PROcalcitonin Impact on Antibiotic Reduction, adverSe Events and AVoidable healthcarE Costs
Phase: NA
Conditions: Pneumonia, Bacterial
Sponsor: Massachusetts General Hospital

 
 
PROcalcitonin impact on antibiotic reduction, adverSe 
events and AVoidable healthcarE costs (ProSAVE): a RCT  
 
 
 
 
Confidential Statement: 
This document is a confidential communication from B·R·A·H·M·S GmbH. 
Acceptance of this document constitutes an agreement by the recipient(s) that 
no unpublished information contained herein will be published or disclosed without B·R·A·H·M·S GmbH’s  
prior written approval, except that this document may be disclosed to appropriate Investigational Review 
Boards (IRBs) under the condition that they are also requested to maintain confidentiality. 
 
Version 18   
Issued on: June 8, 2023  
 
 

PROcalcitonin impact on antibiotic reduction, adverSe events and AVoidable healthcarE costs (ProSAVE): A RCT 
Clinicaltrials.gov Identifier: NCT04158804 
                                                                                                                           
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Signature Page 
Short title: ProSAVE 
 
 
 
Principal Investigator  
Name 
Signature 
Date 
Michael K. Mansour MD, PhD 
Associate Professor of Medicine 
Division of Infectious Diseases 
Massachusetts General Hospital 
 
 
 
Co- Investigators  
Name 
Signature 
Date 
Ramy Elshaboury, PharmD 
Clinical Pharmacy Manager 
Infectious Diseases, Surgery & 
Transplant Pharmacy Services 
Massachusetts General Hospital 
 
 
Ruta Shah, MD 
Division of Infectious Diseases 
North Shore Medical Center 
 
 
Caleb Nannes, MD 
Department of Medicine 
Martha’s Vineyard Hospital 
 
 
Sheetal Kandiah, MD 
Division of Infectious Diseases 
Grady Memorial Hospital 
Atlanta, GA 
 
 
SPONSOR  
Name/Responsibility 
Signature 
Date 
Sascha Johannes, Ph.D. 
Manager, Global Medical Affairs  
B·R·A·H·M·S GmbH 
 
 

PROcalcitonin impact on antibiotic reduction, adverSe events and AVoidable healthcarE costs (ProSAVE): A RCT 
Clinicaltrials.gov Identifier: NCT04158804 
                                                                                                                           
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Joseph Kuti, PharmD, FIDP 
Associate Director, Clinical and 
Economic Studies 
Hartford HealthCare 
Hartford, CT 
 
 
David Adams PharmD, BCIDP 
Clinical Pharmacy Specialist 
Infectious Diseases 
Texas Health Harris Methodist 
Hospital 
Fort Worth, TX 
 
 

PROcalcitonin impact on antibiotic reduction, adverSe events and AVoidable healthcarE costs (ProSAVE): A RCT 
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Table of Contents 
1 
GENERAL INFORMATION ............................................................................................................................ 8 
 
Responsibilities ................................................................................................................................... 8 
 
Compliance Statement ........................................................................................................................ 9 
 
List of Abbreviations ......................................................................................................................... 10 
 
Protocol Synopsis.............................................................................................................................. 12 
 
Treatment Decision Flowchart ........................................................................................................... 19 
 
Study Plan ........................................................................................................................................ 20 
2 
BACKGROUND .............................................................................................................................................. 21 
3 
TRIAL OBJECTIVES ..................................................................................................................................... 21 
 
Primary Objective ............................................................................................................................. 21 
 
Primary Endpoint .............................................................................................................................. 21 
 
Secondary Endpoints......................................................................................................................... 21 
 
Exploratory Endpoints ....................................................................................................................... 22 
4 
STUDY DESCRIPTION ................................................................................................................................ 22 
 
Study Design ..................................................................................................................................... 22 
 
Study Population .............................................................................................................................. 24 
4.2.1 
Inclusion Criteria ............................................................................................................................... 24 
4.2.2 
Exclusion Criteria .............................................................................................................................. 25 
4.2.4 Definition of treatment or readmission for CDI ....................................................................................... 26 
4.2.6 Monthly patient report .......................................................................................................................... 26 
4.2.7 Cross checking charts ............................................................................................................................. 26 
 
Estimated Study Duration and Study Centers ..................................................................................... 27 

PROcalcitonin impact on antibiotic reduction, adverSe events and AVoidable healthcarE costs (ProSAVE): A RCT 
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5 
BLOOD SAMPLING ...................................................................................................................................... 27 
 
Collection of specimen ...................................................................................................................... 27 
 
Handling of specimen and labeling of PCT measurements ................................................................... 27 
6 
RANDOMIZATION AND MEASUREMENT OF PROCALCITONIN ................................................... 28 
 
Randomization ................................................................................................................................. 28 
 
Procalcitonin (PCT) Measurement...................................................................................................... 28 
7 
STUDY DATA ................................................................................................................................................. 28 
 
Clinical Data Collection ...................................................................................................................... 28 
 
Healthcare Resource Utilization Data ................................................................................................. 29 
8 
STATISTICS ................................................................................................................................................... 30 
 
Study Design ..................................................................................................................................... 30 
8.1.1 
Study type ........................................................................................................................................ 30 
8.1.2 
Study goal ........................................................................................................................................ 30 
8.1.3 
Randomization .............................................................................................................................. 30 
 
Mathematical Definitions .................................................................................................................. 30 
8.2.1 
Short antibiotic treatments (“shortABx”, primary endpoint) ............................................................... 30 
8.2.2 
The first secondary endpoint "composite adverse events until day 30” (“CAE30”) ............................... 31 
8.2.3 
The second secondary endpoint “antibiotic exposure at discharge” (“prescribedABx”) ........................ 31 
8.2.4 
The third secondary endpoint “antibiotic duration” ........................................................................... 31 
8.2.5 
The fourth secondary endpoint “days of therapy per 1000 patient days” ............................. 31 
8.2.6 
The fifth secondary endpoint “antibiotic days prescribed at discharge” .............................. 31 
8.2.7 
The sixth secondary endpoint “treatment or readmission for CDI until day 30 after enrollment” ......... 31 
8.2.8 
The seventh secondary endpoint “length of stay in hospital until day 30” (“los30”) ........... 32 
8.2.9 
The eighth secondary endpoint “length of stay in ICU” (“losICU30”) .................................... 32 

PROcalcitonin impact on antibiotic reduction, adverSe events and AVoidable healthcarE costs (ProSAVE): A RCT 
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8.2.10 
The ninth secondary endpoint “ICU admission until day 30” ............................................. 32 
8.2.11 
Exploratory Endpoints ............................................................................................................. 32 
 
Primary Study Hypothesis ................................................................................................................. 32 
 
Analysis Populations ......................................................................................................................... 32 
 
Handling of Missing Data................................................................................................................... 33 
 
Statistical Analysis ............................................................................................................................ 33 
8.6.1 
Descriptive Statistics ......................................................................................................................... 33 
8.6.2 
Primary Analysis of Antibiotic Exposure ............................................................................................. 34 
8.6.3 
Secondary Analysis of CAE30 ............................................................................................................. 34 
8.6.4 
Secondary Analysis of Antibiotic Exposure ......................................................................................... 35 
8.6.5 
Further Secondary and Exploratory Analysis ...................................................................................... 35 
 
Sensitivity Analysis ........................................................................................................................... 36 
 
Sample Size ...................................................................................................................................... 36 
 
Interim Analyses ............................................................................................................................... 38 
 
Safety Analyses for DMC (See DMC Charter for detailed information) ................................................. 39 
 
Health Economic Evaluation .............................................................................................................. 39 
9 
REGULATORY & COMPLIANCE ............................................................................................................... 40 
 
IDE-status & Adverse Device Effect Reporting .................................................................................... 40 
 
Informed Consent ............................................................................................................................. 40 
 
Ethics Approval ................................................................................................................................. 41 
 
Case Report Form (CRF) ..................................................................................................................... 41 
 
Data Management and Confidentiality .............................................................................................. 41 
 
Safety Monitoring ............................................................................................................................. 42 
 
Responsibility and Compliance .......................................................................................................... 42 

PROcalcitonin impact on antibiotic reduction, adverSe events and AVoidable healthcarE costs (ProSAVE): A RCT 
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9.7.1 
Trial Monitoring ................................................................................................................................ 42 
 
Trial and Site Closure ........................................................................................................................ 43 
 
Records Retention ............................................................................................................................ 43 
10 REFERENCES ................................................................................................................................................. 44 
11 APPENDIX A .................................................................................................................................................. 47 
 
PCT Algorithm (Intervention) ............................................................................................................. 47 
 
PCT overruling criteria (Intervention) ................................................................................................. 48 
12 APPENDIX B .................................................................................................................................................. 49 
12.1.1 
Elecsys B·R·A·H·M·S PCTTM package insert V3 ................................................................................. 49 
13 APPENDIX C .................................................................................................................................................. 49 
 
CURB-65 Score9 ................................................................................................................................. 49 
14 APPENDIX D .................................................................................................................................................. 50 
 
PSI Score10 ........................................................................................................................................ 50 
15 APPENDIX E .................................................................................................................................................. 51 
 
Approved Use of PCT......................................................................................................................... 51 
16 APPENDIX F................................................................................................................................................... 53 
17 APPENDIX G...................................................................................................................................................... 53 
 
 
 
 

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1 
GENERAL INFORMATION 
 
Responsibilities 
 
Study Principal Investigator  
Study site #1 
Michael K. Mansour, MD, PhD 
Associate Professor of Medicine 
Division of Infectious Diseases 
Massachusetts General Hospital 
Jackson 1321 
55 Fruit Street,  
 
Boston, Massachusetts 02114  
USA 
Phone: 617-726-6726 
e-mail : MKMANSOUR@PARTNERS.ORG 
Co-Investigator 
Study site # 1 
 
Ramy Elshboury, PharmD, BCPS-AQ ID 
Clinical Pharmacy Manager 
Infectious Diseases, Surgery & Transplant Pharmacy Services 
Massachusetts General Hospital 
55 Fruit Street, GRB005 
Boston, Massachusetts 02114  
USA 
Phone: +1 (617) 724-9158 
Fax: +1 (617) 726-9232 
relshaboury@partners.org 
Co-Investigator  
Study site #2 
 
Ruta Shah, MD 
Division of Infectious Diseases 
North Shore Medical Center  
Salem, MA 
Co-investigator 
Study site #3 
Caleb Nannes, MD 
Department of Medicine 
Hospitalist 
Martha’s Vineyard Hospital 
Co-investigator 
Study site #4 
Sheetal Kandiah, MD 
Division of Infectious Diseases 
Grady Memorial Hospital 
Atlanta, GA 
Co-investigator 
Study site #5 
Joseph Kuti, PharmD, FIDP 
Associate Director, Clinical and Economic Studies 
Hartford HealthCare 
Hartford, CT 
Co-investigator 
Study site #6 
David Adams PharmD, BCIDP 
Clinical Pharmacy Specialist 
Infectious Diseases 
Texas Health Harris Methodist Hospital 
Fort Worth, TX 

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Data Management 
MGH data coordinator,  
Johnny Atallah, MD (full time) 
Hailey Warren (full time) 
Biostatistician 
Jan C. Wiemer, Ph.D. 
Head of Biostatistics 
B·R·A·H·M·S GmbH 
Phone: +49 (0) 3302 883 871 
e-mail: jan.c.wiemer@thermofisher.com 
Sponsor 
B·R·A·H·M·S GmbH 
Neuendorfstraße 25 
16761 Hennigsdorf, Germany 
Contact person: Sascha Johannes, Ph.D. 
Phone: +49 (0) 3302 883 729 
e-mail: sascha.johannes@thermofisher.com 
DMC Biostatistician 
Musie Ghebremichael, PhD 
Massachusetts General Hospital 
Ragon Institute 
400 Technology Square 
Cambridge, MA 02139 
e-mail: Musie_Ghebremichael@dfci.harvard.edu 
DMC Chair 
Jeffrey Gelfand, MD 
Massachusetts General Hospital 
Division of Infectious Diseases 
Phone: 617-726-1796 
e-mail: jgelfand@mgh.harvard.edu 
 
 
Compliance Statement 
 
The trial will be conducted in accordance with the ICH E6, the Code of Federal Regulations on the 
Protection of Human Subjects (45 CFR Part 46). The Principal Investigator will assure that no 
deviation from, or changes to the protocol will take place without prior agreement from the 
Sponsor and documented approval from the Institutional Review Board (IRB), except where 
necessary to eliminate an immediate hazard(s) to the trial participants. All key personnel (all 
individuals responsible for the design and conduct of this trial) have completed Human Subjects 
Protection Training. 
 
