Targeted Reduction of Antibiotics Using Procalcitonin in a Multi-center, Randomized, Double-Blinded, Placebo-Controlled Non-Inferiority Study of Azithromycin Treatment in Outpatient Adults With Suspect Lower Respiratory Tract Infection (LRTI) and a Procalcitonin (PCT) Level of < / = 0.25 ng/mL (TRAP-LRTI)
Phase: NA
Conditions: Lower Respiratory Tract Infection
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Targeted Reduction of Antibiotics Using Procalcitonin in a 
Multi-center, Randomized, Double-Blinded, Placebo-
Controlled Non-Inferiority Study of Azithromycin Treatment 
in Outpatient Adults with Suspect Lower Respiratory Tract 
Infection (LRTI) and a Procalcitonin (PCT) Level of ≤0.25 
ng/mL (TRAP-LRTI) 
 
DMID Protocol Number: 15-0020 
 
DMID Funding Mechanism: Vaccine and Treatment Evaluation Unit 
In Vitro Diagnostic Support Provided by: bioMérieux 
Sponsor: NIH/NIAID/DMID 
 
 
Lead Principal Investigator: Ephraim L. Tsalik, MD, MHS, PhD 
ARLG Principal Investigator:  Ebbing Lautenbach, MD, MPH, MSCE  
 
DMID Clinical Project Manager: Marina Lee, PhD 
 
Version Number: 6.0 
 
28 February 2020 
 

DMID Protocol #15-0020 
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Statement of Compliance 
This trial will be carried out in accordance with Good Clinical Practices (GCP) as required by the 
following: 
• 
United States Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR 
Part 46; 21 CFR Part 50, 21 CFR Part 54, 21 CFR Part 56, and 21 CFR Part 812); 
• 
International Council on Harmonization (ICH) E6; 62 Federal Register 25691 (1997); and 
future revisions. 
• 
The Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule-Final 
Modification (45 CFR Parts 160 and 164); 
• 
National Institutes of Health (NIH) Clinical Terms of Award, as applicable. 
Compliance with these standards provides public assurance that the rights, safety and well-
being of study subjects are protected, consistent with the principles that have their origin in the 
Declaration of Helsinki. 
All key personnel (all individuals responsible for the design and conduct of this trial) have 
completed Human Subjects Protection Training. 

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SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable US federal regulations and ICH guidelines. 
 
Site Investigator(s): 
 
Signed: 
 
Date: 
 
 
Name 
Title 
 
 
 
 
Signed: 
 
Date: 
 
 
Name 
Title 
 
 
 

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TABLE OF CONTENTS 
 
 
Statement of Compliance ............................................................................................................... i 
Signature Page 
 .................................. ii 
List of Abbreviations ...................................................................................................................... v 
Protocol Summary ....................................................................................................................... vi 
 
1 
Key Roles ............................................................................................................................. 6 
2 
Background Information and Scientific Rationale ................................................................ 7 
2.1 
Background Information ........................................................................................... 7 
2.2 
Rationale .................................................................................................................. 8 
2.3 
Potential Risks and Benefits ..................................................................................... 8 
2.3.1 
Potential Risks .............................................................................................. 8 
2.3.2 
Known Potential Benefits .............................................................................. 9 
3 
Objectives .......................................................................................................................... 10 
3.1 
Study Objectives .................................................................................................... 10 
3.2 
Study Outcome Measures ...................................................................................... 11 
3.2.1 
Primary Outcome Measures: ...................................................................... 11 
3.2.2 
Secondary Outcome Measures .................................................................. 12 
3.2.3 
Exploratory Outcome Measures ................................................................. 16 
4 
Study Design ...................................................................................................................... 18 
5 
Study Enrollment and Withdrawal ...................................................................................... 20 
5.1 
Subject Inclusion Criteria ........................................................................................ 20 
5.2 
Subject Exclusion Criteria ...................................................................................... 21 
5.3 
Subject Randomization Criteria .............................................................................. 22 
5.4 
Treatment Assignment Procedures ........................................................................ 22 
5.4.1 
Randomization Procedures ........................................................................ 22 
5.4.2 
Masking Procedures ................................................................................... 23 
5.4.3 
Reasons for Withdrawal and Discontinuation of Treatment ........................ 23 
5.4.4 
Handling of Withdrawals and Discontinuation of Treatment ....................... 24 
5.4.5 
Termination of Study .................................................................................. 24 
6 
Study Intervention/Investigational Product ......................................................................... 25 
6.1 
Study Product Description ...................................................................................... 25 
6.1.1 
Acquisition .................................................................................................. 25 
6.1.2 
Formulation, Packaging, and Labeling ....................................................... 26 
6.1.3 
Product Storage and Stability ..................................................................... 27 
6.2 
Dosage, Preparation and Administration of Study Intervention/Investigational 
Product ................................................................................................................... 27 
6.2.1 
Azithromycin and Placebo .......................................................................... 27 
6.3 
Modification of Study Intervention/Investigational Product for a Subject ................ 27 
6.4.1 
Azithromycin and Placebo .......................................................................... 28 
6.4.2 
VIDAS® B.R.A.H.M.S. Procalcitonin Test Kits ........................................... 28 

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6.4.3 
VIDAS®  Platform ....................................................................................... 28 
6.5 
Assessment of Subject Compliance with Study Intervention/Investigational Product
 ............................................................................................................................... 28 
6.6 
Concomitant Medications/Treatments .................................................................... 29 
7 
Study Schedule .................................................................................................................. 30 
7.1 
Screening ............................................................................................................... 30 
7.3 
Follow-up Visits for Randomized Subjects ............................................................. 31 
7.3.1 
Visit 2 (Day 3 + 1 day) ................................................................................ 31 
7.3.2 
Visit 3 (Day 5 + 3 days) .............................................................................. 32 
7.3.3 
Visit #4 (Day 11 + 3 days) .......................................................................... 33 
7.3.4 
Visit # 5 Final Visit (Day 28 ± 2 days) ......................................................... 33 
7.3.5 
Early Termination Visit ................................................................................ 34 
7.3.6 
Unscheduled Visit ....................................................................................... 34 
7.4 
Follow-up for Non-randomized Subjects ................................................................ 34 
7.4.1 
Visit #5N (Day 28+7) .................................................................................. 34 
8 
Study Procedures/Evaluations ........................................................................................... 35 
8.1 
Clinical Evaluations ................................................................................................ 35 
8.2 
Laboratory Evaluations ........................................................................................... 36 
8.2.1 
Clinical Laboratory Evaluations .................................................................. 36 
8.2.2 
Special Assays or Procedures .................................................................... 36 
8.2.3 
Specimen Preparation, Handling and Shipping .......................................... 36 
9 
Assessment of Safety ........................................................................................................ 38 
9.1 
Specification of Safety Parameters ........................................................................ 38 
9.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters
 ............................................................................................................................... 38 
9.2.1 
Adverse Events .......................................................................................... 38 
9.2.2 
Solicited Adverse Events ............................................................................ 38 
9.2.3 
UADE Definition .......................................................................................... 38 
9.3 
Reporting Procedures ............................................................................................ 39 
9.3.1 
Reporting UADEs Using SAE Forms .......................................................... 39 
9.3.2 Reporting for Studies Conducted Under DMID Sponsorship ........................ 39 
9.3.3. Reporting of Pregnancy .............................................................................. 39 
9.4 
Type and Duration of the Follow-up of Subjects After Adverse Events .................. 39 
9.5 
Halting Rules .......................................................................................................... 40 
9.5.1 
Study Halting Rules .................................................................................... 40 
9.5.2 
Individual Halting Rules (Termination of Study Product Administration) .... 40 
9.6 
Safety Oversight ..................................................................................................... 41 
9.6.1 
Data and Safety Monitoring Board (DSMB) ................................................ 41 
10 
Clinical Monitoring .............................................................................................................. 42 
10.1 
Site Monitoring Plan ............................................................................................... 42 
11 
Statistical Considerations ................................................................................................... 43 
11.1 
Study Hypothesis ................................................................................................... 43 
11.2 
Sample Size Considerations: ................................................................................. 43 

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11.3 
Planned Interim Analyses ....................................................................................... 43 
11.4 
Final Analysis Plan ................................................................................................. 44 
12 
Source Documents and Access to Source Data/Documents ............................................. 50 
13 
Quality Control and Quality Assurance .............................................................................. 51 
14 
Ethics/Protection of Human Subjects ................................................................................. 52 
14.1 
Ethical Standard ..................................................................................................... 52 
14.2 
Institutional Review Board ...................................................................................... 52 
14.3 
Informed Consent Process ..................................................................................... 52 
14.3.1 Informed Consent/Assent Process (in Case of a Minor or others unable to 
consent for themselves) ............................................................................. 53 
14.4 
Exclusion of Women, Minorities, and Children (Special Populations) .................... 53 
14.5 
Subject Confidentiality ............................................................................................ 54 
14.6 
Study Discontinuation ............................................................................................. 54 
14.7 
Future Use of Stored Specimens ........................................................................... 54 
15 
Data Handling and Record Keeping ................................................................................... 56 
15.1 
Data Management Responsibilities ........................................................................ 56 
15.2 
Data Capture Methods ........................................................................................... 56 
15.3 
Types of Data ......................................................................................................... 56 
15.4 
Timing/Reports ....................................................................................................... 57 
15.5 
Study Records Retention ....................................................................................... 57 
15.6 
Protocol Deviations ................................................................................................ 57 
16 
Publication Policy ............................................................................................................... 59 
17 
Literature References ......................................................................................................... 60 
 
SUPPLEMENTS/APPENDICES 
A: Study Schedule 
 
 

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LIST OF ABBREVIATIONS 
 
 
AE 
Adverse Event 
AECOPD 
Acute Exacerbation of Chronic Obstructive Pulmonary Disease 
ARI 
Acute Respiratory Infection 
ARLG 
Antibacterial Resistance Leadership Group 
ATP 
According-to-protocol 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMS 
Clinical Materials Services 
COPD 
Chronic Obstructive Pulmonary Disease 
CRF 
Case Report Form 
DMID 
Division of Microbiology and Infectious Diseases, NIAID, NIH, DHHS 
DOOR 
Desirability Of Outcome Ranking 
DSMB 
Data and Safety Monitoring Board 
ED 
Emergency Department 
FDA 
Food and Drug Administration 
FWA 
Federal-Wide Assurance 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization 
IDES 
Internet Data Entry System 
IEC 
Independent or Institutional Ethics Committee 
IRB 
Institutional Review Board 
ITT 
Intention-to-treat 
JAMA 
Journal of the American Medical Association 
LRTI 
Lower Respiratory Tract Infection 
MOP 
Manual of Procedures 
N 
Number (typically refers to subjects) 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH, DHHS 
NIH 
National Institutes of Health 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
PCT 
Procalcitonin 
RADAR 
Response Adjusted for Days of Antibiotic Risk 
SAE 
Serious Adverse Event 
UADE 
Unanticipated Adverse Device Effect 
VAMC 
Veterans Affairs Medical Center 
 
 

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Protocol Summary 
Title: 
Targeted Reduction of Antibiotics Using Procalcitonin in a Multi-center, 
Randomized, Double-Blinded, Placebo-Controlled Non-Inferiority Study of 
Azithromycin Treatment in Outpatient Adults with Suspect Lower 
Respiratory Tract Infection (LRTI) and a Procalcitonin (PCT) Level of 
≤0.25 ng/mL (TRAP-LRTI) 
 
 
Phase:  
Not Applicable, IDE 
 
 
Population: 
Approximately 560 evaluable, adult subjects, presenting as outpatients 
with suspected LRTI with a PCT level of ≤0.25 ng/mL. In order to achieve 
this number of evaluable subjects, up to 840 will be enrolled.  
 
 
Number of Sites: 
6 
 
 
Study Duration: 
Approximately 36  months 
 
 
Subject 
Participation 
Duration: 
Approximately 28 days 
 
 
Description of 
Agent or 
Intervention: 
 Diagnostic Device: VIDAS© 3 platform and VIDAS® B.R.A.H.M.S 
Procalcitonin (PCT) test 
 
Study Drugs: Azithromycin and placebo  
 
 
Objectives: 
 
 
 
Primary: 
• 
To compare the efficacy of azithromycin versus placebo on Day 5 
(i.e., after 4 days of treatment) in subjects with suspect LRTI and 
PCT levels of ≤0.25 ng/mL at enrollment using a non-inferiority 
approach. 
 
 
Secondary:  
• 
To compare groups receiving azithromycin versus placebo with 
regard to all antibiotic use by Days 11 and 28. 
• 
To compare groups receiving azithromycin versus placebo with 
regard to return visits to a physician’s office or urgent care by Days 
11 and 28. 
• 
To compare groups receiving azithromycin versus placebo with 
regard to emergency department visits by Days 11 and 28. 

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• 
To compare groups receiving azithromycin versus placebo with 
regard to hospitalization by Days 11 and 28 if not hospitalized at 
the enrollment and randomization visit. 
• 
To compare groups receiving azithromycin versus placebo with 
regard to improvement in presenting symptoms by Days 11 and 
28. 
• 
To compare the efficacy of azithromycin versus placebo on Day 11 
in subjects with suspect LRTI and PCT levels of ≤0.25 ng/mL at 
enrollment using a non-inferiority approach.   
• 
To compare the efficacy of azithromycin versus placebo on Day 28 
in subjects with suspect LRTI and PCT levels of ≤0.25 ng/mL at 
enrollment using a non-inferiority approach 
• 
To compare the efficacy of azithromycin versus placebo in subjects 
with suspected LRTI and PCT levels of ≤0.25 ng/mL at Day 5 
using a superiority approach, employing the “Response Adjusted 
for Days of Antibiotic Risk (RADAR)” methodology. 
• 
To compare groups receiving azithromycin versus placebo in 
regard to solicited events by Day 5.  
• 
To compare groups receiving azithromycin versus placebo in 
regard to hospitalization or visits to an ED, outpatient clinic, or 
urgent care center for worsening or persistent LRTI after 
randomization by Day 5. 
• 
To compare groups receiving azithromycin versus placebo in 
regard to improvement in vital sign abnormalities or symptoms 
present at enrollment, on Day 5. 
• 
To compare groups receiving azithromycin versus placebo in 
regard to new vital sign abnormalities or symptoms on Day 5, or 
deterioration in symptoms relative to the enrollment visit on Day 5. 
 
 
Exploratory: 
• 
To compare PCT levels at Day 1 and Day 5 among treatment 
failures in the placebo and azithromycin groups  
• 
To compare the efficacy of azithromycin versus placebo in subjects 
with suspected LRTI and PCT levels of ≤0.25 ng/mL at Day 11 
using a superiority approach, employing the “Response Adjusted 
for Days of Antibiotic Risk (RADAR)” methodology 
• 
To compare groups receiving azithromycin versus placebo in 
regard to solicited events by Day 11.  
• 
To compare groups receiving azithromycin versus placebo in 
regard to hospitalization or visits to an ED, outpatient clinic, or 
urgent care center for worsening or persistent LRTI after 
randomization by Day 11. 

