics in 
some infectious syndromes with no apparent harm35–38 but other studies have 
demonstrated that a strategy of PCT combined with graded treatment recommendations 
provided no added value beyond usual care, despite the careful use of quality-
improvement principles in the deployment of the intervention42.  
 
MeMed BV® (referred to as BV) is a novel diagnostic assay that exploits a targeted, 
multiplexed host protein signature to distinguish between bacterial and non-bacterial 
infection, or no infection (e.g colonization) 47.  The selection of the proteins was based 
on extensive bioinformatic screening followed by computational models to identify the 
combination with the best discriminatory power. The score performs robustly across 
different patient subgroups (age, gender, comorbidities, time from onset of symptoms, 
pathogen species), and is superior to individual or combinations of known biomarkers in 
differentiating between bacterial vs non-bacterial infections48–50. Its diagnostic accuracy 
has now been validated in >20,000 patients presenting with respiratory infections or 
fever without a source in emergency and inpatient wards in different countries, with BV 
score >65 predicting bacterial infection with a sensitivity of 98%, and BV<35 having a 
negative predictive value of 98.8% 51–53. The test is now Health Canada-approved, but 
whether it can be used to support antibiotic treatment decisions in ICU populations is 
not yet known as critically ill patients were excluded from previous studies.   
 
1.2 
Study Rationale 
 
The central question of this study is whether a biomarker-signature -supported antibiotic 
treatment decision matrix can have a beneficial impact on antibiotic use and patient 
outcomes in an ICU population.  
 

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We propose to combine the evaluation of this test pragmatically with an antibiotic 
treatment decision matrix in a manner that mimics real-life but is as close as possible to 
a “best-case” scenario - modeling our study on a successful NIH-funded multicenter trial 
of PCT-guided use of antibiotics which avoided many of the biases that previously led to 
overestimating the benefit of PCT42.  This study will inform researchers, practitioners, 
and health-care administrators whether and how this recently commercialized 
diagnostic assay should be incorporated in routine practice, ensuring diagnostic 
stewardship considerations are integrated within AMS considerations. 
 
1.3 
Potential impact 
 
We anticipate this study will demonstrate that an evidence-based implementation 
strategy of a BV-supported antibiotic treatment decision matrix can lead to a significant 
reduction of antibiotic use without compromising patient safety in an ICU population. If 
antibiotic exposure is not reduced in the intervention group (non-superior), we would not 
recommend implementation of the BV test widely. We would evaluate if the finding can 
be attributed to an unexpectedly lower antibiotic use in the control arm (compared to 
usual practice in ICU) and would recommend hospitals choose either the BV test or 
clinical assessment of prescription quality to reduce antibiotic use in ICU. If our findings 
demonstrate reduction in antibiotic use but evidence of harm in the intervention group, 
we will not recommend widespread implementation of the BV test but would carefully 
analyze our adverse outcome results to determine if select events are driving the overall 
finding. We would further perform subgroup analyses to assess if these outcomes 
occurred predominantly in specific groups.  
 
2. 
MEDICAL DEVICE 
2.1 
Description 
The LIASON® MeMed BV® is an innovative immunodiagnostic solution to differentiate 
bacterial from viral infection. The assay measures and integrates the serum levels of 
circulating host-response protein signatures: TRAIL (tumor necrosis factor-related 
apoptosis inducing-ligand), IP-10 (interferon gamma-induced protein 10) and CRP (C-
reactive protein). The result is a qualitative score – in less than an hour – discriminating 
between the bacterial and viral etiology of an infection.  
 
3. 
STUDY OBJECTIVES AND DESIGN 
 
3.1 
Overall Study Design 
 
BAST-ICU is a Pivotal study, observer-blind,  randomized controlled clinical trial  
designed to evaluate the effect of implementing a BV-supported antibiotic treatment 
decision matrix on antibiotic use and clinical outcomes, comparing the treatment 
decision matrix (intervention) plus standard of care to standard of care alone (control) in 
an ICU population. 
 

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This RCT will be used to determine the effect of implementing a BV-supported antibiotic 
treatment decision matrix on antibiotic use (efficacy) and on a combined clinical 
endpoint among study participants (safety).  
 
3.2 
Objectives  
 
3.2.1 
Primary Objective(s) 
 
To evaluate the combined endpoint of efficacy and safety at 28 days (approximately 4 
weeks). This will include: 
 Efficacy: Assessed by the use of antibiotics. 
 Safety: Assessed by clinical outcomes. 
 
3.2.2 
Secondary Objective(s) 
 
The assessment at 28 days will determine the overall effectiveness and safety of the 
intervention. To evaluate the following parameters: 
 
 Antibiotic-free Days in ICU: The number of days patients remain in the ICU 
without antibiotic treatment. 
 Use of Reserve/Restricted Antibiotics: The frequency and duration of the use of 
reserve or restricted antibiotics. 
 Adherence to Recommendations: The degree of adherence to the recommended 
treatment guidelines and protocols. 
 Incidence of Clinically Significant (Grade IV) Adverse Events: The occurrence of 
severe adverse events classified as Grade IV. 
 Recurrent Infections: The rate of infection recurrence during the study period. 
 Infectious Complications: The incidence of complications arising from infections. 
 Length of Stay in ICU: The duration of the patient's stay in the intensive care unit. 
 Death: The mortality rate during the study period. 
 Colonization with Multi-Drug-Resistant Organisms: The incidence of colonization 
by multi-drug-resistant organisms. 
 
3.2.3 
Exploratory Objectives(s) 
 
 To assess the incidence of colonization or infection with drug-resistant 
organisms. 
 To assess the degree to which age, sex, gender, ethnicity may affect antibiotic 
prescription, appropriateness, and adherence to treatment recommendation 
(physician prescription behavior) 
 
4. 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
Study Procedures will occur in the ICU from both MGH and RVH sites, with the RVH 
site serving as the coordinating center.  
 

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4.1 
Number of Participants 
 
Our target recruitment goal is 600 participants per group (1200 total participants) at 
participating MUHC sites.  
 
During the pilot phase of the study, it was documented that the study population in ICU 
are often incapable of  providing informed consent for themselves due to their health 
condition or due to the fact they are intubated. As of 17-Jun-2025, 40% of otherwise 
eligible patients could not  be approached by the research team as they suddenly lost 
their capacity to consent for themselves. Without the possibility to approach the Legally 
Authorized Representative who makes health decisions on behalf of the patient, there is 
a significant risk the BAST-ICU trial may not meet its enrollment target therefore study 
objectives.  
 
As this study represents minimal risks to participants, that medical decision-making 
remains in the treating team’s hands, and the objectives of the study would not be met if 
only patients with capacity to consent are approached, the inclusion criteria are updated 
to include:  
- 
 Participant who have suddenly lost capacity to consent due to their health 
condition (intensive care) and for whom a Legally Authorized Representative can 
be approached and provide consent for the patient. The research team will seek 
the participant’s consent (confirmation of consent or withdrawal) as soon as the 
participant regains capacity to consent.   
 