Principal Investigator: ________________________________ 
Print/Type Name  
Signed: _____________________________________  
Date: ______________  
 

PROcalcitonin impact on antibiotic reduction, adverSe events and AVoidable healthcarE costs (ProSAVE): A RCT 
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List of Abbreviations 
Abbreviation 
Term 
AB 
Antibiotic 
ADE 
Adverse Drug Events 
ADR 
Adverse Drug Reaction 
AECOPD 
Acute exacerbation of chronic obstructive pulmonary disease 
AHRQ 
Agency for Healthcare Quality and Research 
ALT 
Alanine transaminase 
AST 
Aspartate aminotransferase 
CAE30 
Composite Adverse Events until Day 30 (Primary Endpoint) 
CAP 
Community Acquired Pneumonia 
CBC 
Complete Blood Cell Count 
CDC 
Centers for Disease Control 
CDI 
Clostridium difficile infection 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
CURB 65  
Confusion, Urea nitrogen, Respiratory rate, Blood pressure, 65 years of age and older 
DOT 
Days of Therapy 
EC 
Ethics Committee 
ED 
Emergency Department 
GCP 
Good Clinical Practice 
GDH 
Glutamate dehydrogenase 
(HO) CDI 
Healthcare facility-onset Clostridium difficile infection 

PROcalcitonin impact on antibiotic reduction, adverSe events and AVoidable healthcarE costs (ProSAVE): A RCT 
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IC 
Informed Consent 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ICU 
Intensive Care Unit 
IDSA 
Infectious Disease Society of America 
IDN 
Integrated Delivery Network 
IRB 
Institutional Review Board 
LOS 
Length of stay 
LRTI 
Lower respiratory tract infection 
NAAT 
Nucleic acid amplification test 
NI 
Non-inferiority 
PCT 
Procalcitonin 
prescribedABx 
Antibiotics prescribed at discharge for pneumonia treatment 
RCT 
Randomized controlled trial 
shortABx 
Short treatment of pneumonia with antibiotics (less than 4 days) 
SOFA 
Sequential organ failure assessment 
qSOFA 
Quick sequential organ failure assessment  
ULN 
Upper limit of normal 
 
 
 

PROcalcitonin impact on antibiotic reduction, adverSe events and AVoidable healthcarE costs (ProSAVE): A RCT 
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Protocol Synopsis 
Title 
PROcalcitonin impact on antibiotic reduction, CloStridium difficile infection 
and AVoidable healthcarE costs (ProSAVE): A RCT 
Acronym 
ProSAVE 
Principal investigator 
Michael K. Mansour, MD, PhD 
Associate Professor 
Division of Infectious Diseases, Department of Medicine, Massachusetts 
General Hospital, Boston, Massachusetts, USA 
Sponsor 
B·R·A·H·M·S GmbH 
Neuendorfstrasse 25 
16761 Hennigsdorf, Germany 
Background 
Antimicrobial resistance is one of our most serious health threats. Infections 
from resistant bacteria are now too common, and some pathogens have 
even become resistant to multiple types or classes of antibiotics 
(antimicrobials used to treat bacterial infections).1,2 The binary issue is that 
when antibiotics are prescribed appropriately to treat bacterial infection, 
they are effective and should be prescribed without delay. However, 50% of 
the time antibiotics are misused or prescribed without proper indication.  
 
Lower respiratory tract infections (LRTI) are among the most frequent 
indications for antibiotics and pose a significant risk for excessive exposure 
to antibiotics and increase incidence of CDI. Delay or lack of pathogen 
identification and non-specific clinical and radiographic findings often leave 
clinicians with insufficient evidence to make definitive decisions regarding 
the need for antibiotics.  The Infectious Disease Society of America (IDSA) 
recommends improving antibiotic prescribing practices as an essential 
action. 3 
 
Several novel biomarkers have been proposed as a complementary strategy 
to evaluate the severity of bacterial infection, differentiate viral from 
bacterial etiologies, and improve antibiotic therapy decisions.  Procalcitonin 
(PCT), a pro-inflammatory cytokine that is nearly undetectable in health and 
up regulated in response to endotoxemia, offers significantly more sensitive 
and specific prediction of bacterial infection. Trials comparing PCT-guided 
antibiotic algorithms to standard management show a significant reduction 
in antibiotic exposure without an increase in mortality or treatment failure. 
4,5,6 .  
 
Despite this strong evidence from multiple studies a recent prospective 
multicentric interventional trial in the US fell short of demonstrating 
antibiotic reductions by PCT-guided antibiotic management. 7 Amongst 
other limitations the authors of that study concluded that successful 
implementation of PCT may require closer educational oversight. As such, 
this study will compare effectiveness and safety of antibiotic prescription 

PROcalcitonin impact on antibiotic reduction, adverSe events and AVoidable healthcarE costs (ProSAVE): A RCT 
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guided by a PCT-algorithm via a stewardship team over standard guidelines 
in hospitalized adult patients with suspected or confirmed pneumonia. 
Indication 
Adult patients with suspected pneumonia at time of admission to or while 
admitted to the ED, general ward, intermediate care unit, or ICU. 
Primary Objective 
Determine the difference in antibiotic exposure and healthcare cost and 
assess safety by comparing antibiotic prescription guided by a (i) PCT 
algorithm + stewardship team (intervention) or (ii) standard guidelines 
(control) in hospitalized patients with suspected or confirmed LRTI. 
Study Design 
Prospective, multi-center, randomized-controlled interventional trial 
Enrolling Wards 
ED, admitted floor and ICU teams 
Intervention  
Addition of previously validated PCT algorithms to clinical assessment to 
guide the discontinuation of antibiotics in patients with suspected or 
confirmed pneumonia. 
Primary Endpoint 
 
Proportion of patients with short treatment of pneumonia with antibiotics 
(less than 4 days, “shortABx”)  
 
Secondary Endpoints 
1. Composite safety adverse event rate at 30 days (CAE30). The composite 
endpoint includes: 
a. All-cause in-hospital mortality 
b. All-cause mortality after discharge (as available) 
c. Hospital readmission  
d. Septic shock (vasopressor use for > 1 h) 
e. Mechanical ventilation (via endotracheal tube for respiratory 
failure) 
f. Required dialysis 
g. Lung abscess/empyema 
2. Antibiotic exposure at discharge 
3. Antibiotic duration 
4. Days of Therapy per 1000 patient days (inclusive of antibiotics 
prescribed at discharge) 
5. Antibiotic days prescribed at discharge 
6. Treatment or readmission for CDI until day 30 after enrollment 
7. LOS in hospital until Day 30 
8. LOS on ICU until Day 30 
9. ICU admission until Day 30 
Exploratory Endpoints 
 
All the single variables of the safety endpoint CAE30, see 3.2. “Composite 
adverse events until day 30” 
 
Healthcare Economic 
Endpoints 
Costs associated with primary hospitalization, readmission for CDI, and loss 
of function 
• 
Cost of Antibiotics (total cost of antibiotics per patient inclusive of 
antibiotic, tubing, IV bag, discharge antibiotic prescription) 
• 
Cost of Procalcitonin  
• 
Total per patient cost (including blood cultures and mechanical 
ventilation days) 

PROcalcitonin impact on antibiotic reduction, adverSe events and AVoidable healthcarE costs (ProSAVE): A RCT 
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• 
Antibiotic ADRs (e.g. CDI) 
• 
AB days difference plus prescriptions avoided infection adverse event 
incidence modeling29  
• 
Cost of readmissions 
 
Inclusion Criteria 
- 
Hospitalized adult patients ≥ 18 years of age  
- 
Suspected or confirmed LRTI pneumonia <28 days at time of admission 
to the hospital (ED) who are prescribed antibiotics  
- 
Minimum of 2 (two) blood samples available for PCT value assessment 
between 6 and 48 hours apart.  
Exclusion Criteria 
- 
Patient has tested positive for SARS-CoV-2 
- 
Patients who are not admitted to the hospital 
- 
Patients admitted to home health 
- 
Major surgeries, defined as any procedure in which an incision is made 
with the exception of superficial procedures (eyes, cornea, skin, dental 
procedures), organs removed, or normal anatomy altered (e.g. open 
thoracic, abdominal and/or major orthopedic surgery), in the past 1 
month or expected surgical procedure or patient receiving antibiotics 
for surgical prophylaxis 
- 
Known Pregnancy 
- 
Primary and acquired cell-mediated immune deficiency (HIV with CD4 
<350 cells/mm³; receipt of systemic chemotherapy and/or biologics in 
the past 3 months for reasons other than malignancy) 
- 
Active metastatic cancer or neuroendocrine tumor or liquid tumor 
and/or on check point inhibitors within 3 months or has signs of 
mucositis (e.g. mouth lesions or intestinal bleeding). 
- 
Neutropenia (<1,500 ANC) 
- 
Patients with cystic fibrosis 
- 
Infection where long courses of antibiotics are the standard of care (> 2 
weeks) other than anti-inflammatory reasons 
- 
Concomitant non-pulmonary bacterial infection that requires antibiotic 
therapy based on an active medical team decision 
- 
Antibiotics given for non-infectious indications (e.g. rifaximin for hepatic 
encephalopathy) 
- 
Patients receiving dialysis 
- 
Patients with solid organ transplant, bone marrow transplant or stem 
cell transplant recipient 
- 
ST elevation myocardial infarction 
- 
Prior enrollment into this study within 30 days. 
- 
Patient experiencing major trauma defined as any injury that could 
cause prolonged disability and/or an Injury Severity Score >15, and/or 
burns or patient under extracorporal circulation confirmed by a second 
research staff member. 
- 
Patient with acute viral hepatitis and/or decompensated severe liver 
cirrhosis (Child-Pugh Class C). 

PROcalcitonin impact on antibiotic reduction, adverSe events and AVoidable healthcarE costs (ProSAVE): A RCT 
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- 
Patient with prolonged or severe cardiogenic shock defined as 
decreased cardiac output leading to end organ injury (e.g. severe 
hypotension or AKI or oliguria or altered mental status or cool 
extremities or respiratory distress AND evidence of metabolic acidosis 
on lab testing),  
- 
Patient with pancreatitis, chemical pneumonitis or heat stroke 
- 
Active infection with invasive fungal pathogen (e.g. candidiasis, 
aspergillosis) or plasmodium falciparum malaria or mycobacteria 
- 
Patient under treatment with OKT3 antibodies, OK-432, interleukins, 
TNF-alpha and other drugs stimulating the release of pro-inflammatory 
cytokines or resulting in anaphylaxis. 
- 
Patient is under hospice care 
- 
Patient with ventilator-associated pneumonia 
- 
Patients with untreated, active, and symptomatic autoimmune disease 
- 
Patients 
actively 
enrolled 
in 
other 
clinical 
trial 
involving 
immunomodulatory therapy 
- 
Patients with empyema, abscess, or cavitary/necrotizing pneumonia 
Sample Size 
Bayesian adaptive design with interim analyses after enrollment of 200, 350, 
550 and 650 patients and a maximum number of 700 patients (350 per study 
arm)  
Study Sites 
1. Massachusetts General Hospital, Department of Medicine, Boston, MA, 
USA 
2. North Shore Medical Center, Department of Medicine, Salem, MA, USA 
3. Martha’s Vineyard Hospital, Department of Medicine, Oak Bluffs, MA, 
USA 
4. Grady Memorial Hospital, Department of Medicine, Atlanta, GA, USA 
5. Charlotte Hungerford Hospital, Department of Medicine, Torrington, CT, 
USA 
Study Duration 
 15-24 months depending on patient recruitment per adaptive study design 
(see statistics section below) and 30 days follow-up. 
Safety Considerations 
Multiple RCTs evaluating the addition of PCT algorithms to clinical 
management have shown a safe decrease in antibiotic exposure in LRTI and 
sepsis. 
Antibiotic discontinuation will be determined by clinician interpretation of 
standard clinical, laboratory and radiology parameters along with the 
addition of a PCT algorithm to guide antibiotic decisions. Patients will not 
receive a direct investigational intervention in this study.  
All recommendations outlined in the ICH guidelines for Good Clinical 
Practice will be adhered to throughout this study. 
Data Monitoring Committee (DMC) includes infectious disease experts. The 
DMC can meet at a frequency of their choice with a minimum of two 
meetings during study period at 350 and 550 patients. 

PROcalcitonin impact on antibiotic reduction, adverSe events and AVoidable healthcarE costs (ProSAVE): A RCT 
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An unblinded biostatistician will be available to answer any queries of the 
DMC. 
In addition to safety datasets of the respective number of enrolled patients, 
safety-relevant results of interim analyses about the safety endpoint CAE30 
will also be provided to the DMC, see Section 8.10. 
Test product 
The Elecsys B·R·A·H·M·S PCTTM immunoassay or Abbott Alinity will be used 
to determine PCT concentrations in leftover specimen of routine blood 
draws from patients with pneumonia. 
Statistical Methodology 
For the primary study endpoint "short antibiotic treatments” (proportion of 
patients with short antibiotic treatment of pneumonia less than 4 days, 
“shortABx”) the hypotheses for statistical inference are as follows: 
H0: The probability of patients with short antibiotic treatments of 
pneumonia is smaller or equal in the PCT arm versus the control arm. 
H1: The probability of patients with short antibiotic treatments of 
pneumonia is greater in the PCT arm than in the control arm. 
 