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• 
To compare groups receiving azithromycin versus placebo in 
regard to improvement in vital sign abnormalities or symptoms 
present at enrollment, on Day 11. 
• 
To compare groups receiving azithromycin versus placebo in 
regard to new symptoms on Day 11, or deterioration in symptoms 
relative to the enrollment visit on Day 11. 
 
 
Description of 
Study Design: 
Double-Blind, Placebo-Controlled, Randomized, Non-Inferiority Trial 
 
 
Estimated Time 
to Complete 
Enrollment: 
36 months 
 
 
 
 
 

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Schematic of Study Design: 
  

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1 
KEY ROLES 
Lead Principal 
Investigator: 
        
DMID Clinical Project 
Manager: 
 
Ephraim L. Tsalik, MD, MHS, PhD 
Duke University 
 
 
Marina Lee, PhD 
DMID/NIAID/NIH 
 
 
Partners: 
Ebbing Lautenbach, MD, MPH, MSCE 
Antibacterial Resistance Leadership Group 
 
Dana Wilkins, RN, MSHSA, CCRC 
BioMerieux 
 
Institutions: 
Duke University School of Medicine 
Durham VA Health Care System 
Emory University School of Medicine 
Atlanta VA Health Care System 
Michael E. DeBakey Health Care System 
University of Rochester 
 
Statistical and Data 
Coordinating Center: 
 
The Emmes Corporation 
 

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2 
BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
2.1 
Background Information 
Inappropriate prescribing of antibacterials for viral acute respiratory infection (ARI) contributes to 
increased healthcare costs, unnecessary drug-related adverse effects, and is a major 
contributor to antimicrobial resistance (1-5). Oral antibiotics have been attributed to ~20% of 
Emergency Department (ED) visits for drug-related adverse effects, mostly due to allergic 
reactions (6). In addition, the Centers for Disease Control and Prevention (CDC) recently 
reported ~23,000 deaths annually in the US due to multidrug resistant organisms. Antimicrobial 
stewardship programs have proven effective in driving more appropriate antibiotic use in 
inpatient settings where tight control, mandatory education, and feedback are available. 
However, most inappropriate antimicrobial use occurs in patients with ARIs (7-9). These are 
among the reasons why developing improved diagnostics that can be applied in the outpatient 
setting has been recommended by numerous entities including the Presidential Advisory 
Council on Combating Antibiotic-Resistant Bacteria.  
In the most general terms, infection represents a maladaptive interaction between pathogen and 
host that manifests in clinical disease. However, those outward manifestations (e.g., fever, 
cough, malaise) are non-specific. Identifying the cause of these non-specific symptoms has 
largely focused on pathogen identification. While important, this approach has limitations 
including issues related to low sensitivity, low specificity, inability to distinguish infection from 
colonization, sampling error, and delays between testing and results (10). Different pathogen 
identification strategies overcome some but not all of these limitations. As a complement to 
current pathogen-focused testing, host-based biomarkers can provide useful diagnostic 
information. This is predicated on the observation that patients respond differently to viral and 
bacterial infection. No biomarker has received more attention in this regard than procalcitonin 
(PCT).  
PCT was first described in the setting of sepsis, where concentrations were increased 
compared to non-infectious conditions (11). Moreover, PCT has been used to distinguish 
bacterial from viral infection because interferon gamma production induced by viral infections 
inhibits PCT production (12). As a result, PCT-guided management of LRTI (including COPD 
exacerbation and pneumonia) has been used to withhold antibiotics or shorten the duration of 
antibiotic therapy without adversely affecting outcomes in several European studies (13-15). 
Specifically, low PCT values (≤0.25 ng/mL) were used to generate recommendations that 
antibacterials be withheld. Conversely, high PCT values prompted recommendations that 
antibacterials be provided. The results of these various studies are highlighted in a Cochrane 
database systematic review and showed that antibacterial use decreased by 50% without 
adversely affecting clinical outcomes (16). 

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This placebo-controlled, randomized, double blinded study represents an approach to the 
evaluation of PCT in LRTI that has not previously been evaluated. Based on the above 
evidence, we hypothesize that patients with suspected LRTI and a PCT value, ≤0.25ng/mL, are 
unlikely to have a bacterial infection, and hence, will not benefit from antibacterial therapy. 
Therefore, treatment of these patients with placebo will be non-inferior to antibacterial therapy. 
2.2 
Rationale 
The goal of this study is to demonstrate the ability of a biomarker test to identify a patient 
population in which antibacterial treatment provides no clear benefit. This study will provide 
critical information to curtail the empiric use of antibiotics in a disease area of high antibacterial 
use – non-pneumonia LRTI, which includes tracheitis, tracheobronchitis, acute bronchitis, acute 
asthma exacerbation, and acute exacerbation of chronic obstructive pulmonary disease 
(AECOPD). In these cases, antibiotics are frequently prescribed without proper rationale leading 
to avoidable adverse events and driving antibacterial resistance. The vast majority of acute non-
pneumonia LRTIs presenting in outpatient settings are suspected to be of viral etiology; 
however, most of these cases are still treated with antibiotics. Implementation of diagnostics, 
such as host biomarker-based tests, to inform antibiotic use could reduce unnecessary antibiotic 
prescriptions. The present study focuses on patients with low PCT levels, suggesting the 
absence of a bacterial infection and tests the hypothesis that antibiotics can safely be withheld 
in this population.   
2.3 
Potential Risks and Benefits 
2.3.1 Potential Risks 
The potential risk of placebo therapy is that clinical outcomes may not be equivalent to 
azithromycin among patients with a low PCT value. Specifically, the percent of subjects with 
adequate clinical improvement and without deterioration may be lower in those who did not 
receive azithromycin. There is also a potential risk that treatment with azithromycin may be 
associated with adverse events due to antibiotic-related adverse events. The magnitude of 
these risks is not well established, although a number of randomized trials using a PCT cutoff of 
≤0.25 ng/mL suggest that withholding antibacterials in respiratory tract infections is safe and 
may be associated with better outcomes (16-19). In light of this equipoise, the risks introduced 
in the study are no greater than those encountered in routine clinical practice. In addition, there 
are potential risks associated with the use of azithromycin. As the use of azithromycin in this 
study is consistent with its approved use, potential risks are expected to be the same as those 
documented on the product label: Allergic reactions, hepatotoxicity, Clostrdium difficile-
associated diarrhea, QT prolongation, and gastrointestinal upset (e.g., nausea, vomiting, 
diarrhea, or abdominal pain).  Other treatment-related side effects occurred rarely (<1%). 

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2.3.2 Known Potential Benefits 
If, as assessed by the primary outcome, placebo therapy is non-inferior to azithromycin, then 
not prescribing unnecessary antibiotics will reduce antibiotic exposure among adults with LRTI. 
The potential benefits of reduced antimicrobial exposure involve benefits both to the individual 
patient and the population as a whole.   
Potential benefits to the individual patient include a lower risk of an adverse event associated 
with antibiotic therapy (e.g., antibiotic associated diarrhea, allergic reactions, drug-drug 
interactions, Clostridium difficile infection) and a lower risk of becoming colonized and 
subsequently infected with antibiotic-resistant bacteria.   
Potential benefits to the population include a lower prevalence of colonization with pathogenic 
antibiotic-resistant bacteria among adults treated for LRTI. Since these antibiotic-resistant 
bacteria are transmissible, a lower prevalence of antibiotic-resistant bacterial colonization 
among the population treated for LRTI could decrease the risk of colonization by antibiotic-
resistant bacteria among other persons in the population.  

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3 
OBJECTIVES 
3.1 
Study Objectives 
Primary:  
1. To compare the efficacy of azithromycin versus placebo on Day 5 (i.e., after 4 days of 
treatment) in subjects with suspect LRTI and PCT levels of ≤0.25 ng/mL at enrollment 
using a non-inferiority approach.   
Secondary: 
1. To compare groups receiving azithromycin versus placebo with regard to all antibiotic 
use by Days 11 and 28. 
2. To compare groups receiving azithromycin versus placebo with regard to return visits to 
a physician’s office or urgent care by Days 11 and 28. 
3. To compare groups receiving azithromycin versus placebo with regard to emergency 
department visits by Days 11 and 28. 
4. To compare groups receiving azithromycin versus placebo with regard to hospitalization 
by Days 11 and 28 if not hospitalized at the enrollment and randomization visit. 
5. To compare groups receiving azithromycin versus placebo with regard to improvement 
in presenting symptoms by Days 11 and 28. 
6. To compare the efficacy of azithromycin versus placebo on Day 11 in subjects with 
suspect LRTI and PCT levels of ≤0.25 ng/mL at enrollment using a non-inferiority 
approach.   
7. To compare the efficacy of azithromycin versus placebo on Day 28 in subjects with 
suspect LRTI and PCT levels of ≤0.25 ng/mL at enrollment using a non-inferiority 
approach.   
8. To compare the efficacy of azithromycin versus placebo in subjects with suspected LRTI 
and PCT levels of ≤0.25 ng/mL at Day 5 using a superiority approach, employing the 
“Response Adjusted for Days of Antibiotic Risk (RADAR)” methodology.   
9. To compare groups receiving azithromycin versus placebo in regard to solicited events 
by Day 5.  
10. To compare groups receiving azithromycin versus placebo in regard to hospitalization or 
visits to an ED, outpatient clinic, or urgent care center for worsening or persistent LRTI 
after randomization by Day 5. 

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11. To compare groups receiving azithromycin versus placebo in regard to improvement in 
vital sign abnormalities or symptoms present at enrollment, on Day 5. 
12. To compare groups receiving azithromycin versus placebo in regard to new vital sign 
abnormalities or symptoms on Day 5, or deterioration in symptoms relative to the 
enrollment visit on Day 5. 
Exploratory: 
1. To compare PCT levels at Day 1 and Day 5 among treatment failures in the placebo and 
azithromycin groups  
2. To compare the efficacy of azithromycin versus placebo in subjects with suspected LRTI 
and PCT levels of ≤0.25 ng/mL at Day 11 using a superiority approach, employing the 
“Response Adjusted for Days of Antibiotic Risk (RADAR)” methodology. 
3. To compare groups receiving azithromycin versus placebo in regard to solicited events by 
Day 11.  
4. To compare groups receiving azithromycin versus placebo in regard to hospitalization or 
visits to an ED, outpatient clinic, or urgent care center for worsening or persistent LRTI 
after randomization by Day 11. 
5. To compare groups receiving azithromycin versus placebo in regard to improvement in 
vital sign abnormalities or symptoms present at enrollment, on Day 11. 
6. To compare groups receiving azithromycin versus placebo in regard to new symptoms on 
Day 11, or deterioration in symptoms relative to the enrollment visit on Day 11. 
3.2 
Study Outcome Measures 
3.2.1  Primary Outcome Measures: 
 
The efficacy of azithromycin versus placebo on Day 5 will be based on clinical 
improvement. 
o Clinical improvement will be defined as fulfillment of all the following criteria: 
 
1. Improvement in at least two symptoms present at enrollment (i.e., cough, sputum 
production, chest pain, or difficulty breathing) or one symptom and at least one vital 
sign abnormality present at enrollment.  For symptoms, at least a one-step 
improvement (e.g., improvement from moderate to mild cough) will be considered a 
clinical improvement (Table 1). For vital sign abnormalities, normalization of the 

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presenting abnormal vital sign will be considered a clinical improvement. Qualifying 
vital signs and their normal values will include the following: 
o temperature (<37.8°C or 100.0°F),  
o pulse (<90 bpm),  
o respiratory rate (≤20 breaths per minute),  
2. Absence of deterioration in any qualifying symptom (i.e., cough, sputum production, 
chest pain, or difficulty breathing); or new vital sign abnormality not present at 
enrollment.   For symptoms, at least a one-step deterioration (e.g. worsening from 
mild to moderate cough) will be considered clinical deterioration (Table 1).     
3. Absence of fever in the day preceding or at the Day 5 Visit (fever is defined as 
≥37.8 °C or 100.0 °F, measured anywhere on the body). 
4. No medically attended visit to an ambulatory medical facility (e.g., ED, outpatient 
clinic, urgent care center) or hospitalization for persistent or worsening LRTI at any 
time after randomization (persistent or worsening LRTI is defined as receipt of a 
non-study antibiotic [parenteral or oral] treatment for LRTI or its complication).  
Note: receipt of a non-study antibiotic after study Day 5 will not be regarded as 
satisfying this definition if it is related to a new non-respiratory process that is 
unrelated to the prior diagnosis of LRTI 
 
Table 1. LRTI-related symptoms to define clinical improvement endpoint 
 
Mild 
Moderate 
Severe 
Cough* 
Occasional coughing 
(less than hourly)  
Frequent coughing (1 or 
more times an hour and 
interferes with activity or 
sleep) 
Almost constant 
coughing (never free of 
cough or need to 
cough, makes activity 
or sleep nearly 
impossible) 
Sputum 
production* 
Noticeable as a problem 
but does not interfere 
with activity 
Causes a great deal of 
inconvenience 
An almost constant 
problem  
Chest pain 
Noticeable only when 
coughing 
Noticeable during deep 
breaths and when 
coughing 
Almost constant, 
present even when 
resting, without cough 
Difficulty 
breathing* 
Noticeable during 
strenuous activity, such 
as going up a flight of 
stairs or walking more 
than a block on level 
ground 
Noticeable during light 
activity, or when 
washing or dressing 
Almost constant, 
present even when 
resting 
*Modified from Breathlessness, Cough, and Sputum Scale (BCSS) [18] 
 
3.2.2 Secondary Outcome Measures 
 

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1. 
All antibiotic use from Day 1 through Day 11 and from Day 1 through Day 28 in each 
treatment group 
2. 
The proportion of subjects with one or more unplanned return visits to a physician’s 
office or urgent care for persistent or worsening LRTI from Day 1 through Day 11 and from Day 
1 through Day 28 in each treatment group 
3. 
The proportion of subjects with one or more emergency department visits for persistent 
or worsening from Day 1 through Day 11 and from Day 1 through Day 28 in each treatment 
group 
4. 
The proportion of subjects with one or more hospitalizations for persistent or worsening 
LRTI (if not hospitalized at the enrollment visit) from Day 1 through Day 11 and from Day 1 
through Day 28 in each treatment group 
5. 
The proportion of subjects exhibiting improvement in at least one presenting symptom at 
Day 11 and at Day 28 in each treatment group  
6. 
The efficacy of azithromycin versus placebo on Day 11 will be based on clinical 
improvement. Clinical improvement will be defined as fulfillment of all the following criteria: 
• 
 For subjects who qualified based on the presence of at least two symptoms, then 
improvement must be observed in at least two symptoms present at enrollment (i.e., 
cough, sputum production, chest pain, difficulty breathing, or fever).  For subjects who 
qualified based on the presence of one symptom and at least one vital sign abnormality, 
improvement must be observed in the one symptom present at enrollment. For 
symptoms other than fever, at least a one-step improvement (e.g., improvement from 
moderate to mild cough) will be considered a clinical improvement (Table 1). 
• 
Note: fever will be objectively (≥37.8 °C or 100.0 °F, measured anywhere on the body) 
or subjectively reported by the subject for the day preceding or on the Day 11 visit. For 
Day 11, fever will be used similar to what has been done for Day 5 outcome measure 
definition i.e. clinical improvement requires absence of fever in the day preceding or at 
the Day 11 Visit. 
 