4.2 
Inclusion Criteria 
 
All participants must meet ALL of the following inclusion criteria: 
i. 
Adults (≥18 years) at the time of consent; 
ii. 
Admitted to the Intensive Care Unit (ICU);  
iii. 
Started on antibiotics for any suspected or confirmed infection in the preceding 
72 hours (about 3 days); 
iv. 
Treating doctor(s) willing to consider BV test result in antibiotic treatment 
decision making. 
v. 
Being able to provide informed consent. In case of sudden lost of capacity to 
consent due to the health condition (requires Intensive care), a Legally 
Authorized Representative will be approached by the study team.  
4.3 
Exclusion Criteria 
 
Potential participants who meet ANY of the following criteria will be excluded: 
i. 
Severe immunocompromise/immunosuppression 
a. Congenital immunodeficiency 
b. HIV with CD4 < 200 
c. Active chemotherapy and profound neutropenia (ANC < 100) expected to 
last > 7 days;  

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d. solid organ or stem cell transplant within preceding 6 months AND active 
GVHD 
e. Receiving high dose steroids (Pred > 20mg/day for > or =  2 weeks)   
ii. 
Advanced metastatic cancer irrespective of treatment 
iii. 
Palliative intent, death imminent and inevitable within 4 weeks 
iv. 
Antibiotic to be discontinued within 24h (ex. Prophylaxis)  
v. 
Active infection diagnosed and treated with antibiotics within preceding 2 weeks 
vi. 
Previously included during the same hospitalization 
 
4.4 
Strategies for Recruitment 
 
Participants will be recruited from two ICU clinic sites (MUHC: MGH and RVH).  The ICU 
treating team will identify potential participants and will inform them about the research 
project. If they are interested, treating teams will ask the patient for authorization to be 
approached by the research team. If the potential participants are interested, study 
coordinator will present the study, and the consent process can begin.   
 
Consent process: 
A delegated research staff will read the ICF in its entirety with the participant and explain 
the study protocol. Time and opportunity to discuss with the treating team and relatives 
will be given, and all questions will be answered. After reflection, if the participant agrees 
to participate in the study, the ICF will be signed by the participant and the person 
obtaining the consent. A copy of the signed ICF will be given to the participant for their 
own records. The ICF will also be scanned and placed in their hospital medical chart. 
 
E-consent: 
1) The consent process for e-consent is the same as for wet-ink signature. REDCap, a 
secure FDA part 11 compliant platform, is used to collect signatures from the participant 
and the person obtaining consent and for participant's research file storage during the 
study. If the participant opts for electronic signature, they will receive a link by email which 
will lead them to the REB approved ICF in pdf format uploaded to REDCAP (there is no 
need to submit a e-consent form as the same consent is used).  
 
4.5 
Enrollment Procedures 
 
Upon confirmation of eligibility and consent (Appendix I), each participant will be 
randomly allocated a randomization number and a unique Participant Identification (ID) 
number which will serve as their identifier throughout the study. Once a randomization 
number and Participant ID number have been assigned, they cannot be re-assigned to 
any other participant. This measure ensures that each participant's data remains distinct 
and accurately attributed. A participant cannot receive more than one ID number, 
ensuring that each participant's contributions to the study are accounted for singularly 
and accurately. 
 
All participants will be given a participant identification card identifying them as 
participants in a research study. The card will contain study site contact information 

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(including direct telephone numbers) to be used in the event of an emergency. The 
investigator or qualified designee will provide the participant with a participant 
identification card immediately after the participant provides documented informed 
consent. 
 
4.6 
Co-enrollment Guidelines 
 
Patients can be enrolled in other clinical trials if there is no conflict with the inclusion or 
exclusion criteria of the BAST-ICU study, and the other protocol is not in conflict with the 
means of data collection and publication of this protocol. 
4.7  
Pregnancy and/or breastfeeding 
Pregnant or breastfeeding women can be included in this study if they meet the 
eligibility criteria. Since the study intervention is providing advice on antibiotic therapy 
that has already been prescribed by the treating team, there is no contraindication to 
exclude pregnant or breastfeeding women.  As per standard of care, the pregnancy and 
breastfeeding status of potential participant will be reviewed and documented by the 
treating team.  
5. 
PILOT Testing of Enrollment Processes and BV Score Validation 
Before the implementation of the main study, a pilot phase will be conducted to refine 
the study enrollment procedures and validate the BV Score. Participants will be 
screened and enrolled but will not be randomized for the intervention, and their test 
results will not be used for decision-making.  
5.1 Number of Pilot Participants 
A total of 40 pilot participants will be included. Target population: 
- 
Non-infected post-op patients  (eg. post-cardiac surgery with no clinical, 
radiological or microbiological evidence of infection) (n= 10) 
- 
Non-infected and non post–op patients (eg. CHF, trauma) (n=10) 
- 
Patients with confirmed bacterial infection (eg. confirmed ventilator-associated 
pneumonia, bacteremia) (n = 10) 
- 
Patients with presumed or confirmed viral pneumonia (without a confirmed 
bacterial superinfection) (n = 10) 
 
5.2 Pilot Participant Eligibility Criteria 
Study team members will screen eligible participants that are 18 years old belonging to 
any of the target populations.  
 
5.3 Pilot Procedures 
For each of the participants, a blood sample for BV testing will be collected on the day 
of enrolment and brought to the research laboratory for testing.  
 

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5.4 Pilot Data Collection and Analysis 
Study team members (PI/Co-I and Pharmacist) will assess clinical and laboratory 
parameters and establish a consensus-based determination of bacterial/no-bacterial 
infection independent of BV results. Subsequently, BV results will be plotted on a 
receiver operating characteristic (ROC) curve to verify the cut-off values established by 
the manufacturer (BV <35: low likelihood of bacterial infection; 35 ≤65: equivocal; >65: 
high likelihood of bacterial infection) in this population. 
 
6. 
WITHDRAWAL OF PARTICIPANTS 
6.1 
Withdrawal criteria 
 
A participant may be withdrawn from the study if they meet the following criteria: 
- 
It is deemed in the participant's best interest based on the Investigator's clinical 
judgment. 
- 
The sponsor decides to terminate the study. 
- 
A new health condition arises that necessitates withdrawal. 
- 
The participant or their LAR chooses to withdraw. 
 
In such cases, data collected up to the point of withdrawal will be retained and 
analyzed, unless the participant explicitly requests that their data be destroyed and 
excluded from the analysis. If a participant requests withdrawal after data collection and 
analysis have been completed, the request will be considered on a case-by-case basis. 
 
7. 
RANDOMIZATION AND BLINDING PROCEDURES 
7.1 
Randomization  
 
Eligible participants will be randomized in a 1:1 ratio to either the intervention or control 
groups. Randomization will be stratified by study center to account for site-specific 
participant characteristics and physician practices. This stratification ensures that any 
potential confounding factors associated with the different sites are balanced across the 
treatment groups. 
 
To further ensure the randomization process is robust, block randomization will be 
utilized within each site. The blocks will have varying sizes, determined by an internet-
based randomization tool, to prevent predictability and maintain the integrity of the 
allocation process. The specific block sizes will remain undisclosed to the research 
team and participants to ensure concealment and prevent potential bias. 
 
7.2 
Blinding during Enrollment and Clinical Assessments 
 
All team members remain blinded during the Enrollment and Clinical Assessment 
Stages. The study team, (PI/CO-Is that are ID physicians, pharmacist, and laboratory 
technologist performing BV testing), will remain blinded while conducting the clinical 
assessment and laboratory testing. 