For the first secondary study endpoint “composite adverse events until day 
30” (“CAE30”) the hypotheses for statistical inference are as follows: 
H0: PCT arm is inferior to control arm  in composite safety adverse event 
rate at day 30. 
H1: PCT arm is not inferior to control arm in composite safety adverse event 
rate at day 30. 
For the second secondary study endpoint "proportion of patients with 
antibiotic exposure at discharge”) (“prescribedABx”) the hypotheses for 
statistical inference are as follows: 
H0: The probability of patients with antibiotic exposure at discharge is 
greater or equal in the PCT arm versus the control arm. 
H1: The probability of patients with short antibiotic treatment of pneumonia 
is smaller in the PCT arm than in the control arm. 
 
The analysis of the study endpoints shortABx, CAE30 and 
prescribedABx will be conducted with Bayesian methodology: Differences 
in proportions between study arms will be assessed on the basis 
of posterior probabilities assuming binomially distributed events and 
uninformative uniform priors. Type-1 error is controlled at 2.5%.  
The endpoints shortABx and prescribedABx will be tested for superiority. 
Superiority is specified by more than 98.5% 1 posterior probability for less 
antibiotic exposure in the PCT arm than in the control arm, i.e., more 

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frequent short antibiotic treatments in the PCT arm versus the control arm 
(shortABx) and less frequent antibiotic exposure at discharge in the PCT 
arm versus the control arm (prescribedABx). 
The endpoint CAE30 will be tested for non-inferiority. Non-inferiority is 
specified by 98.5% 1 posterior probability for a smaller CAE30 probability of 
patients of the PCT arm than the CAE30 probability of patients of the 
control arm plus 10% non-inferiority (NI) margin.  
 
For further secondary and exploratory endpoints: 
Distributions of numerical variables will be visualized for all patients and 
separately for PCT and control arm. Study arm-specific distributions will be 
compared with each other by statistical tests (e.g. Wilcoxon rank-sum tests), 
and by comparing descriptive summary measures (e.g. group medians and 
means). 
2 x 2 contingency tables will be reported for counts stratified according to 
study arm (PCT, control) and endpoint level (true/false). Associations 
between study arms and endpoints will be analyzed by statistical tests (e.g. 
chi-square test or Fisher’s exact test). Proportions and two-sided 95% 
confidence intervals or Bayesian 95% credible intervals will be computed for 
all patients and separately for PCT and control arm. 
 
Health Economic Evaluation: 
The clinical outcomes of the study will be analyzed from a health economic 
hospital perspective, extrapolation to third party payer remains optional. 
Clinical data and local cost data will be processed in the previously 
published/under publication Health Economic Model (Janne C Mewes et. 
al., The cost impact of PCT-guided antibiotic stewardship versus usual care 
for hospitalized patients with suspected sepsis or lower respiratory tract 
infections in the US: a health economic model analysis). All available 
information will be used in the model. Missing/confidential cost data will be 
substituted with publicly available data and highlighted accordingly. 
All findings will be discussed in the local hospital context as well as how 
these compare to the overall situation in the United States. 
 

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PROcalcitonin impact on antibiotic reduction, adverSe events and AVoidable healthcarE costs (ProSAVE): A RCT 
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Treatment Decision Flowchart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screen for eligibility 
Randomization (1:1) 
PCT algorithm + Stewardship Team (n= 350) 
 
Standard Group (n=350) 
Standard Workup + PCT Measurement (unblinded) 
Standard Workup + PCT Measurement (blinded) 
<0.10  
ng/mL 
 
0.10 - 0.25 
ng/mL 
Clinical assessment for suspected or confirmed LRTI  
> 0.50  
ng/mL 
>0.25 - 0.50 
ng/mL 
Assess for primary and secondary endpoints by hospital day 30 at discharge 
Follow up at 30 days: assess for CDI, re-hospitalization, survival status by chart review 
IDSA/ATS (CAP) and GOLD (AECOPD) recommendations 
for starting and stopping AB 
Consider 
early AB 
cessation 
(6-24h) 
in the 
absence of 
overruling 
criteria  
 
 
*LRTI PCT Algorithm (Appendix A) 
 #Please see section 4.2 
 Consider 
early AB 
cessation 
(6-24h) 
in the 
absence of 
overruling 
criteria  
 
  
Consider 
AB 
cessation 
daily when 
PCT 
decreases 
>80% from 
peak or 
decrease 
to <0.25 
(ward), 
<0.5 (ICU) 
Consider 
AB 
cessation 
daily when 
PCT 
decreases 
>80% from 
peak or 
decrease 
to <0.25 
(ward), 
<0.5 (ICU) 
Repeat PCT 6-48h (or in the AM) & then daily for one week then 
Mondays, Wednesdays, and Fridays while on AB (unblinded)* 
Repeat PCT 6-48h (or in the AM) & then daily for one week then 
Mondays, Wednesdays, and Fridays while on AB (blinded)# 

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Study Plan  
 
 
Between 
presentation and 
enrollment day 
Screening/ 
Enrollment day 
Per Protocol 
until discharge 
(as available) 
Hospital 
Discharge 
Day 30 
Medical History 
x 
 
 
 
 
Routine Clinical 
Assessment  
x 
x 
x 
 
 
Standard laboratory 
evaluation 
x 
x 
x 
 
 
Inclusion/Exclusion 
 
x 
 
 
 
PCT measurement 
x 
x 
 x*  
 
 
Document presence or 
absence of safety 
endpoints and 
antibiotic prescription 
 
 
 
x 
x 
Follow-up via chart 
review/public record: 
readmission, survival 
status 
 
 
 
 
x 
Follow-up via chart 
review: Readmission 
for CDI 
 
 
 
 
x 
*PCT measurement only until antibiotics are stopped or patient becomes ineligible 
 
 
 
 
 
 
 

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2 
BACKGROUND 
Antimicrobial resistance is one of our most serious health threats. Infections from resistant bacteria are 
now too common, and some pathogens have even become resistant to multiple types or classes of 
antibiotics (antimicrobials used to treat bacterial infections).1,2 The binary issue is that when antibiotics 
are prescribed appropriately to treat bacterial infection, they are effective and should be prescribed 
without delay. However, 50% of the time antibiotics are misused or prescribed without proper indication.  
 
Lower respiratory tract infections (LRTI) are among the most frequent indications for antibiotics and pose 
a significant risk for excessive exposure to antibiotics and increase incidence of CDI. Delay or lack of 
pathogen identification and non-specific clinical and radiographic findings often leave clinicians with 
insufficient evidence to make definitive decisions regarding the need for antibiotics.  The Infectious 
Disease Society of America (IDSA) recommends improving antibiotic prescribing practices as an essential 
action. 3 
 
Several novel biomarkers have been proposed as a complementary strategy to evaluate the severity of 
bacterial infection, differentiate viral from bacterial etiologies, and improve antibiotic therapy decisions.  
Procalcitonin (PCT), a pro-inflammatory cytokine that is nearly undetectable in health and up regulated 
in response to endotoxemia, offers significantly more sensitive and specific prediction of bacterial 
infection. Trials comparing PCT-guided antibiotic algorithms to standard management show a significant 
reduction in antibiotic exposure without an increase in mortality or treatment failure 4,5,6.  
Despite this strong evidence from multiple studies a recent prospective multicentric interventional trial 
in the US fell short of demonstrating antibiotic reductions by PCT-guided antibiotic management. 7 
Amongst other limitations the authors of that study concluded that successful implementation of PCT 
may require closer educational oversight. As such, this study will compare effectiveness and safety of 
antibiotic prescription guided by a PCT-algorithm via a stewardship team over standard guidelines in 
hospitalized adult patients with suspected or confirmed pneumonia.  
3 
TRIAL OBJECTIVES 
 
Primary Objective 
 
Determine the difference in antibiotic exposure and healthcare cost and assess safety by comparing 
antibiotic prescription guided by a (i) PCT algorithm + stewardship team (intervention) or (ii) standard 
guidelines (control) in hospitalized patients with suspected or confirmed pneumonia.  
 
Primary Endpoint 
 
The primary study endpoint is the superiority endpoint short antibiotic treatments (proportion of patients 
with short treatment of pneumonia with antibiotics less than 4 days, “shortABx”).  
 
 
Secondary Endpoints  

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The secondary study endpoints are as follows: 
 
1. Safety non-inferiority endpoint: Composite safety adverse event rate at 30 days (CAE30). The 
composite endpoint includes: 
a. All-cause in-hospital mortality 
b. All-cause mortality after discharge (as available) 
c. Hospital readmission  
d. Septic shock (vasopressor use for > 1 h) 
e. Mechanical ventilation (via endotracheal tube for respiratory failure) 
f. Required dialysis 
g. Lung abscess/empyema/cavitation/necrotizing pneumonia 
 
In the case a patient is enrolled with mechanical ventilation, such an event is not considered to be an 
adverse event due to its occurrence before randomization. If the patient is then extubated during their 
hospital stay, re-intubation is only classified as an adverse event if it occurs at least 24 hours post 
extubation. 
 
In the case a patient is enrolled with septic shock, such an event is not considered to be an adverse event 
due to its occurrence before randomization. If the patient then has a resolved septic shock during their 
hospital stay, developing a new septic shock is only classified as an adverse event if it occurs at least 24 
hours post resolution of the initial septic shock. 
 
In the case a patient develops a safety adverse event at any point on the day of enrollment post 
randomization, such an event will be classified as an adverse event. 
 
2. Antibiotic exposure at discharge (superiority endpoint) 
3. Days of Therapy per 1000 patient days (inclusive of antibiotics prescribed at discharge) 
4. LOS in hospital until Day 30 
5. LOS on ICU until Day 30 
6. ICU admission until Day 30 
 
Exploratory Endpoints 
1. Treatment or readmission for CDI until day 30 after enrollment 
2. All the single variables of the safety endpoint CAE30, see 3.2.“Composite adverse events until 
day 30” 
4 
STUDY DESCRIPTION 
 
Study Design 
The study will be conducted as a prospective, randomized controlled, multicenter, interventional 
trial whereby individual patients will be evaluated for eligibility and then randomized to one of two 
arms: 

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(i) 
Antibiotic prescription guided by a PCT algorithm and stewardship team (PCT arm): 
antibiotic treatment recommendations will be made by the stewardship team. The 
stewardship team will discuss PCT algorithm overruling with the primary care team.  
(ii) 
antibiotic prescription guided by current guidelines (control arm): treating clinicians 
will be blinded to PCT results and antibiotic treatment decisions will be at the 
discretion of the treating clinician based on standard of care guidelines. 
Antibiotic exposure (duration and DOT), safety outcomes and associated healthcare costs will be 
compared between groups throughout enrollment and follow up.   
Screening, (D0) Baseline and (D1) PCT measurement 
Patients will be consecutively screened for eligibility one day after their admission to an inpatient 
bed. Research staff will be responsible for screening admissions and antibiotic orders for potential 
enrollment and randomization. A dedicated stewardship team at each site will implement the 
intervention algorithm. The stewardship team will ensure PCT results and appropriate algorithm 
interventions are addressed (via phone, email, messaging system, or in person) with the primary 
provider as well as document assigned protocol adherence and deviations. 
 
Upon review of inclusion/exclusion criteria, study subjects will be randomized 1:1 into one of two 
groups: (i) PCT algorithm + stewardship team arm or (ii) the standard care arm. PCT results will be 
unblinded in the (i) PCT algorithm + stewardship team arm and blinded in the (ii) standard care 
group.  
 
Potential subjects resulting from the initial EPIC screen are not considered subjects. Subjects are 
defined as those who meet criteria for entry into the study. Non-eligible subjects are those who 
have met an exclusion criterion at some point during the study.  
 
Upon randomization, the research staff will send a welcome message to both the standard of care 
and intervention teams. Enrollment PCT values consist of one value from the day of randomization 
(D1) and one value from a previous day 6-48 hours prior (D0). All PCT measurements throughout 
the study should be obtained using discarded blood from routine lab work. All PCT values ordered 
by the study team for patients in the intervention arm will be released in EPIC, while those of the 
standard of care arm will be suppressed.  
 
After the PCT results are available, the stewardship team will review both the D0 and D1 results 
as a pair and provide an antibiotic recommendation (PCT intervention arm only) using the 
stewardship team recommendation template to the primary provider service on enrollment day. 
If the stewardship team is discordant with the PCT algorithm (see section 1.5 for algorithm), they 
will be sent a discordance survey (see Appendix G). If the primary team is discordant with the 
stewardship recommendations, a reason for discordance survey will be sent out and recorded in 
REDCap (see Appendix H). Patient information will be recorded in REDCap for both the 
intervention and standard of care arms. 
 