• 
Note: vital signs were not recorded at Days 11 and 28. Therefore, the subcomponents of 
clinical improvement at Day 11 and 28 are different from the subcomponents of clinical 
improvement used for the primary outcome measure at Day 5 (i.e., subcomponents at 
Day 11 and 28 do not include any reference to vital signs measures).  
• 
Absence of deterioration in any qualifying symptom (i.e., cough, sputum production, 
chest pain, difficulty breathing, or fever).  For symptoms other than fever, at least a one-
step deterioration (e.g. worsening from mild to moderate cough) will be considered 
clinical deterioration (Table 1).     
• 
No medically attended visit to an ambulatory medical facility (e.g., ED, outpatient clinic, 
urgent care center) or hospitalization for persistent or worsening LRTI at any time after 
randomization (persistent or worsening LRTI is defined as receipt of a non-study 
antibiotic [parenteral or oral] treatment for LRTI or its complication).  Note: receipt of a 
non-study antibiotic after study Day 11 will not be regarded as satisfying this definition if 

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it is related to a new non-respiratory process that is unrelated to the prior diagnosis of 
LRTI. 
7. 
The efficacy of azithromycin versus placebo on Day 28 will be based on clinical 
improvement. Clinical improvement will be defined as fulfillment of all the following criteria: 
• 
Improvement in at least two symptoms present at enrollment (i.e., cough, sputum 
production, chest pain, difficulty breathing, or fever).  For symptoms other than fever, at 
least a one-step improvement (e.g., improvement from moderate to mild cough) will be 
considered a clinical improvement (Table 1).  
• 
Note: fever will be objectively (≥37.8 °C or 100.0 °F, measured anywhere on the body) 
or subjectively reported by the subject for the day preceding or on the Day 28 visit.  
• 
Note: vital signs were not recorded at Days 11 and 28. Therefore, the subcomponents of 
clinical improvement at Day 11 and 28 are different from the subcomponents of clinical 
improvement used for the primary outcome measure at Day 5 (i.e., subcomponents at 
Day 11 and 28 do not include any reference to vital signs measures).  
• 
Absence of deterioration in any qualifying symptom (i.e., cough, sputum production, 
chest pain, difficulty breathing, or fever).  For symptoms other than fever, at least a one-
step deterioration (e.g. worsening from mild to moderate cough) will be considered 
clinical deterioration (Table 1).     
• 
No medically attended visit to an ambulatory medical facility (e.g., ED, outpatient clinic, 
urgent care center) or hospitalization for persistent or worsening LRTI at any time after 
randomization (persistent or worsening LRTI is defined as receipt of a non-study 
antibiotic [parenteral or oral] treatment for LRTI or its complication).   
8. 
Outcome assessed employing a superiority analysis using the “Response Adjusted for 
Days of Antibiotic Risk (RADAR)” approach.   
o The endpoint/outcome measure is the composite overall Desirability Of 
Outcome Ranking (DOOR) at Outcome Assessment on Day 5 
o DOOR is defined as follows:  
 
Each subject is evaluated according to the ordinal clinical outcome 
(See Table 2 below) 
 
DOOR is then assigned according to two rules: 
• 
When comparing two subjects with different ordinal clinical 
outcomes, the subject with a better clinical outcome receives 
a higher rank. 
• 
When comparing two subjects with the same ordinal clinical 
outcomes, the subject with fewer days of antibiotic use 
receives a higher rank. 
 
Table 2. Ordinal Clinical Outcomes Assessed at Day 5 
 
 
Adequate Clinical Improvement*  
(Assessed at Outcome Assessment 
Day 5) 
Solicited Events** 
(Assessed through Outcome 
Assessment Day 5) 

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1 
Yes 
None 
2 
Yes 
Mild (Grade 1) 
3 
Yes 
Moderate (Grade 2) 
4 
Yes 
Severe (Grade 3)  
5 
No adequate clinical improvement with 
no medically attended events 
None or any grade 
6 
No adequate clinical improvement with 
ED, outpatient clinic, or urgent care 
center visit but no hospitalization 
None or any grade 
7 
No adequate clinical improvement with 
hospitalization 
None or any grade 
8 
Death (any cause) 
-- 
* Clinical improvement as defined in section 3.2.1. 
**Solicited events are defined in Table 3. 
 
Table 3. Solicited Adverse Events for RADAR-DOOR ranking 
 
 
Mild 
Moderate 
Severe 
Abdominal pain  
Mild or intermittent and 
does not interfere with 
daily activity 
Moderate or persistent 
and interferes with daily 
activity but did not 
necessitate a medical 
visit or absenteeism  
Prevents daily activity 
and resulted in medical 
visit or absenteeism 
Vomiting  
1 episode/day  
2-3 episodes/day  
≥4 episodes/day  
Diarrhea  
Looser than normal 
stools occurring 3-6 
times/day 
Looser than normal 
stools >6 times/day  
Bloody diarrhea or 
diarrhea that requires 
clinical evaluation, 
laboratory testing, or 
hospitalization 
Allergic reaction 
New localized rash or 
itching without rash 
New diffuse rash 
covering multiple areas 
of the body  
New rash requiring 
clinical visit  
Candidiasis 
Mild mucocutaneous 
candidiasis, with no 
treatment  
Moderate 
mucocutaneous 
candidiasis, requiring 
topical or other over-
the-counter treatment 
Severe mucocutaneous 
candidiasis; requires 
urgent clinical 
evaluation, intravenous 
treatment, or 
hospitalization 
 
9.  
Proportion of subjects reporting solicited adverse events from Day 1 to Day 5 in each 
treatment group 
10. 
Proportion of subjects reporting one or more hospitalization or visits to an ED, outpatient 
clinic, or urgent care center (after randomization) for worsening or persistent LRTI from Day 1 
through Day 5 in each treatment group 

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11. 
The proportion of subjects exhibiting improvement in at least two presenting signs or 
symptoms at Day 5 in each treatment group 
12. 
The proportion of subjects exhibiting worsening or deterioration in at least one or more 
symptoms at Day 5 in each treatment group. The proportion of subjects with a new occurrence 
of a vital sign abnormality at Day 5 in each treatment group. 
 
3.2.3 Exploratory Outcome Measures 
 
1. 
Mean change in PCT levels from Day 1 and Day 5 among subjects in the placebo and 
azithromycin groups and among subjects with clinical improvement and clinical failures in each 
treatment group 
2. 
Response Adjusted for Days of Antibiotic Risk (RADAR) analysis at Day 11 (as 
described for Day 5 in Section 3.2.2 except temperature will be the only vital sign assessed at 
Day 11)  
3. 
Proportion of subjects reporting solicited adverse events from Day 1 to Day 11 in each 
treatment group 
4. 
Proportion of subjects reporting one or more hospitalization or visits to an ED, outpatient 
clinic, or urgent care center for worsening or persistent LRTI from Day 1 through Day 11 in each 
treatment group 
5. 
The proportion of subjects exhibiting improvement in at least two presenting signs or 
symptoms at Day 11 in each treatment group 
6. 
The proportion of subjects exhibiting at least one new symptom on Day 11 in each 
treatment group. The proportion of subjects with a deterioration of one or more symptom relative 
to enrollment at Day 11 in each treatment group. 
 
Table 4. Ordinal Clinical Outcomes Assessed at Day 11 
 
 
Adequate Clinical Improvement*  
(Assessed at Outcome Assessment 
Day 11) 
Solicited Events** 
(Assessed through Outcome 
Assessment Day 11) 
1 
Yes 
None 
2 
Yes 
Mild (Grade 1) 
3 
Yes 
Moderate (Grade 2) 
4 
Yes 
Severe (Grade 3)  
5 
No adequate clinical improvement with 
no medically attended events 
None or any grade 
6 
No adequate clinical improvement with 
ED, outpatient clinic, or urgent care 
center visit but no hospitalization 
None or any grade 
7 
No adequate clinical improvement with 
hospitalization 
None or any grade 
8 
Death (any cause) 
-- 

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* Clinical improvement as defined in section 3.2.1 except temperature will be the only 
vital sign assessed at Day 11. 
**Solicited events are defined in Table 3. 
 

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4 
STUDY DESIGN 
This is a randomized, double-blinded, placebo-controlled, non-inferiority multicenter clinical trial 
of azithromycin vs. placebo in adults presenting as outpatients with suspect LRTI and a PCT 
level of ≤0.25 ng/mL, as a strategy for reducing antibiotic prescriptions. The study is designed 
and powered for the primary analysis of a comparison of the efficacy of azithromycin versus 
placebo on Day 5 (i.e., after 4 days of treatment) in subjects with suspect LRTI and PCT levels 
of ≤0.25 ng/mL at enrollment using a non-inferiority approach.  
Subjects with suspect LRTI, (see Eligibility criteria #1) will be screened for the study. Qualifying 
symptom duration must be ≥24 hours and ≤28 days. Individuals fulfilling inclusion criteria will be 
approached to provide informed consent prior to the determination of the PCT level. After 
consent is obtained, the individual will have blood collected for PCT and a nasopharyngeal 
swab obtained for etiology testing. The PCT value is expected to be available to the investigator 
within 2 hours of the blood draw. All other clinical evaluation including laboratory testing and 
radiographic testing will be performed at the discretion of the treating clinician.   
Subjects with a PCT value ≤0.25 ng/mL will be randomized 1:1 to receive oral azithromycin or 
placebo for five days. Randomization will occur during the same encounter as the enrollment 
visit.  First dose of study drug should be taken within 24 hours of randomization.  If a subject 
qualifies for randomization but chooses not to randomize they will not be included in the 
analysis for the randomized group. These subjects will be withdrawn from the study due to 
subject withdrawal. 
Randomized subjects will have efficacy measured from the time of the first dose of study drug 
through approximately Day 28. Efficacy outcome assessments include assessment of 
presenting signs and symptoms, vital signs, antibiotic usage, return visits to a physician’s office, 
emergency department visits, urgent care, and hospitalizations. In addition, subjects will have 
blood collected for repeat PCT sample at Day 5.  
Subjects with a PCT value >0.25 will not be randomized.  Providers will be notified that the 
patient will not be randomized and therefore, the treating provider should make treatment 
decisions. These subjects will have their charts reviewed through approximately 28 days after 
screening to assess for return visits to a physician’s office, emergency department visits, urgent 
care, and hospitalizations. Chart review will also identify whether antimicrobials were prescribed 
at the enrollment visit or subsequent visits through 28 days. Clinical information obtained 
through routine care, as detailed in Section 8.2.1, will also be documented for these subjects. 
This data will be used to support future research. 
 
Subjects will be invited to contribute blood for PAXgene RNA collection at the enrollment visit 
(Visit #1) for future use (see Appendix A, Schedule of Events). Additional informed consent will 
be obtained for future use sample collection. 

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Details on study procedures and evaluations and study schedule are included in Sections 7 and 
8 and Appendix A Schedule of Events. 
 
The primary outcome measure is the non-inferiority of placebo versus azithromycin on Day 5 
will be based on clinical improvement. The secondary outcome measures include outcomes on 
Days 11 and 28, and RADAR analysis.  See Section 3 for additional details. 

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5 
STUDY ENROLLMENT AND WITHDRAWAL 
The study will recruit potential subjects 18 years of age or older who are suspected to have 
LRTI. In order to meet the primary objective, the study requires 560 evaluable subjects 
(approximately 280 per group). Taking into account subjects who withdraw, fail to complete Visit 
3, or do not meet other inclusion criteria for the ATP population at Day 5 as defined in Section 
11.4, this study will randomize approximately 674 enrolled subjects (approximately 337 per 
group) with PCT ≤0.25. ng/milk Potential subjects will be recruited from hospital-based 
outpatient settings including EDs and clinics within our study sites in North Carolina (Duke 
University Hospital, Durham VA Medical Center), Georgia (Emory University Hospital and 
Atlanta VA Medical Center), New York (University of Rochester) and Texas (Houston VA 
Medical Center).  
Clinical research personnel will approach patients meeting the clinical criteria (see inclusion 
criteria below) to discuss the study with them. Those who agree to participate will be consented 
for study enrollment and for future use samples. Declination to participate in collection of future 
use samples will not affect participation in the primary study. All enrolled subjects will have 
samples obtained including blood for PCT measurements and nasopharyngeal swabs for 
etiology testing. Subjects with a PCT ≤0.25 ng/mL will be randomized 1:1 to receive oral 
azithromycin or placebo.   
Subjects with a PCT >0.25 ng/mL will not be randomized and will not receive study treatment.  
These subjects will have their charts reviewed for roughly 28 days after enrollment. Providers 
will be notified that the patient will not be randomized and therefore, the treating provider should 
make treatment decisions. 
This type of consenting ensures that only patients who are willing to proceed to randomization 
and subsequent study activities are screened for PCT levels. Potential subjects will be identified 
at any time following clinical diagnosis of LRTI. Other forms and/or mechanisms of recruitment 
may also be used. The local IRB will approve recruitment materials prior to use. 
A study clinician licensed to make medical diagnoses must confirm the subject meets Inclusion 
and Exclusion Criteria. No exemptions are granted on Subject Inclusion/Exclusion Criteria in 
DMID-sponsored studies. Questions about eligibility will be directed toward the DMID Medical 
Officer. 
5.1 
Subject Inclusion Criteria 
Subjects must meet all of the inclusion criteria to be enrolled in this study. 
1. Clinician suspected LRTI1 based on the presence of at least two qualifying symptoms2 
OR one qualifying symptom and at least one qualifying vital sign.3  
 

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1 
LRTI will include acute bronchitis, tracheitis, tracheobronchitis, asthma exacerbation, and acute 
exacerbation of COPD but does not include known pneumonia. 
2 
New cough, worsening of chronic cough, new sputum production, increased volume or purulence of 
chronic sputum production, chest pain, and difficulty breathing 
3 
Fever (Provider or patient-measured temperature ≥37.8°C (100.0°F) or patient-reported feverishness), 
tachycardia of ≥90 beats/minute, tachypnea of >20 breaths/minute 
2. Males and females age ≥18 years old.  
3. Presentation ≥24 hours and ≤ 28 days after the onset of at least one qualifying symptom 
related to the acute episode of illness.  
4. Ability to understand study procedures and willing and able to comply with all required 
procedures and visits for the entire length of study. 
5. Provide written informed consent before initiation of any study procedures. 
5.2 
Subject Exclusion Criteria 
All subjects meeting any of the exclusion criteria at baseline will be excluded from study 
participation. 
1. Hospitalized prior to screening and enrollment. Subjects enrolled in clinic or ED setting 
and then hospitalized during the same clinical encounter may be included.   
2. Chronic pulmonary conditions at the investigator’s discretion4  
4 Such as: 
• 
Noninvasive ventilation use for any indication other than obstructive sleep apnea 
• 
Long-term invasive mechanical ventilation for any indication 
• 
Known diagnosis of cystic fibrosis or chronic bronchiectasis.  
3. Receipt of an investigational product within 30 days prior to Day 1 or plans to potentially 
start any investigational product within 30 days after the subject’s anticipated study 
completion. 
4. Current enrollment in another clinical trial of an investigational agent  
5. Known or suspected infection at any other anatomic site requiring antibacterial therapy. 
6. Immunosuppression.5  
5 Includes: 
• 
HIV infection with CD4<200 based on last known measurement or patient-reported value  
• 
History of hematologic malignancies 

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• 
Receipt of chemotherapy within the previous 6 months or anticipated receipt of chemotherapy 
during the study period (1 month) 
• 
Known to have an absolute neutrophil count of <500 cells/mL or an expectation of an absolute 
neutrophil count of <500 cells/mL during course of the study, 
• 
Current systemic corticosteroid use (equivalent of 20mg prednisone per day for ≥2 weeks within the 
last month) 
• 
Systemic non-steroid immunosuppressive or biologic therapy for transplant, rheumatologic 
conditions, or other conditions within the last month. Biologics used specifically for control of 
moderate to severe asthma, including anti-IgE monoclonal antibody therapy (Xolair) or IL-5 
monoclonal antibodies (Mepolizumab and Reslizumab) are allowed.  
7. Contraindication to the use of azithromycin including history of allergy or intolerance to 
azithromycin or known prolonged QTc interval (>500msec).  
8. Any condition that in the judgment of the referring provider or site investigator precludes 
participation because it could affect subject safety or ability of subject to participate in 
this trial. 
9. Prior use of azithromycin in the past two weeks.  
10. Use of any systemic antibiotic in the previous 24 hours. 
11. Previous randomization in this trial.  
5.3 
Subject Randomization Criteria 
Once enrolled, to be eligible for randomization subjects also must have PCT ≤0.25 ng/mL.  
 
