A Phase 1, Open-label, Evaluation of a 13C-urea Breath Test for the Detection of Urease-producing Bacteria in Patients Diagnosed With Pneumonia in the Emergency Department
Conditions: Pneumonia, Bacterial
Sponsor: University of New Mexico

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UNIVERSITY OF NEW MEXICO
CLINICAL STUDY PROTOCOL
Compound Name:
13C-Urea solution for nebulization
Protocol Number:
16-327 Amendment #6
Protocol Title: 
A Phase 1, open-label, evaluation of a 13C-urea breath test for the 
detection of urease-producing bacteria in patients with pneumonia 
in the emergency department.
Date of Protocol:
20 April 2018  
Principal 
Investigator:
Justin T Baca, MD, PhD 
Department of Emergency Medicine 
Assistant Professor of Emergency Medicine 
University of New Mexico 
Phone: 505-272-5062 
Email: jtbaca@salud.unm.edu
Co-Investigator:
Jon Femling, MD, PhD 
Department of Emergency Medicine 
Assistant Professor Emergency Medicine 
University of New Mexico
Email: JFemling@salud.unm.edu 
Sub-Investigator:
Richard M Nowak, MD, MBA, FACEP, FAAEM
Department of Emergency Medicine
Clinical Professor of Emergency Medicine
Director, Emergency Medicine Clinical Trials Center 
Clinical Center Principal Investigator for 16-327
Henry Ford Hospital
Detroit, Michigan 
Email: RNowak1@hfhs.org

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Unauthorized copying or use of this information is prohibited
INVESTIGATOR’S AGREEMENT
By signing below, I confirm that I have read this protocol and agree

to assume responsibility for the proper conduct of the study at this site

to conduct the study according to the procedures described in this protocol and any future 
amendments

not to implement any deviation from, or changes to, the protocol without written approval 
from the Institutional Review Board or Independent Ethics Committee, except where 
necessary to eliminate an immediate hazard to subject(s)

that I am aware of and will comply with all applicable regulations and guidelines
Investigator’s Signature
Date
Investigator’s Name (Print)
Investigator’s Title (Print)
Site Address:

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SYNOPSIS (PAGE 1 OF 4)
Name of Sponsor/Company:  
Justin T Baca, MD, PhD
University of New Mexico
Protocol Number:  16-327
Name of Study Drug/Device:  13C-Urea 
solution for nebulization 
Protocol Title:  A Phase 1, open-label, evaluation of a 
13C-urea breath test for the detection of urease-producing 
bacteria in patients with pneumonia in the emergency 
department.
Name of Active Ingredient: 13C-urea
Phase of Development:  1
Objective:  The primary objective of this study is to determine the ability of a 13C-urea breath test to 
detect urease producing pathogens in patients with pneumonia as confirmed on sputum culture results.
Additional objectives of this study will include:

Determine optimal times for post-nebulization breath collection

Evaluate the safety and tolerability of the 13C-urea breath test in patients with pneumonia
Methodology:  
This is a Phase 1, open-label evaluation of an inhaled 13C-urea breath test in the identification of 
urease positive bacteria in patients diagnosed with pneumonia in the emergency department (ED). 
This study will enroll up to 75 adult male and female subjects at two US sites in two cohorts. 
Adult subjects will be screened for participation in two dosing cohorts to be enrolled sequentially.  
Cohort A will enroll 15 subjects presenting to the study sites with pneumonia symptomatology that is 
planned for outpatient treatment.  Following enrollment and review of the safety of dosing in Cohort 
A, subjects receiving a diagnosis of pneumonia in the ED that are planned for admission will be 
screened for enrollment in Cohort B. Eligible subjects will provide informed consent, medical history, 
and samples for laboratory testing (including pregnancy testing for females of childbearing potential) 
during screening. Subjects will be evaluated for their CURB-65 Pneumonia Severity Score, and 
Community-Acquired Pneumonia Severity Index (PSI) where required data are available. 
Prior to breath test administration, Cohort B subjects will provide a oropharyngeal swab for bacterial 
identification via next generation sequencing (NGS) plus a sputum sample for bacterial culture and 
NGS; the sputum sample may be induced, or collected as part of initial ED workup if appropriate 
culture has been ordered. Subjects will undergo breath test with collection of baseline breath samples 
(up to 6), followed by complete nebulization of 13C-urea solution. Immediately following the end of 
nebulization, breath collection bag samples will be collected at up to 6 time points with at least 1 
minute intervals within 10 minutes post-nebulization.  Exhaled breath bags will be centrally processed 
to determine the change in exhaled 13CO2 levels. Vital signs, including resting blood pressure, resting 
pulse, respiratory rate, peripheral oxygen saturation, and temperature will be collected prior to, and 
following completion of, nebulization treatment. In the event of bronchospasm, during or following 
nebulization, albuterol rescue will be available for treatment at the discretion of the investigator.
Once required tests are complete, the subject will be treated/followed according to standard 
institutional protocol/practice. The subjects’ clinical course will be followed for at least 24 hours, 
where possible, to document the final diagnosis and outcome.

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SYNOPSIS (PAGE 2 OF 4)
Name of Sponsor/Company:  
Justin T Baca, MD, PhD
University of New Mexico
Protocol Number:  16-327
Name of Study Drug/Device:  13C-Urea 
solution for nebulization 
Protocol Title:  A Phase 1, open-label, evaluation of a 
13C-urea breath test for the detection of urease-producing 
bacteria in patients with pneumonia in the emergency dept.
Name of Active Ingredient: 13C-urea
Phase of Development:  1
Number of subjects to be enrolled:  This study will enroll up to 75 adult male and female subjects in 
two dosing cohorts. 
Number of study sites:  2
Study country location:  United States
Criteria for inclusion:  Subjects must meet all of the following criteria to be considered eligible for the study:
Cohort A Only: 
1.
be a man or woman age 18-70, inclusive
2.
have suspected bacterial pneumonia on presentation to the study site based on clinical signs and 
symptoms 
3.
be expected to be treated on an outpatient basis in the opinion of the treating clinician at time of 
enrollment OR a definitive decision to admit has not been made, and the subject meets ALL of the 
following criteria; Pulse <125 beats per minute, Systolic blood pressure ≥100 mmHg, Respiratory rate 
≤24 breaths per minute, Temperature >35C, and Temperature <40C. Subjects who are expected to be 
placed in an ED observation unit are eligible if they meet all of the defined vital sign criteria
Cohort B Only: 
4.
be a man or woman age 18-85, inclusive, 
5.
have a diagnosis of suspected bacterial pneumonia on presentation to the study site based on findings of 
a positive chest x-ray or advanced radiology and clinical signs and symptoms 
6.
be planned for admission to the hospital ward/floor in the opinion of the treating clinician at time of 
enrollment 
7.
be capable of providing a spontaneous or induced sputum for analysis
Both Cohorts A and B:
8.
be capable of completing the breath test according to the clinical judgement of the investigator
9.
be able to understand the study procedures, agree to participate in the study program, and voluntarily 
provide written informed consent
Criteria for exclusion:  Subjects who meet any of the following criteria will be excluded from the study:
1.
have a known allergy to urea or any excipient in the nebulized solution
2.
be pregnant or have a positive urine pregnancy test 
3.
have evidence of active oral infection, such as abscess or dense exudate, that requires antibiotic therapy
4.
have known diagnosis of cystic fibrosis or bronchiectasis
5.
have a known or suspected acute asthma exacerbation on presentation
6.
have received treatment with oral or intravenous (IV) antibiotics in the preceding 2 days prior to 
screening, unless antibiotic failure is suspected
OR
Cohort A: have received treatment with oral or IV antibiotics greater than 6 hours prior to breath test
Cohort B: have received treatment with oral or IV antibiotics greater than 4 hours prior to breath test
7.
have an acute illness or other condition that, as determined by the investigator, would preclude 
participation in the study

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SYNOPSIS (PAGE 3 OF 4)
Name of Sponsor/Company:  
Justin T Baca, MD, PhD
University of New Mexico
Protocol Number:  16-327
Name of Study Drug/Device:  13C-Urea 
solution for nebulization 
Protocol Title:  A Phase 1, open-label, evaluation of a 
13C-urea breath test for the detection of urease-producing 
bacteria in patients with pneumonia in the emergency 
department.
Name of Active Ingredient: 13C-urea
Phase of Development:  1
Investigational product:  13C-urea solution for nebulized administration
Reference therapy:  NA
Duration of treatment:  Enrolled subjects will receive a single nebulized dose of 13C-urea with 
subsequent breath collection.  Subjects will complete all study evaluations during a single ED visit.
Criteria For Evaluation
Efficacy:  
Efficacy endpoints will include the following:

Evaluate the exhaled 13CO2 levels at each time point post-nebulization

Evaluate the relationship between the exhaled 13CO2 levels at each time point and subject’s 
causative pathogen based upon sputum culture or NGS  

Evaluate the sensitivity and specificity of the 13C-urea breath test for urease producing 
pathogens 

Evaluate the positive and negative predictive value of the 13C-urea breath test for urease 
producing pathogens

Correlation of the 13C-urea breath test with CURB65 in subjects with sputum cultures positive 
for urease pathogens 

Correlation of the 13C-urea breath test with PSI in patients with sputum cultures positive for 
urease pathogens 

Univariate association of all study variables with urease pathogen caused pneumonia 

Multi-variate logistic regression model for urease pathogen caused pneumonia utilizing study 
variables that are significant in univariate analysis to compute odds ratio for each model 
variable and overall explanation of variance by model
Safety: 
Safety endpoints will include:

Incidence of adverse events (AEs)

Incidence of death, transfer to ICU, or intubation

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SYNOPSIS (PAGE 4 OF 4)
Name of Sponsor/Company:  
Justin T Baca, MD, PhD
University of New Mexico
Protocol Number:  16-327
Name of Study Drug/Device:  13C-Urea 
solution for nebulization 
Protocol Title:  A Phase 1, open-label, evaluation of a 
13C-urea breath test for the detection of urease-producing 
bacteria in patients with pneumonia in the emergency 
department.
Name of Active Ingredient: 13C-urea
Phase of Development:  1
Statistical methods:
Sample size determination:  
The sample size for this study was selected based on prior exposures and existing safety data. 
Descriptive statistical analysis of results are planned  as findings from this study will be used in order 
to appropriately determine the sample size requirements for future definitive evaluations of inhaled 
13C-urea in an adequately powered study of efficacy in this population.
Study populations:  
Intent-to-Treat (ITT) Analysis Set:  The ITT set will include all subjects who receive nebulized 
13C-urea.  The ITT analysis set is also referenced as the Safety Analysis Set.  Safety analysis will be 
performed using the ITT set.
Modified Intent-to-Treat (mITT) Analysis Set:  The mITT subjects include all ITT subjects who 
provide at least one post-dose breath sample.  Efficacy analysis will be performed on the mITT analysis 
set.
Efficacy analysis:
Breath test exhaled 13CO2 results at each time point will be presented for the overall population for 
determination of optimal breath sampling time.  Relationship between the exhaled 13CO2 at each time 
and subject’s pneumonia diagnosis and pathogen (determined by sputum culture or NGS) will be 
examined.  The time point where exhaled 13CO2 can reliably predict the presence of urease positive 
pathogen in subjects with pneumonia diagnosis will be considered as the optimal time for 13C-urea 
breath test sampling.
The proportion of subjects with breath test positive/negative determination will be compared to sputum 
culture or NGS results when available.   Correlation analyses will be performed where sufficient data 
are available.
Safety analysis:  
The Medical Dictionary for Regulatory Activities (Version 18 or higher) will be used to classify all 
AEs with respect to system organ class and preferred term.  AEs will be summarized for the safety 
analysis set.
 