(D2+) Daily PCT measurements 

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For patients who are still eligible and on antibiotics, PCT should be measured daily for one week 
and then Monday, Wednesday, and Friday in both arms. If there are no results on a Monday, the 
PCT will be measured on Tuesday, Wednesday, and Friday. If there are no results on a Wednesday, 
the PCT will be measured on Monday, Thursday, and Friday.  
 
For PCT arm patients, the stewardship team will review available PCT results and provide an 
antibiotic recommendation to the primary provider service on the same calendar day. Antibiotic 
monitoring and/or discontinuation will be guided by clinical assessment (medical history, physical 
exam, imaging and standard laboratory evaluations) as well as the PCT algorithm (Appendix A, 
LRTI) and pre-defined overruling criteria (Appendix A, 11.2). If the stewardship team is discordant 
with the PCT algorithm, a discordance survey will be requested (Appendix G). In case of 
discordance between the primary team and the stewardship team, a discordance survey will also 
be requested (Appendix H). 
 
The stewardship team will provide a recommendation every day (Monday-Friday) that the patient 
has a PCT result. Patients will not receive recommendations on weekends, holidays or pre-
planned absences. If the stewardship team wants to repeat the same recommendation for 
multiple days in a row, they must indicate in their communication to the team that this is a 
standing recommendation and the medical team will not receive further communications until 
the stewardship team decides to change their recommendation. If the medical team changes, the 
new medical team will receive a recommendation.  
 
In both arms, selection of antibiotic agent, dosing and route of administration will be at the 
discretion of the treating clinician. 
 
For patients in the control arm,  PCT results will be blinded to the stewardship and primary service 
team. Select research staff will be unblinded to the PCT values and will record them into REDCap. 
Antibiotic monitoring and/or discontinuation will be guided by standard care guidelines including 
clinical assessment (medical history, physical exam, and imaging and standard laboratory 
evaluations).  
 
 
Study Population  
Hospitalized adult patients with suspected or confirmed pneumonia at time of admission or while 
admitted to the ED who are prescribed antibiotics (including septic patients with respiratory focus).  
Studies show that PCT is not affected by certain cancers so those patients will be included. Several 
studies have shown that PCT is a promising and reliable infection marker in patients with cancer30,31. 
Neuroendocrine tumors and the presence of metastases have been linked to false positive PCT 
values32,33. Thus, metastatic cancer, liquid tumors, neuroendocrine tumors and unstable patients 
who are on check point inhibitors or experiencing mucositis (e.g. mouth lesions or intestinal bleeds) 
will not be included.  
4.2.1 
Inclusion Criteria 
- 
Hospitalized adult patients ≥ 18 years of age  

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- 
Suspected or confirmed LRTI pneumonia <28 days at time of admission to the hospital 
(ED) who are prescribed antibiotics. 
- 
 Minimum of 2 (two) blood samples available for PCT value assessment between 6 and 48 
hours apart.  
4.2.2 
 Exclusion Criteria  
- 
Patient has tested positive for SARS-CoV-2 
- 
Patients who are not admitted to the hospital 
- 
Patients admitted to home health 
- 
Major surgeries, defined as any procedure in which an incision is made with the 
exception of superficial procedures (eyes, cornea, skin, dental procedures), organs 
removed, or normal anatomy altered (e.g. open thoracic, abdominal and/or major 
orthopedic surgery), in the past 1 month or expected surgical procedure or patient 
receiving antibiotics for surgical prophylaxis 
- 
Known Pregnancy 
- 
Primary and acquired cell-mediated immune deficiency (HIV with CD4 <350 cells/mm³; 
with receipt of systemic chemotherapy and/or biologics in the past 3 months for reasons 
other than malignancy) 
- 
Active metastatic cancer or neuroendocrine tumor or liquid tumor and/or on check 
point inhibitors within 3 months or has signs of mucositis (e.g. mouth lesions or 
intestinal bleeding). 
- 
Neutropenia (<1,500 ANC) 
- 
Patients with cystic fibrosis  
- 
Infection where long courses of antibiotics are the standard of care (more than 2 weeks) 
other than for anti-inflammatory reasons 
- 
Concomitant non-pulmonary bacterial infection that requires antibiotic therapy based on 
an active medical team decision.  
- 
Antibiotics given for non-infectious indications (e.g. rifaximin for hepatic encephalopathy) 
- 
Patients receiving dialysis 
- 
Patients with solid organ transplant, bone marrow transplant or stem cell transplant 
recipient 
- 
ST elevation myocardial infarction 
- 
Prior enrollment into this study within 30 days  
- 
Patient experiencing major trauma defined as any injury that could cause prolonged 
disability and/or an Injury Severity Score >15, and/or burns or patient under extracorporal 
circulation confirmed by a second research staff member. 
- 
Patient with acute viral hepatitis and/or decompensated severe liver cirrhosis (Child-Pugh 
Class C). 
- 
Patient with prolonged or severe cardiogenic shock defined as decreased cardiac output 
leading to end organ injury (e.g. severe hypotension or AKI or oliguria or altered mental 
status or cool extremities or respiratory distress AND evidence of metabolic acidosis on 
lab testing).  
- 
Patient with pancreatitis, chemical pneumonitis or heat stroke 
- 
Active infection with invasive fungal pathogen (e.g. candidiasis, aspergillosis) or 
plasmodium falciparum malaria or mycobacteria 

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- 
Patient under treatment with OKT3 antibodies, OK-432, interleukins, TNF-alpha and other 
drugs stimulating the release of pro-inflammatory cytokines or resulting in anaphylaxis. 
- 
Patient is under hospice care 
- 
Patient with ventilator-associated pneumonia 
- 
Patients with untreated, active, and symptomatic autoimmune disease 
- 
Patients actively enrolled in other clinical trial involving immunomodulatory therapy.  
- 
Patient with empyema, abscess, or cavitary/necrotizing pneumonia 
 
4.2.3 Definition of suspected or confirmed LRTI  
-Pneumonia requires one respiratory symptom plus one finding during auscultation or one 
sign of infection evidenced by core temperature of 38C, shivering, or a leukocyte count 
greater than 12,000u/µL or less than 4,000u/µL independent of antibiotic pretreatment. 
- 
pneumonia will be defined as a new infiltrate on chest radiograph as defined by the 
IDSA/ATS 2007 CAP Guidelines.  
4.2.4 Definition of treatment or readmission for CDI 
- 
Treatment for CDI which consists of oral vancomycin, fidaxomicin, or oral or IV 
metronidazole or fecal microbiota transplantation 
- 
Hospital re-admission within 30 days after enrollment coded for a primary diagnosis of 
CDI using ICD-10 
 
4.2.5 Definition ‘until day 30’ 
Day 30 is defined as the thirtieth calendar day after ED or hospital admission. 
4.2.6 Monthly patient report 
A report with the names and dates of birth of all Mass General Brigham enrolled patients will be created 
in REDCap every month. This report will be checked to make sure there are no duplicate patients 
enrolled at different sites within 30 days of the patient’s original enrollment.  
4.2.7 Cross checking charts 
Information entered in REDCap by research staff will be subject to detailed cross check by one of the 
other unblinded study coordinators. Select study coordinators will be checking information from 
another site using EPIC.  
Information to be cross-checked includes: 
Admission date 
Discharge Date 
PCT values 
Composite adverse events 
Antibiotics names (enrollment and daily) 
Antibiotics doses 

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Discharge antibiotics names 
Discharge antibiotics doses 
Discharge antibiotics duration 
Survival at day 30 
 
In the case of errors in 3 different sections and/or a 15% error of all values, all information 
related to the enrolled subject will be cross-checked by the study coordinator. 
 
Estimated Study Duration and Study Centers 
Start of enrollment  
 
Feb 2021 
Last patient out 
 
 Jun 2023 
1. Massachusetts General Hospital, Department of Medicine, Boston, MA, USA 
2. North Shore Medical Center, Department of Medicine, Salem, MA, USA 
3. Martha’s Vineyard Hospital, Department of Medicine, Oak Bluffs, MA, USA 
4. Grady Memorial Hospital, Department of Medicine, Atlanta, GA, USA 
5. Charlotte Hungerford Hospital, Department of Medicine, Torrington, CT, USA 
6. Texas Health Harris Methodist Hospital-Fort Worth, Department of Pharmacy, Fort 
Worth, TX, USA 
5 
BLOOD SAMPLING 
 
Collection of specimen 
Left over serum from daily routine sampling will be collected in every study patient (intervention 
and control) and PCT will be measured. Samples should be processed according to clinics’ 
standard operating procedures to gain serum.  
 
Handling of specimen and labeling of PCT measurements 
All sample processing should occur at room temperature (RT) at the time points specified in 
section 4.1.  Samples should be processed according to the Elecsys B·R·A·H·M·S PCTTM or Abbott 
Alinity package insert, depending on site.  
All samples will be coded in the eCRF using a unique study identifier.  
 

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6 
RANDOMIZATION AND MEASUREMENT OF PROCALCITONIN 
 
Randomization 
Admitted patients will be screened, and eligible patients will be randomly assigned in a 1:1 ratio 
to the (i) PCT algorithm + stewardship team arm or (ii) the standard care arm.  
 
 
Procalcitonin (PCT) Measurement  
Procalcitonin will be measured with the Elecsys B·R·A·H·M·S PCT™ assay or Abbott Alinity and site 
personnel will be responsible for PCT measurements according to standard hospital procedure.  
 
PCT results will be unblinded in the PCT arm (i.e. antibiotic management guided by the PCT 
algorithm + stewardship team) and blinded in the control arm  (i.e. antibiotic management guided 
by standard of care). Research staff will enter PCT results in the eCRF (REDCap) and also ensure 
that the stewardship team views the results and makes a recommendation for PCT arm patients 
at the time frames specified in section 4.1.  
 
Every site will have an SOP or delegation log with all key personnel listed including the core lab 
director/manager who will have confirmed that their site has PCT testing validated and ready for 
use.   
 
If during the hospital course, patients meet an enrollment ineligibility criterion (e.g., developed a 
non-pulmonary infection, had to undergo a major surgery…), PCT levels will stop being measured 
and no further intervention from the stewardship team will be made. However, patients will 
continue to be monitored.  
7 
STUDY DATA 
Data from the participating patients will be collected in electronic Case Report Forms (“CRF”) (see 9.4 
Case Report Form). These clinical parameters will be collected to determine the clinical status of the 
patients.  
 
Clinical Data Collection 
The following clinical parameters will be collected in the corresponding eCRFs:  
• 
Socio-demographics at baseline PCT measurement D0 only (age, gender, race, weight) 
• 
Hospitalization Details (Enrollment date, time, number of days in the ICU, number of days in 
the general ward, number of mechanical ventilation days; admission date, time, diagnosis; 
discharge date, time diagnosis; ICU admission, date, time, reason for ICU and hospital 
admission) 
• 
Medical History (history of present illness, list of chronic conditions) 
• 
Clinical Assessment (date, time, physical exam, chief complaint, suspected site of infection, 
PSI, CURB 65 score) 

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• 
Vital Signs at rest (heart rate, respiratory rate, blood pressure, SpO2,) 
• 
Imaging Results for each image ordered while enrolled (Chest radiograph, Chest CT: Date, 
time, results summary) 
• 
Laboratory Values included in the standard care of a patient hospitalized with suspected 
infection, daily as available (date, time of blood draw; Complete Blood Count (CBC), serum 
creatinine, aspartate aminotransferase (AST), alanine transaminase (ALT) and serum total 
bilirubin, C-reactive Protein (CRP), lactate, # of blood cultures taken per patient, blood and 
sputum culture results (date/time, infecting pathogen), urine legionella and/or urine 
pneumococcus (if available), Procalcitonin (PCT)) 
• 
Antibiotic Therapy (agent, dosing, date and time at start and stop). More specifically, each 
agent will be documented daily as being started, continued or stopped including date and 
time of start and stop. 
• 
Antibiotic Therapy Decision Rationale at start/stop (reasons for starting, stopping and/or not 
starting new therapy (drop down: PCT Algorithm + clinical status, improving clinical status, 
worsening signs and symptoms, clinical assessment did not match PCT algorithm, other (free 
text)). 
• 
Presence of pre-defined overruling criteria (indicated according to Appendix A, 11.2)  
• 
Reason if recommendation from stewardship team is overruled (Clinician gave antibiotics 
before recommendation was available; Clinician believes bacterial infection present; Clinician 
unfamiliar/uncomfortable/disagrees with PCT value; Attending physician overruled; Patient
’ s clinical condition is worsening/severely ill; Borderline PCT result; Patient 
expectations/satisfaction 
required 
antibiotics; 
COPD 
exacerbation/flare 
for 
anti-
inflammatory properties (particularly for azithromycin);  Meets guideline criteria for ABX in 
COPD flare;  Other, free text)) 
• 
Antibiograms – antibiotic susceptibility will be collected to determine evolution of multi-drug 
resistant flora.  
• 
Secondary infections – microbiological evidence of secondary infection will be captured to 
monitor patients throughout the patient’s hospitalization 
• 
Concomitant Therapy - (list of current medications)  
• 
Azithromycin (query at time of randomization and on study day 5 if used for non-antibiotic 
purposes according to Appendix G) 
• 
Survival status (at ICU discharge, hospital discharge, 30-days after discharge if available) 
• 
CDI status occurs during hospitalization or is identified upon rehospitalization within 30 days 
after enrollment 
• 
Disposition (date last follow up and disposition: dead, alive, unknown) 
• 
Complications until Day30 (Septic shock, mechanical ventilation, renal failure, lung 
abscess/empyema, development of pneumonia in non-pneumonia LRTI: date and time at 
start and stop) 
 
Healthcare Resource Utilization Data 

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• 
Cost of Antibiotics (total cost of antibiotics per patient inclusive of antibiotic, tubing, IV bag, 
discharge antibiotic prescription) 
• 
Total per patient cost (including blood cultures and mechanical ventilation days) 
• 
Antibiotic ADRs (e.g. CDI) 
• 
AB days difference plus prescriptions avoided, and infection adverse event incidence 
modeling29  
• 
Cost of readmissions 
• 
Cost of Procalcitonin  
8 
STATISTICS 
 
For more detailed information regarding the statistics portion, please refer to the Statistical Analysis 
Plan (SAP). 
 