5.4 
Treatment Assignment Procedures  
5.4.1 Randomization Procedures  
Per International Council on Harmonisation (ICH) guideline E6: Good Clinical Practice (GCP), 
screening records will be kept at each participating site to document the reason why an 
individual was screened, but failed trial entry criteria. The reasons why individuals failed 
screening will be recorded on screening logs maintained by each site. Once consented and 
upon entry of demographic data and confirmation of eligibility for this trial, the subject will be 
enrolled. Only if the PCT is confirmed to be ≤0.25 ng/mL, will the subject be randomly assigned 
to 1 of 2 groups (1:1 ratio) to receive either azithromycin or placebo. Subjects with a PCT >0.25 
ng/mL will remain enrolled but will not be randomized to receive study drug. 
Enrollment of subjects will be performed online using AdvantageEDC. Lists of randomized 
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in The Emmes Corporation’s Internet Data Entry System (IDES). IDES will assign each 
randomized subject a treatment code from the list after the necessary data has been entered 
into the system. Each site will have a supply of bottles pre-labeled with treatment numbers. 
Once a participant is assigned a treatment number, the corresponding bottle will be distributed 
to the participant.  An unblinded pharmacist at each site will be provided with a treatment key, 
which links the treatment code to the actual treatment assignment, which will be kept in a 
secure place. Subjects will be stratified by site. 
Instructions for subject enrollment are included in the Manual of Procedures (MOP). Manual 
back-up randomization procedures are provided in the MOP for use in the event that the site 
temporarily loses access to the Internet or the online enrollment system is unavailable.  
5.4.2 Masking Procedures  
This is a double-blind clinical trial with respect to treatment arm. Subjects, investigators, study 
personnel performing any study-related assessments following randomization, and laboratory 
personnel performing assays will be blinded to treatment group assignment. 
The study product and placebo will be dispensed by the site Research Pharmacist. The study 
product will be labeled with a numerical code that ensures site investigators, site staff, and 
subjects remain blinded to the treatment assignment. For subjects randomized to placebo, the 
placebo will resemble the appearance of the active study product. All study products will be 
packaged with an identical appearance. The site Research Pharmacist will be blinded to the 
treatment assignment at the time product is dispensed but may be unblinded to an individual 
subject’s treatment assignment, if clinically indicated as determined by the treating clinician and 
the study’s site investigator. 
5.4.3 Reasons for Withdrawal and Discontinuation of Treatment 
Subject Withdrawal  
Subjects may voluntarily withdraw their consent for study participation at any time and for any 
reason, without penalty.  
A subject may withdraw or be withdrawn from the study for any of the following reasons:  
• 
Withdrawal of consent  
• 
Subject lost to follow-up  
• 
Termination of the study  
• 
As deemed necessary by the site principal investigator or appropriate sub-
investigator for noncompliance or other reasons 
• 
Any new information becomes available that makes further participation unsafe.  

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Subjects who wish to withdraw from further study participation will be asked to continue to 
participate in follow-up visits. At the time of withdrawal, subjects will undergo an early 
termination visit, if they are not willing to participate in the remaining follow-up visits.  
If a subject experiences any individual halting rule, as defined in Section 9.5.2, they will 
discontinue treatment with the study drug but will not be withdrawn from the study.  
5.4.4 Handling of Withdrawals and Discontinuation of Treatment 
The primary reason for withdrawal from the study will be recorded on the Study Status data 
collection form. Subjects will be encouraged to complete an Early Termination Visit. Although 
subjects are free to withdraw at any time or may be withdrawn by the site principal investigator 
or appropriate sub-investigator at any time, subjects who receive at least one dose of study 
product will be encouraged to remain in the study for follow-up safety assessments. 
Every attempt will be made to follow all protocol defined safety follow-up (solicited adverse 
events) to resolution or stabilization. 
Subjects who withdraw, or are withdrawn or terminated from the study, or discontinue treatment 
will not be replaced. 
5.4.5 Termination of Study  
The National Institute of Allergy and Infectious Diseases (NIAID), or each site’s IRB of record 
may discontinue the study at any time. Should the study be discontinued prior to completion, 
any subjects on study will complete study visits, if medically appropriate, but no new subjects 
will be enrolled.  
Although the study Sponsor has every intention of completing this study, it reserves the right to 
terminate this study at any time for clinical or administrative reasons. Reasons for termination 
include, but are not limited to, study closure due to DSMB review and recommendation and at 
the discretion of DMID. 

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6 
STUDY INTERVENTION/INVESTIGATIONAL PRODUCT 
6.1 
Study Product Description 
Azithromycin 
Azithromycin, USP is an azalide antibiotic and is derived from erythromycin. Azithromycin as the 
dehydrate, is a white crystalline powder with a molecular formula of C38H72N2O12•2H2O and a 
molecular weight of 785.0. 
 
VIDAS® B.R.A.H.M.S Procacitonin Test 
The VIDAS® B.R.A.H.M.S PCT is an automated test for use on the VIDAS instruments for the 
determination of human procalcitonin in human serum or plasma using the Enzyme-Linked 
Fluorescent Assay (ELFA) technique. The VIDAS® B.R.A.H.M.S PCT is intended for use in 
conjunction with other laboratory findings and clinical assessments 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. It is also used in conjunction with other laboratory findings and clinical 
assessments to aid in decision making on antibiotic therapy for patients with suspected or 
confirmed LRTI, or patients with suspected or confirmed sepsis.  
6.1.1 Acquisition  
6.1.1.1 Azithromycin and Placebo 
  
 
Over-encapsulation, packaging, and labeling of study drug will be performed according to 
applicable regulatory requirements. All study drugs (azithromycin and placebo) will be 
distributed through the DMID Clinical Materials Services (CMS, Fisher BioServices).   
Study product (azithromycin and matching placebo) will be shipped from the DMID CMS to the 
study sites upon request and approval by DMID. 
6.1.1.2 VIDAS® B.R.A.H.M.S Procalcitonin Research Test Kits 
The VIDAS® B.R.A.H.M.S PCT Kits for the trial will be provided by bioMerieux and distributed 
through the DMID Clinical Materials Services (CMS). The kits will be manufactured following 
current good manufacturing practices (cGMP) and labeled as investigational use only (IUO). 
The kits will be shipped to CMS under controlled condition defined by the package insert (also 
refer as IFU) with tracking documents. CMS will be responsible for maintaining the kits under 
proper condition, distributing the kits to the testing labs, and controlling the inventory and 
accountability after receiving products from bioMerieux. The VIDAS® B.R.A.H.M.S PCT will be 
shipped from the DMID CMS to the study sites upon request and approval by DMID.  

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6.1.1.3 VIDAS® 3 Platform Research Lab 
The VIDAS® 3 platform will be provided, installed and qualified by field service engineers (FSE) 
from bioMerieux prior to initiation of the clinical evaluation. The participating laboratory sites will 
be CLIA-certified laboratories (or equivalent) capable of performing VIDAS® B.R.A.H.M.S PCT 
testing on VIDAS®3 platform and reporting the results to clinical sites within turnaround time 
defined in this trial.  
Annual maintenance will also be provided by bioMerieux. The general maintenance will be 
performed by the testing laboratory per the user’s manual. After the completion of the trial, the 
instruments will be deinstalled by bioMerieux FSE and shipped back to bioMerieux 
6.1.1.4 VIDAS® B.R.A.H.M.S Procalcitonin Clinical Test Kits 
 
With prior approval of DMID, CLIA certified clinical laboratory services for VIDAS® B.R.H.A.M.S. 
procalcitonin measurement may be used.  Test kits will be obtained through routine clinical 
laboratory procedures. Results will be reported to the study team within the protocol specified 
time frame.  
6.1.2 Formulation, Packaging, and Labeling 
6.1.2.1 Azithromycin and Placebo 
Azithromycin will be supplied as 250 mg over encapsulated tablets. Each capsule will contain 
one-250mg azithromycin tablet and an inert filler. 
Placebo will be supplied as matching capsules containing an inert filler. In order to maintain the 
blind, the capsules are the same size, weight, and color as the capsules containing 
Azithromycin tablets.  
Additional details will be provided in the protocol-specific MOP. 
All study products will be packaged in identical containers each containing 6 capsules. Each 
container will also be labeled in compliance with applicable regulatory requirement, including the 
FDA- required cautionary statement “Caution-New drug-Limited by Federal (or United States) 
Law to Investigational Use Only.” 
6.1.2.2  VIDAS® B.R.A.H.M.S Procalcitonin Test Kits 
The VIDAS® B.R.A.H.M.S. PCT kit consists of 60 tests. The contents of the kit are 60 PCT 
strips (each strip consists of 10 wells), 60 ready to use solid phase receptacles (SPR) coated 
with mouse monoclonal anti-human procalcitonin immunoglobulins, 2 lyophilized PCT controls 
C1 and C2, 2 lyophilized PCT calibrators S1 and S2 and a master lot entry card (MLE).  

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6.1.3 Product Storage and Stability 
 
6.1.3.1 Azithromycin and Placebo 
Azithromycin and placebo capsules must be stored at 20°C to 25°C (68°F to 77°F); excursions 
between 15°C and 30°C (59°F and 86°F) are permitted.  [See USP Controlled Room 
Temperature]. 
6.1.3.2  VIDAS® B.R.A.H.M.S Procalcitonin Test Kits 
The VIDAS® B.R.A.H.M.S. PCT kit must be stored at 2°C to 8°C (35° to 46°F). DO NOT Freeze 
reagents, with the exception of calibrators and controls after reconstitution. All unused reagents 
must be stored at 2°C to 8°C (35° to 46°F). Additional information and details can be found in 
the package insert. 
6.2 
Dosage, Preparation and Administration of Study 
Intervention/Investigational Product 
6.2.1 Azithromycin and Placebo 
Azithromycin 500 mg or placebo (administered orally as two 250 mg capsules or two matching 
placebo capsules) as a single dose within 24 hours of randomization, followed by Azithromycin 
250 mg or placebo (administered orally as one 250 mg capsule or one matching placebo 
capsule) once daily for 4 days (Day 2 through Day 5).   
Capsules should be maintained as dispensed and not scored, cut, crushed, or otherwise divided 
for ease of swallowing. The capsules will be administered with water sufficient for the subject to 
swallow the required number of capsules.  
6.3 
Modification of Study Intervention/Investigational Product for a 
Subject 
 
No modifications of study product are planned at this time. If a subject experiences any 
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6.4 
Accountability Procedures for the Study 
Intervention/Investigational Product(s) 
6.4.1  Azithromycin and Placebo  
After receipt of the study product, the site Principal Investigator (PI) is responsible for 
distribution and disposition of these study products, and has ultimate responsibility for drug 
accountability. As this is a blinded study, the site PI will delegate this responsibility to the 
unblinded site pharmacist. Study product records must be maintained and document logs of 
receipt, accountability, and storage temperature conditions. These study product accountability 
and dispensing logs must be maintained in the study file. Upon completion of the study and after 
the final monitoring visit, unused study product that has not been dispensed will be retained until 
monitored and released for disposition as per the Sponsor. 
6.4.2  VIDAS® B.R.A.H.M.S. Procalcitonin Test Kits  
After receipt of the VIDAS PCT kits, the site PI is responsible for distribution and disposition of 
these kits, and has the ultimate responsibility for PCT kits accountability. The site PI will 
delegate this responsibility to the site CLIA certified laboratory personnel.  
VIDAS PCT kits must be maintained and document logs of receipt, accountability, and storage 
temperature conditions. These kit accountability logs must be maintained in the study file. Upon 
completion of the study and after the final monitoring visit, unused kits will be retained until 
monitored and released for disposition as per the Sponsor.  
When a clinical laboratory performs procalcitonin testing, standard operating procedures as 
defined by CLIA guidelines will be used to document the receipt, accountability, and storage of 
PCT kits. 
6.4.3  VIDAS®  Platform 
The normal maintenance of the VIDAS® platform will be performed and documented by the 
laboratory. Annual maintenance of the VIDAS® 3 instruments will be provided by bioMerieux. 
For sites where PCT is measured in a CLIA-certified clinical laboratory, maintenance will be 
performed according to standard operating procedures as defined by CLIA. 
6.5 
Assessment of Subject Compliance with Study 
Intervention/Investigational Product  
The investigator will maintain records documenting all study products (azithromycin or 
placebo) administered to each subject for the entire study period. Subjects will be asked to 
complete a memory aid and bring their study product containers to Study Visit 3. The 
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concomitant medications, temperature, solicited events, and specified symptoms. The study 
coordinator/investigator will document any missed doses of study product and provide 
counseling per study sites’ routine procedures to promote compliance with study product. 
The information on the memory aid will be recorded on a source document, but the memory 
aid will not be collected from the subject. If a subject’s memory aid is not available, study 
product compliance will be obtained by subject interview. In addition, the subject will be 
reminded to bring the study product container for the purpose of maintaining drug 
accountability. If the study product container is available, product compliance will be verified 
by checking that the number of remaining pills (if any) is consistent with the memory aid 
review. The study coordinator/investigator will record how study product compliance 
information was obtained including options for interview, memory aid review, and study 
product container verification.  Empty study product bottles will be discarded in accordance 
with site standard operating procedures. 
6.6 
Concomitant Medications/Treatments 
Administration of any medications, therapies, or vaccines including dose and frequency, will be 
recorded on the appropriate data collection form. Concomitant medications will include all 
current medications and medications taken within 30 days prior to signing the informed consent 
form. Prescription and over-the-counter drugs will be included, as well as herbals, vitamins, and 
supplements. Any symptomatic treatment received on the day of/during the enrollment visit will 
not be recorded unless it is a non-study systemic antibiotic. 
 