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TABLE OF CONTENTS
SYNOPSIS (PAGE 1 OF 4) ............................................................................................................3
TABLE OF CONTENTS.................................................................................................................7
LIST OF ABBREVIATIONS........................................................................................................11
1.
INTRODUCTION......................................................................................................12
2.
STUDY OBJECTIVE.................................................................................................14
3.
INVESTIGATIONAL PLAN.....................................................................................15
3.1.
Overall Study Design..................................................................................................15
3.2.
Rationale for Study Design and Control Groups........................................................16
3.3.
Clinical Study Sites.....................................................................................................16
4.
STUDY POPULATION.............................................................................................17
4.1.
Inclusion Criteria ........................................................................................................17
4.2.
Exclusion Criteria.......................................................................................................17
4.3.
Discontinuation of Subjects........................................................................................18
4.3.1.
Procedures for Withdrawal.........................................................................................18
4.3.2.
Replacement of Subjects.............................................................................................18
4.4.
Lifestyle Guidelines....................................................................................................18
4.4.1.
Confinement ...............................................................................................................18
4.4.2.
Diet .............................................................................................................................18
5.
TREATMENTS..........................................................................................................19
5.1.
Administration of Study Medication ..........................................................................19
5.2.
Identity of Study Medication......................................................................................19
5.3.
Method of Assigning Subjects to Treatment Groups .................................................19
5.4.
Selection of Doses ......................................................................................................19
5.5.
Selection of Timing of Dose.......................................................................................19
5.6.
Blinding and Unblinding of Study Medications.........................................................19
5.7.
Treatment Compliance................................................................................................19
5.8.
Drug Accountability ...................................................................................................20
5.9.
Packaging, Labeling, and Storage ..............................................................................20
5.10.
Prior and Concomitant Medications...........................................................................20
5.11.
Concomitant Interventions and Procedures................................................................20

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6.
STUDY PROCEDURES............................................................................................21
6.1.
Efficacy Assessments .................................................................................................21
6.1.1.
Sample Collection.......................................................................................................21
6.1.2.
Processing of Breath Samples ....................................................................................21
6.2.
Demographic and Baseline Characteristics Assessment ............................................22
6.2.1.
Demographics.............................................................................................................22
6.2.2.
Medical History ..........................................................................................................22
6.2.3.
Clinical Laboratory Tests ...........................................................................................22
6.2.4.
Physical Examination .................................................................................................22
6.3.
Safety Assessments Description.................................................................................22
6.3.1.
Clinical Laboratory Tests ...........................................................................................22
6.3.2.
Vital Sign Measurements............................................................................................23
6.3.3.
Follow-Up Contact .....................................................................................................23
6.4.
Assessments by Visit..................................................................................................23
6.4.1.
Screening Procedures..................................................................................................23
6.4.2.
Breath Test Procedures...............................................................................................24
6.4.3.
Follow-Up...................................................................................................................24
6.5.
Appropriateness of Assessments ................................................................................24
6.6.
Clinical Stopping Rules & Safety Data Review.........................................................24
7.
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND SERIOUS 
SUSPECTED ADVERSE REACTIONS...................................................................25
7.1.
Definition of an Adverse Event..................................................................................25
7.2.
Definition of a Serious Adverse Event.......................................................................26
7.2.1.
Serious Adverse Events That Occur After Study Completion ...................................26
7.3.
Definition of a Suspected Adverse Reaction (SAR)...................................................26
7.4.
Definition of a Serious Suspected Adverse Reaction (SSAR) ...................................26
7.5.
Recording and Evaluating Adverse Events and Serious Adverse Events ..................27
7.5.1.
Assessment of Intensity..............................................................................................27
7.5.2.
Assessment of Causality.............................................................................................27
7.5.3.
Assessment of Outcome .............................................................................................28
7.5.4.
Assessment of Expectedness ......................................................................................28
7.6.
Follow-up of Adverse Events and Serious Adverse Events.......................................28
7.7.
Prompt Reporting of Serious Adverse Events............................................................29

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7.8.
Regulatory Reporting Requirements ..........................................................................30
8.
SAFETY MONITORING PLAN...............................................................................31
8.1.
Background.................................................................................................................31
8.2.
Purpose .......................................................................................................................31
8.3.
Assessment Personnel.................................................................................................31
8.4.
Planned Review Process.............................................................................................31
9.
STATISTICAL METHODOLOGY...........................................................................33
9.1.
Determination of Sample Size....................................................................................33
9.2.
Study Endpoints..........................................................................................................33
9.2.1.
Efficacy Endpoints......................................................................................................33
9.2.2.
Safety Endpoints.........................................................................................................33
9.3.
General Considerations for Statistical Analysis .........................................................34
9.3.1.
Analysis Datasets........................................................................................................34
9.3.2.
Test Hypothesis and P Value Justification.................................................................34
9.3.3.
Procedures for Handling Missing Data.......................................................................34
9.4.
Study Population Summaries......................................................................................34
9.4.1.
Disposition..................................................................................................................34
9.4.2.
Demographics.............................................................................................................34
9.4.3.
Protocol Violations.....................................................................................................34
9.4.4.
Treatment Compliance................................................................................................34
9.4.5.
Prior and Concomitant Medications...........................................................................35
9.5.
Efficacy Analysis........................................................................................................35
9.6.
Safety and Tolerability Evaluations............................................................................35
9.6.1.
Extent of Exposure .....................................................................................................35
9.6.2.
Adverse Events...........................................................................................................35
9.6.3.
Clinical Laboratory Tests ...........................................................................................36
9.6.4.
Subgroup Analyses for Safety Endpoints...................................................................36
9.7.
Interim Evaluation ......................................................................................................36
10.
STUDY ADMINISTRATION ...................................................................................37
10.1.
Regulatory and Ethical Considerations ......................................................................37
10.1.1.
Regulatory Authority Approval..................................................................................37
10.1.2.
Ethical Conduct of the Study and Ethics Approval....................................................37

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10.1.3.
Informed Consent .......................................................................................................38
10.1.4.
Investigator Reporting Requirements.........................................................................38
10.2.
Study Monitoring........................................................................................................39
10.3.
Quality Assurance.......................................................................................................39
10.4.
Study and Site Closure................................................................................................39
10.5.
Records Retention.......................................................................................................40
10.5.1.
Health Insurance Portability and Accountability Act of 1996....................................40
10.5.2.
Financial Disclosure ...................................................................................................40
10.5.3.
Access to Original Records ........................................................................................40
10.5.4.
Archiving of Study-Related Documents.....................................................................40
10.6.
Provision of Study Results and Information to Investigators.....................................41
10.7.
Subject Tracking.........................................................................................................41
11.
REFERENCES ...........................................................................................................42
APPENDIX A.
SCHEDULES OF STUDY VISITS AND PROCEDURES .............................43
APPENDIX B.
INVESTIGATOR OBLIGATIONS ..................................................................45
APPENDIX C.
STUDY-SPECIFIC INFORMATION...............................................................47
Appendix C.1:
Safety Review Form ........................................................................................47
APPENDIX D.    BMI CALCULATION......................................................................................49
APPENDIX E.    CLINICAL MONITORING PLAN..............................................................50

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LIST OF ABBREVIATIONS
Abbreviation
Definition
AE
adverse event
BMI
body mass index
BP
Blood Pressure
CFR
(United States) Code of Federal Regulations
ºC
degrees Centigrade
CRF
case report form
ED
Emergency department
ºF
degrees Fahrenheit
G
Gram
GCP
Good Clinical Practice
GMP
Global Medication Performance
H
Hour
HIV
Human immunodeficiency virus
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IV
Intravenous
Kg
Kilogram
m2
square meters
Mg
Milligram
mL
Milliliter
NF
National Formulary
Ng
Nanogram
pH
negative log of hydrogen ion concentration
SAR
suspected adverse reaction
SAE
serious adverse event
US
United States
USP
United States Pharmacopeia

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1.
INTRODUCTION
Rapid identification of respiratory pathogens remains a global concern affecting initiation of 
therapy, and pharmacotherapy selection.  The lack of rapid point of care tests that can provide 
clinicians with some indication of which pathogen(s) is causing disease may lead to selection of 
inappropriate therapy, in particular to overuse of broad spectrum antibiotics. 
Urease producing organisms represent a virulent set of pathogens which may be present in 
respiratory infections including Pseudomonas aeruginosa, Staphylococcus aureus, and 
Klebsiella pneumoniae.  Identification of the presence or absence of urease activity may allow 
clinicians to narrow the spectrum of suspected infections, confirming the need for antimicrobial 
therapy and influencing therapy selection.  
The breath test is based upon a modification of existing breath testing technology that detects 
and monitors a biomarker associated with peptic ulcers.  The mechanism of action for detecting 
urease-containing bacteria in the lungs is the same as for detecting another urease-containing 
bacterium, Helicobacter pylori, in the stomachs of patients with peptic ulcers.
For the intended indication, inhaled 13C-urea will be catalytically hydrolyzed into 13C-carbon 
dioxide (13CO2 ) if urease is present in the  bacterial pathogens causing the pneumonia (I).  
13CO(NH2)2 + 3H2O 
 13CO2 + 2NH4OH
(I)
urease
→
CO2 contains predominantly 12C but a small amount of 13C is present.  Since the urea is produced 
with 13C-urea  all CO2 generated by hydrolysis  with urease will be 13CO2.  By measuring the 
ratio of 13CO2/12CO2 in exhaled breath samples before and after inhalation of 13C-urea, the 
presence of urease-containing bacteria can be detected.  In the absence of urease-containing 
bacteria in the lungs, the isotopic ratio of 13C /12C in the baseline and test breath samples will be 
approximately the same.  If urease-containing bacteria are present within the lungs, the 
concentration of exhaled 13CO2 will be increased measurably in the test breath sample relative to 
baseline.    It is anticipated that urease-producing bacteria can be detected within 5 minutes of 
initiating the breath test.
The University of New Mexico conducted a proof of concept study of the 13C-urea Breath Test in 
3 normal volunteers and 3 Cystic Fibrosis (CF) patients with known pseudomonas colonization. 
Two doses of isotonic 13C-urea (20 mg and 50 mg) were used.   All doses were tolerated well 
with no significant AEs.  The exhaled 13CO2 was higher in the CF subjects with both doses but 
separation was better with the 50 mg dose.   In this study the first breath samples were taken at 5 
minutes after 13C-urea nebulization and results rapidly declined in the next samples.  These 
results suggest that breath sampling should be started sooner after the completion of nebulization 
of the 13C-urea 
Mycobacteria tuberculosis contains urease and 13C-urea breath test was shown to detect TB in a 
rabbit model.   Subsequently a study has been initiated in patients with suspected TB infection in 
South Africa.  This study has evaluated the administration of a 50 mg nebulized dose of 13C-urea 
with subsequent breath collection and analysis for exhaled 13CO2 concentrations.  This study has 
administered doses of 13C-urea to over 100 subjects for TB screening.  Doses were well tolerated 

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with a low incidence of mild AEs and no nebulization treatments requiring premature 
discontinuation.
The current study is proposed to expand the experience of 13C-urea testing in patients with a 
diagnosis of pneumonia in the ED.  This study will evaluate the tolerability of dosing in this 
population, as well as the correlation of testing results with bacterial culture observations.