Study Design 
8.1.1 
Study type 
Prospective randomized controlled two-arm multi-center trial, see Section 4.  
 
8.1.2 
Study goal 
The study goal is to validate that a specified PCT algorithm applied to non-COVID-19 patients 
hospitalized with suspected pneumonia 
1. reduces antibiotic exposure specified as an increase of short antibiotic pneumonia treatments 
lasting less than 4 days, 
2. is not inferior concerning safety according to composite adverse events until day 30, and  
3. reduces antibiotic exposure specified as a decrease of antibiotics prescribed at discharge for 
pneumonia treatment. 
 
8.1.3 
Randomization  
Patients will be randomized with equal 50% probability to the two treatment arms “PCT arm” and 
“control arm”, see Section 6. Block randomization per study site will be applied, with random block 
length in order to prevent the possibility of predicting study arm assignments.  
 
 
Mathematical Definitions 
8.2.1 
Short antibiotic treatments (“shortABx”, primary endpoint)  
will be encoded as the proportion of patients per study arm (PCT arm, control arm) with less than 4 
days of antibiotic duration  
“antibiotic duration” (third secondary endpoint) is defined as the number of days per patient with 
antibiotic treatment for pneumonia comprising the number of days of antibiotic treatment during 
hospitalization (“ABx-dayshospital”, starting with the first day of PCT measurement which is one day 

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before enrollment into the study, counting all days with antibiotics not marked “not used for 
pneumonia”) and the number of prescribed days of antibiotic treatment at hospital discharge 
(“ABx-daysprescribed at discharge”, counting all days with antibiotics marked “to treat pneumonia”). The 
resulting sum will be bounded up to a maximum follow-up time of 30 days: 
Antibiotic duration = min( 30, ABx-dayshospital + ABx-daysprescribed at discharge ) 
8.2.2 
The first secondary endpoint "composite adverse events until day 30” (“CAE30”)  
will be encoded as the patient level Boolean inclusive disjunction (“OR”) of the following eight binary 
(true/false) single adverse event endpoints (1a) all-cause in-hospital mortality, (1b) all-cause mortality 
after discharge (as available), (2) septic shock (vasopressor use for > 1 h), (3) mechanical ventilation (via 
endotracheal tube), (4) needed dialysis, (5) lung abscess/empyema or (6) hospital readmission.  
 
The variable CAE30 mirrors the safety endpoint for pneumonia used in the study ProACT8. And, also as in 
ProACT, the endpoint will be analyzed in the form of study-arm-specific proportions, see Section 8.6. 
 
8.2.3 
The second secondary endpoint “antibiotic exposure at discharge” (“prescribedABx”)  
will be encoded as the proportion of patients per study arm (PCT arm, control arm) with antibiotic 
prescription for pneumonia treatment at discharge from index hospitalization.  
8.2.4 
The third secondary endpoint “antibiotic duration” 
will be computed per patient as described in Subsection 8.2.2. 
8.2.5 
The fourth secondary endpoint “days of therapy per 1000 patient days”  
will be computed per patient i as follows (i: index distinguishing different study patients): 
 
     DoT( patient i ) = antibiotic  duration( patient i ) / los30( patient i ) x 1000 
 
with length of stay of patient i  
 
     los30( patient i ) = min( 30, number of hospital days of patient i ). 
 
Note that DoT( patient i ) is not capped by 1000 because antibiotic  duration also includes antibiotics 
days prescribed at discharge while los30 only counts the number of in-hospital days. 
 
8.2.6 
The fifth secondary endpoint “antibiotic days prescribed at discharge” 
will be computed per patient as the number of prescribed days of antibiotic treatment at hospital 
discharge counting all days with antibiotics marked “to treat pneumonia”.  
 
8.2.7 
The sixth secondary endpoint “treatment or readmission for CDI until day 30 after 
enrollment” 
will be encoded in binary Boolean form (“true”: patient treated or re-hospitalized for CDI until day 30 
after enrollment, otherwise “false”). 

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8.2.8 
The seventh secondary endpoint “length of stay in hospital until day 30” (“los30”)  
will be computed per patient as described in the previous subsection. 
 
8.2.9 
The eighth secondary endpoint “length of stay in ICU” (“losICU30”)  
will be computed analogously to los30 but will only count days on ICU: 
 
     losICU30 = min(30, number of ICU days of patient i ). 
 
8.2.10 The ninth secondary endpoint “ICU admission until day 30”  
will be encoded per patient in binary form (“true”: patient admitted to ICU within study follow-up time 
of 30 days, otherwise “false”). 
 
8.2.11 Exploratory Endpoints 
All the individual variables constituting the composite safety endpoint “composite adverse events until 
day 30” will be considered as exploratory endpoints and be encoded in Boolean-binary form (true/false). 
 
 
Primary Study Hypothesis 
 
For the primary study endpoint “short antibiotic treatments” (“shortABx”; proportion of patients with 
short antibiotic treatments of pneumonia less than 4 days) the study hypotheses for statistical inference 
are as follows: 
 
H0: The probability of patients with short antibiotic treatment of pneumonia is smaller or equal in the 
PCT arm versus the control arm. 
 
H1: The probability of patients with short antibiotic treatment of pneumonia is greater in the PCT arm 
than in the control arm. 
 
Note that the study goal is one-sided: to validate a shortABx probability in the PCT arm that is higher 
than the shortABx probability in the control arm (see Section 8.6 and 8.9; one-sided statistical testing at 
2.5% significance level controlled for multiple testing / interim analyses. Bayesian statistics with 
uninformative priors will be applied for analysis (see Section 8.6.2).  
 
 
Analysis Populations 
The intention-to-treat (“ITT”) patient population will comprise all randomized non-COVID-19 patients.  
The per-protocol (“PP”) patient population will comprise all ITT patients  
(a) fulfilling study inclusion criteria,  
(b) not meeting study exclusion criteria at enrollment,  
(c) even if meeting study exclusion criterion after enrollment or meeting a pre-defined overruling 
criterion, 

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(d) with PCT measurements performed daily in the first week and thereafter at least every 48 hours 
during hospitalization and antibiotic treatment,  
(e) if assigned to PCT group, antibiotic steward ship team recommendation given to the treating 
physician on enrollment day and for each PCT measurement taken Monday-Friday described under d) 
and antibiotics stopped according to the PCT algorithm. An exception will be made if the stewardship 
team decides the patient will be given the same recommendation throughout their hospitalization.  
 
Consequently, it should be noted that stewardship team recommendations should also be provided for 
patients meeting pre-defined overruling criteria (e.g., need for ICU care) since such patients may still 
qualify for the per-protocol population. 
 
Patients of the PCT arm who are discharged before that day’s PCT has resulted will be excluded from the 
per protocol population. Patients in the PCT arm who were continued on antibiotics despite a 
weekend/holiday/no stewardship team member available PCT value that would have resulted in an 
stewardship team recommendation to stop antibiotics will also be excluded from the per protocol 
population. Patients in the PCT arm whose antibiotics were discontinued despite weekend/holiday/no 
stewardship team member available PCT value that would have resulted in continuation of antibiotics 
will also be excluded. 
 
(f) if assigned to control group, no PCT measurements to treating physician during index hospitalization. 
 
Primary analysis of the superiority endpoint “antibiotic exposure” will be conducted on the basis of the 
ITT patient population. Analysis of the non-inferiority endpoint “composite adverse events until day 30” 
will be conducted on the basis of PP and ITT patient population. PP-results will be compared and 
discussed with corresponding results obtained for ITT patient population.  
 
 
Handling of Missing Data 
Complete case analysis will be conducted as long as the fraction of missing values for “composite 
adverse events until day 30” and “antibiotic exposure” (“short antibiotic treatments” and “antibiotic 
exposure at discharge”) remain in the range of up to 5%. If the number of missing values turns out to be 
above 5%, an additional analysis will be conducted using multiple or Bayesian imputation. In any case, 
the possible impact of missing values on study results will be assessed by sensitivity analysis using 
worst-case and best-case imputations. 
 
 
Statistical Analysis 
8.6.1 
 Descriptive Statistics 
The first step of statistical data analysis will comprise the application of conventional data cleaning and 
checking procedures including assessment of missing data and outliers, and uni- and bivariate 
plausibility checks. Data verifications and if applicable corrections will be requested. 
 
Next, a thorough description of the overall study sample and of the two randomized study arms will be 
conducted for the two analysis populations ITT and PP. Frequency counts will be used for nominal 
variables and means with standard deviations or medians with inter-quartile ranges will be used for 
numerical variables as appropriate. Statistical hypothesis tests will be used to check the success of 

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randomization, e.g. chi-square test, Wilcoxon signed-rank test or t-test. 
 
8.6.2 
Primary Analysis of Antibiotic Exposure 
The primary endpoint “short antibiotic treatments” will be analyzed for superiority. We will assess the 
differences in proportions by Bayesian analysis assuming binomially distributed events (beta-distributed 
study-arm specific probabilities) and uninformative uniform priors.  
 
More specifically, the following generative model will be used: 
NSPCT  ~  Binomial( NPCT, pPCT )  
NSCtrl  ~  Binomial( NCtrl, pCtrl )  
pPCT, pCtrl  ~  Uniform( 0, 1 )  
with   
NSPCT, NSCtrl : number of patients with shortABx of the PCT arm and control arm, respectively  
NPCT, NCtrl :  number of patients randomized to the PCT arm and control arm, respectively  
pPCT, pCtrl :  shortABx probability for patients of the PCT arm and control arm, respectively  
 
Differences between study-arm specific probabilities will be computed by Monte Carlo simulation with 
sampling from study-arm specific posterior probabilities. Success of the analysis of antibiotic exposure is 
specified by more than 98.5% 1 posterior probability for more frequent short antibiotic treatments in 
the PCT arm than in the control arm, i.e.,   
 
     Probability[ prob( short-ABx | PCT arm ) >  prob( short-Abx | control arm ) ] > 98.5%   
with   
     prob( short-ABx | PCT arm ) :  probability of short antibiotic treatment   
                                                           for patients randomized to the PCT arm,  
     prob( short-ABx | control arm ) :  probability of short antibiotic treatment   
                                                                 for patients randomized to the control arm. 
 
The primary analysis will be conducted based on the ITT population. The analysis will also be conducted 
based on the PP patient populations and ITT- and PP-results will be compared and discussed. 
 
8.6.3 
Secondary Analysis of CAE30 
 
The first secondary endpoint “composite adverse events until day 30” (CAE30) will be analyzed for safety 
non-inferiority of the PCT arm vs. the control arm on the basis of the PP patient population. The analysis 
will also be conducted on the basis of the ITT patient populations and ITT- and PP-results will be 
compared and discussed. Differences in proportions of CAE30 between PCT arm and control arm will be 
assessed by Bayesian analysis assuming binomially distributed events (beta-distributed study-arm 
specific CAE30 probabilities) and uninformative uniform priors. More specifically, the following 
generative model will be used: 
NEPCT  ~  Binomial( NPCT, pPCT )  
NECtrl  ~  Binomial( NCtrl, pCtrl )  

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pPCT, pCtrl  ~  Uniform( 0, 1 )  
with   
NEPCT, NECtrl : number of patients with CAE30 of the PCT arm and control arm, respectively  
NPCT, NCtrl :  number of patients randomized to the PCT arm and control arm, respectively  
pPCT, pCtrl :  CAE30 probability for patients of the PCT arm and control arm, respectively  
 
Differences between study-arm specific CAE30 probabilities will be computed by Monte Carlo simulation 
sampling CAE30 probabilities pPCT, pCtrl from their analytically computed study-arm specific posterior 
probabilities. Study success is specified by more than 98.5%1 posterior probability for a CAE30 
probability of patients of the PCT arm smaller than the CAE30 probability of patients of the control arm 
plus 10% (NI margin):   
  
     Probability( CAE30 probability of PCT arm < CAE30 probability of control arm + 10% ) > 98.5% 1,           
 
or with the above introduced notation  
 
        Probability( pPCT < pCtrl  + 0.1) > 98.5% 1 .   
 