Subjects will also be asked specifically about the use of non-study systemic antibiotics following 
enrollment and through the last study visit, but no concomitant medications other than 
antibiotics will be recorded after enrollment. 
 
Use of new medication should prompt evaluation for the presence of a new diagnosis of chronic 
medical disease or condition.  
Medications that might interfere with the evaluation of the study product or may compromise 
subject safety should not be used during the study. Medications in this category include the 
prohibited medications per the Subject Exclusion Criteria (see Section 5.2). In addition, the site 
principal investigator or appropriate sub-investigator may identify other medications that should 
not be used due to a risk to subject safety. 

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7 
STUDY SCHEDULE 
7.1 
Screening 
Each study site will determine the most efficient procedures to identify potentially eligible 
subjects from primary care clinics, urgent care centers, and emergency departments (EDs) 
affiliated with the study clinical trial centers. Providers will be informed about the study and 
provided with a TRAP-LRTI information pamphlet summarizing the study design and subject 
eligibility criteria. Providers may also be asked to alert their patients about their practice’s 
participation in the TRAP-LRTI study, instructing them that study personnel may contact them to 
discuss potential research opportunities.  
The identification of potentially eligible subjects will vary by site and practice setting and will 
include direct communication with providers, review of clinical intake logs, and electronic health 
record (EHR) alerts that automatically screen for LRTI cases from medical records.  
Suspected LRTI will be defined as specified in eligibility criteria #1. 
Once a potentially eligible subject with suspected LRTI is identified, study staff will coordinate 
with clinical providers based on local site practice. Study staff will then approach the eligible 
subject to explain the study protocol and describe the inclusion/exclusion criteria.   
7.2 
Enrollment/Baseline- Visit 1 (Day 1) 
At the Enrollment Visit, study staff will obtain written informed consent from the subject for the 
primary study and for future use of samples and data. Declination to participate in collection of 
future use samples will not affect participation in the primary study. After the subject has had the 
opportunity to ask questions and has signed the informed consent document, the following 
activities will be performed:  
• 
Eligibility criteria for enrollment will be reviewed; 
• 
An assessment of LRTI signs and symptoms will be made 
• 
Blood samples will be obtained and used for PCT measurement and future use (if 
consented).  
Additional information will be obtained from the subject as follows: 
• 
A complete medical history and sociodemographic data will be obtained by direct 
interview of the subject and medical record review 
• 
A physical examination will be performed to determine general appearance and focused 
HEENT, neck, cardiopulmonary, and abdominal examinations; vital signs, including 

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temperature, blood pressure, pulse rate, respiratory rate, and pulse oximetry (obtained 
clinically). 
* Note: physical examinations may be performed by physicians, advanced practice 
nurses, physician assistants, or nurses obtained either by study investigators or as part 
of clinical care.  
• 
Concomitant medications taken in the last 30 days will be recorded based on subject 
report or medical record review (see section 6.6. for details) 
• 
A nasopharyngeal swab specimen will be collected for respiratory viral testing and 
banking. 
The PCT value is expected to be available to the investigator within 2 hours of the blood draw. 
The study team will not report PCT results to the subject or the provider. Once the subject’s 
PCT value is available, subjects with a PCT > 0.25 ng/mL will not be randomized. Providers will 
be notified that the patient will not be randomized and therefore, the treating provider should 
make treatment decisions. 
Subjects with PCT ≤ 0.25 ng/mL will be randomized 1:1 to receive oral azithromycin or placebo 
and the following procedures will be performed: 
• 
Study product will be dispensed and study staff will review the study product with the 
subject and review the study product storage and dosing instructions. Preferably, the 
study staff will witness the subject take the first dose of study product, which will be 
recorded on the memory aid.  
• 
Subjects will be provided with a memory aid and other study-related materials to record 
daily temperature, solicited events, specified symptoms, concomitant medications, daily 
dose administration, and any unscheduled medical visits. Study staff will instruct the 
subject to complete the memory aid in order to assess adherence and to bring the aid 
and the medication bottle with them to Visit 3. Study staff will also train subjects on 
proper completion of the memory aid used to assess specific, solicited events. 
7.3 
Follow-up Visits for Randomized Subjects 
7.3.1 Visit 2 (Day 3 + 1 day) 
Study subjects will be evaluated on Day 3 via telephone. During the telephone call, study 
personnel will assess LRTI signs and symptoms. If the study team identifies concerns about 
worsening of clinical status, the subject will be advised to seek care from his/her provider or the 
nearest ER if indicated. Study staff will assist in facilitating the follow up appointment. This 
includes signs or symptoms of pneumonia (including fever, increased difficulty breathing, or 
increased/worsening cough) or development of a severe solicited event. The study staff will also 
review any new or changed concomitant medications with the subject. UADEs will be recorded if 
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Study staff will also ask about medication compliance and any solicited adverse events. 
7.3.2 Visit 3 (Day 5 + 3 days) 
The visit on Day 5 will represent the primary outcome assessment and will include an 
assessment of LRTI signs and symptoms. Also at Day 5, blood samples will be collected for 
repeat PCT testing. To permit evaluation of the secondary RADAR outcomes, all clinical 
parameters pertinent to the RADAR assessment will be ascertained at this time. This will be an 
in-person visit conducted at the study site. This visit can also be conducted in the subject’s 
home. 
Prior to this visit, study staff will make a preliminary assessment of the clinical response using 
the electronic health record to determine whether any of the following events have occurred 
after randomization and anticipated receipt of at least one dose of study agent. 
• 
The subject had a medically attended visit to an ED, urgent care, or clinic; 
• 
The subject was hospitalized during a separate clinical encounter following the enrollment 
encounter 
• 
The subject received non-study, systemic antibiotic therapy 
At the Day 5 visit, study staff will complete the following procedures: 
• 
Assessment of clinical improvement including: 
o  Review and collection of vital signs 
o  Assessment and grading of LRTI symptoms 
o  Occurrence of any medically attended visits 
o  Receipt of any non-study systemic antibiotics  
• 
Abbreviated physical examination to include general appearance and focused HEENT, 
neck, cardiopulmonary, and abdominal examinations;  
• 
Review of the subject’s memory aid  
• 
Assess and record any solicited events and UADEs 
• 
Review of memory aid and study product bottle (if available) to assess treatment 
compliance 
• 
Obtain blood sample for PCT testing 
• 
Review of study product bottle for drug accountability, if available; 
If the subject develops signs or symptoms of pneumonia (including fever, increased work of 
breathing, increased/worsening cough, or new pulse oximetry reading ≤90%) or develops a 
severe solicited event, the subject will be referred to his/her primary care provider or local 
urgent care center/ED. Study staff will assist in facilitating the follow up appointment. The study 

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staff will share all pertinent information related to the study with the treating clinician including 
treatment arm assignment if clinically indicated as determined by the treating clinician and the 
study’s site investigator. 
7.3.3 Visit #4 (Day 11 + 3 days) 
Study subjects will be evaluated on Day 11 via telephone. Secondary and exploratory outcome 
measures will be assessed at this follow up. Study staff will complete the following procedures: 
• 
Assessment of clinical improvement including: 
o  Review and collection of temperature 
o  Assessment and grading of LRTI symptoms 
o  Occurrence of any medically attended visits 
o  Receipt of any non-study systemic antibiotics  
• 
Review of the subject’s memory aid  
• 
Assess and record any solicited events and UADEs 
If the subject develops signs or symptoms of pneumonia (including fever, increased work of 
breathing, or increased/worsening cough) or develops a severe solicited event, the subject will 
be referred to his/her primary care provider or local urgent care center/ED. Study staff will 
assist in facilitating the follow up appointment. The study staff will share all pertinent information 
related to the study with the treating clinician including treatment arm assignment if clinically 
indicated as determined by the treating clinician and the study’s site investigator. 
7.3.4 Visit # 5 Final Visit (Day 28 ± 2 days) 
Study subjects will be evaluated on Day 28 via telephone. Secondary outcome measures will be 
assessed at this follow up. Study staff will complete the following procedures: 
• 
Assessment of clinical improvement including: 
o  Review and collection of temperature 
o  Assessment and grading of LRTI symptoms 
o  Occurrence of any medically attended visits 
o  Receipt of any non-study systemic antibiotics  
• 
Assess and record any UADEs 
If the subject develops signs or symptoms of pneumonia (including fever, increased work of 
breathing, or increased/worsening cough) or develops a severe solicited event, the subject will 
be referred to his/her primary care provider or local urgent care center/ED. Study staff will assist 
in facilitating the follow up appointment. The study staff will share all pertinent information 

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related to the study with the treating clinician including treatment arm assignment if clinically 
indicated as determined by the treating clinician and the study’s site investigator. 
The study staff will also review any new or changed con-commitment medications with the 
subject.  A review of the medical record will also be done to recording results of clinical 
laboratory evaluations as specified in Section 8.2.1.   
The exact date of the follow-up visit will be documented throughout the study.   
7.3.5 Early Termination Visit 
Subjects who are withdrawn from the study will be asked to complete an early termination visit. 
Procedures at the early termination visit will be identical to the next scheduled visit for outcome 
assessment. Subjects who withdraw from the study will be asked if they agree to receive a 
follow-up phone call approximately one week after their withdrawal, which will constitute the 
early termination visit.  If the subject agrees, study staff will determine if any follow-up medical 
care was sought, any solicited adverse events occurred or if there was any change in medical 
history.  
If the subject presents to the Early Termination visit with symptoms concerning for active illness 
in need of medical attention, such as fever and/or elevated respiratory rate, the study team will 
refer the subject to seek care and to follow up with their primary care provider. 
UADEs will be recorded if any occur. 
7.3.6 Unscheduled Visit 
N/A 
7.4 
Follow-up for Non-randomized Subjects 
7.4.1 Visit #5N (Day 28+7) 
At enrollment, subjects with a PCT level > 0.25 ng/ml will still have data and samples collected 
but they will not be randomized. Their charts will be reviewed through 28 days after enrollment 
in order to support future use research.  This may include recording the results of clinical 
laboratory evaluations as specified in Section 8.2.1.  Review of medical history will be 
performed to determine whether medically attended visits or receipt of systemic antibiotics have 
occurred. 
 

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8 
STUDY PROCEDURES/EVALUATIONS 
8.1 
Clinical Evaluations 
A medical history will be obtained by direct interview during the screening process. Potential 
subjects will be queried regarding a history of significant comorbidities, current medications, and 
allergies including drug allergies. Medication history (concomitant medications) will include a 
review of all medications taken in the last 30 days (see section 6.6. for details). Use of non-
study systemic antibiotics will be reviewed at each visit following enrollment. Concomitant 
medications will be reported in the eCRF.  Prescription and over-the-counter drugs will be 
included as well as herbals, vitamins and supplements. Use of new medication should prompt 
evaluation for the presence of a new diagnosis of an acute or chronic medical disease or 
condition. At follow-up visits, an interim medical history will be obtained by interview of subjects 
noting any changes since the previous clinic visit or contact. The interim medical history should 
include an assessment for new medical conditions. 
At the enrollment visit (Day 1), a clinical assessment to assess eligibility will occur, which will 
include vital signs (temperature, blood pressure, pulse, respiratory rate, and pulse oximetry). If 
indicated based on subject’s medical history or medical/nursing assessment, a physical 
examination, conducted as part of the clinical care  or by a study clinician licensed to make 
medical diagnoses*, will occur. This could include a focused HEENT, neck, cardiopulmonary, 
and abdominal examinations.  
An assessment of clinical improvement will occur at each follow-up visit. The assessment will 
include documentation of maximum temperature in the preceding 24 hours; normalization of 
respiratory rate (at the in-person visit); presence and extent of cough, sputum production, chest 
pain, and difficulty breathing; occurrence of medically attended visits including visits to the 
emergency department (ED), primary care physician, study physician, and urgent care; 
hospitalizations; and use of non-study systemic antibiotics (parenteral or oral). Vital signs 
(temperature, blood pressure, pulse, pulse oximetry, and respiratory rates) will be collected at 
the enrollment visit and at each in-person follow-up visit.   
Solicited event assessments will include an assessment of solicited events occurring from the 
time of enrollment through Visit 4 (Day 11+3 days). All subjects will be instructed to complete a 
subject memory aid from the time of enrollment through Visit 4 (Day 11+3 days). Subject 
memory aids will be reviewed with the subject for any discrepancies or missing data and data 
will be recorded by study coordinators. 
* Note: physical examinations may be performed by physicians, advanced practice nurses, 
physician assistants, or nurses. 

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8.2 
Laboratory Evaluations 
8.2.1 Clinical Laboratory Evaluations  
No clinical safety laboratory studies will be performed as part of this protocol. 
To further describe the enrolled population, we will document the following from existing site 
medical records and laboratory results: 
• 
White blood cell count and differential including site-specific normal ranges, 
• 
Results of blood or respiratory tract cultures, antigen tests, or molecular assays, and 
• 
Streptococcal pneumoniae or Legionella pneumophila serotype 1 urinary antigen testing. 
8.2.2 Special Assays or Procedures 
N/A 
8.2.3 Specimen Preparation, Handling and Shipping 
8.2.3.1  Instructions for Specimen Preparation, Handling, and Storage 
At the time of enrollment, a serum or plasma sample and nasopharyngeal sample will be 
collected. If the subject consented for future use, then PAXgene Blood RNA will also be 
collected. Another serum or plasma sample will be obtained at the Day 5 visit. 
Nasopharyngeal specimens will be collected using flocked swabs. These swabs will be placed 
in universal transport medium. See the MOP for detailed instructions on processing and storage 
of these samples. 
If the subject consented for future use, the PAXgene tubes should be inverted 8-10 times and 
stored upright at room temperature for a minimum of two hours prior to processing. Refer to the 
MOP for detailed instructions on processing and storage of these samples. 
The sample collection, preparation, and testing must follow the VIDAS B.R.A.H.M.S 
Procalcitonin (PCT) package insert, also referred to as Instruction for Use (IFU).  Additional 
details are described in the MOP. For this protocol it is preferred that a green-top lithium heparin 
tube is used for the collection of plasma but a red-top serum separator tube is also allowable. 
Note: Blood sampling tube results may vary from one manufacturer to another depending on 
the materials and additives use. It is the responsibility of each laboratory to validate the type of 
sample tube used and to follow the manufacturer’s recommendations for use. 
It is recommended not to use samples which appear to be hemolyzed, lipemic, or icteric and, if 
possible, to collect a new sample. 

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Samples collected in EDTA tubes cannot be used for PCT testing in this trial. 
Specific instructions are included in the Manual of Procedures (MOP).  
8.2.3.2 Specimen Shipment 
Nasopharyngeal swabs and serum/plasma samples will be shipped on dry ice to the DMID CMS 
in batches using only IATA-approved Category B shipping boxes. All packages will be labeled 
and documented correctly per current regulations, and a detailed manifest will be included. 
Packages will be shipped priority overnight, tracked en route, and delivery will be confirmed to 
ensure the package arrived in good condition. A specimen tracking log will be completed for 
every shipment.  
Specific instructions will be included in the Manual of Procedures (MOP). 
 