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2.
STUDY OBJECTIVE
The primary objective of this study is to determine the ability of the 13C-urea breath test to detect 
urease producing pathogens in patients with pneumonia as confirmed on sputum culture results.
Additional objectives of this study will include:

Determine optimal times for post-nebulization breath collection

Evaluate the safety and tolerability of the 13C-urea breath test in patients with pneumonia

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3.
INVESTIGATIONAL PLAN
3.1.
Overall Study Design
This is a Phase 1, open-label evaluation of an inhaled 13C-urea breath test in the identification of 
urease positive bacteria in patients diagnosed with pneumonia in the emergency department 
(ED). This study will enroll up to 75 adult male and female subjects at two US sites in two 
cohorts. 
Adult subjects will be screened for participation in two dosing cohorts to be enrolled 
sequentially. Cohort A will enroll 15 subjects presenting to the study sites with pneumonia 
symptomatology that is planned for outpatient treatment. Following enrollment and review of the 
safety of dosing in Cohort A, subjects receiving a diagnosis of pneumonia in the ED that are 
planned for admission will be screened for enrollment in Cohort B. Eligible subjects will provide 
informed consent, medical history, and samples for laboratory testing (including pregnancy 
testing for females of childbearing potential) during screening. Subjects will be evaluated for 
their CURB-65 Pneumonia Severity Score, and Community-Acquired Pneumonia Severity Index 
(PSI) where required data are available. 
Prior to breath test administration, Cohort B subjects will provide a sputum sample for bacterial 
culture; sample may be induced, or collected as part of initial ED workup if appropriate culture 
has been ordered. Subjects will undergo breath test with collection of baseline breath samples 
(up to 6), followed by complete nebulization of 13C-urea solution. Immediately following the end 
of nebulization, breath collection bag samples will be collected at up to 6 time points with at 
least 1 minute intervals within 10 minutes post-nebulization.  Exhaled breath bags will be 
centrally processed to determine the change in exhaled 13CO2 levels. Vital signs, including 
resting blood pressure, resting pulse, respiratory rate, peripheral oxygen saturation, and 
temperature will be collected prior to, and following completion of, nebulization treatment.  In 
the event of bronchospasm, during or following nebulization, albuterol rescue will be available 
for treatment at the discretion of the investigator.
After administration of nebulized 13C-urea solution, subjects will be monitored at the study site 
for any adverse events.  Adverse events directly related to nebulizer administration would be 
expected to present within minutes of nebulization. Evidence shows that, generally, symptoms of 
anaphylaxis appear between 1-15 minutes after exposure to an agent.  Symptoms of anaphylaxis 
may present as lightheadedness, dizziness, difficulty breathing, wheezing, hives, swelling under 
the skin, rashes, and/or nausea. The study team will monitor subjects for 20 minutes after 
nebulization for any adverse events. All subjects will receive standard care in the hospital setting 
prior to and after completion of study procedures.  Subjects will sign and be given a copy of the 
consent form which has contact information and instructions that they should return to the 
emergency department if they suspect they are suffering from any symptoms related to the 
nebulization. The instructions in the consent form also specify that, if returning to the emergency 
department at the corresponding study site with symptoms they believe are due to the study, they 
should bring the consent form with them to the ED and ask that the study site Principal 
Investigator be immediately called and notified on their return. In Cohort A, all safety 
observations prior to discharge, and in Cohort B the clinical course over the hospital admission, 

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will be reviewed and submitted to the safety monitoring committee as described below in 
Sections 7 and 8.
Once required tests are complete, the subject will be treated/followed according to standard 
institutional protocol/practice. The subjects’ clinical course will be followed for at least 24 hours, 
where possible, to document the final diagnosis and outcome.
3.2.
Rationale for Study Design and Control Groups
This study will evaluate the safety and accuracy of the use of the 13C-urea breath test in 
identifying urease positive organisms in newly diagnosed cases of pneumonia in the ED.  Urease 
producing organisms represent a virulent set of pathogens which may be present in respiratory 
infections including Pseudomonas aeruginosa, Klebsiella pneumonia and Staphylococcus 
aureus.  Use of the 13C-urea breath test may allow for rapid determination of bacteria presence 
that could provide guidance to future antibiotic selection.  In this study, the 13C-urea breath test 
observations will be compared to bacterial identification upon sputum culture.
3.3.
Clinical Study Sites
There are two clinical sites for this study:

Site 01 = University of New Mexico Health Sciences Center, 2211 Lomas Blvd NE, 
Albuquerque, NM
o
Subject recruiting done at UNM Sandoval Regional Medical Center and Main 
Emergency Departments (Cohort A, B) and co-located Urgent Care clinic (Cohort A 
only)
o
Study procedures done in exam room at ED (Cohort A, B) or adjacent Clinical & 
Translational Sciences Center (Cohort A only, ~100 yards from ED/Urgent Care Clinic)

Site 02 = Henry Ford Hospital, 2799 W. Grand Blvd, Detroit, MI
o
Subject recruiting done at ED (Cohort A, B)
o
Study procedures done in ED exam room (Cohort A, B)

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4.
STUDY POPULATION
4.1.
Inclusion Criteria
Subjects must meet all of the following criteria to be considered eligible to participate in the 
study:
Cohort A Only: 
1. be a man or woman age 18-70, inclusive
2. have suspected bacterial pneumonia on presentation to the study site based on clinical 
signs and symptoms
3. be expected to be treated on an outpatient basis in the opinion of the treating clinician 
at the time of enrollment OR a definitive decision to admit has not been made, and the 
subject meets ALL of the following criteria; Pulse <125 beats per minute, Systolic 
blood pressure ≥100 mmHg, Respiratory rate ≤24 breaths per minute, Temperature 
>35C, and Temperature <40C. Subjects who are expected to be placed in an ED 
observation unit are eligible if they meet all of the defined vital sign criteria
Cohort B Only: 
4. be a man or woman age 18-85, inclusive, 
5. have a diagnosis of suspected bacterial pneumonia on presentation to the study site 
based on findings of a positive chest x-ray or advanced radiology and clinical signs 
and symptoms 
6. be planned for admission to the hospital ward/floor in the opinion of the treating 
clinician at the time of enrollment
7. be capable of providing a spontaneous or induced sputum for analysis
Both Cohorts A and B:
8. be capable of completing the breath test according to the clinical judgement of the 
investigator
9. be able to understand the study procedures, agree to participate in the study program, 
and voluntarily provide written informed consent
4.2.
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from participating in the study:
1. have a known allergy to urea or any excipient in the nebulized solution
2. be pregnant or have a positive urine pregnancy test 
3. have evidence of active oral infection, such as abscess or dense exudate, that requires 
antibiotic therapy
4. have known diagnosis of cystic fibrosis or bronchiectasis
5. have a known or suspected acute asthma exacerbation on presentation
6. have received treatment with oral or intravenous (IV) antibiotics in the preceding 2 days 
prior to screening, unless antibiotic failure is suspected

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OR
Cohort A Only:
    have received treatment with oral or IV antibiotics for > 6 hours prior to breath test
Cohort B Only:
    have received treatment with oral or IV antibiotics for > 4 hours prior to breath test
7. have an acute illness or other condition that, as determined by the investigator, would 
preclude participation in the study
4.3.
Discontinuation of Subjects
4.3.1.
Procedures for Withdrawal
A subject may be discontinued from the study by the investigator at any time if either determines 
that it is not in the subject’s best interest to continue.  Subjects who withdraw consent or who are 
discontinued from the study before completing all protocol-specified assessments should be 
evaluated by the investigator before leaving the hospital.  The date and the primary reason for 
discontinuation will be recorded on the subject’s case report form (CRF).
4.3.2.
Replacement of Subjects
Subjects who do not complete 13C-urea nebulization and all scheduled breath sample collection 
time points may be replaced in this study.
4.4.
Lifestyle Guidelines
4.4.1.
Confinement
All study related procedures will be performed in the ED or following hospital admission in a 
single visit lasting less than approximately four hours.  The duration of hospitalization following 
breath test completion for disease management will be at the discretion of the healthcare facility.
4.4.2.
Diet
Subjects will not be allowed food or drinks for 15 minutes before the start of nebulization 
through completion of the final breath sample.

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5. TREATMENTS
5.1.
Administration of Study Medication
Administration of 13C-urea solution will be completed using an Aerogen Aeroneb Solo nebulizer 
device, within 60 minutes following reconstitution with 3 mL of sterile water for injection.  The 
solution will be nebulized until the full dose has been administered, with subjects breathing 
normally through their mouths using the nebulizer mouthpiece.  The start and stop time of 
nebulization will be recorded in the subject CRF.  The time nebulization is completed or 
discontinued will be considered Time 0 for post-dose breath sample collection.
5.2.
Identity of Study Medication
Lyophilized 13C-urea will be provided in 50 mg single-dose vials for reconstitution using 3 mL 
of sterile water for injection.  Inactive ingredients include: Lactose Monohydrate, Tromethamine, 
and Dilute Hydrochloric Acid (to adjust pH).  
5.3.
Method of Assigning Subjects to Treatment Groups
All subjects will receive a single 50 mg dose of inhaled 13C-urea.
5.4.
Selection of Doses
The dose of 13C-urea has been selected based on clinical use in a subset of subjects.  
Administration of 50 mg inhaled 13C-urea has been well tolerated in health volunteers and cystic 
fibrosis patients, while producing detectable levels of 13CO2 in subjects with cystic fibrosis with 
known bacterial infections (Raissy et al., 2016) (IDE #G120190; unpublished).  The safety and 
efficacy of the administered dose of 13C-urea has also been well tolerated in an evaluation of 97 
subjects with and without TB infection in an ongoing study conducted by Avisa Pharma in South 
Africa (Unpublished, Avisa Pharma).
5.5.
Selection of Timing of Dose
Administration of 13C-urea will be conducted prior to, or within 4 hours following, initiation of 
antibiotic therapy in subjects with a pneumonia diagnosis in the ED.  In these subjects it is 
anticipated that adequate infection burden will be present to produce measurable levels of 13CO2 
upon breath analysis within 10 minutes post-nebulization (Raissy et al., 2016).  Timing of 
optimal post-dose breath collection for 13CO2 analysis will be evaluated during this study. 
5.6.
Blinding and Unblinding of Study Medications
All study participants will receive 13C-urea, no blinding or dummy doses will be utilized in this 
study.
5.7.
Treatment Compliance
Study personnel will oversee administration of 13C-urea while subjects are present in the ED or 
hospital.  The exact date and start and stop times of nebulization will be recorded, as well as the 
times of post-dose breath collection.