8.6.4 
Secondary Analysis of Antibiotic Exposure 
The second secondary endpoint “antibiotic exposure at discharge” will be analyzed for superiority. We 
will assess the differences in proportions by Bayesian analysis assuming binomially distributed events 
(beta-distributed study-arm specific probabilities) and uninformative uniform priors. More specifically, 
the same generative model will be used as the one for short antibiotic treatments (see Section 8.6.2). 
Differences between study-arm specific probabilities will be computed by Monte Carlo simulation with 
sampling from study-arm specific posterior probabilities. Success of the analysis of antibiotic exposure at 
discharge is specified by more than 98.5% 1 posterior probability for less antibiotic exposure of the PCT 
arm than of the control arm, i.e.   
     Probability[ prob( discharge-ABx | PCT arm ) <  prob( discharge-ABx | control arm ) ] > 98.5%  
with   
     prob( discharge-ABx | PCT arm ) :  probability of prescribed antibiotics at hospital discharge   
                                                                   for patients randomized to the PCT arm  
     prob( discharge-ABx | control arm ) :  probability of prescribed antibiotics at hospital discharge   
                                                                         for patients randomized to the control arm      
 
The analysis will be conducted first based on the ITT population. The analysis will also be conducted 
based on the PP patient populations and ITT- and PP-results will be compared and discussed. 
 
8.6.5 
Further Secondary and Exploratory Analysis 
 
1 Simulation of the selected adaptive Bayesian design with specified interim analyses based on 200, 350, 550, and 
650 patients showed that the one-sided type-I error was controlled to be below 2.5% by choosing the value 98.5% 
as the threshold for study success. See [SAP4.0] for more information. 

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 Secondary and exploratory endpoints will be analyzed according to variable type:  
 
Numerical endpoints:  
 
Distributions of numerical variables will be visualized for all patients and separately for PCT and control 
arm. Study arm-specific distributions will be compared with each other by statistical tests (e.g. Wilcoxon 
rank-sum tests), and by comparing descriptive summary measures (e.g. group medians and means).   
 
Binary endpoints: 
2 x 2 contingency tables will be reported for counts stratified according to study arm (PCT, control) and 
endpoint level (true/false). Associations between study arms and endpoints will be analyzed by 
statistical tests (e.g. chi-square test or Fisher’s exact test). Proportions and two-sided 95% confidence 
intervals or Bayesian credible intervals will be computed for all patients and separately for PCT and 
control arm.  
 
Sensitivity Analysis 
Sensitivity analysis will be conducted to assess the robustness of primary and secondary analysis results.  
• 
The results obtained for ITT and PP patient population will be compared and discussed.  
• 
Safety analysis (as described in Section 4.4) will also be conducted for the alternative safety 
endpoint definition CAE30’ only counting safety adverse events that occur at least 24 hours after 
patient randomization. The results will be compared and discussed with the results for counting all 
safety adverse events after patient randomization.    
• 
For endpoints CAE30, shortABx, and prescribedABx the study-arm specific proportions will be 
compared and discussed with the corresponding proportions that were obtained for the two run-in 
studies that were performed for accurate calculation of sample size and required power; these first 
two ProSAVE pilot-level study batches were named “ProSAVE-1 & -2” (comprising 95 (ITT) and 60 
(PP) non-COVID patients not transferred to ICU within 24 hours, patients enrolled from 2020-05-28 
to 2021-02-24). 
• 
The safety endpoint CAE30 will be analyzed and discussed regarding its individual constituent 
adverse event variables. 
 
 
Sample Size  
We plan to enroll an adequate number of patients for the study by a Bayesian adaptive design with a 
maximum number of 700 patients and interim analyses after the enrollment of 200 patients, 350 
patients, 550 patients and 650 patients. 
Sample size estimation was based on the observed results of the first two ProSAVE pilot-level study 
batches, see Table 8.1 (analysis population and endpoint specific results; “ProSAVE-1 & -2” comprising 
95 (ITT) and 60 (PP) non-COVID patients not transferred to ICU within 24 hours, patients enrolled from 
2020-05-28 to 2021-02-24). 5000 clinical trials were simulated per analysis setting (study 
endpoint, analysis population and assumed fixed sample size from 200 to 700 patients) with the 
distribution of events according to predictive posterior distributions (computed for the assumed sample 
sizes from pilot posterior probability distributions derived with uninformative conjugate priors). The 
corresponding statistical power estimates were determined as the proportions of study successes when 
applying the analyses and success criteria specified in Section 8.6.   
 

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We considered a sample size of about 500 patients to be adequate for the study because a statistical 
power of 90% was reached with 500 patients for the safety endpoint CAE30 assuming pilot ITT results.   
 
In order to account for additional sources of variation and missing data, e.g. due to seasonal changes 
during the year, possible influences of a potential fourth wave of COVID-19 and the inclusion  
of additional study sites, we specifed the study design in an adaptive way with planned interim analyses 
after 200, 350, 550 and 650 patients and a maximum number of 700 enrolled patients.  
  
Table 8.1: Pilot study results for the safety endpoint “CAE30” and for the antibiotic exposure endpoints 
“shortABx” and “prescribedABx” for ITT and PP patient populations.  
Simulation scenario  
Pilot study results  
n  
Endpoint  
Data  
PCT  
Control  
n  
npos  
n  
npos  
1  
CAE30  
pilot, ITT  
48  
3  
47  
10  
2  
pilot, PP  
30  
1  
30  
7  
3  
shortABx  
pilot, ITT  
48  
14  
47  
5  
4  
pilot, PP  
30  
12  
30  
3  
5  prescribedABx  pilot, ITT  
47  
15  
46  
24  
6  
pilot, PP  
30  
7  
29  
19  
  
Table 8.2: Estimation of statistical power (i.e. proportion of simulated trials reaching study success) for 
the three study endpoints “CAE30”, “shortABx” and “prescribedABx” with fixed sample sizes from 200 to 
700 patients (total; 100 to 350 patients per study arm) assuming effect sizes (estimate and 
uncertainty) of the “ProSAVE-1 & -2” pilot data results.   
Data  
# Patients  
Statistical Power  
Total  
Per arm  
CAE30  
shortABx  
prescribedABx  
pilot, ITT  
200  
100  
79%  
82%  
76%  
300  
150  
84%  
86%  
81%  
400  
200  
87%  
90%  
86%  
500  
250  
90%  
92%  
87%  
600  
300  
91%  
93%  
88%  
700  
350  
92%  
94%  
90%  
pilot, PP  
200  
100  
88%  
94%  
98%  
300  
150  
91%  
96%  
99%  
400  
200  
93%  
97%  
99%  
500  
250  
93%  
98%  
100%  
600  
300  
95%  
98%  
99%  
700  
350  
95%  
98%  
100%  
The adequacy of the study design was re-assessed for the following changes: (a) exchange of primary 
endpoint and (first) secondary endpoint (new primary endpoint: shortABx, new first secondary 
endpoint: CAE30), (b) change of CAE30 inference from superiority to non-inferiority, and (c) change of 

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the times of interim analyses from 500 and 600 patients to 550 and 650 patients, respectively. The 
evaluation of the study design was done analogously to the initially applied method described in Section 
2.3.2 of [SAP3.0] (clinical trial Monte Carlo simulations based on pilot study results). The new 
simulations (including some improved approximations of protocol and data generation) for the 
implemented changes resulted in an increase of the analysis parameter  from 0.9785 to 0.985 in order 
to keep type-I error control at 2.5%. We valued the new design adequate with statistical powers of 99%, 
75% and 48% to show shortABx superiority, CAE30 non-inferiority and prescribedABx superiority, 
respectively, assuming half of the effects observed in the pilot study concerning antibiotic exposure 
(RRshortABx = 1.9 and RRprescribedABx = 0.8) and considerably smaller CAE30 effects than observed in the pilot 
study (RRCAE30 = 0.9 for one tenth of the effect observed in the pilot study). 
 
Interim Analyses 
Interim analyses will be conducted after the enrollment of 200 patients, 350 patients, 550 patients and 
650 patients.  
After the enrollment of 200 and 350 patients an interim analysis will be conducted applying a 
criterion for potentially stopping for futility. A non-binding recommendation to stop patient enrollment 
for futility will be given if interim results are not in a “promising zone” to reach the CAE30 success 
criterion. More specifically, the stopping recommendation will be given if the posterior predictive 
probability of CAE30 success (i.e., proving non-inferiority) with the maximum number of 700 patients is 
below a specific futility cut-off FN = 0.1 with N = 200 or 350 representing the respective enrollment 
status:  
  
Probability(CAE30 success with 700 patients | interim data ) < FN , i.e.  
Probability( Posterior predictive probability( pPCT < pCtrl  + 0.1, 700 patients | interim data ) > 98.5% 1 ) < 0.1 
 
After the enrollment of 550 and 650 patients an interim analysis will be conducted applying criteria to 
stop potentially (a) for futility or (b) for study success:   
 
a. 
Stopping for futility:   
A non-binding recommendation to stop patient enrollment for futility will be given if interim results are 
not in a “promising zone” to reach the CAE30 success criterion. More specifically, enrollment will be 
stopped if the posterior predictive probability of CAE30 success with the maximum number of 
700 enrolled patients is below a specific futility cut-off FN = 0.1 with N = 550 or 650 representing the 
respective enrollment status:   
 
     Probability(CAE30 success with 700 patients | interim data ) < FN, i.e.  
     Probability( Posterior predictive probability( pPCT < pCtrl + 0.1, 700 patients | interim data )  > 98.5% 1 ) < 0.1 
  
b. 
Stopping for success:   
Enrollment will be stopped for success if interim results reveal a sufficiently high probability 
that success criteria are reached for the endpoints CAE30, shortABx and prescribedABx. More 
specifically, enrollment will be stopped if the posterior predictive probabilities of the three 
endpoints CAE30, shortABx and prescribedABx for the respective number 

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of enrolled patients are above the cut-off SN = 0.9:  
 
     Probability( CAE30 success with enrolled patients | interim data ) > SN AND  
     Probability( shortABx success with enrolled patients | interim data ) > SN AND  
     Probability( prescribedABx success with enrolled patients | interim data ) > SN  
 
Note: Use of the posterior predictive probability will allow to conduct the interim analysis in a timely 
manner without the need to wait for the completion of the 30 days follow-up times of all 
patients. Thereby, missing or incomplete endpoint data of enrolled patients will be imputed by 
predicted endpoint data including its respective level of uncertainty.  
The cut-off parameters of the stopping criteria F200, F350, F550, F650, S550 and S650 were specified 
by numerical simulations as F200 = F350 = F550 = F650 = 0.1 and S550 = S650 = 0.9 to assure a sufficiently 
controlled one-sided type-I error < 2.5% and a sufficiently high statistical power (study success 
probability) assuming pilot study results, see [SAP3.0].    
 
 
 
 
 
 Safety Analyses for DMC (See DMC Charter for detailed information) 
Safety analyses will be conducted at least twice when 350 and 550 patients are enrolled. The DMC will 
receive corresponding safety datasets and safety relevant interim analysis results:  
a. Safety datasets will be on patient level and comprise at least the following information: study 
arm assignment, CAE30, and all single binary CAE30 endpoint components. The DMC may request 
additional data at its discretion.  
b. As safety relevant interim analysis results the DMC will receive:   
a. A contingency table of study arm (PCT, control) vs. safety endpoint CAE30 (event 
occurred yes/no/NA; NA for patients with incomplete follow-up and no event yet)  
b. 95% credible intervals of study-arm specific CAE30 probabilities and of the difference in 
CAE30 probability between study arms (complete case analysis)  
c. Posterior probability distributions on the basis of all patients with CAE30 data (complete 
case analysis) of  
a. study-arm specific posterior probability distributions of CAE30   
b. the difference in CAE30 probability between study arms  
d. Predictive posterior distributions on the basis of all enrolled patients (including patients with 
missing or incomplete CAE30 data) of   
a. study-arm specific posterior probability distributions of CAE30   
b. difference in CAE30 probability between study arms  
 Health Economic Evaluation 
The clinical outcomes of the study will be analyzed from a health economic hospital perspective, 
extrapolation to third party payer remains optional. Clinical data and local cost data will be processed in 
the previously published/under publication Health Economic Model (Janne C Mewes et. al., The cost 
impact of PCT-guided antibiotic stewardship versus usual care for hospitalized patients with suspected 
sepsis or lower respiratory tract infections in the US: a health economic model analysis).28 All available 
information will be used in the model. Missing/confidential cost data will be substituted with publicly 
available data and highlighted accordingly. 
 