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9 
ASSESSMENT OF SAFETY 
9.1 
Specification of Safety Parameters 
As the safety profile of azithromycin is well established, and this trial is not powered to detect 
new, unknown safety signals, there will be no azithromycin-related Adverse Event (AE) 
collection or Serious Adverse Events (SAEs) reporting during this study only solicited adverse 
events will be collected. 
Additionally, a blood draw is minimum risk since there is no more risk than the normal standard 
of care. 
The collection of the nasopharyngeal swabs is minimum risk with some discomfort possibly 
experienced by the subject; in some cases, it may cause mild bleeding. This risk is no greater 
than encountered during the collection of such swabs for routine clinical care. 
9.2 
Methods and Timing for Assessing, Recording, and Analyzing 
Safety Parameters 
9.2.1 Adverse Events  
Adverse Event (AE): International Council on Harmonisation (ICH) E6 defines an AE as any 
untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product regardless of its causal relationship to the study treatment. FDA defines 
an AE as any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product. 
9.2.2 Solicited Adverse Events 
Solicited adverse events are common and known to occur following administration of the study 
product. Solicited adverse events will be recorded according to the study timeline. Solicited 
adverse events will be used to determine DOOR assignment as summarized in Table 3, Section 
3. 
9.2.3 UADE Definition 
An unanticipated adverse device effect (UADE) per 21 CFR 812.3(s): is defined as any serious 
adverse effect on health or safety or any life-threatening problem or death caused by, or 
associated with a device if that effect, problem, or death was not previously identified in nature, 
severity, or degree of incidence in the investigational plan or application (including a 

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supplementary plan or application), or any other unanticipated serious problem associated with 
a device that relates to the rights, safety, or welfare of subjects. 
9.3 
Reporting Procedures 
 
9.3.1 Reporting UADEs Using SAE Forms 
Unanticipated adverse device effect (UADE) are unexpected and will be reported appropriately 
should any occur. Any UADE must be entered into AdvantageEDCSM (within 24 hours of site 
awareness) and reported to the IRB. Please see the protocol-specific MOP for details regarding 
this procedure. 
9.3.2 Reporting for Studies Conducted Under DMID Sponsorship 
Any UADEs will be collected from the first study enrollment through study completion.  The Site 
Investigator is responsible for documenting and reporting all UADEs that are reported during the 
study, regardless of their relationship to study procedures. 
Information to be collected includes a record of any concomitant medication, event description, 
time of onset, clinician’s assessment of severity and relationship to study procedures/study 
device.  All UADEs will be followed to adequate resolution or stabilization.  Resolution of an 
UADE is defined as the return to pre-enrollment status or stabilization of the condition with the 
expectation that it will remain chronic.  Time of resolution/stabilization of the event will be 
collected for device procedure related UADEs. 
DMID will evaluate each report of a UADE in accordance with 21CFR812.46(b). DMID will notify 
the FDA, all participating site principal investigators (i.e., all principal investigators to whom the 
sponsor is providing study device), and all reviewing IRBs through the participating sites’ 
principal investigators.  Notification will occur as soon as possible but in no case later than 10 
working days after the sponsor is notified of the UADE. Relevant follow up information to a 
safety report will be provided as soon as the information is available.  
9.3.3. Reporting of Pregnancy 
The only active treatment in this study is azithromycin, which is a pregnancy Class B drug. It is 
used as a standard treatment in pregnant women.  As such, pregnancy will neither be screened 
for nor reported but may be collected per medical history. 
9.4 
Type and Duration of the Follow-up of Subjects After Adverse 
Events 
Study related solicited events and UADEs will be followed until resolved or considered stable.  

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9.5 
Halting Rules 
9.5.1 Study Halting Rules 
Subject safety data will be reviewed on an ongoing basis. If any of the following events occur 
while a subject is on study, then enrollment will be stopped, and data will be reviewed. A 
decision to proceed or to terminate the trial will be made in consultation with the DSMB 
(including the independent safety monitor), NIH/NIAID/DMID, and the clinical investigators.  
Further study enrollment will be halted for DSMB review/recommendation if any of the following 
are reported:   
• 
Hospitalization of 5 subjects (or ≥5% if more than 100 subjects randomized) that 
requires intensive care due to persistent/worsening LRTI within 28 days of initiation of 
study treatment 
• 
More than 10 subjects (≥10% if more than 100 subjects randomized) require 
hospitalization for persistent/worsening LRTI within 3 days of initiation of study treatment  
• 
More than 20 subjects (≥20% if more than 100 subjects randomized) require the 
administration of non-study directed systemic antibiotic therapy for persistent/worsening 
LRTI within 3 days of initiation of study treatment 
• 
Any subject experiences death (that is not the result of trauma or accident) prior to Visit 
4 (Day 11+3 days) and that is suspected to be related to study treatment (or 
participation).  
9.5.2 Individual Halting Rules (Termination of Study Product Administration) 
Study product administration may be discontinued if any of the following criteria are met: 
• 
Any clinical adverse event (AE), intercurrent illness, or other medical condition occurs 
that, in the opinion of the investigator, continued receipt of study product would not be in 
the best interest of the subject; 
• 
New onset of illness or condition that meets exclusion criteria, at the investigator’s 
discretion   
• 
Inadequate clinical response that requires off-study antimicrobial therapy.  
o Subjects who require off-study antimicrobial therapy will be defined as having an 
inadequate clinical response.  
Subjects may stop study drug treatment at any time of their own volition or at the advice of their 
treating provider or the study investigators.  Subjects who stop study product for any reason will 
be regarded as having withdrawn from treatment but not as having withdrawn from the study 
(i.e, subjects will be asked to continue to participate in follow-up visits). All subjects with an 
inadequate clinical response will be referred to a non-study healthcare provider for evaluation 
and possible treatment outside of the clinical study. If requested, unblinding can occur if 
clinically indicated as determined by the treating clinician and the study’s site investigator. 
At the time of withdrawal, subjects will undergo an early termination visit if they are not willing to 
participate in the remaining follow-up visits. 

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9.6 
Safety Oversight  
9.6.1 Data and Safety Monitoring Board (DSMB)  
 
Safety oversight will be conducted by a DSMB that is an independent group of experts that 
monitors subject safety and advises DMID. The DSMB members will be separate and 
independent of study personnel participating in this trial and should not have scientific, financial 
or other conflict of interest related to the study. The DSMB will consist of members with 
appropriate expertise to contribute to the interpretation of the data from this trial.  
 
The DSMB will review study progress and subject, clinical and safety data at the following time 
points:  
• Annually at the completion of each respiratory disease season;  
• Final review meeting, approximately 6-8 months after clinical database lock to review 
the cumulative unblinded safety and efficacy data for this trial. The data will be provided 
in a standard summary format;  
• Ad hoc when a halting rule is met, for immediate concerns regarding observations 
during the study, or as needed.  
 
The DSMB will operate under the rules of a DMID-approved charter that will be written at the 
organizational meeting of the DSMB. At this time, each data element that the DSMB needs to 
assess will be clearly defined. Procedures for DSMB reviews/meetings will be defined in the 
charter. The DSMB will review applicable data to include, but not limited to, study progress and 
subject, clinical, and safety data that may include enrollment and demographic information, 
medical history, concomitant medications, physical examination, dosing, and solicited events. 
Additional data may be requested by the DSMB, and interim statistical reports may be 
generated as deemed necessary and appropriate by DMID. The DSMB may receive data in 
aggregate and presented by group. The DSMB will meet and review this data at scheduled time 
points or ad hoc as needed during the study as defined in the DSMB charter. As an outcome of 
each review/meeting, the DSMB will make a recommendation as to the advisability of 
proceeding with study product administration, and to continue, modify, or terminate the study.  
 
DMID, the PI, or the DSMB chair may convene the DSMB on an ad hoc basis according to 
protocol criteria or if there are immediate concerns regarding observations during the course of 
the study. The DMID Medical Monitor is empowered to stop enrollment and study treatment if 
the halting criteria is met or in case of any safety concern.  

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10 
CLINICAL MONITORING   
10.1 Site Monitoring Plan 
Site monitoring is conducted to ensure that the human subject protections, study and laboratory 
procedures, study intervention administration, and data collection processes are of high quality 
and meet sponsor, ICH/GCP guidelines and applicable regulations, and that the study is 
conducted in accordance with the protocol, protocol-specific MOP and applicable sponsor 
standard operating procedures.  DMID, the sponsoring agency, or its designee will conduct site-
monitoring visits as detailed in the clinical monitoring plan. 
Site visits will be made at standard intervals as defined by DMID in a separate monitoring plan 
and may be made more frequently as directed by DMID.  Monitoring visits will include, but are 
not limited to, review of regulatory files, accountability records, eCRFs, informed consent forms, 
medical and laboratory reports, and protocol and GCP compliance.  Site monitors will have 
access to the study site, study personnel, and all study documentation according to the DMID-
approved site monitoring plan.  Study monitors will meet with site principal investigators to 
discuss visit findings.   

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11 
STATISTICAL CONSIDERATIONS 
11.1 Study Hypothesis 
The primary hypothesis is that placebo therapy is non-inferior in efficacy to azithromicyn 
treatment in terms of clinical improvement rates when administered to adults with suspect lower 
respiratory tract infection (LRTI) and a procalcitonin level of ≤0.25 ng/mL. The primary time point 
of interest is 4 days after administration of study product (i.e. Day 5).  
Null hypothesis:  πplacebo – πazithromycin  ≤  -12.5%, 
Alternative hypothesis (non-inferiority): πplacebo – πazithromycin  >  -12.5%, 
where π represents the probability of clinical improvement at study Day 5.  12.5% is the non-
inferiority margin used for this study. 
11.2 
Sample Size Considerations:  
The study will be powered to the primary endpoint of clinical improvement with 560 participants 
included in the according-to-protocol analysis population at Day 5. To achieve this sample size, 
approximately 674 enrolled subjects will need to be randomized (1:1) to placebo or azithromycin 
treatment to have 80% power to rule out a 12.5% increase in the clinical improvement rate with 
antibiotic therapy compared to placebo assuming a clinical improvement rate of 57.6% in each 
group using a two-sided 95% confidence interval with continuity correction, in a per-protocol 
analysis (i.e., allowing for 16.9% loss in each treatment group to follow up/rescue medication).  
The primary analysis will include an intention-to-treat (ITT) estimation of the difference in 
proportions of subjects with clinical improvement at Day 5 in the antibiotic and placebo groups 
with a two-sided 95% confidence interval.   
11.3 Planned Interim Analyses 
11.3.1 Safety Review 
An interim safety review may include enrollment and demographic information, medical history, 
concomitant medications, physical examination, dosing compliance, and solicited adverse 
events. Additional data may be requested by the DSMB, and interim statistical reports may be 
generated as deemed necessary and appropriate by DMID. The DSMB may receive data in 
aggregate and presented by treatment arm. The DSMB may also be provided with expected 
and observed rates of the expected AEs in an unblinded fashion and may request the treatment 
assignment be unblinded for an individual subject if required for safety assessment. The DSMB 
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review this data at scheduled time points or ad hoc as needed during this trial as defined in the 
DSMB charter. As an outcome of each review/meeting, the DSMB will make a recommendation 
as to the advisability of proceeding with the study treatments, and to continue, modify, or 
terminate this trial. 
Additionally, this trial will be monitored to determine if any of the study halting rules described in 
Section 9.5.1 are met. 
11.3.2 Interim Analysis of Efficacy, Futility, and Safety 
There will be no interim analysis of efficacy or futility. An interim analysis will be performed to 
assess the assumptions used for sample size calculations including rate of adequate clinical 
improvement, rate of evaluable subjects and the frequency of enrolled subjects with PCT ≤0.25 
ng/mL 
Assumptions underlying the original target sample size of 420 subjects were assessed by a 
planned, interim, blinded analysis after approximately 210 subjects completed or terminated 
from the study.  Original assumptions were that the overall rate of clinical improvement at Visit 3 
would be 80% and there would be  no more than 15% unevaluable  subjects  (i.e. withdraw, fail 
to complete Visit 3 or didn’t meet other inclusion criteria for the according-to-protocol population 
at Day 5, as defined in Section 11.4) In this interim analysis, the required sample size needed 
for 80% power to rule out a 12.5% increase in the clinical improvement rate with antibiotic 
therapy compared to placebo was computed using the observed overall rate of clinical 
improvement across both treatment groups and the observed proportion of subjects eligible for 
a per-protocol analysis at Day 5. Due to findings at the interim analysis, new sample size 
estimates have been generated to account for actual observed rates of clinical improvement 
and protocol deviations that preclude inclusion in the primary analysis. 
 
11.4 Final Analysis Plan  
The intention-to-treat (ITT) analysis population will consist of all randomized subjects. 
According-to-protocol (ATP) analysis populations will consist of subjects with no major protocol 
deviations regarding inclusion/exclusion criteria that consumed 5 doses of study product by Visit 
3. The first dose of study drug should be taken within 24 hours of randomization. Subjects who 
miss a scheduled dose but resume the recommended dosing schedule within 24 hours remain 
eligible for ATP. However, in order for a subject to be eligible for the ATP-5 analysis, Visit 3 
should be performed on or after the last day of study drug consumption while remaining within 
the 5+3 window. The ATP-5 analysis population will have the further restriction that the subjects 
must have completed an in-person Visit 3 within the protocol-defined time window.  The ATP-11 
analysis population will consist of the ATP analysis population with the further restriction that the 
subjects must have completed Visit 4 within the protocol-defined time window.  The ATP-28 

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analysis population will consist of the ATP analysis population with the further restriction that the 
subjects must have completed Visit 5 within the protocol-defined time window.  
Unless otherwise stated, all hypothesis tests and confidence intervals will be two-sided with 
α=0.05.  Statistical tests and confidence intervals will not correct for multiplicity. 
11.4.1 Primary Analysis 
The non-inferiority of placebo versus azithromycin with respect to clinical improvement on at 
Visit 3 (as defined in Section 3.2.1), using a non-inferiority margin of 12.5%, will be determined 
for the ITT analysis population using a 95% confidence interval of the difference in proportions 
of clinical improvement as constructed using multiple imputation of clinical improvement with 
linear regression.  The study Day that Visit 3 occurred on will be included as a covariate.  A 
lower bound of the confidence interval greater than -12.5% will result in the conclusion of non-
inferiority of placebo.  At minimum, the imputation model will utilize available information 
collected at baseline and any completed study visits.  Further details of the imputation model will 
be described in the SAP. 
11.4.2 Secondary Analyses 
1. The non-inferiority analysis of placebo versus azithromycin with respect to clinical 
improvement at Visit 3 (as defined in Section 3.2.1), using a non-inferiority margin of 
12.5%, will be repeated as described in Section 11.4.1 using the ATP-5 analysis 
population.   
 
2. The non-inferiority analysis of placebo versus azithromycin with respect to clinical 
improvement at Visit 4 (as defined in Section 3.2.1), using a non-inferiority margin of 
12.5%, will be repeated as described in Section 11.4.1 using the ITT analyses 
population as well as ATP-11 analysis population.  
  
3. The non-inferiority analysis of placebo versus azithromycin with respect to clinical 
improvement at Visit 5 (as defined in Section 3.2.1), using a non-inferiority margin of 
12.5%, will be repeated as described in Section 11.4.1 using the ITT analyses 
population as well as ATP-28 analysis population.   
 