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5.8.
Drug Accountability
The investigator (or designee) will sign for the investigational product (IP) when it is received.  
The IP (13C-urea) must be handled and stored as described and administered only to those 
subjects formally entered into the study.
At the completion of the study, and after reconciliation of all delivery and usage records, any 
unused IP will be returned or destroyed per written instructions.
5.9.
Packaging, Labeling, and Storage
13C-urea will be provided in single use glass vials for reconstitution prior to nebulization.  Non-
blinded labels will be utilized for this study, to include product identifier, lot number, expiration, 
and a disclaimer for investigational use.
Prior to reconstitution, 13C-urea will be stored within a range of 15ºC to 30ºC (59ºF to 86ºF).  
Once reconstituted, 13C-urea solution will be utilized within 60 minutes.
All study medication will be stored in an area with restricted access.  A temperature log or chart 
will be maintained to monitor the environment.
5.10.
Prior and Concomitant Medications
All medications taken by subjects within 7 days prior to receiving 13C-urea will be recorded on 
the CRF. If a medication is started to treat an AE, the medication must be recorded on the 
Concomitant Medications page of the CRF.
5.11.
Concomitant Interventions and Procedures
All interventions or procedures within 7 days prior to receiving the 13C-urea, whether diagnostic 
or therapeutic, will be recorded on the CRF, along with time, date, and reason for the 
intervention or procedure.  If an intervention or procedure is implemented to treat an AE, the 
event must be recorded on the AE page of the CRF, along with all relevant information.

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6.
STUDY PROCEDURES
Schedules of study procedures for overall study assessments and day-of-dosing assessments are 
provided in Appendix A.
6.1.
Efficacy Assessments
6.1.1.
Sample Collection
Baseline breath collection will be completed within 30 minutes prior to nebulization using up to 
six breath collection bags.  Sufficient exhaled breaths to fill the bag will be collected at each 
defined time point.  Breath collection will be by direct exhalation into a bag, or by a breath 
capture device attached to the nebulizer.  
Up to six post-nebulization breath samples will be collected within 10 minutes after completing 
the nebulized dose, at intervals of 1 minute or greater. Breath collection will be by direct 
exhalation into a bag, or by a breath capture device attached to the nebulizer.    
Samples will be collected within ±1 minute of the scheduled post-dose time.  Actual times will 
be recorded for all samples as the time of first collected exhaled breath.
Sputum samples will be collected by trained study personnel per standard clinical practice within 
15 minutes of the breath test. In brief, subjects will be asked to take several deep breaths and 
then produce a forceful cough. The subject will be encouraged to expectorate into a sample cup, 
and the sputum sample will be sent for culture. If the subject has difficulty producing a sputum 
sample, nebulized saline may be used to loosen secretions and encourage sputum production.
A oropharyngeal swab will be collected per standard clinical practice, and the sample will be 
preserved for microbiome analysis. A portion of the collected sputum sample will be preserved 
for microbiome analysis.
Sample collection will be performed according to GCP in a room in the emergency department 
or Clinical and Translational Sciences Center (adjacent to UNM-ED, Cohort A only).
6.1.2.
Processing of Breath Samples
Breath collection bags will be immediately sealed following collection and labeled with the 
subject number and collection time point until processed.  Breath samples will be centrally 
processed, and resulting levels will be recorded in the subject CRF.
The breath testing will be performed by Metabolic Solutions, a CLIA accredited laboratory 
(CLIA ID #30D0970292) at their facility in Nashua, NH.  Breath samples from each study 
subject will be labeled with the de-identified study subject ID, the date and time of collection, 
and a study ID.  The breath samples from a study subject will be shipped overnight via FedEx in 
an approved and appropriately labeled shipping container.  One container is used for each subject 
and will hold the 300 ml breath bags collected from the subject. Metabolic Solutions will 
measure the CO2 concentrations in each bag and also the 13CO2 change over baseline for the 
post-nebulization breath bags.  They will also properly dispose of the breath bags after 
measurement.  The Metabolic Solutions measurements will be tied to the de-identified study 

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subject ID and collection date/time in the subsequent report sent to the PI for entry into the 
subject's case report form.
6.1.3.
Processing of samples for microbiome analysis
A oroopharyngeal swab and a portion of the collected sputum sample will be preserved with a nucleic 
acid protectant that also neutralizes infectious organisms, such as Zymo Biosciences DNA/RNA shield or 
equivalent. We will conduct microbial sequencing to determine the presence of microorganisms and their 
relative abundance. To this end, total nucleic acid (DNA and/or RNA) will be isolated to allow for 
microbiome analysis by sequencing. Microbiome sequencing will be done at UNM laboratories under 
direct supervision of the study investigators. Sequencing will be conducted on a next generation 
sequencing system, such as the Illumina MiSeq sequencer. The microbiome content will be determined 
through bioinformatic analysis of the sequencing reads with a taxonomic database such as the Greengenes 
Consortium Database, Kraken database or a similar microbiome classification database.    These samples 
with be labeled with the de-identified study subject ID, the date and time of collection, and a study ID. 
Raw sequence data generated from the sequencer in the format of a .fastq file and labeled only with the 
study number and no identifying data may be transferred, stored, and analyzed using web and/or cloud-
based solutions.  
6.2.
Demographic and Baseline Characteristics Assessment
6.2.1.
Demographics 
Demographics information will be collected during screening visit including age, sex, ethnicity, 
race, weight, height, BMI.  CURB-65 Pneumonia Severity Score, and/or Community-Acquired 
Pneumonia Severity Index (PSI) may be determined when required data are available.
6.2.2.
Medical History
The investigator or designee will document each subject’s medical history during the screening 
visit.  Documentation of medical history should report tobacco use and diagnostic criteria for 
healthcare associated pneumonia, including hospitalization within 90 days, residence in nursing 
home or long term care facility, recent visit to hospital or hemodialysis unit, or receipt of IV 
antibiotics, chemotherapy or wound care within 30 days.  When available ED diagnostic chest x-
ray should be reported in the medical history and included in the subject file.  
6.2.3.
Clinical Laboratory Tests
The investigator or designee will document results of laboratory tests collected in the course of 
routine care during the subject’s hospitalization.  These results will be collected on the CRF. 
6.2.4.
Physical Examination
The investigator or designee will perform a physical examination (HEENT, cardiovascular, 
respiratory, gastrointestinal, neurological, dermatologic, and musculoskeletal systems) during the 
screening visit.  The oral cavity should be examined for evidence of oral infection (i.e. abscess) 
as part of the physical examinations (examination by a dentist is not required).    

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The Principal Investigator may perform a physical examination (the extent of which is 
determined by the study investigator) at any time during the study if indicated by change in a 
subject’s medical condition.
6.3.
Safety Assessments Description 
6.3.1.
Clinical Laboratory Tests
During screening, subjects will have samples collected for testing as follows:
Sputum:
-
Bacterial culture (only required for Cohort B)
Urine
-
Pregnancy test (female subjects)
Laboratory tests do not need to be repeated if samples have already been collected as part of the 
presenting or admission workup for the current ED visit or hospitalization. 
6.3.2.
Vital Sign Measurements
Resting vital signs will include resting blood pressure, resting pulse, respiratory rate, peripheral 
oxygen saturation, and temperature; temperature will only be required for vital signs collected 
for screening.  Resting tests must be obtained after resting (seated/supine) for ≥ 5 minutes.   
Vital signs including blood pressure, heart rate, respiratory rate and peripheral oxygen saturation 
will be recorded prior to nebulization, and following completion of sample collection.  Subjects 
will have continuous pulse oximetry monitoring during sample collection and urea nebulization, 
and any change in oxygen requirement will be recorded.  
Actual times will be recorded in the subject CRF.  
6.3.3.
Follow-Up Contact
After 48 hours post breath test administration, all subjects will receive a follow-up safety contact. 
The safety contact should be completed between 48 and 96 hours post breath test administration.  
For subjects who have been discharged, follow-up contact will be performed via telephone 
contact (up to 3 attempts) by a study investigator or designee.  For subjects who remain inpatient 
at the hospital, the follow-up will be performed in person.  Safety follow-up will include a chart 
review as well as discussion with the subject regarding their treatment course and current status.
6.4.
Assessments by Visit
6.4.1.
Screening Procedures
Investigators and research staff from the Emergency Department will assist in the identification 
of subjects through the clinical site Emergency Departments or UNM-HSC Urgent Care clinic 
(part of the UNM site and located next to the ED, Cohort A only).  ED Research staff are trained 
in the identification and referral of subjects for currently active research studies.  Research staff 
will identify subjects by asking ED staff and providers if they are currently caring for any 
patients that meet the protocol case description and by evaluating potentially eligible subjects 

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with in Firstnet (UNM) or EPIC (HFH) who present with a reason for visit that would put them 
at reasonable suspicion for pneumonia (e.g. possible pneumonia, difficulty breathing, COPD 
etc.).   Research staff will not discuss informed consent with potential study subjects or retain 
any PHI. 
Research staff will not participate in the identification of subjects or any part of this study until 
they have completed required CITI training and are added as team members on the study.
A waiver of HIPAA authorization may be sought for screening purposes only, so that eligible 
subjects are evaluated and enrolled as soon as possible after arrival so as to complete study 
procedures prior to antibiotic administration.  The waiver may be necessary for facilitating 
subject enrollment without interfering with antibiotic administration times.
Subjects meeting the eligibility criteria listed in Section 4 may be enrolled in the study after the 
nature and purpose of the protocol have been explained to them, and they have voluntarily 
granted written informed consent to participate.  All subjects will undergo screening prior to 
13C-urea administration.  The following safety-related procedures will be performed as part of 
screening for all subjects:
Medical history (Section 6.2.2)
Physical examination (Section 6.2.3)
Clinical laboratory testing (Section 6.3.1)
Vital signs (Section 6.3.2)
Urine pregnancy testing (Section 6.3.1; where appropriate)
Measurement of body weight and height and calculation of BMI (Section 6.2.3)
6.4.2.
Breath Test Procedures 
After successful completion of the screening procedures, subjects will undergo breath test 
administration.  The following assessments will be conducted as part of the breath test 
procedures for all subjects:
Breath sample collection (Section 6.1.1)
13C-urea administration (Section 5)
Vital signs (excluding temperature; Section 6.3.2)
Monitoring of AEs (Section 7)
6.4.3.
Follow-Up 
All subjects will undergo follow-up 48 hours following breath test administration to include:

Follow-up Safety Contact (Section 6.3.3)

Monitoring of AEs (Section 7)
6.5.
Appropriateness of Assessments
Study assessments are appropriate to evaluate the objectives of the study while monitoring the 
safety of 13C-urea administration.  Measurement of exhaled 13CO2 levels has been widely utilized 
in the analysis of patients receiving oral 13C-urea in other indications.

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6.6.
Clinical Stopping Rules & Safety Data Review
This study will be discontinued if it is determined that there is a significant safety risk posed 
towards study subjects.  Potential safety risks will be evaluated on an ongoing basis during the 
study by the independent medical monitor.  Clinical data will be presented to the independent 
medical monitor in cohorts of subjects as listed in the procedure (Section 8).  The independent 
medical monitor will adjudicate AEs and determine whether enrollment may be continued for the 
study.  Following enrollment of the 15 subjects in Cohort A, enrollment into Cohort B will not 
begin until the independent medical monitor performs an overall review of safety in the cohort.  
If the independent medical monitor determines that no safety concerns are present, and that no 
increased risk is apparent for subjects with advance symptomatology (Cohort B), then enrollment 
may proceed with the next study Cohort.  The independent medical monitor will continue to 
review safety data in cohorts of subjects, however enrollment may continue during review.  In 
the event an SAE is reported in a subject, enrollment should be halted until the event can be 
reviewed by the independent medical monitor, and determined whether enrollment should be 
continued.