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These clinical parameters will be multiplied with the respective cost per unit, e.g. 1 day of mechanical 
ventilation, and its differences will be calculated, to understand the changes in cost when using PCT. All 
cost results per clinical parameter will be aggregated to average cost of 1 patient of each group, finally 
the cost of each study group will be modelled.  
 
All findings will be discussed in the local hospital context as well as how these compare to the overall 
situation in the United States. 
9 
REGULATORY & COMPLIANCE 
 
IDE-status & Adverse Device Effect Reporting 
The proposed IVD study is exempt from most provisions of the IDE regulation as it fulfills all of the 
following criteria. The IVD:  
- is properly labeled in accordance with 21 CFR 809.10(c);  
- is noninvasive; 
- does not require an invasive sampling procedure that presents significant risk;  
- does not by design or intention introduce energy into a subject; and 
-is not used as a diagnostic procedure without confirmation of the diagnosis by another, 
medically established diagnostic product or procedure. 
 
Elecsys B·R·A·H·M·S PCTTM immunoassay or Abbott Alinity will be used according to the Indications 
for Use outlined in the package insert and cleared by the FDA as safe and efficacious for the 
intended population. Events such as death or worsening of a medical condition will be considered 
study endpoints and not device related or study related adverse events.   
 
Adverse device effects are reportable if they include deaths and serious injuries that the medical 
device under investigation may have caused or contributed to, i.e., the device may have directly 
caused the events or played a role in the events.  
 
The IVD test will be used in a laboratory with trained lab personnel following the manufacturer’s 
instructions for use in the package insert and analyzer manual. Therefore, there is no risk of 
serious device related adverse events to the patient. Laboratory staff will follow the instruction 
for use of the device including information on limitations, warnings and precautions. Therefore, 
there is no risk of serious device related adverse events to the laboratory staff. 
 
Informed Consent 
Procalcitonin will be measured and interpreted within the context of its intended use as cleared 
by the FDA. Additionally, Procalcitonin will use leftover serum from routine blood draws and 
results will be interpreted in conjunction with other clinical and laboratory parameters by an 
Antibiotic Stewardship Team. As such, Informed Consent will be waived for this study. 

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Ethics Approval 
It is the investigator’s responsibility to ensure that this Study Protocol is reviewed and approved 
by the appropriate Institutional Review Board (“IRB”)/Ethics Committee (“EC”) (21 CFR 50). If 
applicable, the IRB/EC must also review and approve the site’s Informed Consent form (“IC form”) 
form and any other written information provided to the patient prior to any enrollment of 
patients and any advertisement that will be used for patient recruitment. The investigator must 
forward to the B·R·A·H·M·S GmbH copies of the IRB/EC approval or letter indicating the trial is 
waived from obtaining informed consent which must be received and approved by the 
B·R·A·H·M·S GmbH prior to the start of the trial. 
 
If, during the trial, it is necessary to amend either the Study Protocol or the Informed Consent 
form (if applicable), the Principal Investigator will be responsible for ensuring the IRB/EC reviews 
and approves these amended documents. If applicable, the IRB/EC approval of the amended IC 
form must be obtained before new patient consent to take part in the trial using this version of 
the form. Copies of the IRB/EC approval, and as applicable, of the amended IC form, must be 
forwarded to the B·R·A·H·M·S GmbH as soon as available. 
 
Case Report Form (CRF) 
The data of this study will be obtained by using a web-based electronic case report form (“CRF”). 
Access to the CRF will be provided via sign on link to a web accessible secured database using 
role based authenticated user accounts. Users have data entry access for all subjects from their 
site but data from different sites is segregated by application. At each site, only unblinded 
research staff will have access to all PCT results of patients (both arms). At predefined points for 
interim analysis and at the end of the study, the Principal Investigator or study team members 
will transfer all eCRF data to B·R·A·H·M·S GmbH for analysis. 
 
 
Data Management and Confidentiality  
Protocol deviations will be monitored and, if evaluable, included in the ITT analysis. 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and 
the B·R·A·H·M·S GmbH and their agents. This confidentiality is extended to cover testing of 
biological specimens and 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 will be released to any unauthorized 
third party without prior written approval of the Sponsor. 
 
B·R·A·H·M·S GmbH and other authorized representatives, and representatives of the IRB may 
inspect all documents and records required to be maintained by the investigator, including but 
not limited to, medical records, pharmacy records, and imaging results for the participants in this 
study. The clinical study sites will permit access to such records.  

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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 stored in 
a secure location for as long a period as dictated by local IRB and Institutional regulations.  
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored. This will not include the participant’s contact or 
identifying information. Rather, individual participants and their research data will be coded by a 
unique study identification number. The study data entry and study management systems used 
by clinical sites will be secured and password protected.  
 
Safety Monitoring  
Safety oversight will be under the direction of a Data Monitoring Committee (DMC) composed 
of individuals with the appropriate expertise, including infectious diseases. The DMC will meet 
approximately every six months to assess safety data by querying safety outcomes in a 
proportion of study subjects in each arm. 
 
Responsibility and Compliance  
Quality Assurance (“QA”) is maintained to meet practice standards required by the IRB, regulatory 
agencies. The principal investigator and site investigators will ensure regulatory and clinical study 
requirements. The internal requirements for the institution are maintained by the institution. 
 
9.7.1 
Trial Monitoring 
In accordance with applicable regulations, Good Clinical Practice (“GCP”), the investigator will 
ensure quality oversight and adherence to this protocol.  
 
In particular, the investigator or his delegate will: 
• 
Check and assess the progress of the trial 
• 
Review trial data collected 
• 
Conduct Source Document Verification 
• 
Identify any issues and address their resolution 
 
This will be done in order to verify that the: 
• 
Data are authentic, accurate, and complete 
• 
Safety and rights of patients are being protected 
• 
Trial is conducted in accordance with the currently approved protocol (and any 
amendments), and all applicable regulatory requirements 
 
The investigators agree to allow BRAHMS direct access to all relevant documents including 
electronic medical records or provide copies of all relevant medical records during a trial audit. 

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The investigator will also allocate his/her time and the time of his/her staff to the sponsor to 
discuss findings and any relevant issues. 
 
In addition to contacts during the trial, BRAHMS will also contact the site prior to the start of the 
trial to discuss the protocol and data collection procedures with site personnel. 
 
Trial and Site Closure 
Upon completion of the trial, the following activities, when applicable, must be conducted by the 
research staff, principal investigator and B·R·A·H·M·S GmbH as appropriate: 
• 
Data clarifications and/or resolutions 
• 
Review of site trial records for completeness 
 
In addition, B·R·A·H·M·S GmbH reserves the right to temporarily suspend or prematurely 
discontinue this trial either at a single site or at all sites at any time and for any reason. The 
principal investigator will inform all trial investigators if the trial is suspended or terminated. The 
investigators will inform their local /national regulatory authorities (as appropriate) of the 
suspension or termination of the trial and the reason(s) for the action. If required by applicable 
regulations, the investigator must inform the IRB/EC promptly and provide the reason for the 
suspension or termination. 
 
Records Retention 
In accordance with applicable regulatory requirements, following closure of the trial, the 
investigator will maintain a copy of all site trial records in a safe and secure location. All records, 
documents, and supporting material related to the study are required to be retained for a minimum 
of two years after the latter of either the termination or completion of the study or the date the 
records are no longer required for supporting a premarket approval application in compliance with 
21 CFR 812.140(d) or a premarket notification. 
 
 

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10 REFERENCES 
1. World Health Organization. Antimicrobial Resistance Global Report on Surveillance, 2014. Geneva, 
Switzerland. Available at: 
http://apps.who.int/iris/bitstream/10665/112642/1/9789241564748_eng.pdf. Accessed 10 
February 2017. 
2. Department of Health and Human Services. The Center for Disease Control and Prevention 
Antibiotic Resistance Trends in the United States. Washington, DC. Available at: 
https://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf. Accessed 20 February 2017. 
3. McDonald LC, Gerding DN, Johnson S, et al. Clinical Practice Guidelines for Clostridium difficile 
Infection in Adults and Children: 2017 Update by the Infectious Society of America (IDSA) and the 
Society for Healthcare Epidemiology of America (SHEA). CID, 2018; 66(7) e1-e48. 
4. Schuetz, P., et al., Effect of procalcitonin-guided antibiotic treatment on mortality in acute 
respiratory infections: a patient level meta-analysis. Lancet Infect Dis, 2017. 
5. Wirz, Y., et al., Effect of procalcitonin-guided antibiotic treatment on clinical outcomes in intensive 
care unit patients with infection and sepsis patients: a patient-level meta-analysis of randomized 
trials. Crit Care, 2018. 22(1): p. 191. 
6. de Jong, E., et al., Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic 
treatment in critically ill patients: a randomised, controlled, open-label trial. Lancet Infect Dis, 2016. 
16(7): p. 819-827. 
7. Huang, D.T., et al., Procalcitonin-Guided Use of Antibiotics for Lower Respiratory Tract Infection. N 
Engl J Med, 2018. 
8. Huang, D.T. et al: Design and rationale of the Procalcitonin Antibiotic Consensus Trial (ProACT), a 
multicenter randomized trial of procalcitonin antibiotic guidance in lower respiratory tract infection. 
BMC Emergency Medicine (2017) 17:25 1-10 
9. FDA Guidance for Industry:  Non-Inferiority Clinical Trials to Establish Effectiveness. U.S. Department 
of Health and Human Services, Food and Drug Administration, Nov 2016 
(https://www.fda.gov/downloads/Drugs/Guidances/UCM202140.pdf) 
10. Walsh et al.: Impact of Procalcitonin Guidance with an Educational Program on Management of 
Adults Hospitalized with Pneumonia. The American Journal of Medicine, 2018 
11. Townsend et al: Procalcitonin-guided antibiotic therapy reduces antibiotic use for lower respiratory 
tract infections in a US medical center: results of a clinical trial (submitted) 
12. Schuetz P, Kutz A, Grolimund E, et al. Excluding infection through procalcitonin testing improves 
outcomes of congestive heart failure patients presenting with acute respiratory symptoms: results 
from the randomized ProHOSP trial. Int J Cardiol 2014; 175:464-72. 
13. Bouadma L, Luyt CE, Tubach F, et al. Use of procalcitonin to reduce patients' exposure to antibiotics 
in intensive care units (PRORATA trial): a multicenter randomised controlled trial. Lancet 2010; 
375:463-74. 
14. Christ-Crain, et al., Swiss Med Wkly 2005; 135: 451-460. 
Procalcitonin in bacterial infections: Hype, Hope, more or less? 
15. Christ-Crain M. et al., Am. J. Resp. Crit. Care Med. 2006; 174: 84–93. 
Procalcitonin Guidance of Antibiotic Therapy in Community-acquired Pneumonia. 
16. Stolz D.et al., Chest 2007; 131(1): 9-19. 
Antibiotic Treatment of Exacerbations of COPD: A Randomized, Controlled Trial Comparing 
Procalcitonin-Guidance With Standard Therapy. 