4. Using the ATP-11 and ATP-28 analysis populations, respectively, the mean number of 
days of antibiotic use from Day 1 until Visit 4 or Visit 5 will be computed for placebo 
versus azithromycin, in addition to an estimated difference in means and associated 
95% confidence intervals.  The significance of the difference in means will be tested by a 
t-test. 
 
5. Using he ATP-11 and ATP-28 analysis populations, respectively, the proportion of 
subjects with one or more return visits to a physician’s office or urgent care for persistent 
or worsening LRTI at any time after randomization by Visit 4 or by Visit 5 will be 

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computed for placebo versus azithromycin, in addition to an estimated odds ratio and 
associated 95% confidence intervals.  The significance of the difference in proportions 
will be tested by a Fisher’s Exact Test. 
 
6. Using he ATP-11 and ATP-28 analysis populations, respectively, the proportion of 
subjects with one or more emergency department visits for persistent or worsening LRTI 
at any time after randomization by Visit 4 or by Visit 5 will be computed for placebo 
versus azithromycin, in addition to an estimated odds ratio and associated 95% 
confidence intervals.  The significance of the difference in proportions will be tested by a 
Fisher’s Exact Test.  
 
7. Using the subsets of the ATP-11 and ATP-28 analysis populations, respectively, 
consisting of subjects not hospitalized at the enrollment and randomization visit, the 
proportion of subjects with one or more hospitalizations for persistent or worsening LRTI 
at any time after randomization by Visit 4 or by Visit 5 will be computed for placebo 
versus azithromycin, in addition to an estimated odds ratio and associated 95% 
confidence intervals.  The significance of the difference in risk will be tested by a Fisher’s 
Exact Test.  
 
8. Using the ATP-11 and ATP-28 analysis populations, respectively, the proportions of 
subjects exhibiting improvement in at least one presenting symptom (Table 1) by Visit 4 
or by Visit 5 will be computed for placebo versus azithromycin, in addition to an 
estimated odds ratio and associated 95% confidence intervals.  The significance of the 
difference in proportions will be tested by a Fisher’s Exact Test. The analysis will be 
repeated, analyzing each symptom individually. 
 
9. The Day 5 DOORs (an ordinal outcome defined in Section 3.2.3) will be compared 
between the placebo and azithromycin arms. The sum of the probability that a randomly 
selected subject will have a better DOOR if assigned to the placebo arm plus one-half 
the probability of equal DOORs will be estimated. The null hypothesis to be tested is that 
the probability is equal to 0.50 (lack of superiority of azithromycin therapy).  The analysis 
will be carried out using the ITT analysis population, with missing DOOR values (treated 
as continuous) imputed using multiple imputation, utilizing linear regression models. The 
analysis will be repeated using the ATP-5 population.  At minimum, the imputation model 
will utilize available information collected at baseline and any completed study visits.  
Further details of the imputation model will be described in the SAP.  The Mann-Whitney 
U statistic will be combined across the imputed datasets to give the test statistic and 
Rubin’s Rules used to define distribution of the test statistic under the null hypothesis.  A 
point estimate of the estimand will be computed by dividing combined test statistic by the 
number of pairwise comparisons and a 95% confidence interval of the estimand will be 
computed by inverting the described test of the null hypothesis. 
 

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10. Using the ATP-5 analysis population, forest plots of 95% confidence intervals for the 
difference in proportions of subjects with each solicited event (a component of DOOR) 
collected through Visit 3, for each severity threshold (mild or greater, moderate or 
greater, or severe) will be generated.  Tests for differences in proportions between 
treatment arms will be given by Fisher’s exact tests. 
 
11. Using the ATP-5 analysis population, a forest plot of 95% confidence intervals for the 
difference in proportions of subjects with one or more visits to an ED, one or more visits 
to an outpatient clinic, or one or more visits to an urgent care center or one or more 
hospitalizations for persistent or worsening LRTI at any time after randomization (a 
component of clinical improvement and DOOR) will be generated.  Tests for differences 
in proportions between treatment arms will be given by Fisher’s exact tests. 
 
12. Using the ATP-5 analysis population, for each qualifying vital sign (temperature, pulse, 
respiratory rate, or pulse oximetry) and symptom (cough, sputum production, chest pain, 
or difficulty breathing), improvement in the sign or symptom at Visit 3 compared to 
baseline in subjects with the symptom or vital sign abnormality at baseline (a component 
of clinical improvement and DOOR) will be analyzed.  A forest plot of 95% confidence 
intervals for the difference in proportions of subjects with improvement in the symptom or 
sign will be generated.  Tests for differences in proportions between treatment arms will 
be given by Fisher’s exact tests.  
 
13. Using the ATP-5 analysis population, for each qualifying symptom (cough, sputum 
production, chest pain, or difficulty breathing), deterioration in the symptom at Visit 3 
compared to baseline (a component of clinical improvement and DOOR) will be 
analyzed in subjects having the symptom at baseline.  A forest plot of 95% confidence 
intervals for the difference in proportions of subjects with deterioration in the symptom 
will be generated. Tests for differences in proportions between treatment arms will be 
given by Fisher’s exact tests.  
 
14. Using the ATP-5 analysis population, for each vital sign (temperature, pulse, respiratory 
rate, or pulse oximetry), new occurrence of a vital sign abnormality at Visit 3 compared 
to baseline (a component of clinical improvement and DOOR) will be analyzed in 
subjects without the sign abnormality at baseline.  Additionally, the proportion of subjects 
with fever in the 24 hours preceding or at Visit 3 (fever is defined as ≥37.8 °C or 100.0 
°F, measured anywhere on the body), unless related to a new process that is unrelated 
to the prior diagnosis of LRTI will be analyzed. A forest plot of 95% confidence intervals 
for the difference in proportions of subjects with new occurrence of a sign abnormality at 
Visit 3 compared to baseline or fever in the 24 hours preceding or at Visit 3 will be 
generated.  Tests for differences in proportions between treatment arms will be given by 
Fisher’s exact tests. 
11.4.3 Exploratory Analyses 

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1. Using the ATP-5 analysis population, mean changes in PCT levels at Visit 3 relative to 
baseline will be computed for placebo versus azithromycin, in addition to an estimated 
difference in mean PCT changes and associated 95% confidence intervals.  Significance 
of a difference in mean PCT changes between treatment groups will be tested by a 
Wilcoxon test.  Details of the analysis will be described in the SAP. 
 
2. Using the ATP-5 analysis population, logistic regression will be used to test whether 
changes in PCT levels at Visit 3 relative to baseline are associated with clinical 
improvement at Visit 3, after accounting for treatment assignment. 
 
3. The Day 11 DOORs (an ordinal outcome defined in Section 3.2.3) will be compared 
between the placebo and azithromycin arms. The sum of the probability that a randomly 
selected subject will have a better DOOR if assigned to the placebo arm plus one-half 
the probability of equal DOORs will be estimated. The null hypothesis to be tested is that 
the probability is equal to 0.50 (lack of superiority of azithromycin therapy).  The analysis 
will be carried out using the ITT analysis population, with missing DOOR values (treated 
as continuous) imputed using multiple imputation, utilizing linear regression models. The 
analysis will be repeated using the ATP-11 population.  At minimum, the imputation 
model will utilize available information collected at baseline and any completed study 
visits.  Further details of the imputation model will be described in the SAP.  The Mann-
Whitney U statistic will be combined across the imputed datasets to give the test statistic 
and Rubin’s Rules used to define distribution of the test statistic under the null 
hypothesis.  A point estimate of the estimand will be computed by dividing combined test 
statistic by the number of pairwise comparisons and a 95% confidence interval of the 
estimand will be computed by inverting the described test of the null hypothesis. 
 
4. Using the ATP-11 analysis population, forest plots of 95% confidence intervals for the 
difference in proportions of subjects with each solicited event (a component of DOOR) 
collected through Visit 4, for each severity threshold (mild or greater, moderate or 
greater, or severe) will be generated.  Tests for differences in proportions between 
treatment arms will be given by Fisher’s exact tests. 
 
5. Using the ATP-11 analysis population, a forest plot of 95% confidence intervals for the 
difference in proportions of subjects with one or more visits to an ED, one or more visits 
to an outpatient clinic, or one or more visits to an urgent care center or one or more 
hospitalizations for persistent or worsening LRTI at any time after randomization (a 
component of clinical improvement and DOOR) will be generated.  Tests for differences 
in proportions between treatment arms will be given by Fisher’s exact tests. 
 
6. Using the ATP-11 analysis population, for each qualifying symptom (cough, sputum 
production, chest pain, or difficulty breathing) and for fever, improvement in the symptom 
or fever at Visit 4 compared to baseline in subjects with the symptom or fever will be 

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analyzed.  A forest plot of 95% confidence intervals for the difference in proportions of 
subjects with improvement in the symptom or fever will be generated.  Tests for 
differences in proportions between treatment arms will be given by Fisher’s exact tests.  
 
7. Using the ATP-11 analysis population, for each qualifying symptom (cough, sputum 
production, chest pain, or difficulty breathing), deterioration in the symptom at Visit 4 
compared to baseline will be analyzed in subjects having the symptom at baseline.  A 
forest plot of 95% confidence intervals for the difference in proportions of subjects with 
deterioration in the symptom will be generated.  Tests for differences in proportions 
between treatment arms will be given by Fisher’s exact tests.  
 
8. Using the ATP11 analysis population, the proportion of subjects with fever in the 24 
hours preceding or at Visit 4 (fever is defined as ≥37.8 °C or 100.0 °F, measured 
anywhere on the body), unless related to a new process that is unrelated to the prior 
diagnosis of LRTI will be analyzed. A forest plot of 95% confidence intervals for the 
difference in proportions of subjects with fever in the 24 hours preceding or at Visit 4 will 
be generated.  Tests for differences in proportions between treatment arms will be given 
by Fisher’s exact tests. 
 
 
 
 
 
 

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12 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of ICH E6 GCP, and regulatory and institutional requirements for 
the protection of confidentiality of subjects.  As part of participating in a DMID-sponsored, DMID-
affiliated or manufacturer-sponsored study, each site will permit authorized representatives of 
the sponsor(s), DMID, and regulatory agencies to examine (and when required by applicable 
law, to copy) clinical records for the purposes of quality assurance reviews, audits and 
evaluation of the study safety and progress.  
Source data are all information, original records of clinical findings, observations, or other 
activities in a study necessary for the reconstruction and evaluation of the trial. Examples of 
these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions certified 
after verification as being accurate and complete, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, and subject files and records kept at the pharmacy, at the 
laboratories, and medico-technical departments involved in the clinical study. 

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13 
QUALITY CONTROL AND QUALITY ASSURANCE 
Following a written DMID-accepted site quality management plan, each participating site is 
responsible for conducting routine quality assurance (QA) and quality control (QC) activities to 
internally monitor study progress and protocol compliance.  Each site principal investigator will 
provide direct access to all trial-related sites, source data/data collection forms, and reports for 
the purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory 
authorities.  Each site principal investigator will ensure all study personnel are appropriately 
trained and applicable documentations are maintained on site. 
The SDCC will implement quality control procedures for the data entry system and generate 
database quality control checks.  Any missing data or data anomalies will be communicated to 
the site(s) for clarification and resolution. 
The VIDAS®3 Instruments and VIDAS® B.R.A.H.M.S Procalcitonin (PCT) have been 
commercialized in US. Both products used in this trial will be labeled with investigational use 
only (IUO) but they are manufactured with quality assured using the same standards with the 
commercialized products.  Prior to the trial testing, the VIDAS®3 Instruments will be qualified by 
field service engineers (FSE) from bioMerieux to ensure that the instruments meet all the 
requirements. There will be routine maintenance to be performed by the testing lab to ensure 
that the instruments are under good condition. The instruments will also be checked annually by 
FSE from bioMerieux as annual maintenance. bioMerieux will provide support on any issues 
and anomalies during the trials through remote or on-site assistance.   
VIDAS® B.R.A.H.M.S PCT testing are ensured by both calibration before the initiation of the trial 
testing and every 28 days during the trial. Internal controls are included in each patient sample 
testing run to provide validation of testing results of the specific run.  
If any of the following situations identified, repeat testing should be performed:  
• In the event of invalid control(s), the entire run must be repeated. Only the valid repeat 
result will be taken into account. 
• In the event of established human error, or if the system does not give any results, 
repeat testing will be performed. Only the valid repeat result will be taken into account. 
More details can be found in the product insert.  
 

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14 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
14.1 Ethical Standard 
The site principal investigator will ensure that this trial is conducted in full conformity with 
principles of the Belmont Report:  Ethical Principles and Guidelines for the Protection of Human 
Subjects of Research of the National Commission for the Protection of Human Subjects of 
Biomedical and Behavioral Research (April 18, 1979) and codified in 45 CFR 46, 21 CFR 50 
and 56, and ICH E6; 62 Federal Regulations 25691 (1997), if applicable.  The site principal 
investigator’s Institution will hold a current Federal Wide Assurance (FWA) issued by the Office 
of Human Research Protection (OHRP) for federally funded research. 
14.2 Institutional Review Board 
Prior to enrollment of subjects into this trial, the approved protocol and informed consent form 
will be reviewed and approved by the appropriate IRB listed on its FWA. 
The responsible official for the IRB will sign the IRB letter of approval of the protocol prior to the 
start of this trial and a copy will be provided to DMID.  The IRB Federal Wide Assurance number 
will be provided to DMID. 
Should amendments to the protocol be required, the amendments will be written by the sponsor 
and provided to the site principal investigator for submission to the IRB prior to implementation. 
14.3 Informed Consent Process 
The site principal investigator will choose subjects in accordance with the eligibility criteria 
detailed in Section 5.  Before any study procedures are performed, subjects must sign an 
informed consent form that complies with the requirements of 21 CFR Part 50 and 45 CFR 46 
and the local IRB. 
Informed consent is a process that is initiated prior to an individual agreeing to participate in a 
trial and continuing throughout the individual’s trial participation.  Before any study procedures 
are performed, subjects will receive a comprehensive explanation of the proposed study 
procedures and study interventions/products, including the nature and risks of the trial, alternate 
therapies, any known AEs, the investigational status of the components, and the other elements 
that are part of obtaining proper informed consent.  Subjects will also receive a detailed 
explanation of the proposed use and disclosure of their protected health information.  Subjects 
will be allowed sufficient time to consider participation in the trial, after having the nature and 
risks of the trial explained to them, and have the opportunity to discuss the trial with their family, 
friends or legally authorized representative or think about it prior to agreeing to participate. 