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7.
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND 
SERIOUS SUSPECTED ADVERSE REACTIONS
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE, SAE, or Serious Suspected Adverse Reaction (SSAR) as provided in 
this protocol.  During the study, when there is a safety evaluation, the investigator or site staff 
will be responsible for detecting AEs and SAEs, as detailed in this section of the protocol.
7.1.
Definition of an Adverse Event
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.
An AE may be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a study medication, whether or not 
considered causally associated with the use of the study medication.  Any abnormal laboratory 
value deemed clinically significant by the investigator, regardless of causal relationship, must be 
reported as an AE.
Examples of an AE include the following:
significant or unexpected worsening or exacerbation of the condition or indication under 
study
exacerbation of a chronic or intermittent preexisting condition, including either an 
increase in frequency or intensity of the condition (e.g., abnormal physical examination 
finding)
signs, symptoms, or clinical sequelae of a suspected interaction
signs, symptoms, or clinical sequelae of a suspected overdose of the study medication or 
a concurrent medication (overdose per se should not be reported as an AE or SAE, unless 
nonserious or serious sequelae occur)
The following examples are not considered AEs:
medical or surgical procedure (e.g., endoscopy, appendectomy), although the condition 
that leads to the procedure is an AE
anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) (including 
laboratory values) present or detected at the start of the study that do not worsen
the disease or disorder being studied, or expected progression, signs, or symptoms of the 
disease or disorder being studied, unless they become more severe or occur with a greater 
frequency than expected for the subject’s condition
All AEs, whether volunteered, elicited, or noted on physical examination, and regardless of 
causality or seriousness, will be assessed and recorded on the CRF beginning after administration 
of study medication through approximately 2 hours after administration.  SAEs (see Sections 7.2 
and 7.3) will be assessed and recorded after administration of study medication through the last 
study follow-up (as described in Section 6.4.3).

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7.2.
Definition of a Serious Adverse Event
An SAE is defined as any event that meets the following criteria:
It results in death or is life-threatening (i.e., presents an immediate risk of death from the 
event as it occurred).  (This criterion is not intended to include an AE that, had it 
occurred in a more severe form, might have caused death.)
It results in persistent or substantial disability or incapacitation.  (This criterion is not 
intended to include experiences of relatively minor medical significance, such as 
uncomplicated headache, diarrhea, or sprained ankle.)
It results in unplanned hospitalization.
It results in prolongation of an existing hospitalization.
It is a congenital anomaly or birth defect.
It requires medical or surgical intervention to prevent any of the above outcomes.
Medical and scientific judgment should be exercised in determining whether an AE is serious 
when considering important medical events that may not be immediately life-threatening or 
result in death or hospitalization, but may jeopardize the subject or may require intervention to 
prevent any of the other outcomes listed.  Examples of such medical events that may also be 
considered serious include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm, blood dyscrasias, or convulsions that do not result in 
hospitalization.
Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline does not meet the definition of an SAE.
Social or convenience admission to a hospital or prolongation of a hospitalization for social or 
convenience reasons not associated with the occurrence of an AE does not meet the definition of 
an SAE.
7.2.1.
Serious Adverse Events That Occur After Study Completion
If an investigator becomes aware of an SAE or death that occurs in a subject more than 48 hours 
after the subject receives study medication and that investigator considers the event to be related 
to the study medication, the investigator is obligated to report the SAE.
7.3.
Definition of a Suspected Adverse Reaction (SAR)
A SAR is defined as any adverse event for which there is a reasonable possibility that the 
adverse event was caused by the study drug.  For the purposes of safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug.
7.4.
Definition of a Serious Suspected Adverse Reaction (SSAR)
A SSAR is any Suspected Adverse Reaction (SAR) that is determined to be serious, based on the 
outcomes of a SAE described in Section 7.2; i.e. death, life-threatening, causes or prolongs 

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inpatient hospitalization, causes a persistent of significant incapacity or substantial disruption of 
the ability to conduct normal life functions, or a congenital abnormality/birth defect.
7.5.
Recording and Evaluating Adverse Events and Serious Adverse 
Events
The investigator will attempt to establish a diagnosis of the event on the basis of signs, 
symptoms, or other clinical information.  In such cases, the diagnosis, not the individual signs or 
symptoms, should be documented as the AE or SAE.
7.5.1.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during the 
study, using his or her clinical judgment.  The intensity of each AE and SAE recorded on the 
CRF should be assigned to one of the following categories:
mild:  an event that is easily tolerated by the subject, causes minimal discomfort, and 
does not interfere with everyday activities
moderate:  an event that is sufficiently discomforting to interfere with normal everyday 
activities
severe:  an event that prevents normal everyday activities
An AE that is assessed as severe should not be confused with an SAE.  Severity is a term used to 
describe the intensity of a specific event, and both AEs and SAEs can be assessed as severe.  The 
event itself, however, may be of relatively minor medical significance (such as a severe 
headache).  This is not the same as serious, which is based on the subject’s or event’s outcome or 
on action criteria usually associated with events that pose a threat to a subject’s life or 
functioning (see Section 7.2).
7.5.2.
Assessment of Causality
The investigator is obligated to use his or her clinical judgment to assess the relationship 
between the study medication and the occurrence of each AE or SAE.  The investigator will 
assess the relationship to the study medication by using the following criteria:
Definitely Related:  An AE has a strong temporal relationship to the study drug.  The AE 
is most likely explained by study drug.  Dechallenge and rechallenge (if possible) are 
positive.  The AE is consistent with a known response to the study drug.  Another 
etiology is unlikely or significantly less likely.
Probably Related:  An AE has a strong temporal relationship to the study drug.  The AE 
is more likely explained by study drug than by another cause.  Dechallenge (if 
performed) is positive.
Possibly Related:  An AE has a reasonable temporal relationship to study drug.  The AE 
could have been due to another equally likely cause.  Dechallenge is positive.
Not Related:  The subject did not receive the study drug OR the AE has no temporal 
relationship to study drug OR the AE has a much more likely alternate etiology OR the 
AE is due to an underlying or concurrent illness or effect of another drug.

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Even in situations in which minimal information is available for the initial SAE report, it is 
important that the investigator always make an assessment of causality for every event before 
transmitting the SAE reporting form and AE CRF page(s) to the medical monitor.  The causality 
assessment is one of the criteria used when determining regulatory reporting requirements.  The 
investigator may change his or her opinion of causality in light of follow-up information and 
amend the SAE reporting form and AE CRF page(s) accordingly.
7.5.3.
Assessment of Outcome
All SAEs must be followed until they are resolved, the condition stabilizes, the events are 
otherwise explained, or the subject is lost to follow-up.  The investigator will assess the outcome 
of the event by using the following terms:
Resolved:  The event resolved or the subject recovered without sequelae.  An event 
(either serious or nonserious) occurred and had an endpoint, and the subject experienced 
no restrictions.  Examples include stent placement for coronary artery disease (a device 
implanted is not a sequela), an appendectomy (a scar is not a sequela), a postoperative 
wound infection, or an upper respiratory tract infection.
Resolved with sequelae:  The event has at least one secondary outcome that may result 
in permanent disability, functional limitation, or both.  Such sequelae are usually limited 
to SAEs.  Examples include hip replacement resulting in foot drop (foot drop is not the 
intended outcome but is a risk of surgery), stroke resulting in paralysis, or emboli 
formation after a bacterial infection resulting in a renal infarct and loss of renal function.
Not resolved:  At the end of the study, a nonserious event either has not changed in 
intensity or may not have recovered to baseline values, and the outcome is unknown.  
Examples include headache, low-grade fever, or nausea.
Unknown: The subject has withdrawn from the study prematurely or is lost to follow-up, 
and the status of the event is unknown.
Death
7.5.4.
Assessment of Expectedness
For the purposes of safety reporting, adverse events and suspected adverse events should be 
assessed as being expected or unexpected.  An AE or SAR is considered unexpected if it is not 
listed in the investigator brochure or is not listed at the specificity or severity that has been 
observed; or, if an investigator brochure is not required or available, is not consistent with the 
risk information described in the general investigational plan or elsewhere in the current 
application.
7.6.
Follow-up of Adverse Events and Serious Adverse Events
Nonserious AEs will be followed after the study visit, until an appropriate resolution can be 
documented.
After the occurrence of an AE or SAE, the investigator is required to follow each subject 
proactively and provide further information on the subject’s condition.  All AEs and SAEs 

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documented at a previous visit or contact are designated as ongoing and will be reviewed at 
subsequent visits or contacts.
SAEs will be followed until the event resolves, the condition stabilizes, the event is otherwise 
explained, or the subject is lost to follow-up.  The investigator will ensure that follow-up 
information includes results of any additional laboratory tests or investigations, histopathologic 
examinations, or consultations with other healthcare professionals that serve to clarify the nature 
of the event, the cause of the event, or both.
New or updated information will be recorded on the originally completed SAE reporting form 
and CRF pages, with all changes signed and dated by the investigator.  The updated SAE 
reporting form and CRF pages should be resubmitted within the time frames outlined in 
Section 7.7.
7.7.
Prompt Reporting of Serious Adverse Events 
Once the investigator determines that an event meets the protocol definition of an SAE, he or she 
must notify the medical monitor within 24 hours.
ANY SAE OR ANY OUTCOME OF DEATH DUE TO ANY CAUSE, WHICH OCCURS 
DURING THE COURSE OF THIS STUDY, REGARDLESS OF RELATIONSHIP TO 
STUDY MEDICATION, MUST BE REPORTED IMMEDIATELY (within 24 hours).
COMPLETE THE SAE DETAILS REPORTING FORM AND FORWARD BY E-MAIL 
TO THE MEDICAL MONITOR AND THE FOLLOWING CONTACT:
Mark Schuyler, MD
Medical Safety Monitor
Telephone:    505 925-4197 
E-mail:          mschuyler@salud.unm.edu
In the initial e-mail, the investigator must provide the following CRF pages, completed to the 
greatest extent possible:
AE record
medical history
prior and concomitant medications
Also, the following documents are to be forwarded:  any laboratory results, diagnostic test 
results, or medical reports relevant to the SAE.
E-mail transmission is the preferred method to transmit SAE information.  In rare circumstances 
and in the absence of e-mail capacity, notification by fax or telephone is acceptable, with a copy 
of the SAE reporting form and CRF pages sent by overnight mail.  Initial notification via 
telephone does not replace the need for the investigator to complete the SAE reporting form and 
CRF pages within the time frames outlined.
If the investigator does not have all information regarding an SAE, he or she must not wait to 
receive additional information before notifying the medical monitor of the event.  The form must 

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be updated when additional information is received.  Follow-up information received on all 
SAEs must be forwarded to the medical monitor by using the same procedure and timelines as 
for an initial report.
7.8.
Regulatory Reporting Requirements 
The investigator must promptly report all SAEs in accordance with the procedures detailed in 
Section 7.7, “Prompt Reporting of Serious Adverse Events.”  The investigator/medical monitor 
has a legal responsibility to notify, as appropriate, both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  Prompt 
notification of SAEs by the investigator to the appropriate project contact for SAE receipt is 
essential so that SSARs that are either unexpected or observed with increasing occurrence, be 
reported and legal obligations and ethical responsibilities regarding the safety of other subjects 
are met.
An investigator letter is prepared for any SAR that is attributable to study medication, serious, 
and unexpected.  The purpose of the investigator letter is to fulfill specific regulatory and Good 
Clinical Practice (GCP) requirements regarding the product under investigation.
The investigator, or responsible person according to local requirements, must comply with 
requirements related to the reporting of SAEs to the IRB or IEC.