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7.3 
Unblinding at the Intervention Stage 
 
The results of the MeMed BV test, a diagnostic tool used in the study, will only be 
disclosed for participants in the experimental group. This means that only those in the 
experimental arm and their treating teams may have access to this specific information, 
which may influence their treatment. The study and treating team will be informed of the 
treatment group assignment when the intervention begins, specifically when the clinical 
assessment is completed.  
 
8. 
STUDY PROCEDURES 
8.1 
Study Flow Chart 
 
 
 
 
 
 

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8.2 
Schedule of Events 
 
Procedures 
Screening  
Day 0 
Day 11  Day 3  Day 7  Day 14  Day 28   
Visit Window 
-3 days 
 
 
± 1 day ± 1 day ± 1 day + 2 days 
Enrollment   
Informed Consent 
X 
 
 
 
 
 
 
Eligibility Assessment  
X 
 
  
  
  
  
  
Randomization   
  
 
X  
  
  
  
  
Interventions  
Prescription assessment   
X 
  
  
  
  
Research Blood Collection for BV 
Testing 
X 
BV test reporting2   
  
 
X 
  
  
  
  
Treatment recommendation   
  
 
X 
  
  
  
Assessments  
Demographics   
X 
 
  
  
  
  
Medical History   
X 
 
  
  
  
  
Diagnostics/microbiological results   
X 
X 
X 
X 
X 
X 
X 
Adherence to treatment 
recommendation   
  
 
  
X 
 X 
X  
X  
Signs/symptoms of infection   
 X 
X 
X 
X 
X 
X 
X 
Antibiotic use   
X 
 
X 
X 
X 
X 
X 
Adverse events, safety outcomes   
 
 X 
 X 
X 
X 
X 
Outcome / disposition   
  
 
  
  
  
  
X 
1Day 1 is defined as the day of randomization until 11:59 pm of the same day.  
2BV test result for intervention group only.  

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8.3 
Screening Period (-3 days to 0 days) 
 
Prior to enrollment, potential participants will be evaluated to determine that they fulfill 
the entry requirements as set forth in Sections 3.2 and 3.3. Participants are expected to 
enroll as soon as possible after eligibility is confirmed. 
 
The Investigator will perform a preliminary assessment of the participant’s eligibility. 
Prior to screening, the Investigator or designee will explain the study to the 
participant/LAR in lay terms. If the participant/LAR consents to participation in the study, 
during a 1 hour visit the following will be performed: 
 
- 
Complete the informed consent process with participant/LAR. 
- 
Provide participant/LAR with a copy of signed and dated consent form.  
- 
Assign Participant ID from REDCap.  
- 
Perform the assessment of inclusion/exclusion criteria. 
- 
Obtain the participant’s medical history, pre-existing or active conditions. 
- 
Collect the following data on participant: 
o Demographics: Age, sex, gender, ethnicity, ;  
o Admission data: date of admission to the hospital and ICU  
o Medical History  
o Antibiotic prescription; name of drug, dose, start and end date 
o Clinical status; vital signs, temperature (T max day -2 to Day 1), ventilation 
status; need for vasopressor support (type and dose)  
o Data on infection; site, microbiological results, signs and symptoms of 
infection 
o Basic laboratories; hematological, biochemical (routine) 
o Imaging; pertinent X-ray and/or CT scans 
o Baseline status of MDRO colonization: swab results for MRSA, VRE, CPE 
 
8.4 
Baseline Visit (Day 0) 
 
Study team (Pharmacist and PI/Co-I) perform a clinical assessment of the participant to 
establish a baseline assessment of the antibiotic prescription (indication and 
appropriateness of antibiotic) and enter the assessment into the eCRF.  
 
- 
Collect the following data on participant: 
o Antibiotics prescribed (start and end dates, name, dose) 
o Microbiological results  
o Colonization status for MDRO  
o Signs and symptoms of infection   
o Adverse events related to antibiotics if any 
o Laboratory values for creatinine, liver, hematology 
- 
Research Blood Collection; Collect up to 5 mL (1 teaspoon) of blood for research 
laboratory BV testing and analysis 
 
 

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8.5 
Randomization and Intervention (Day 1) 
 
Study team will enter study ID in randomization system and obtain a study group 
assignment. Based on the assignment, BV test result is communicated to the blinded 
team.  
 
The study team (Pharmacist and PI/Co-I) finalize treatment recommendation for both 
groups (BV value only available for the intervention group) by placing the 
recommendation in the medical chart.   
 
- 
Collect the following data on participant: 
o Antibiotics prescribed (start and end dates, name, dose) 
o Microbiological results  
o Colonization status for MDRO  
o Signs and symptoms of infection   
o Adverse events related to antibiotics if any 
o Laboratory values for creatinine, liver, hematology 
 
8.6 
Follow-Up (Days 3, 7, & 14 ± 1 day) 
 
- 
Collect the following data on participant: 
o Review adherence of antibiotic treatment recommendation. 
o Antibiotics prescribed (start and end dates, name, dose) 
o Microbiological results  
o Colonization status for MDRO  
o Signs and symptoms of infection   
o Adverse events related to antibiotics if any 
o Laboratory values for creatinine, liver, hematology 
 
8.7 
End of Study Visit EOSV (Day 28 + 2 days) 
 
If participant is discharged prior to Day 28, provide a BAST-ICU discharge packet (28-
day antibiotic use diary and report any symptoms). Every effort should be made to 
complete the Day 28 visit by conducting a remote call. 
 
- 
Collect the following data on participant: 
o Review adherence of antibiotic treatment recommendation. 
o Antibiotics prescribed (start and end dates, name, dose) 
o Microbiological results  
o Colonization status for MDRO  
o Signs and symptoms of infection   
o Adverse events related to antibiotics if any 
o Laboratory values for creatinine, liver, hematology 
o Vital status: date of death, date of discharge from ICU, date of discharge 
from hospital  
o Disposition upon discharge from ICU  

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o Final clinical outcomes and DOOR ranking 
 
8.8 
Study Procedures common to both groups: Assessment of antibiotic 
prescription 
 
Before recruitment of the first patient, the investigators at each site (MGH and RVH) 
ensure that all legal and regulatory requirements are met. No patients are to be 
screened or included until the trial starts by the project coordinator.  
 
For all participants, the study team (Pharmacist and PI/Co-I) will review the medical 
chart and complete a standard prescription quality assessment form. All participants will 
have baseline data consisting of: 
 
- 
Sociodemographic information 
- 
Comorbidities, current medications 
- 
Vital signs  
- 
Test results and therapeutics relevant to current illness  
- 
Antibiotics prescribed and received 
 
Based on this assessment, they will arrive at a rating of the antibiotic prescription that 
includes 3 domains: Appropriateness of diagnostics, necessity of antibiotics, and choice 
of antibiotics. 
 
8.9 
Antibiotic treatment decision procedure specific to the control group 
 
For the control group, the BV test result will remain masked to investigators and treating 
team members.  
 
The antimicrobial stewardship study team (Pharmacist and PI/Co-I) will issue antibiotic 
treatment suggestions following the standard decision matrix outlined below. The 
recommendation will be shared with the treating team. 
 