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Informed consent forms describing in detail the study interventions/products, study procedures, 
risks and possible benefits are given to subjects.  The informed consent form must not include 
any exculpatory statements.  Informed consent forms will be IRB-approved and subjects will be 
asked to read and review the appropriate document.  Upon reviewing the appropriate document, 
the site principal investigator (or designee) will explain the research study to subjects and 
answer any questions that may arise.  Subjects must sign the informed consent form, and 
written documentation of the informed consent process is required prior to starting any study 
procedures/interventions being done specifically for the trial, including administering study 
product. 
DMID will provide the site principal investigator, in writing, any new information that significantly 
impacts the subjects' risk of receiving the investigational product.  This new information will be 
communicated by the site principal investigator to subjects who consent to participate in the trial 
in accordance with IRB requirements.  The informed consent document will be updated and 
subjects will be re-consented per IRB requirements, if necessary. 
Study personnel may employ recruitment efforts prior to obtaining study consent if a patient-
specific screening consent is on record or if the IRB has agreed that chart review is allowed 
without a fully executed screening consent. In cases where there is not a patient-specific 
screening consent on record, site clinical staff may pre-screen via chart review and refer 
potential subjects to the research staff. Research staff would obtain written consent per the 
standard informed consent process before conducting protocol-specific screening activities.  
Subjects will be given a copy of all informed consent forms that they sign. By signing the 
informed consent form, subjects agree to complete all evaluations required by the trial, unless 
the subject withdraws voluntarily, or is withdrawn or terminated from the trial for any reason. 
The rights and welfare of subjects will be protected by emphasizing to subjects that the quality 
of their medical care will not be adversely affected if they decline to participate in or withdraw 
from this trial. 
14.3.1 Informed Consent/Assent Process (in Case of a Minor or others 
unable to consent for themselves)  
N/A 
14.4 Exclusion of Women, Minorities, and Children (Special 
Populations) 
This study is focused on individuals aged 18 or greater of all racial, ethnic, and gender/sex 
categories.  
   
 

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14.5 Subject Confidentiality 
Subjects will have code numbers and will not be identified by name. Subject confidentiality is 
strictly held in trust by the participating investigators, their staff, and the sponsor(s) and their 
agents.  
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. 
All information provided by the Sponsor and all data and information generated by the 
participating site as part of the trial (other than a subject’s medical records) will be kept 
confidential by the site principal investigator and other study personnel to the extent permitted 
by law. This information and data will not be used by the site principal investigator or other study 
personnel for any purpose other than conducting the trial. These restrictions do not apply to: (1) 
information which becomes publicly available through no fault of the site principal investigator or 
other study personnel; (2) information which is necessary to disclose in confidence to an IRB 
solely for the evaluation of the trial (3) information which is necessary to disclose in order to 
provide appropriate medical care to a study subject; or (4) study results which may be published 
as described in Section 16.  
The study monitor, applicable regulatory authorities, such as the FDA, or other authorized 
representatives of the sponsor may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, clinic, or 
hospital) and pharmacy records for the subjects in this study.  The clinical study site will permit 
access to such records. 
14.6 Study Discontinuation 
If the trial is discontinued, subjects who sign the informed consent form, and are randomized 
and treated will continue to be followed for safety assessments. No further study treatment will 
be administered. 
14.7 Future Use of Stored Specimens 
Subjects will be asked for permission to keep any samples for use in future research studies. 
Samples may be stored temporarily at the local site or longer term at DMID CMS central clinical 
storage facility. Samples may be shared with other investigators at other institutions, provided 
that appropriate human subject protection plans are in place and DMID has been consulted and 
approved of the use. The samples will not be sold or used directly for production of any 
commercial product. No human genetic tests  (i.e., DNA testing) will be performed on samples, 
although measures of gene expression may be performed. Each sample will be encoded 
(labeled) only with a barcode and a unique tracking number to protect subject’s confidentiality. 

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There are no benefits to subjects in the collection, storage and subsequent research use of 
specimens. Reports about future research done with subject’s samples will not be kept in their 
health records. 
Subjects may be given the option to decide if they want their samples to be used for future 
research or have their samples destroyed at the end of the trial. The subject’s decision can be 
changed at any time prior to the end of the trial by notifying the study doctors or nurses in 
writing. However, if the subject originally consents to future use and subsequently changes 
his/her decision, any data from a previously collected sample may still be used for this research. 

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15 
DATA HANDLING AND RECORD KEEPING 
The investigator is responsible to ensure the accuracy, completeness, legibility, and timeliness 
of the data reported.   
Data collection forms will be derived from the eCRFs and provided by the SDCC to the sites to 
record and maintain data for each subject enrolled in the study.  All source documents should 
be completed in a neat, legible manner to ensure accurate interpretation of data.  Permanent ink 
is required to ensure clarity of reproduced copies.  When making a change or correction, the 
original entry should be crossed out with a single line, and the change should be initialed and 
dated.  Do not erase, overwrite, or use correction fluid or tape on the original.  
Data reported in the eCRF should be consistent with the data collection form/source documents 
or the discrepancies should be documented.   
The sponsor and/or its designee will provide guidance to investigators on making corrections to 
the data collection forms and eCRFs.   
15.1 Data Management Responsibilities 
All source documents and laboratory reports must be reviewed by the clinical team and data 
entry staff, who will ensure that they are accurate and complete.  Adverse events must be 
graded, assessed for severity and causality, and reviewed by the site PI or designee. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site PI.  During the study, the investigator must maintain complete and accurate 
documentation for the study. 
Emmes will serve as the Statistical and Data Coordinating Center for this study and will be 
responsible for data management, quality review, analysis, and reporting of the study data. 
15.2 Data Capture Methods 
Clinical data (including solicited events, UADEs, and concomitant medications) and clinical 
laboratory data will be entered into a 21 CFR Part 11-compliant Internet Data Entry System 
(IDES) provided by Emmes.  The data system includes password protection and internal quality 
checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, 
or inaccurate.  Clinical data will be entered directly from the source documents.  
15.3 Types of Data 
Data for this study will include clinical, laboratory, safety, and outcome measures. 

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15.4 Timing/Reports 
A final report will be prepared following the availability of all the safety and efficacy data. Interim 
safety reports may be generated for the DSMB safety review.  
After full analysis and final reporting is complete, and upon request and DMID approval, the 
SDCC will provide the participating sites with a summary of results by treatment group and/or 
subject treatment assignments. In this regard, the participating sites requesting such information 
to share with study subjects must do so in compliance with their respective IRB guidelines. 
15.5 Study Records Retention 
Records and documents pertaining to the conduct of this study, including data collection forms, 
source documents, consent forms, laboratory test results, and medication inventory records 
shall be retained until at least 2 years after the last approval of a marketing application in an ICH 
region or at least 2 years have elapsed since the formal discontinuation of clinical development 
of the investigational product. The site must contact DMID for authorization prior to the 
destruction of any study records. Informed consent forms for future use will be maintained as 
long as the sample exists.  
15.6 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, Good Clinical Practice 
(GCP), or Manual of Procedures requirements. The noncompliance may be either on the part of 
the subject, the investigator, or the study site staff. As a result of deviations, corrective actions 
are to be developed by the site and implemented promptly.  
These practices are consistent with ICH E6:  
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
5.1 Quality Assurance and Quality Control, section 5.1.1  
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
It is the responsibility of the site to use continuous vigilance to identify and report deviations 
within 5 working days of identification of the protocol deviation, or within 5 working days of the 
scheduled protocol-required activity. All deviations must be promptly reported to DMID, via the 
Emmes IDES  
All deviations from the protocol must be addressed in study subject source documents. A 
completed copy of the DMID Protocol Deviation Form (IDES form) must be maintained in the 
regulatory file, as well as in the subject’s source document. Protocol deviations must be sent to 

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the local IRB/IEC per their guidelines. The site PI/study staff is responsible for knowing and 
adhering to their IRB/IEC requirements. 

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16 
PUBLICATION POLICY 
This study will be conducted in accordance with the following publication and data sharing 
policies and regulations: 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has 
access to the published results of NIH funded research. It requires scientists to submit final 
peer-reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed 
Central upon acceptance for publication. 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-
Funded Clinical Trial Information and the Clinical Trials Registration and Results Information 
Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and results 
information from this trial will be submitted to ClinicalTrials.gov. Following completion of the 
study, the investigator is expected to publish the results of this research in a scientific journal.   
 
  

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17 
LITERATURE REFERENCES 
1. 
Gould IM. Antibiotic resistance: the perfect storm. International Journal of Antimicrobial 
Agents. 2009;34, Supplement 3(0):S2-S5. 
2. 
Kim JH, Gallis HA. Observations on spiraling empiricism: its causes, allure, and perils, 
with particular reference to antibiotic therapy. Am J Med. 1989;87(2):201-6. 
3. 
Lee GC, Reveles KR, Attridge RT, Lawson KA, Mansi IA, Lewis JS, 2nd, et al. 
Outpatient antibiotic prescribing in the United States: 2000 to 2010. BMC medicine. 2014;12:96. 
4. 
Obama B. Executive Order - Combating Antibiotic-Resistant Bacteria. In: House TW, 
editor.: Office of the Press Secretary; 2014. 
5. 
Fleming-Dutra KE, Hersh AL, Shapiro DJ, et al. PRevalence of inappropriate antibiotic 
prescriptions among us ambulatory care visits, 2010-2011. JAMA. 2016;315(17):1864-73. 
6. 
Lode H. Safety and tolerability of commonly prescribed oral antibiotics for the treatment 
of respiratory tract infections. Am J Med. 2010;123(4 Suppl):S26-38. 
7. 
Shapiro DJ, Hicks LA, Pavia AT, Hersh AL. Antibiotic prescribing for adults in ambulatory 
care in the USA, 2007-09. The Journal of antimicrobial chemotherapy. 2014;69(1):234-40. 
8. 
Hersh AL, Shapiro DJ, Pavia AT, Shah SS. Antibiotic prescribing in ambulatory 
pediatrics in the United States. Pediatrics. 2011;128(6):1053-61. 
9. 
Goossens H, Ferech M, Vander Stichele R, Elseviers M, Group EP. Outpatient antibiotic 
use in Europe and association with resistance: a cross-national database study. Lancet. 
2005;365(9459):579-87. 
10. 
Somerville LK, Ratnamohan VM, Dwyer DE, Kok J. Molecular diagnosis of respiratory 
viruses. Pathology. 2015;47(3):243-9. 
11. 
Assicot M, Gendrel D, Carsin H, Raymond J, Guilbaud J, Bohuon C. High serum 
procalcitonin concentrations in patients with sepsis and infection. Lancet. 1993;341(8844):515-
8. 
12. 
Linscheid P, Seboek D, Nylen ES, Langer I, Schlatter M, Becker KL, et al. In vitro and in 
vivo calcitonin I gene expression in parenchymal cells: a novel product of human adipose tissue. 
Endocrinology. 2003;144(12):5578-84. 
13. 
Albrich WC, Dusemund F, Bucher B, Meyer S, Thomann R, Kuhn F, et al. Effectiveness 
and safety of procalcitonin-guided antibiotic therapy in lower respiratory tract infections in "real 
life": an international, multicenter poststudy survey (ProREAL). Arch Intern Med. 
2012;172(9):715-22. 
14. 
Briel M, Schuetz P, Mueller B, Young J, Schild U, Nusbaumer C, et al. Procalcitonin-
guided antibiotic use vs a standard approach for acute respiratory tract infections in primary 
care. Arch Intern Med. 2008;168(18):2000-7; discussion 7-8. 
15. 
Schuetz P, Christ-Crain M, Thomann R, Falconnier C, Wolbers M, Widmer I, et al. Effect 
of Procalcitonin-Based Guidelines vs Standard Guidelines on Antibiotic Use in Lower 
Respiratory Tract Infections: The ProHOSP Randomized Controlled Trial. JAMA. 
2009;302(10):1059-66. 
16. 
Schuetz P, Muller B, Christ-Crain M, Stolz D, Tamm M, Bouadma L, et al. Procalcitonin 
to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst 
Rev. 2012;9:CD007498. 
17. 
Christ-Crain M, Jaccard-Stolz D, Bingisser R, Gencay MM, Huber PR, Tamm M, et al. 
Effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract 
infections: cluster-randomised, single-blinded intervention trial. Lancet. 2004;363(9409):600-7. 

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18. 
Christ-Crain M, Stolz D, Bingisser R, Muller C, Miedinger D, Huber PR, et al. 
Procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: a randomized 
trial. Am J Respir Crit Care Med. 2006;174(1):84-93. 
19. 
Stolz D, Christ-Crain M, Bingisser R, Leuppi J, Miedinger D, Muller C, et al. Antibiotic 
treatment of exacerbations of COPD: a randomized, controlled trial comparing procalcitonin-
guidance with standard therapy. Chest. 2007;131(1):9-19. 
 
 
 

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Appendix A: Schedule of Events 
Visit #1 
Screening, 
Enrollment, & 
Randomization 
Visit #2* 
Visit #3 
Visit #4* 
Visit #5* 
Early 
Termination 
Visits 
Visit 5N 
(non-
randomized 
Subjects) 
Visit Number 
01 
02 
03 
04 
05 
 
5N 8 
Visit Day1 
Day 1 
Day 3 +1 
Day 5 +3 
Day 11 +3 
Day 28 ±2 
 
Day 28+7 
Obtain Informed 
Consent 
X 
 
 
 
 
 
 
Assessment of 
Sociodemographic 
Data 
X 
 
 
 
 
 
 
Randomization2 
X 
 
 
 
 
 
 
Dispense study 
drug3 
X 
 
 
 
 
 
 
Collection of study 
product bottle 
 
 
X 
 
 
X7 
 
Review 
inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
Assessment of 
medication 
compliance 
 
X 
X 
 
 
X7 
 
Assessment of 
Solicited AEs  
 
X 
X 
X 
 
X 
 
Assessment of 
UADEs 
 
X 
X 
X 
X 
X 
 
Medical history4 
X 
 
X 
X 
X 
X 
X8 
Physical exam5 
X 
 
X 
 
 
X7 
 
Vital signs6 
X 
 
X 
 
 
X7 
 
Assessment of 
LRTI signs and 
symptoms 
X 
X 
X 
X 
X 
X 
 
Concomitant 
medications9 
X 
X 
X 
X 
X 
X 
X8 
Distribute Memory 
Aid and Study-
Related Materials 
X 
 
 
 
 
 
 
Review Memory 
Aid 
 
X 
X 
X 
 
X7 
 
Serum or Plasma 
PCT 
X 
 
X 
 
 
X7 
 
Nasopharyngeal 
Swab 
 
X 
 
 
 
 
 
 
PAXgene Blood 
RNA (for future 
use, if consented) 
X 
 
 
 
 
 
 
Footnotes: 
* 
Phone call assessment. 
1. 
There will be a window around each of the scheduled follow-up assessments to allow for subject and staff 
flexibility.  
2. 
Subjects with a PCT ≤0.25 ng/mL who satisfy the inclusion criteria with no exclusion criteria will be enrolled 
and randomized.  

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3. 
Study drug will be azithromycin or placebo. 
4. 
Medical history will include: drug allergies, co-morbidities.  
5. 
Physical exam will include: assessment of general appearance, a focused HEENT, neck, cardiopulmonary, 
and abdominal examination 
6. 
Vital signs:  temperature, pulse, blood pressure, respiratory rate, and pulse oximetry will be recorded. Care 
related exam findings and vital signs may be used. 
7. 
These will be performed if indicated as part of the next regularly scheduled visit. 
8. 
All data will be collected from a medical record review only. The subject will not be contacted. 
9. 
All concomitant medications will be documented at Visit #1. Any symptomatic treatment received on the day 
of/during the enrollment visit will not be recorded unless it is a non-study systemic antibiotic.