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8.
SAFETY MONITORING PLAN
The Independent Safety Monitoring for Pneumonia Urease Positive Organism Screening 
Protocol (#16-327)
8.1.
Background
A Safety Monitoring Committee (SMC), comprising the Independent Medical Monitor (or 
designee) and each Principal Investigator (or designee) will provide ongoing safety surveillance 
of the study. This committee will be responsible for monitoring study conduct and safety data.
The SMC will review the safety experience of each subject and the cumulative occurrences of 
adverse events. Through regularly scheduled and ad hoc meetings or teleconferences, the SMC 
will provide ongoing review of safety data to determine whether subject entry and treatment are 
appropriate, whether the protocol meets appropriate needs for safety monitoring and conduct, 
and whether continued study conduct is justified. The Clinical study site Principal Investigator 
will be notified accordingly when actions in response to safety concerns or protocol 
modifications occur and should ensure that the IRB is notified in a timely manner.
8.2.
Purpose
Provide independent review and surveillance of adverse effects observed after subject exposure 
to a nebulized urea solution (test article) used as a tool to screen for urease positive organisms in 
subjects presenting with clinical signs and symptoms of pneumonia. 
8.3.
Assessment Personnel
A qualified Independent Medical Monitor will be a physician experienced in the assessment of 
lower respiratory infections, and use of nebulized solutions in such patients, and with sufficient 
training and experience to evaluate the safety associated with of use of the test article in these 
subjects.
For this program, one or more physicians from the institution who are not involved in the 
enrollment or assessment of study subjects, but who are Board Eligible or Board Qualified in 
EM, Critical Care, or Pulmonology will review subject case reports to evaluate adverse events 
which may or may not be related to administration of test article per the schedule described 
below, and advise on the safety of continued subject enrollment. For this study, Mark Schuyler, 
MD has agreed to be the independent medical monitor (Section 7.7). 
8.4.
Planned Review Process
Frequency: Greater than 100 subjects have had the test article administered to date without the 
occurrence of serious adverse effects (SAEs). Therefore, this protocol intends for the safety 
monitoring review to be performed in cohorts as follows:

Subjects #1    through  3 = Group 1

Subjects #4    through  6 = Group 2

Subjects #7   through 10 = Group 3

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
Subjects #11 through 15 = Group 4

Subjects #16 through 20 = Group 5

Subjects #21 through 25 = Group 6

Subjects #26 through 30 = Group 7

Subjects #31 through 35 = Group 8

Subjects #36 through 45 = Group 9

Subjects #46 through 55 = Group 10

Subjects #56 through 65 = Group 11

Subjects #66 through 75 = Group 12
Each group of subjects will be reviewed to assess whether any SAEs or other significant safety 
events have occurred. Safety review will be documented using the study safety review form 
provided in Appendix C.1, to be completed by the independent medical monitor (or appropriate 
designee) and acknowledged by the study investigator.  If an SAE has occurred, the independent 
medical monitor will evaluate whether the observed SAE is definitely or possibly related to test 
article administration, or if there is no likely relationship between the SAE and test article. 

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9.
STATISTICAL METHODOLOGY
9.1.
Determination of Sample Size
The sample size for this study was selected based on prior exposures and existing safety data. 
Descriptive statistical analysis of results are planned  as Findings from this study will be used in 
order to appropriately determine the sample size requirements for future definitive evaluations of 
inhaled 13C-urea in an adequately powered study of efficacy in this population.
9.2.
Study Endpoints
9.2.1.
Efficacy Endpoints
Efficacy endpoints will include the following:

Evaluate the exhaled 13CO2 levels at each time point post-nebulization

Evaluate the relationship between the exhaled 13CO2 levels at each time point and 
subject’s causative pathogen based upon sputum culture or NGS analysis 

Evaluate the sensitivity and specificity of the 13C-urea breath test for urease producing 
pathogens 

Evaluate the positive and negative predictive value of the 13C-urea breath test for urease 
producing pathogens

Correlation of the 13C-urea breath test with CURB65 in subjects with sputum cultures or 
NGS results positive for urease pathogens 

Correlation of the 13C-urea breath test with PSI in patients with sputum cultures or NGS 
results positive for urease pathogens 

Univariate association of all study variables with urease pathogen caused pneumonia 

Multi-variate logistic regression model for urease pathogen caused pneumonia utilizing 
study variables that are significant in univariate analysis to compute odds ratio for each 
model variable and overall explanation of variance by model
9.2.2.
Safety Endpoints
Safety endpoints will include the following:
Incidence of all AEs 
Incidence of death, transfer to ICU, or intubation

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9.3.
General Considerations for Statistical Analysis
9.3.1.
Analysis Datasets 
Intent-to-Treat (ITT) Analysis Set: The ITT set will include all subjects who receive nebulized 
13C-urea.  The ITT set is also referenced as the Safety analysis set.  All safety analysis will be 
based on the ITT analysis set.
Modified Intent-to-Treat (mITT) Analysis Set:  The mITT subjects include all ITT subjects who 
provide at least one post-dose breath sample.  The mITT analysis set will be used for efficacy 
analysis.
9.3.2.
Test Hypothesis and P Value Justification
No formal statistical hypothesis will be examined.  When a p-value is produced from an analysis, 
the nominal p-value will be reported as is without adjustment for multiplicity.
9.3.3.
Procedures for Handling Missing Data 
Unless indicated otherwise, no imputation will be done for missing data.  However, AEs with 
missing severity assessments will be tabulated as “severe,” and AEs with missing relationship 
assessments will be tabulated as “related” for the purpose of analysis; and the missing data will 
be presented in data listing as is.
9.4.
Study Population Summaries
Population summaries will be provided for the safety analysis set included in this study.
9.4.1.
Disposition
The summary tables will provide frequency counts for subject disposition (all treated subjects, 
subjects who completed the study, subjects who discontinued from the study, and reason for 
discontinuation) for the study overall and for each cohort.  Identification numbers for 
discontinued subjects will also be included in the tables.
Disposition in terms of number of subjects excluded from each analysis sets (ITT and mITT) will 
also be provided for the overall population and for each cohort.
9.4.2.
Demographics
The demographic summary will include descriptive statistics for age, sex, race, weight, height, 
and BMI for the overall study population.  
9.4.3.
Protocol Violations
All protocol violations and deviations will be identified.
9.4.4.
Treatment Compliance
All doses of study medication will be overseen by study personnel.  The exact time of initiation 
and completion of nebulization will be documented within each subject’s CRF.  No formal 
summary of treatment compliance will be produced.

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9.4.5.
Prior and Concomitant Medications
All prior and concomitant medications will be tabulated for the overall study population.  Prior 
and concomitant medications will be coded to the therapeutic drug classes and generic drug 
names using the World Health Organization (WHO) Drug classifications version 1Q2015 or 
higher.
9.5.
Efficacy Analysis
Breath test exhaled 13CO2 results at each time point will be presented for the overall population 
for determination of optimal breath sampling time.  Relationship between the exhaled 13CO2 at 
each time and subject’s pneumonia diagnosis and pathogen (determined by sputum culture) will 
be examined.  The time point where exhaled 13CO2 can reliably predict the presence of urease 
positive pathogen in subjects with pneumonia diagnosis will be considered as the optimal time 
for 13C-urea breath test sampling.
The proportion of subjects with breath test positive/negative determination will be compared to 
sputum culture results when available.   Correlation analyses will be performed where sufficient 
data are available.
9.6.
Safety and Tolerability Evaluations
All analyses will be provided for the overall group.
9.6.1.
Extent of Exposure
All subjects will receive Study drug 13C-urea solution via Aerogen Aeroneb Solo nebulizer 
device.  The solution will be nebulized until the full dose has been administered, with subjects 
breathing normally through their mouths using the nebulizer mouthpiece.  
No formal exposure summary will be prepared.
9.6.2.
Adverse Events
The Medical Dictionary for Regulatory Activities (Version 18 or higher) will be used to classify 
all AEs with respect to system organ class and preferred term.
Three types of summaries will be produced for the AE summary:
1. an overall summary of AEs: number of subjects with at least one event and number of 
events for each severity for all AEs, and SAEs
2. a summary table of AEs and SAEs by system organ class and preferred term and severity 
3. a summary table of AEs and SAEs by preferred terms in descending order of total 
incidence
AEs will be tabulated by cohort and for study overall.  AEs that lead to premature 
discontinuation from the study or to death will be listed separately via data listings.   
9.6.3.
Clinical Laboratory Tests
The study will not have routine clinical safety laboratory tests.  Bacterial culture results will be 
summarized for the study overall.

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9.6.4.
Subgroup Analyses for Safety Endpoints
No subgroup analysis is planned for safety endpoints.
9.7.
Interim Evaluation
No interim analysis is planned for this study. 

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10.
STUDY ADMINISTRATION
10.1.
Regulatory and Ethical Considerations
10.1.1.
Regulatory Authority Approval
The investigator will obtain approval to conduct the study from the appropriate regulatory 
agency in accordance with any applicable country specific regulatory requirements before any 
site may initiate the study in that country.
10.1.2.
Ethical Conduct of the Study and Ethics Approval
This study will be conducted according to GCP; US 21 Code of Federal Regulations (CFR) Part 
50 (Protection of Human Subjects); US 21 CFR Part 56 (IRBs); US 21 CFR Part 54 (Financial 
Disclosure); International Conference on Harmonization (ICH) Guidance for Industry, E6 GCP: 
Consolidated Guidance; the Nuremberg Code; and, where applicable, the principles of the 
Declaration of Helsinki (Recommendations guiding Medical Doctors in Biomedical Research 
Involving Human Subjects).  
10.1.2.1.
Ethics Committees
The investigator is responsible for ensuring that this protocol, the site’s informed consent form, 
and any other information that will be presented to potential subjects (e.g., advertisements or 
information that supports or supplements the informed consent form) are reviewed and approved 
by the appropriate IRB or IEC.  The investigator agrees to allow the IRB or IEC direct access to 
all relevant documents.  The IRB or IEC must be constituted in accordance with all applicable 
regulatory requirements.  
If the protocol, the informed consent form, or any other information that the IRB or IEC has 
approved for presentation to potential subjects is amended during the study, the investigator is 
responsible for ensuring that the IRB or IEC reviews and approves, where applicable, these 
amended documents.  The investigator must follow all applicable regulatory requirements 
pertaining to the use of an amended informed consent form, including obtaining IRB or IEC 
approval of the amended form, before new subjects consent to take part in the study using the 
new version of the form.  IRB or IEC approval of the consent forms must be obtained in addition 
to the approval given for the clinical study.  Regulatory review and approval may be required in 
some countries before IRB or IEC approval can be sought.
10.1.2.2.
General Considerations
The ethical standards defined within GCP are intended to ensure the following:
Human subjects are provided with an adequate understanding of the possible risks of 
their participation in the study, and they have a free choice to participate or not.
The study is conducted with diligence and in conformance with the protocol in such a 
way as to ensure the integrity of the findings.
The potential benefits of the research justify the risks.