PROcalcitonin impact on antibiotic reduction, adverSe events and AVoidable healthcarE costs (ProSAVE): A RCT 
Clinicaltrials.gov Identifier: NCT04158804 
                                                                                                                           
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17. Briel M. et al., Arch Intern Med. 2008; 168(18): 2000-7. 
Procalcitonin-guided antibiotic use vs a standard approach for acute respiratory tract infections in 
primary care. 
18. Burkhardt O. et al., Eur. Resp. J. 2010; 36(3): 601-7. 
Procalcitonin guidance and reduction of antibiotic use in acute respiratory tract infection. 
19. Kristoffersen K. B. et al., Clin. Microbiol. Infect. 2009; 15(5): 481-7. 
Antibiotic treatment interruption of suspected lower respiratory tract infections based on a single 
procalcitonin measurement at hospital admission--a randomized trial. 
20. Long W. et al., Respirology. 2011; 16(5): 819-24. 
 Procalcitonin guidance for reduction of antibiotic use in low-risk outpatients with community-
acquired pneumonia. 
21. Nobre V. et al., Am. J. Resp. Crit. Care Med. 2008; 177: 498–505. 
Use of Procalcitonin to Shorten Antibiotic Treatment Duration in Septic Patients: A Randomized 
Trial. 
22. Schroeder S. et al., Langenbecks Arch Surg 2009;394(2): 221-6. 
Procalcitonin (PCT)-guided algorithm reduces length of antibiotic treatment in surgical intensive care 
patients with severe sepsis: results of a prospective randomized study 
23. Hochreiter M. et al., Crit Care 2009; 13(3), R83.  
Procalcitonin to guide duration of antibiotic therapy in surgical intensive care patients: a randomized 
prospective controlled trial. 
24. Branche A.R. et al., J Infect Dis. 2015; 212(11): 1692-700. 
Serum Procalcitonin Measurement and Viral Testing to Guide Antibiotic Use for Respiratory 
Infections in Hospitalized Adults: A Randomized Controlled Trial, 
25. Verduri A. et al., PLoS One 2015; 10(3): e0118241 
Antibiotic treatment of severe exacerbations of chronic obstructive pulmonary disease with 
procalcitonin: a randomized noninferiority trial. 
26. Corti C. et al., Int. J. Chron. Obstruct. Pulmon. Dis. 2016; 11: 1381-9 
Point-of-care procalcitonin test to reduce antibiotic exposure in patients hospitalized with acute 
exacerbation of COPD. 
27. Long W. et al., Zhonghua Nei Ke Za Zhi [Chinese journal of internal medicine] 2009; 48(3): 216-9. 
The value of serum procalcitonin in treatment of community acquired pneumonia in outpatient, 
28. Janne C Mewes et. al., The cost impact of PCT-guided antibiotic stewardship versus usual care for 
hospitalized patients with suspected sepsis or lower respiratory tract infections in the US: a health 
economic model analysis (submitted to PLOS One) 
29. Jan Wiemer, Statistical Analysis Plan: ProSAVE, Version 3.0, 2022-04-05. [SAP3.0] 
30. Vincenzi, B., Fioroni, I., Pantano, F., Angeletti, S., Dicuonzo, G., Zoccoli, A., ... & Tonini, G. (2016). 
Procalcitonin as diagnostic marker of infection in solid tumors patients with fever. Scientific 
Reports, 6(1), 1-6 
31. Macchioni, D., Chesi, G., Cottafavi, L., Loria, P., Lonardo, A., & Maurantonio, M. (2013). Use of 
procalcitonin for the differential diagnosis of fever in cancer patients: an observational study. Italian 
Journal of Medicine, 7(3), 166-171. 
32. Avrillon, V., Locatelli-Sanchez, M., Folliet, L., Carbonnaux, M., Perino, E., Fossard, G., ... & Couraud, 
S. (2015). Lung cancer may increase serum procalcitonin level. Infectious Disorders-Drug Targets 
(Formerly Current Drug Targets-Infectious Disorders), 15(1), 57-63. 

PROcalcitonin impact on antibiotic reduction, adverSe events and AVoidable healthcarE costs (ProSAVE): A RCT 
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33. Garoutte, C., Poulet, C., Obstler, J. B., Bourgeois, A. M., Khamis, W., Dewolf, M., ... & Andrejak, C. 
(2016). Procalcitonin serum levels in patients with stage IV non-small cell lung cancer in first line of 
chemotherapy. 
 
 

PROcalcitonin impact on antibiotic reduction, adverSe events and AVoidable healthcarE costs (ProSAVE): A RCT 
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11 APPENDIX A 
 PCT Algorithm (Intervention) 
 
 
 
STOP Antibiotics! 
Stop Antibiotics. 
Yes Antibiotics. 
YES Antibiotics! 
Bacterial infection 
highly unlikely 
Bacterial infection 
unlikely 
Bacterial infection 
likely 
Bacterial 
infection/sepsis 
highly likely 
Consider early 
cessation 
(6-24 hours) 
 
Consider 
 cessation 
Monitor for 
cessation daily. 
STOP AB when PCT 
decreases by >80% 
OR reaches an 
absolute value of 
<0.25 (ward),  
<0.5 (ICU) 
Monitor for 
cessation daily. 
STOP AB when PCT 
decreases by >80% 
OR reaches an 
absolute value of 
<0.25 (ward),        
<0.5 (ICU) 
Repeat PCT daily with AM labs and monitor for stopping criteria 
Procalcitonin (PCT) Level ng/mL 
<0.1ng/mL 
0.1 – 0.25 ng/mL 
>0.25 – 0.5 ng/mL 
>0.5 ng/mL 

PROcalcitonin impact on antibiotic reduction, adverSe events and AVoidable healthcarE costs (ProSAVE): A RCT 
Clinicaltrials.gov Identifier: NCT04158804 
                                                                                                                           
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 PCT overruling criteria (Intervention) 
 
 
Antibiotics can be continued in the following situations despite reaching stopping criteria: 
•    Respiratory instability (taken at rest) 
o  RR > 30 breaths per min 
• 
Oxygen saturation <90% on 6 liters of oxygen/minute 
o RR>18 with sustained need (1 hour) for oxygen >4L 
• 
Hemodynamic instability (systolic <90 for more than 1 hour) or vasopressor use >1 hour 
• 
Life-threatening co-morbidity 
• 
Need for ICU care 
• 
PCT < 0.1 PSI V (>130) or CURB-65 >3 
• 
PCT >0.1 and < 0.25 PSI >= IV (91-130) or CURB-65 >2 
• 
Severe immunosuppression 
 

PROcalcitonin impact on antibiotic reduction, adverSe events and AVoidable healthcarE costs (ProSAVE): A RCT 
Clinicaltrials.gov Identifier: NCT04158804 
                                                                                                                           
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12 APPENDIX B 
12.1.1 Elecsys B·R·A·H·M·S PCTTM package insert V3   
 
https://usdiagnostics.roche.com/download/en/document/technical/ms/07301715501v3.pdf 
  
13 APPENDIX C 
 CURB-65 Score9 
(https://www.mdcalc.com/curb-65-score-pneumonia-severity)  
 
 
 
 

PROcalcitonin impact on antibiotic reduction, adverSe events and AVoidable healthcarE costs (ProSAVE): A RCT 
Clinicaltrials.gov Identifier: NCT04158804 
                                                                                                                           
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14 APPENDIX D 
 PSI Score10 
(https://www.mdcalc.com/psi-port-score-pneumonia-severity-index-cap#evidence) 
 
 
 
 
 

PROcalcitonin impact on antibiotic reduction, adverSe events and AVoidable healthcarE costs (ProSAVE): A RCT 
Clinicaltrials.gov Identifier: NCT04158804 
                                                                                                                           
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15 APPENDIX E 
 Approved Use of PCT 
 
Used in conjunction with other laboratory findings and clinical assessments, procalcitonin (PCT) is intended for 
use as follows: 
• 
to aid in the risk assessment of critically ill patients on their first day of ICU admission for progression to 
severe sepsis and septic shock, 
• 
to determine the change in PCT level over time as an aid in assessing the cumulative 28-day risk of all-
cause mortality for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in 
the emergency department or other medical wards prior to ICU admission,  
• 
to aid in decision making on antibiotic therapy, for inpatients or patients in the emergency department 
with suspected or confirmed lower respiratory tract infections (LRTI) – defined as community-acquired 
pneumonia (CAP), acute bronchitis, and acute exacerbation of chronic obstructive pulmonary disease 
(AECOPD), 
• 
to aid in decision making on antibiotic discontinuation for patients with suspected or confirmed sepsis. 
 
Two systematic literature reviews were performed to produce both study and patient-level meta-analyses, which 
are studies that combine and contrast data from multiple sources to identify patterns among study results (FDA 
public docket FDA-2016-N-2880). The study-level meta-analysis used aggregate descriptive information 
extracted from publications, and the patient-level meta-analysis used aggregate patient-level data from the raw 
dataset of each study. Each meta-analysis used random-effects models and calculated point estimates, 
differences, odds ratios (OR), interquartile ranges (IQRs) and 95% confidence intervals as appropriate. The 
endpoints evaluated were: proportion of subjects initiating antibiotics, duration of antibiotic therapy, exposure 
to antibiotics, length of hospital stay, mortality, and complications (patient level only). 
The study-level meta-analysis encompassed 11 randomized control trials (RCTs) 12,14,15-20,,24-27 which were 
published between 2004-2016, and included 4090 patients. 
The patient-level meta-analysis encompassed 13 RCTs 12-23, 27 which were published between 2004-2011, and 
included 3142 patients as listed below. 
 
Publication 
N patients 
PCT device 
Bouadma, 2010 
630 
B·R·A·H·M·S PCT sensitive KRYPTOR® 
Briel, 2008 
300 
B·R·A·H·M·S PCT sensitive KRYPTOR® 
Burkhardt, 2010 
550 
B·R·A·H·M·S PCT sensitive KRYPTOR® 
Christ-Crain, 2004 
243 
B·R·A·H·M·S PCT sensitive KRYPTOR® 
Christ-Crain, 2006 
302 
B·R·A·H·M·S PCT sensitive KRYPTOR® 
Hochreiter, 2009 
110 
B·R·A·H·M·S PCT LIA® 
Kristoffersen, 2009 
223 
B·R·A·H·M·S PCT sensitive KRYPTOR® 
Long, 2011 
172 
B·R·A·H·M·S PCT sensitive KRYPTOR® 

PROcalcitonin impact on antibiotic reduction, adverSe events and AVoidable healthcarE costs (ProSAVE): A RCT 
Clinicaltrials.gov Identifier: NCT04158804 
                                                                                                                           
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Long, 2009 
127 
B·R·A·H·M·S PCT LIA® 
Nobre, 2008 
79 
B·R·A·H·M·S PCT sensitive KRYPTOR® 
Schroeder, 2009 
27 
B·R·A·H·M·S PCT LIA® 
Schuetz, 2009 
1381 
B·R·A·H·M·S PCT sensitive KRYPTOR® 
Stolz, 2007 
226 
B·R·A·H·M·S PCT sensitive KRYPTOR® 
 
These meta-analyses concluded that PCT guided antibiotic therapy resulted in: 
• 
19.2% reduction in relative antibiotic initiation for all patients 
• 
38% reduction in overall antibiotic exposure (i.e. total days of antibiotic therapy) for inpatients 
• 
51% reduction in overall antibiotic exposure (i.e. total days of antibiotic therapy) for patients who presented 
to the Emergency Department and other associated clinics, but were not admitted 
• 
2.9 day reduction in antibiotic duration [1.25 day reduction in study-level] 
• 
3.6 day reduction in total antibiotic exposure [2.79 day reduction in study-level] 
• 
No negative effects in regards to mortality, complications, or length of stay 
 
Overview of the patient-level meta-analysis: 
Parameter 
Standard Care Therapy 
PCT Guided Therapy 
N 
included 
N (%) or Days, 
median (IQR) 
N 
included 
N (%) or Days, 
median (IQR) 
Initiation of antibiotics 
1606 
1420 (88.4%) 
1536 
1096 (71,4%) 
Duration of antibiotics 
1420 
10 (7, 12) 
1096 
7 (4, 10) 
Total exposure of antibiotics 
1606 
9 (8, 12) 
1536 
5 (0, 8) 
30 day mortality 
1606 
119 (7.4%) 
1536 
103 (6.7%) 
Complications 
1606 
339 (21.1%) 
1536 
276 (18.0%) 
Hospital length of stay 
1583 
6 (0, 13) 
1508 
7 (0, 12) 
 
 
 

PROcalcitonin impact on antibiotic reduction, adverSe events and AVoidable healthcarE costs (ProSAVE): A RCT 
Clinicaltrials.gov Identifier: NCT04158804 
                                                                                                                           
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16 APPENDIX F 
Stewardship Team Discordance Survey: 
Reason(s) for discordance:  
1-  Respiratory Rate > 30 breaths per min  
2- Patient has significant oxygen desaturation  
3-  Patient is hemodynamically unstable (e.g. hypotensive or use of vasopressors)  
4-  Patient has life-threatening co-morbidity or need for intensive care  
5- Patient has worsening symptoms  
6-  Patient has PSI of IV or CURB-65 > 3 or Gold>or=3  
7-  Patient was started on immunosuppressants  
8- Concomitant or localized infection or confirmed pathogen present requiring antibiotics (e.g. 
abscess, empyema, parapneumonic effusion)  
9- You believe bacterial infection is present  
10- You disagree with the PCT algorithm  
11- Antibiotics are given for non-infectious or anti-inflammatory properties  
12- Antibiotics are given for non-pulmonary infection  
13- Other (please specify): 
  
 
17 APPENDIX G 
 
Medical Team discordance Survey:  
Reason(s) for discordance: 
1-  Respiratory Rate > 30 breaths per min  
2- Patient has significant oxygen desaturation  
3- Patient is hemodynamically unstable (e.g. hypotensive or use of vasopressors)  
4-  Patient has life-threatening co-morbidity or need for intensive care  
5- Antibiotics are given for non-infectious or anti-inflammatory purposes  
6-  Patient has worsening symptoms  
7- patient has PSI of IV or CURB-65 > 3 or GOLD criteria >or= 3  
8- Patient was started on immunosuppressants  
9- Concomitant or localized infection or confirmed pathogen present requiring antibiotics (e.g. 
abscess, empyema, parapneumonic effusion)  
10- You believe bacterial infection is present while microbiological evidence is lacking  

PROcalcitonin impact on antibiotic reduction, adverSe events and AVoidable healthcarE costs (ProSAVE): A RCT 
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11- You are unfamiliar/uncomfortable/disagree with PCT-guided antibiotic decision making  
12-  Patient expectations/satisfaction required antibiotics  
13- Antibiotics given for non-pulmonary infection  
14- Other (please specify):