Necessity of 
antibiotics  
Recommendation on antibiotic treatment 
Clearly not indicated  
STOP (strong recommendation) 
Somewhat indicated 
Stop (moderate recommendation) or continue --> review 
choice* 
Indicated (Justified) 
Continue antibiotic --> review choice *   
Cannot be rated  
Consider expert (ID) consultation  
 
For all cases where necessity of antibiotics was rated as “somewhat indicated” or 
“indicated”, the choice of antibiotics will be rated. The final recommendation (to stop, 
continue or change antibiotic) is shared with the treating team.   
 
 
  

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Choice of antibiotic 
Recommendation on antibiotic treatment 
Far too broad 
Change drug (strong recommendation) 
Somewhat too broad 
Consider changing drug (moderate recommendation) 
Appropriate choice 
Continue same drug 
Somewhat too narrow 
Change drug  
Cannot be rated 
Consider expert consultation (ID) 
 
8.10 
Antibiotic treatment decision procedure specific to the experimental group 
 
The result of the BV test will be unmasked for the investigators and combined with the 
prescription assessment form using the decision matrix below. The final 
recommendation (to stop, continue or change antibiotic treatment) will be shared with 
the treating team.  
 
Necessity of 
antibiotics   
BV score < 35  
BV ≥ 35 ≤ 65  
BV > 65  
Clearly not 
indicated  
STOP* 
STOP*  
Expert consultation  
Somewhat 
indicated  
STOP*  
STOP**    
Continue ***   
Justified  
Expert 
consultation  
Continue ***  
Continue ***  
Cannot be rated  
STOP*  
STOP**  
Continue ***   
*Strong recommendation; **Moderate recommendation; ***review choice of antibiotic  
 
In all cases of “continue antibiotic treatment***”, rate the choice of antibiotic. The final 
recommendation (to stop, continue or change the antibiotic) will be shared with the 
treating team.  
 
Choice of antibiotic:  
 
Recommendation 
Far too broad 
Change drug  
Somewhat too broad 
Change drug  
Appropriate choice 
Continue same drug  
Somewhat too narrow 
Change drug  
Cannot be rated 
Expert consultation  
 
8.11 
Table 1 Data Collection 
 
At enrollment  
Demographics: Age, sex, gender, ethnicity 
Admission data: Date of admission to hospital, date of admission to ICU 
Reason for admission to hospital, reason for admission to ICU 
Comorbidities (diabetes, cardiovascular, liver, renal, ...) 

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Antibiotic prescription: name of drug, dose, start and end date 
Suspected/confirmed Diagnosis (according to treating team) 
Clinical status:  
Vital signs, temperature (T max day -2 to Day 1), ventilation status; Need for 
vasopressor support (type and dose) 
Data on infection: 
Site, Microbiological results 
Signs and symptoms of infection 
Basic laboratories: Hematological, biochemical (routine) 
Imaging: Pertinent Xray, CT scans  
Baseline status of MDRO colonization: swab results for MRSA, VRE, CPE 
During study period 
Antibiotics prescribed (start and end dates, name, dose) 
Antibiotic treatment recommendation, date of recommendation, adherence to 
recommendation 
Microbiological results 
Colonization status for MDRO 
New signs and symptoms of infection  
Adverse events related to antibiotics 
Laboratory values for creat, liver, hematology 
End of study 
Vital status: date of death, date of discharge from ICU, date of discharge from hospital 
Disposition upon discharge from ICU 
Final clinical outcomes and DOOR ranking 
 
9. 
CLINICAL AND LABORATORY EVALUATIONS 
9.1 
Clinical Evaluations  
 
After informed consent has been obtained, a research member with appropriate training 
will record the listed information on the eCRF. The initial evaluation will document 
reasons for ICU admission, current presentation and symptoms, working diagnosis, the 
reason for antibiotic therapy, and results of laboratory and diagnostic investigations. 
Patients will be monitored for 28 days or until death, with an End of Study Visit (EOSV) 
conducted at the conclusion. 
 
Data collected during follow-up visits will include antibiotic prescriptions, symptoms of 
infections, laboratory and radiological results from the treating team, and adverse 
events. Antibiotic data will be extracted from the APSS (Lumed) application, while 
clinical diagnosis and evolution data will be sourced from patient charts and direct 
observation. Adverse events will be reported as part of the primary safety outcome. 
 

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All data will be collected on an electronic case report form (CRF). Original study forms 
(source documents) will be kept on file at the study site. All data will be kept for at least 
7 years after the study's close.   
 
9.2 
Schedule of Clinical Evaluations and Data Collection 
 
 
Clinical 
data  
Laboratory 
data  
Microbiological 
data  
Radiological 
data  
Antibiotic use data  
Baseline  Signs and 
symptoms of 
infection; 
syndrome  
MeMedBV; 
CRP and PCT 
if collected by 
treating team  
Micro collected 
since enrollment 
by treating team  
Pertinent 
radiological 
findings if 
available  
Start dates for all 
antibiotics prescribed 
since enrollment   
Day 3  
New signs of 
infection  
Standard of 
care (if 
available: 
CBC, SMA-7, 
LFTs, CRP, 
PCT)   
 
Results of all 
Micro cultures 
collected since 
enrollment)   
findings 
pertinent for 
source of 
infection  
Start and end dates 
for all antibiotics; 
follow-up adherence 
to treatment 
recommendation  
Day 7  
New signs of 
infection  
Or adverse 
events from 
antibiotics  
Standard of 
care (if 
available: 
CBC, SMA-7, 
LFTs, CRP, 
PCT)  
Results of all 
Micro cultures 
collected since 
enrollment)  
 
 
Start and end dates 
for all antibiotics  
Day 14  New signs of 
infection or 
adverse 
events from 
antibiotics  
 
Standard of 
care (if 
available: 
CBC, SMA-7, 
LFTs, CRP, 
PCT)  
 
Results of all 
Micro cultures 
collected since 
enrollment)  
 
Imaging findings 
pertinent for 
new infection or 
source of initial 
infection  
Start and end dates 
for all antibiotics  
 
Day 28 
+/- 2  
Outcome 
Status  
Standard of 
care (if 
available: 
CBC, SMA-7, 
LFTs, CRP, 
PCT)  
 
Results of all 
Micro cultures 
collected since 
enrollment)  
 
Start dates for 
all antibiotics 
prescribed since 
enrollment   
Start and end dates 
for all antibiotics  
 
Obtain blood sample; freshly collected sample should be processed (clotting, 
centrifugation and serum separation) within two hours for testing (see lab manual).     
 
9.3 
Specimen Collection and Laboratory Evaluations 
 
Personnel who collect specimens from participants must use personal protective 
equipment (PPE) in accordance with their institution guidelines. Collection kits will be 
provided to participating sites along with a laboratory manual describing the collection of 
quality samples as well as instructions for specimen processing, safe storage 
requirements and packaging to the research lab for analysis. 

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Aside from the initial BV testing, the study team will not request any additional blood 
work but will collect data on laboratory, microbiological and pertinent radiological 
findings requested by the treating team.  
  