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10.1.3.
Informed Consent
The informed consent form must reflect the required elements of informed consent specified in 
21 CFR Part 50.25.  The final informed consent form must be approved by the IRB or IEC.  If 
any new information becomes available that might affect subjects’ willingness to participate in 
the study, or if any amendments to the protocol require changes to the informed consent form, 
the IRB or IEC must provide written approval of any revisions to the informed consent form in 
advance of its use.
Consenting will occur according to GCP and clinical site practices in the emergency department 
or Clinical and Translational Science Center (adjacent to UNM-ED, Cohort A only).
Investigators must provide subjects with all the information necessary to make an informed 
decision about their participation in the study, including the nature and intended purpose of the 
study, possible benefits, and possible risks.
All information in the informed consent form should be provided in a language (whether written 
or spoken) that is as nontechnical as practical and that is understandable to the subjects.
Before written informed consent is obtained, the subject should be given ample time and 
opportunity to inquire about the details of the study.  All questions must be answered to the 
satisfaction of the subject (or his or her legally authorized representative). 
This study requires administration of nebulized urea within 4 hours of administration of 
antibiotics.  Subjects will be told that if they wish to participate in the study, they will need to 
decide to participate within 3 hours of receiving antibiotics in the emergency department in order 
to participate in the study.  The study procedures will not delay or interfere with antibiotic 
administration.
Before a subject undergoes procedures specific to the protocol, the informed consent form must 
be signed and dated by the subject (or his or her legally authorized representative) and any other 
signatories as required by the IRB or IEC.
If a subject (or legally authorized representative) cannot read, a short form approved by the IRB 
or IEC may be used.  Only the short form itself is to be signed by the subject or the 
representative.  However, the witness shall sign both the short form and a copy of the summary, 
and the person actually obtaining the consent shall sign the copy of the summary in accordance 
with 21 CFR 50.27 (b2).
After all required signatures have been obtained, a copy of the informed consent form should be 
provided to the subject, and the original must be kept on file at the site and made available for 
review.  Documentation of the informed consent discussion must be noted in the subject’s case 
history.
10.1.4.
Investigator Reporting Requirements
The clinical site investigators are responsible for completing and maintaining adequate and 
accurate CRFs and source documentation.  Source documentation constitutes original records 
(first point of entry, either hard copy or electronic), which may include progress notes, 
medication administration records, operation reports, laboratory reports, discharge summaries, 
and so on.  All CRFs should be completed contemporaneously in their entirety and stored in a 
confidential and locked location.

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All patient records relating to the present study will be kept in a locked cabinet in the locked ED 
Research Offices within the UNMH Emergency Department (2211 Lomas Blvd NE, Suite 1303 
and 1304) and Henry Ford Hospital Emergency Department (2799 W. Grand Blvd, Detroit, MI  
48202), as appropriate. Only approved study personnel will have key access to the research 
materials.  All study materials with PHI will be de-identified prior to transmission to the study 
sponsor. The link between research records and patient identifiers will be destroyed prior to 
archiving the study records. We intend to archive study records in a locked cabinet in the IDTC 
file room at 700 Camino de Salud NE after study closure. Henry Ford Hospital will archive study 
records in a locked cabinet located in the Emergency Department research office at 2799 W. 
Grand Ave. after study closure.
Study information will be entered in an Excel spreadsheet located on a dedicated laptop housed 
at the UNM Emergency Department Research Office.  The database will only be accessible to 
IRB approved study staff and will not contain subject identifiers.
10.2.
Study Monitoring
The site investigator is responsible for ensuring the proper conduct of the study with regard to 
subject protection, ethics, protocol adherence, site procedures, and integrity of the data.  
Qualified study monitors will review all aspects of the study according to Good Clinical 
Practices and for compliance with applicable government regulations.  The investigator agrees to 
allow monitors direct access to all site information, clinical data, supplies and dispensing and 
storage areas during monitoring visits.  The site investigator and staff are responsible for being 
available during monitoring visits for consultation. See Appendix E for details of the study 
monitoring plan.
10.3.
Quality Assurance
A regulatory authority or an IRB representative may visit the study site at any time during the 
study or after completion of the study to perform audits or inspections.  The purpose of an audit 
or regulatory inspection is to examine systematically and independently all study-related 
activities and documents to determine whether these activities were conducted according to the 
protocol, GCP, ICH guidelines, and any other applicable regulatory requirements.  It is the site 
investigators’ responsibility to inform the Principal Investigator immediately in the event of an 
audit notification.
10.4.
Study and Site Closure
If the investigator or officials from regulatory agencies discover conditions arising during the 
study that indicate that the study should be halted or that the study site should be closed, this 
action may be taken after appropriate consultation between the study investigators.  Conditions 
that may warrant termination of the study include, but are not limited to, the following:
discovery of an unexpected, serious, or unacceptable risk to the subjects enrolled in the 
study
submission of knowingly false information from the research facility to the study monitor 
or regulatory agencies

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failure of the investigator to comply with GCP (e.g., ICH guidelines, regulatory agency 
guidelines)
insufficient adherence to protocol requirements or an unacceptably high rate of missing, 
erroneous, or improperly collected data
evidence from the blinded data of sufficient technical problems with the study that one 
could believe with a high degree of certainty that subjects are being exposed to the 
investigational drug without a realistic expectation of evaluable data
a decision on the part of the investigator to suspend or discontinue testing evaluation or 
development of the product
failure of the investigator to enroll subjects into the study at an acceptable rate
10.5.
Records Retention
10.5.1.
Health Insurance Portability and Accountability Act of 1996
The investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of subjects’ health information, including, but not limited to, 
the Standards for Individually Identifiable Health Information, 45 CFR Parts 160 and 164 (the 
Health Insurance Portability and Accountability Act of 1996 privacy regulation).  The 
investigator shall ensure that study subjects authorize the use and disclosure of protected health 
information in accordance with the privacy regulations of the Health Insurance Portability and 
Accountability Act.
10.5.2.
Financial Disclosure
Financial disclosure is not required for this study.
10.5.3.
Access to Original Records
Regulatory authorities expect that monitors, auditors, and representatives of national and 
international government regulatory agency bodies have access to original source documentation 
(see examples in Section 10.1.4) to ensure data integrity.  “Original” in this context is defined as 
the first documentation of an observation and does not differentiate between hard-copy and 
electronic records.
10.5.4.
Archiving of Study-Related Documents
Records related to this clinical study must be retained either for at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed since 
the formal discontinuation of clinical development of the investigational product. 
10.6.
Provision of Study Results and Information to Investigators
The investigator and study staff will have access to the research results and will be able to link 
the results to a particular subject.  The investigator and study staff will be directed to hold this 
information confidentially.

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10.7.
Subject Tracking
Drug accountability logs, a subject identification log (to be retained by the investigator only), 
and a subject enrollment log will be used to track subject participation in the study.

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11.
REFERENCES
Raissy, H. H., Timmins, G., Davies, L., Heynekamp, T., Harkins, M., Sharp, Z. D., & Kelly, H. W. (2016). A 
Proof of Concept Study to Detect Urease Producing Bacteria in Lungs Using Aerosolized 13 C-Urea. 
Pediatric Allergy, Immunology, and Pulmonology, 29(2), 68–73. 
http://doi.org/10.1089/ped.2015.0619

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APPENDIX A. SCHEDULES OF STUDY VISITS AND PROCEDURES

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Table 1:  Schedule of Study Procedures
Treatment
Procedure
Screening
Pre-
Treatment
Nebulization
0-10 Minutes Post-
Nebulization
Follow-Up
48 Hours Post Breath 
Test
Informed Consent
X
Inclusion/Exclusion 
Evaluation
X
Demographics and Medical 
History
X
Physical Examination
X
Sputum Collection
Xb
Oroopharyngeal Swab
Xb
Urine Pregnancy Test
X
Breath Sample Collection
Xa
Xa
Vital Signs
X
X
X
X
13C-urea Administration
X
Safety Contact
X
Prior and Concomitant 
Medication
<-------------------------------------- X ---------------------------------------->
Adverse Event Monitoring
<------------------- X -------------------->
a Up to 6 samples collected pre- and post-nebulization
b Only required for Cohort B

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APPENDIX B. INVESTIGATOR OBLIGATIONS
As an investigator, you are responsible for ensuring that the study is conducted according to the 
protocol, the signed Statement of Investigator, and all applicable regulations.
Debarment
Individuals ineligible to conduct or be involved with clinical studies, including those ineligible as 
a result of debarment under the Generic Drug Enforcement Act of 1992, will not be allowed to 
conduct or work on this study.  
Institutional Review Board
You are required to obtain initial and continuing review and approval by an IRB or IEC that 
complies with the requirements specified in 21 CFR Part 56.  Before initiating the trial, you must 
have written approval from the IRB or IEC for the protocol, informed consent form, subject 
recruitment procedures (e.g., advertisements), and any other written information to be provided 
to the subjects.  You must submit the Investigator’s Brochure and any updates to the IRB or IEC 
for review.  The IRB or IEC must also provide written approval of any amendments to the 
protocol that affect the conduct of the study and any changes to the informed consent form in 
advance of use.  If the duration of the study is longer than 1 year, re-approval by the IRB or IEC 
must be obtained on a yearly basis (or at more frequent intervals if required by the IRB or IEC).  
You must provide reports of all SAEs from your site to the IRB or IEC.  You are also responsible 
for providing the IRB or IEC with Safety Reports of any SAEs from any other study conducted 
with the study medication.  
Confidentiality and Safety of Subjects
You are responsible for protecting the rights, safety, and welfare of subjects under your care and 
for the control of the drug(s) under investigation.
You are responsible for keeping a record of all screened subjects, including full names and last 
known addresses.  All subjects will be identified on the CRFs by initials and subject numbers.  
Demographic information including date of birth, sex, and race will also be recorded on the 
CRFs.  Confidentiality of subject data will be maintained in accordance with local laws.
In addition to your responsibilities for reporting AEs identified during the course of a subject’s 
participation in the study, you must also report any SAEs that occur within 30 days after the last 
dose of study medication (regardless of relationship to study medication) and any serious adverse 
drug reactions (SAEs for which you consider that there is a reasonable possibility that the study 
medication caused the response) that you become aware of at any time (even if the event occurs 
more than 30 days after the subject’s last exposure to study medication).  This obligation is in 
addition to any protocol-specified requirement for reporting AEs occurring after the last dose of 
study medication.  Please refer to Sections 7.7 and 7.8 of this protocol for contact information 
and SAE reporting requirements.

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Study-Related Records
You are required to maintain complete and accurate study documentation in compliance with 
current GCP standards and all applicable federal, state, and local laws, rules, and regulations 
related to the conduct of a clinical study.
You are required to make all study documentation promptly available for inspection, review, or 
audit at your study site upon request by the investigator or any appropriate regulatory agencies.
Accountability of the Investigational Product
You or your designee (i.e., the pharmacist) is responsible for accountability of the investigational 
product at the site.  You or your designee must maintain records of the product’s delivery to the 
site, inventory at the site, use by each subject, and the return/destruction of any unused product.  
These records must include dates; quantities; batch, serial, or lot numbers; and expiration dates 
(if applicable).
You should ensure that the investigational product is used only in accordance with the protocol.