The initial blood tests requested for BV testing will be collected from all participants on 
enrollment day. Testing will be performed according to the manufacturer’s instructions in 
the research space of the MI4 CRP (see lab manual). The personnel performing the 
measurements will be blinded to clinical information and results of other investigations. 
Within 24 hours of testing, BV results will be provided to the study team only for the 
intervention group; results of the control group will remain hidden.  All lab materials 
used for this testing will be supplied by research funds.  
 
9.3.1 Research Blood Collection Serum Specimen 
 
Blood will be collected in 1 x 6mL yellow top SST vacutainer on Enrollment. Study 
personnel will collect equal amounts of serum into pre-labelled 2 mL cryovials. 
Research blood samples should be processed within two hours for testing. Detailed 
instructions for the collection, storage and shipment of the serum samples are provided 
in the Laboratory Manual.  
  
10. RISK MANAGEMENT 
10.1 
Risk Management 
 
 We have implemented several procedures  to minimize  potential risks to participants. 
These include: 
- 
Specific study inclusion and exclusion criteria to minimize risks for specific high-
risk populations   
- 
Participants will have one additional blood sample (about 3-5mL) to be combined 
with usual bloodwork, on the day of enrollment. The risk of blood sampling 
includes bleeding, bruising and pain at the drawing site. These risks will be 
reduced by trying, as much as possible, to collect blood when other standard of 
care blood tests are being collected. 
- 
The study ensures that standard of care is provided to all participants, with the 
clinician making final treatment decisions. While the study team's 
recommendations on antibiotic therapy may inform the treating team, they are 
not obligatory. The study team mitigates risks associated with potentially 
insensitive or non-specific biomarker assessments by prioritizing clinical 
judgment and suggesting expert consultations in cases of significant 
discrepancies.  
- 
Confidentiality risks are minimized by coding participant information and securely 
storing it in compliance with MUHC REB policies. 
 

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11. EVALUATION, RECORDING, AND REPORTING OF ADVERSE EVENTS  
In this RCT, the primary safety outcome will encompass all significant potential adverse 
events related to the cessation or withholding of antibiotics. These adverse outcomes 
will be integrated into the primary safety outcome measure and will not be reported 
separately as Adverse Events (AEs) or Serious Adverse Events (SAEs) elsewhere in 
the study. 
 
Despite our comprehensive approach, unforeseen adverse events may still occur. 
Therefore, ongoing monitoring of AEs is essential to ensure participant safety and 
maintain data integrity. 
 
11.1 
Definitions 
 
11.1.1 Adverse Event (AE) 
 
An AE is any untoward medical occurrence in a participant or clinical investigation 
participant, administered a study medication/intervention (e.g., recommendation for 
antibiotic cessation), which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of 
a medicinal (investigational) study medication/intervention, whether related to the 
medicinal (investigational) study medication/intervention. 
 
11.1.2 Serious Adverse Events (SAEs) 
 
An SAE is any untoward medical occurrence that: 
 Results in death; 
 Is life-threatening (i.e., event in which the subject was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe); 
 Requires inpatient hospitalization or prolongation of existing hospitalization (i.e., 
all medical events leading to hospitalizations will be recorded and reported as 
Serious Adverse Events, except for: hospitalization planned before inclusion into 
the study or out-patient treatment with no hospitalization). Note that an elective 
hospital admission will not be considered as a serious adverse event; 
 Results in persistent or significant disability/incapacity (i.e., persistent or significant 
disability or incapacity” means that there is a substantial disruption of a person’s 
ability to carry out normal life functions); 
 Is a congenital anomaly/birth defect 
11.2 
Event Reporting 
 
We will capture all major potential adverse events related to antibiotic 
cessation/withholding in the combined primary safety outcome. The adverse outcomes 

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comprising the primary safety outcome will be included in outcome reporting and not 
reported a second time as Adverse Events (AE) or Serious Adverse Events (SAE).  
 
However, as with any procedure or intervention, there may be adverse events that are 
currently unknown. Monitoring of AE is critical to the participants safety and data 
integrity. An AE will be defined as any untoward medical occurrence (unfavorable and 
unintended sign, symptoms or disease) in a participant temporally associated with the 
study intervention (eg. recommendation for cessation of antibiotics) but not necessarily 
related to participation in the study.  A SAE will be defined as an untoward medical 
occurrence that results in death, is life-threatening or requires prolongation of ICU stay, 
results in disability or incapacitation.  
 
AE and SAE will be recorded when reported by the treating team or study team nurse or 
when documented in the medical record. If a reportable SAE, the site PI will be review 
the pertinent records (including medical notes, laboratory and radiographic data). The 
information, along with the site PI’s impression of the diagnosis, will be recorded in the 
eCRF. The site PI will assess causality between the event and the intervention using 
best clinical judgement.   
 
11.3 
Criteria for Adverse Events related to antibiotics 
 
Adverse event1 
Definition 
Non-C. difficile 
associated 
diarrhea 
> 3 loose stools per day associated with Antibiotic use, in absence of 
laxative or pre-existing enteritis (C. diff excluded from this category) 
C. Difficile 
infection 
Clinical signs and symptoms consistent with CDI and PCR test 
positive (and no laxatives) 
Nausea/vomiting 
Nausea and vomiting associated with antibiotic administration, in the 
absence of alternative explanation 
Hematologic 
Anemia: hemoglobin <10g/dL 
Leucopenia: WBC < 4500 cells/uL 
Thrombocytopenia: platelets <150x103/uL with levels below patient’s 
baseline and in absence of bleeding or myelosuppressive therapy 
Hepatobiliary 
Cholestasis (bili > 51umol/L) or transaminitis (ALT, AST > 3x baseline) 
in the absence of existing hepatobiliary disease or recent biliary 
instrumentation 
Renal 
Increase in serum creatinine > 1.5x patient’s baseline in the absence 
of precipitating factors such as intravenous contrast or other 
nephrotoxic agents, and not related to sepsis 
Neurologic 
Altered mental status, peripheral neuropathy, seizures in the absence 
of pre-existing neurological conditions or substance-related toxic 
events and unrelated to infectious syndrome 
Dermatologic 
Rash, including hives, non-hives rashes, red man syndrome – 
temporally associated with antibiotics; resolution with antibiotic 
cessation  

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Cardiac 
QTc>440 ms in males or >460ms in females in absence of pre-
existing arrhythmias, based on >2 ECGs 
Anaphylaxis 
Acute onset respiratory compromise, hypotension, or end organ 
dysfunction within minutes after antibiotic administration, without 
alternative explanations 
Myositis 
Increase in creatine kinase level >5 x patient’s baseline, in absence of 
statin use or pre-existing myopathy 
1Adapted from Tamma et al, JAMA 2017 
 
11.3.1 AE Descriptions and Reporting 
 
AEs and SAEs will be documented when reported or noted in the participant's medical 
records by the treating team. 
 
11.3.2 Intensity 
 
The severity of each AE, including laboratory and testing abnormalities and results, will 
be graded according to Common Terminology Criteria for Adverse Events (CTCAE). 
 
 
11.4 
Reporting and Evaluation of SAEs  
 
11.4.1 SAEs 
 
The Site PI will review relevant records provided by the research team such as medical 
notes, laboratory results, and radiographic data. This information, along with the Site 
PI’s assessment and diagnosis, will be recorded in the electronic Case Report Form 
(eCRF). 
 
12. STATISTICAL CONSIDERATIONS 
12.1 Rationale 
Instead of evaluating safety and efficacy separately, we will apply an approach that is 
increasingly used in trials comparing therapeutic interventions for selected infectious 
diseases to provide a global evaluation of the benefits and risks of the intervention: 
Desirability of Outcome Ranking (DOOR), which can further be combined with antibiotic 
use outcomes, Response Adjusted for Duration of Antibiotic Risk (RADAR) 55–59. In this 
approach, trial participants are ranked with respect to the desirability of their overall 
outcome, and during study analysis, the distribution of DOORs are compared between 
study arms. These are further analyzed with antibiotic use outcomes under the principle 
that less antibiotic use is better, but not at the expense of clinical outcomes. All 
participants will have a DOOR assigned based on a review of the individual patient 
during the course of the study, where the ranking will be constructed from a defined 
number of mutually exclusive hierarchical levels ranging from least desirable (death) to 
most desirable (e.g., cure, no adverse events). Using such a combined endpoint will 

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enable us to determine if BV-supported antibiotic treatment recommendation will yield 
better outcomes than usual care alone.   
12.2 Definitions for clinical outcomes and ranking of outcome categories (DOOR) 
Points are assigned for overall outcomes, with pre-specified definitions for treatment 
failure, complications and adverse events related to antibiotic use. All clinical outcomes 
will be reviewed by a 3-member clinical review panel, and all AE will be reviewed by a 
different 3-member panel (the Data Safety and Monitoring Committee). The panels will 
consist of experienced ID, Pharmacy and ICU experts (to be named) blinded to 
intervention and patient identity. 
 
Clinical outcome 
Definition 
Treatment failure 
Signs and symptoms of initial event (infectious illness) 
within 72h of end of antibiotic treatment 
Infection persistence 
Continued presence of signs and symptoms and of original 
causative pathogen at end of antibiotic treatment 
Infection recurrence  
New infection due to at least one of the original causative 
agents found at baseline (initial event) 
Infectious complication 
Signs and symptoms requiring surgical or other procedure 
in organ involved in initial event (eg. empyema post 
pneumonia) occurring >72h after end of antibiotic treatment  
 
We will determine how many DOOR events (AE, infection recurrence etc.) occurred for 
each participant, then assign a mutually exclusive rank.   
 
RANK   
Criteria 
1 
Survival, clinical benefit of treatment, with NONE of treatment failure, persistence, 
recurrence, complication AND NONE of Grade IV adverse event (AE)  
2   
Survival, clinical benefit of treatment, with NONE of treatment failure, persistence, 
recurrence, complication, AND at least one of AE    
3   
Survival, at least one of treatment failure, persistence, recurrence, complication, AND NONE 
of AE  
4   
Survival, at least one of treatment failure, persistence, recurrence, complication AND at least 
one AE   
5   
Death    
 
12.3 RADAR Score 
The antibiotic use will be defined as number of days with antibiotic treatment (DOT, 
aggregate sum of days for which any amount of a specific antibiotic is given, eg. if 2 
different antibiotics for 5 days, DOT = 10 / days in ICU.   
 

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12.4 Sample Size and Justification 
DOOR-RADAR requires fewer patients than conventional non-inferiority analysis but 
since a major objective of this study is to enable a detailed analysis of adverse events 
related to antibiotic use, we have calculated a sample size that would enable separate 
analysis of clinical outcomes and antibiotic use (Sample size calculations detailed in 
Appendix I).  
  
Testing hypothesis 1 (H1): We desire at least 80% power to test our primary hypothesis 
that BV-supported antibiotic treatment decision can lead to reducing antibiotic exposure 
using a one-sided significance of 0.05. Demonstrating H1 would require a sample size 
of 352 participants per group for a mean difference in antibiotic days of 1.5 (SD 8 days). 
Based on studies evaluating AMS interventions in the ICU, we estimate a 1.5 days 
difference between the 2 groups to be significant14,18,36. Further, it would be equivalent 
to a 20% decrease in total antibiotic days, a reasonable assumption considering 
antibiotics are “clearly not indicated” or “only somewhat (dubious) indicated” in about 
30% of cases based on prior retrospective audits of prescription quality.  
Testing hypothesis 2 (H2):  BV-supported antibiotic treatment algorithm does not lead to 
worse clinical outcomes. Studies using combined endpoints of adverse outcomes have 
estimated between 10-25% rates of combined adverse outcomes (death, septic shock, 
mechanical ventilation, renal failure)38,42,43. A meta-analysis of PCT-guided antibiotic 
treatment in patients with infection and sepsis in ICU reported all-cause mortality rates 
of 23% at 30-days35. Studies evaluating adverse events specifically related to antibiotic 
use in hospitalized patients suggest rates of 12% within 30 days. We expect a 
combined adverse outcome rate of 18-20% and will set a non-inferiority margin at 4%. A 
sample size of 529 patients per group (1060 in total) will therefore provide 80% power to 
demonstrate H2 (a robust safety evaluation), and yet be exceptionally well powered for 
efficacy (with preserved power under a wide range of assumptions).  
  
12.5 Expected Study Recruitment Flow Chart 
 

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12.6 Estimations of Adverse Outcomes in ICU  
 Combined severe (Grade IV) adverse events secondary to antibiotics (excluding 
renal): 5-10%  
 Overall Acute kidney injury in ICU (all cause): 26-67%  
 Drug induced liver injury:  rare (16-19/100,000)  
 All cause ICU Mortality: 3-28% (MUHC ICU mortality: 13%; median length of stay 
in (IQR): 3.2 days (1.5, 7.6)) 
12.7 Primary Analysis 
The primary analysis will be an intent-to-treat (ITT) and will include 2 interim analyses at 
1/3 and 2/3 enrolment. The final analysis will use Lan-DeMets stopping rules62. We will 
also perform per-protocol analyses where the treatment recommendations were 
followed.  
12.8 Frequency of Analyses 
Our approach for interim monitoring is to test H1 first (null H1: no difference between 
intervention and control in terms of antibiotic exposure). Should the null H1 be rejected 
at the first interim, then the second hypothesis (H2: no significant difference in 
combined endpoint of adverse events between the 2 groups) will be assessed and 
decision to continue will be based on H2. If H1 is not rejected at the interim, then H2 will 
not be assessed until the final analysis. We estimate that H1 testing may cross the pre-
specified boundary at one of the interim analyses, but H2 testing may only meet non-
inferiority once full sample size is enrolled.   
 
Based on data for MUHC (2019-
2020):   
Admissions per year: n = 2800 (n = 8400 
for 3 years)  
Discharge <48h: 1050/y, n = 3150  
Admissions > 48h: 1750/year; n = 5250 
for 3 years 
Inclusion: 60% of all admissions are 
started on antibiotics, n = 3150 
Potential exclusions: 13% of admitted 
patients are severely 
immunocompromised, so n= 410  
Enrollment: expect 50% of approached 
patient to consent; n = (3150-410)*50% = 
1370 
Maximal sample size required: 1060 

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12.9 Final Analysis 
We will compare the difference in antibiotic use between groups by a one-sided test 
comparing the mean duration of antibiotic use.We will also compare the DOOR 
distribution between groups, and the DOOR probability of having a more desirable 
outcome in intervention group versus control. A DOOR probability of 50% will indicate 
no statistical difference between groups. We will additionally calculate the probabilities 
specific to each component (AE, infectious complications, etc), using methods 
described in prior studies57. We will further perform descriptive analyses for secondary 
outcomes, and modeling to examine whether confounding factors (Age, qSOFA or 
Charlson comorbidity scores) impacted estimates of intervention effect and safety. 
Randomization quality will also be evaluated for potential differences between arms for 
baseline variables. Chi-Square tests will be used for categorical measures and t-tests or 
Wilcoxon tests for continuous measures.  
We anticipate that the percentage of missing data will be negligible as the outcomes of 
interest are part of routine data collection in the ICU setting and the observation period 
of interest is while the patient is in the hospital. In the event some data is lost (eg. 
Medical chart is misplaced or lost, electronic medical data inadvertently deleted), we will 
not replace those lost to follow-up and the data from those participants will be included 
in the Intention-to-Treat analysis. We will also conduct a sensitivity analysis of those lost 
to follow-up to ensure there is no systematic bias. 
  
12.10  Sub-Group Analyses:  
Studies have shown significant gender differences in antibiotic use with women being 
27% more likely to receive antibiotics in their lifetime than men63. This has at least in 
part been attributed to health-seeking behavior, and gender disparities tend to diminish 
with older age and comorbidities64. More recently, studies conducted in the US have 
shown significant disparities in rates of inappropriate antibiotic prescriptions related to 
race and ethnicity, with blacks and Hispanics more at risk of receiving inappropriate 
prescriptions than whites65. We will specifically conduct subgroup analyses to determine 
if sex, gender, ethnicity impact not only antibiotic prescription quality and clinical 
outcomes, but also the treating team’s adherence to BV-guided treatment 
recommendations.  Our study sites service a large proportion of the First Nations, Inuit 
and Metis populations of Quebec, with medivac transfers for procedures and 
hospitalizations.   
 
13. DATA MANAGEMENT 
All participant data will be entered by study staff into the secure web-based REDCap 
data entry system and uploaded to the study database server via secure hospital 
server. Each study team member will have specific access and rights defined by their 
study role. The system will fulfil standards of good epidemiological practice, and security 

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and data protection standards. Data will be entered accurately and comprehensively by 
the responsible site staff. 
 
Any identifying data will be maintained separately from clinical, laboratory and follow-up 
data for added security and confidentiality.  
 
13.1 
Data Monitoring and Auditing 
 
Data monitoring will be performed by data monitoring study team member based at the 
central (Glen) site, for completeness and plausibility, logic checks for accuracy, and will 
send queries to the study nurses in cases of ambiguity or errors. Data documentation 
will be performed continuously. Data verification for primary outcomes will be a priority. 
 
The study coordinator may perform on-site monitoring of documentation by comparing 
data entry with source documents (eg. participant records) for completeness and 
chronology, logic checks for accuracy and trend analysis to identify problem areas.  The 
site PIs will cooperate in resolving any queries or findings made during the monitoring 
process.  
 
The Data safety and monitoring board (DSMB) will provide independent monitoring of 
interim results and make recommendations for continuation, modification or termination 
of the study. The DMSB will meet at two planned interim analyses for safety, at 
completion, and at any other needed interval.  
 
13.2 
Data Safety and Monitoring Committee (DSMC)  
 
This committee will be composed of at least 3 members, with at least one expert for 
each of infectious diseases, ICU, and pharmacy. The committee will be independent 
from the steering committee, and will initially define all the event triggers that would 
prompt unscheduled review, as well as review of interim and cumulative data for 
evidence of efficacy and safety. They will review data quality and completeness, factors 
that might compromise data confidentiality or affect outcomes. They will conclude each 
review with recommendation to the steering committee whether the study should 
continue without change, be modified, or terminated.    
 
13.3 
Record Keeping 
 
13.3.1 Source Documents 
 
Source documents are where data are first recorded, and from which participants’ eCRF 
data are obtained. These include, but are not limited to, hospital records (from which 
medical history and previous and concurrent medication may be summarized into the 
CRF), clinical and office charts, laboratory and pharmacy records, diaries, microfiches, 
radiographs, and correspondence. eCRF entries will be considered source data if the 
eCRF is the site of the original recording (e.g. there is no other written or electronic 
record of data).   

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The Investigator must maintain adequate and accurate source documents upon which 
CRFs for each participant are based. They are to be separate and distinct from CRFs 
except for cases in which the Sponsor has pre-determined that direct data entry into 
specified pages of the participant’s CRF is appropriate. These records should include 
detailed notes on: 
 
● Oral and written communication with participant regarding the study treatment 
(risks/benefits) 
● Participation in trial and signed and dated informed consent forms  
● Inclusion and exclusion criteria details  
● Visit dates  
● Adverse events  
● Results of relevant examinations  
● Laboratory printouts 
● Participant’s exposure to any concomitant therapy (start/stop dates, dosing details) 
● Reason for premature discontinuation (if applicable) 
● Enrollment number 
● Methods of contraception and fertility status (if applicable) 
● Compliance/non-compliance protocol deviation information 
 
13.3.2 Record Retention  
 
The Investigator will maintain all study records according to the ICH-GCP and 
applicable regulatory requirement(s). Records will be retained for 7 years, in 
accordance with applicable regulatory requirement(s). If the Investigator withdraws from 
the responsibility of keeping the study records, custody must be transferred to a person 
willing to accept the responsibility and the Sponsor notified. The Investigator should 
ensure that no destruction of medical records occurs without the written approval of the 
Sponsor. 
 
14. GENERAL TRIAL CONDUCT CONSIDERATIONS 
14.1 Trial Oversight  
A trial steering committee will be composed of at least 5 of the study co-applicants 
including biostastician and the NPA. The committee will meet once before the study 
begins, and at least twice per year during the study. This committee will strive to ensure 
scientific integrity, progress towards timelines, adherence to protocol and analysis plan. 
They will consider all recommendations from the Independent Data Safety and 
Monitoring Committee (DSMC), advise on major decisions such as continuing or 
terminating the trial and timely dissemination of trial results.   
 
14.2 Trial Coordination 
The study will be coordinated by the Clinical Research Platform of the McGill 
Interdisciplinary Initiative in Infection and Immunity (CRP-MI4) and the ICU infections 

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platform both based at the McGill University Health Centre, which will provide support in 
the form of highly trained personnel, equipment, lab infrastructure and resources. Initial 
training for laboratory testing will be provided by the company Diasorin, who will have 
no other role in this trial. Adverse events that comprise the primary safety outcome will 
be included in the outcome reporting, and not reported a second time as AEs related to 
the intervention. The site PIs will be responsible to review pertinent records, assess 
causality between adverse events and intervention using their best clinical judgement, 
and notify the trial steering committee of any AE that is serious, unexpected and 
possibly related to the study intervention within 48 hours of recognition.   
 
14.3 Participating MUHC Sites 
The Montreal General Hospital (MGH) provides emergency services (including 
advanced trauma care), medical and surgical services (general, orthopedic, thoracic, 
plastics, neurosurgery) and 24-bed capacity ICU. The Royal Victoria Hospital (RVH 
provides emergency, medical, hematology-oncology, transplant (solid and stem-cell), 
and surgical services (general, urology, hepato-biliary, and cardiac), and a 32-bed 
capacity ICU. We expect to recruit the required sample size based on the volume of 
admissions to both ICUs. Both sites benefit from an established AMS program. Total 
days of antimicrobial treatment (DOT) in the ICUs of the MUHC was 1067/1000 patient-
days (every ICU patient receives on average 1.1 antimicrobials/day spent in ICU). The 
study sites therefore have sufficient volume and diversity of eligible participants, 
infrastructure, and expertise to effectively implement the study procedures.  
 
14.4 Protocol Deviations  
Protocol deviations and incidents of non-compliance which do not involve risk to 
participants must be reported as “NC”. Examples of these include: 
- 
Deviating from the protocol without risk to the participant 
- 
Obtaining consent using an outdated form with no other substantive difference 
other than date 
 
The study site coordinator will be responsible for notifying the DSMB regarding event 
reporting within 48h of their knowledge of AE that are categorized as serious, 
unexpected and related.  
 
Other reportable events will be recorded on the eCRF, entered into the database and 
reported in the DSMB in routine reports.  
 
14.5 Intervention Adherence 
To improve intervention adherence, the pilot phase, start-up and education efforts will 
be focused on key logistic steps required to accomplish the intervention. We will 
conduct in-service training to raise awareness about the procedures leading to the BV-
guided antibiotic treatment recommendations among ICU physicians, with the main 
message being to “pay attention, but the final decision is entirely yours”. We will further 
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blood, lab receipt, assay time, assay completion to reporting; time to clinical 
assessment; time to receipt of treatment recommendation (delegated study team 
member will document information receipt). If clinicians choose to continue antibiotics 
even if the recommendation was to stop antibiotics, a study team member (Pharmacist 
or PI/Co-I) will gently query the clinician and record reasons for non-adherence (no 
other questions will be asked of the clinician). All cases of non-adherence to treatment 
recommendations will be reviewed by the investigators. 
 
15. STUDY ETHICAL CONSIDERATIONS 
15.1 Informed Consent  
All participants or, when appropriate or the participant’s legally authorized 
representative (LAR) will be given detailed information about the study. Informed 
Consent Form (ICF) describing in detail the study intervention(s), study procedures, 
anticipated benefits, and potential risks will be given to each participant. 
Participants/LAR must voluntarily provide their informed consent to participate in the 
study by reading and completing an ICF prior to any research procedures being 
perform. The informed consent will be signed and dated by the participant/LAR and the 
person who conducted the informed consent discussion. Each participant should have 
sufficient opportunity to discuss the study and consider the information in the consent 
process prior to agreeing to participate. Participants may withdraw consent at any time 
during the trial. The original signed informed consent form will be retained in the 
participant’s study files and a copy will be provided to the participant. 
 
15.2 Institutional Review Board, Ethics Committee, or Research Ethics Board 
The McGill University Health Centre Research Ethics Board (REB) will review all 
appropriate study documentation to safeguard the rights, safety, and well-being of the 
participants. The study will be conducted only at sites where ethics approval has been 
obtained. A copy of the protocol (including protocol amendments), all versions of 
informed consent forms, and other information to be completed by participants and any 
proposed advertising/recruitment materials must be reviewed and approved by the REB 
prior to implementation of the trial. The PI will be responsible for obtaining REB 
approval of the annual Continuing Review throughout the duration of the study and will 
notify the REB of serious adverse events as applicable within seven days of the 
recorded event. The PI will seek prior ethics approval for any protocol deviations except 
when the change is intended to eliminate an immediate hazard to participants. In this 
case, the protocol deviation will be promptly reported. 
 
15.3 Confidentiality 
The trial will conform to the International Conference for Harmonization and Good 
Clinical Practice (ICH-GCP) regulations and guidelines, the Tri-Council Policy 
Statement: Ethical Conduct for Research Involving Humans 2 (2022), and the current 
revision of the Declaration of Helsinki. All the information collected during the trial will 
remain strictly confidential to the extent required and provided by law. For risk mitigation 

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of disclosing personal information from study participants, we will use double coding of 
participants' ID and remove identifying information like name, address, and date of birth. 
Participants will be identified only by means of a participant ID specific to each 
participant. All records will be kept in a secure locked location, accessible only by 
special computer login and password that are provided only to authorize study 
personnel. Participant confidentiality and privacy will be strictly held in trust by the 
participating investigators, their staff, and the sponsor. This confidentiality is extended to 
cover testing of biological samples in addition to the clinical information relating to 
participants. Therefore, the study protocol, documentation, data, and all other 
information generated will be held in strict confidence. No information concerning the 
study, or the data generated, will be released to any unauthorized third party without 
prior written approval of the PI.  
 
Sensitive information including any data containing protected health information (PHI) 
will be stored on a separate secured database under the responsibility of the site PI. 
The study participant’s contact information will be securely stored at each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept 
in a secure location for 7 years.    
 
16. DISCLOSURE AND PUBLICATION POLICY 
Study results will be published in a PubMed referenced journal, regardless of findings 
(positive or negative trial), without the use of professional writers. Collaborators with 
satisfactory contributions to the study will be invited to participate on the writing of 
eventual manuscripts. Authorship policy will follow ICMJE criteria. Paid research 
personnel (eg. study nurses) and other contributors (eg. members of treating teams who 
provided medical care of study participants) who do not meet criteria for authorship, will 
be acknowledged but not listed as authors.  
 
The protocol outline will be posted on ClinicalTrials.Gov, and we will plan to publish a 
trial methodology and the statistical plan. We will provide access to data as soon as the 
study is completed, and the main manuscripts are published. Our final dataset will 
include de-identified demographic and clinical information, outcome data and BV 
values. Protected health information or patient identifiers will not be part of any dataset. 
We will employ a Data Use and Publications Request form to review all requests; only 
after these have been approved by the steering committee will we generate datasets to 
share with other researchers in response to specific needs.  
 
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18. Appendix I: Sample Size Calculations 
For all calculations below – Type I error = 0.05, Power = 0.8, One-sided test  
Sample size required for Hypothesis 1 that BV-supported antibiotic treatment 
recommendation leads to reducing antibiotic exposure. 
  
Expected difference in 
mean # of days on 
antibiotics  
Standard deviation of  
Days of antibiotics in 
ICU  
Sample size required per 
group  
1.5 days  
10 days  
550  
1.5 days  
8 days  
352  
1.5 days  
6 days  
198  
1.5 days  
4 days  
89  
  
Sample size required for Hypothesis 2 that BV-guided antibiotic treatment 
recommendation does not lead to worse clinical outcomes.  
Risk of adverse 
events in BV group  
Risk of adverse 
events in control 
group  
Non-inferiority 
margin  
Sample size 
required  
Per group  
32%  
30%  
4%  
6612  
30%  
30%  
4%  
1624  
28%  
30%  
4%  
708  
22%  
20%  
4%  
5128  
20%  
20%  
4%  
1238  
18%  
20%  
4%  
529  
17%  
15%  
4%  
4154  
15%  
15%  
4%  
986  
13%  
15%  
4%  
414