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APPENDIX C. STUDY-SPECIFIC INFORMATION
Appendix C.1:
Safety Review Form 

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Protocol 16-327 - Safety Review Form
Date Reviewed: 
______________________________________
Subjects Reviewed: 
______________________________________
Reviewer: 
______________________________________
Were any significant safety observations identified?   Yes (describe below)         No
Subject 
ID
Description of event
Serious 
(Y/N)
Intensity
Relationship to 
treatment 
Intensity: Mild, Moderate, Severe
Relationship to treatment: Not related, Possibly related, Probably related, Definitely related
Other safety observations to report?   N/A
_______________________________________________________________________
_______________________________________________________________________
_______________________________________________________________________
Determination of review:
 Safe to proceed with enrollment
 Additional review required, hold enrollment
 Other, Describe: ______________________________
_______________________________________________
Reviewer Signature / Date
_______________________________________________
Investigator Acknowledgement, Signature / Date

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APPENDIX D.    BMI CALCULATION
Body Mass Index Calculations
Body Mass Index
Weight in kilograms / (height in meters)2
Meters = inches × 0.0254; kilograms = pounds × 0.45
Example:
For a man who weighs 165 pounds and is 71 inches tall:
165 × 0.45 = 74.25 kg
71 × 0.0254 = 1.8 m
74.25 / (1.8 × 1.8) = 22.9 kg/m2

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APPENDIX E.    CLINICAL MONITORING PLAN
A Phase 1, Open-label Evaluation of a 13C-
Urea Breath Test for the Detection of Urease-
producing Bacteria in Patients with 
Pneumonia in the Emergency Department
Clinical Monitoring Plan
Version 1.1, May 22, 2017
Study #: NCT03100760

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Table of Contents 
1 Introduction to the Monitoring Plan .............................................................. 3 
2 Regulatory Documents .................................................................................. 3
3 Study Initiation Activities............................................................................... 4
3.1 Timing................................................................................................................ 4
3.2 Pre-Initiation Communication........................................................................... 4 
3.3 Site Initiation Activities ..................................................................................... 4
3.4 Site Initiation Reports........................................................................................ 5 
4.5 Follow-up Communications............................................................................... 5
4 Monitoring Activities....................................................................................... 5 
4.1 Initial Site Visit ................................................................................................... 5 
4.2 Periodic Site Visits ............................................................................................. 5 
4.3 Telephone Contacts and Documentation .......................................................... 6
4.4 Pre-Visit Communication ................................................................................... 6 
4.5 In House Monitoring Activities........................................................................... 6
4.6 CRF Completion ................................................................................................. 7
4.7 CRF Guidelines ................................................................................................... 7  
4.8 Source Document Requirements ....................................................................... 7 
4.9 Source Document Verification (SDV) ................................................................. 8 
4.10 Subject Screening and Enrollment ..................................................................  9
4.11 Regulatory Binder ............................................................................................ 9 
4.12 Data Query Process, eCRF Locking .................................................................. 10 
4.13 Protocol Deviations/Violations........................................................................ 10 
4.14 Site Supplies..................................................................................................... 10 
4.15 Monitoring Visit Reports.................................................................................. 11 
4.16 Follow-up Communications and Activities ...................................................... 11
5 Site Closure Activities...................................................................................... 11 
5.1 Timing................................................................................................................. 11 
5.2 Pre-Visit Communication ................................................................................... 11 
5.3 Site Closure Visit Activities.................................................................................. 12
5.4 Follow-up Communications................................................................................ 12

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5.5 Site Closure Visit Report...................................................................................... 12
1 Introduction to the Monitoring Plan
 
This study specific monitoring plan is intended to ensure consistency in the scope of work performed 
between the University of New Mexico Health Sciences Center-Emergency Medicine (UNMHSC-EM) 
department, as the responsible party for Clinical Operations, and the investigative sites. A Clinical 
Research Organization (CRO) is being retained to conduct the clinical data monitoring for UNMHSC-EM 
and all other clinical sites. This monitoring plan is written to ensure and verify that the study will be 
conducted according to the study protocol, FDA/ICH Regulations and Guidelines, applicable regulatory 
requirements, and all State and Local laws. 
2 Regulatory Documents 
Monitoring activities will follow previously established CRO SOPs and Work Instructions, and contractual 
requirements, unless identified to be in conflict with UNMHSC-EM SOPs. If new SOPs are released, they 
will supersede the previous versions unless otherwise documented by the Study Manager. Instructions 
for completion of the case report forms (CRF) will be part of site training. 
CRO will be responsible for the collection of each site’s regulatory documents for the remainder of the 
study. 
Specific requests in the aforementioned Work Instructions may be altered as needed by UNMHSC-EM to 
address current study needs. A site’s Regulatory File includes but is not limited to the following 
documents: 
♦ IRB/EC approved Informed Consent Documents and Protocol Approval Letters, 

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♦ Investigator Agreements, 
♦ Investigator and co-Investigator CVs and current licensure, 
♦ Signed protocol signature pages including any amendments, 
♦ Clinical Laboratory Certification and Accreditation, e.g. CAP, CLIA, laboratory normal ranges, and the 
CV and license of the Lab Director, 
♦ Sample Case Report Form, and
♦Monitoring documentation including confirmation of visits, follow-up letters to investigative sites, and 
monitoring reports. Note: With the exception of the Initiation Visit Report, all Monitoring Visit Reports 
are filed only with the Master Site File at UNMHSC-EM and not in the sites’ Regulatory Binder.
The following additional documents will be collected from each site in addition to the documents listed 
above and submitted to UNMHSC-EM:
♦ A copy of the Delegation Log (Signature and Responsibility)
♦ A copy of the Clinical Supplies Receiving and Return logs
♦ A copy of the Specimen Shipment Log
♦ A copy of the Screening and Enrollment Log and all updates
♦ Safety monitoring reports
♦ Reports of Serious Adverse Events
3 Study Initiation Activities
3.1 Timing
CRO will conduct Site Initiations for the selected sites. If new sites are added, CRO will also conduct 
those Site Initiations. The Site Initiation will be scheduled once budgets are agreed upon, contracts 
executed, IRB approval and supplemental investigational device exemption (IDE) approval has been 
obtained and the IRB approval letter provided to UNMHSC-EM. 
3.2 Pre-Initiation Communication

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An CRO representative will contact the site to confirm the appropriate staff members who should be in 
attendance during the Site Initiation. The Site Initiation will be scheduled at a time in which all potential 
study staff members are able to attend. A letter confirming the Site Initiation including the agenda will 
be sent to the site within 5 working days of the Site Initiation.
Prior to the Site Initiation it will be confirmed that the site is able to send and receive e-mail. 
3.3 Site Initiation Activities 
Site Initiation activities and discussions include, but are not limited to: 
♦ a discussion of the Investigator’s responsibilities, 
♦ the informed consent process, 
♦ enrollment expectations, 
♦ protocol review (including inclusion/exclusion criteria) and study procedures, 
♦ regulatory document requirements, 
♦ maintenance of all study logs, 
♦ clinical supplies accountability, 
♦ local privacy law compliance (e.g. HIPAA) and pre-study authorization (US sites only), 
♦ source document requirements, 
♦ CRF completion and query resolution, 
♦ safety monitoring reporting, and 
♦ serious adverse event reporting. 
The CRA will be responsible for the following tasks during the Site Initiation: 
♦ Review of protocol, 
♦ Review of good clinical practices, 
♦ Train the site study personnel on study procedures, 
♦ Review the site’s regulatory and study files, 
♦ Documentation of the roles, responsibilities, and changes in staff (Delegation Log (Signature and 
Responsibility), 
♦ Verify the clinical supplies storage conditions are adequate, 
♦ Verify site has received all study specific documentation and supplies, 
♦ Verify that site is adequately trained on procedures regarding third party vendors and couriers who 
will be shipping specimens 

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♦ Review study material resupply procedures, and
♦ Review specimen collection resupply procedures. 
3.4 Site Initiation Reports 
The Initiation Report must be prepared by the CRA who conducted the Site Initiation. The report shall be 
submitted to the UNMHSC-EM Study Manager in a timely manner (suggested within 10 working days) 
from the date of the Site Initiation. 
3.5 Follow-up Communications 
The CRA will send a follow-up letter to the site within 5 working days following the Site Initiation. This 
letter will highlight the activities of the Site Initiation, and resolution to any unanswered questions that 
were raised during the visit. Outstanding regulatory issues will also be addressed in the letter. A copy of 
the Initiation Visit Report will be included with the letter. 
4 Monitoring Activities 
4.1 Initial Site Visit 
The first monitoring visits for Cohort A and B are targeted to be performed after a site enrolls their first 
3 subjects into each cohort. This initial visit is intended to ensure that the study is conducted according 
to the protocol and that the CRFs are being completed accurately.  
 
4.2 Periodic Site Visits
The CRA will schedule the second site visit after the last subject is enrolled for Cohort A at each site and 
has completed the study through the patient follow-up call.  
The CRA will schedule the second site visit for Cohort B after approximately 15 patients have been 
enrolled at a given site and then again for a final visit once all subjects have been enrolled in Cohort B 
and the CRFs completed through the patient discharge from the hospital.

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Additional monitoring visits can be scheduled based on the study site enrollment rates with monitoring 
visits occurring at a frequency established by UNMHSC-EM and agreed to by the sites, according to the 
sites’ enrollment rate and the number of open cases. 
4.3 Telephone Contacts and Documentation 
Telephone or e-mail communication with each site will be performed initially on a weekly basis until it is 
apparent to the CRA the site has become comfortable with study procedures, after which, contact 
should be made no less than every 2 weeks and the CRA has not identified any site specific problems 
that may warrant more frequent contact. Site Coordinators are encouraged to call the monitor with any 
questions whatsoever to ensure compliance with protocol. The monitor should document any 
conversations the CRA believes is significant to the study timeline, regulatory considerations, protocol 
adherence, subject safety, and any other issues team members should be made aware of. 
E-mail correspondence with a site regarding significant study-related issues, e.g. topics of discussion 
directly related to the conduct of the study, should be copied to the Study Manager and any other 
UNMHSC-EM personnel as applicable. Significant study-related e-mails will be maintained in UNMHSC-
EM Master Files. UNMHSC-EM clinical staff will print the final string of email correspondence for filing in 
NCT03100760 Master Files. 
When generating e-mail communication documenting significant study-related issues, a new e-mail shall 
be generated for each specific issue with the appropriate subject identified in the “RE:” section of the e-
mail header, beginning with the study name in capital letters, e.g. “RE: NCT03100760, Specimen 
Shipment”. E-mail strings may be utilized as long as the subject matter does not change. 
4.4 Pre-Visit Communication 
As sites reach the enrollment goal that will trigger a monitoring visit, an CRA (or delegate) will contact 
the site to schedule a monitoring visit. A letter confirming the visit will be sent to the site within 5 
working days of the visit. 
4.5 In House Monitoring Activities 
The Study Manager will have access to e-mailed PDFs of the site(s)’ CRFs. The CRF PDF does not contain 
any Protected Health Information (PHI).  The Study Manager should review subject data online routinely 

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throughout the course of the study. Prior to each site visit, the CRA should ensure the site staff complete 
all appropriate visit pages.
In house monitoring activities may include but are not limited to the following: 
♦ Query status: CRAs will check the query status and discuss this with the sites as required, 
♦ Withdrawals: Study Manager will track the number of subjects withdrawn from each site, 
♦ Patients screened: Study Manager will review the screening and enrolment logs provided for their 
sites to ensure subjects are being screened and enrolled according to the protocol, 
♦ Subjects enrolled: Study Manager will track number of subjects enrolled and confirm CRFs are being 
completed in a timely manner. 
4.6 CRF Completion 
Only the site staff listed on the Delegation Log (Signature and Responsibility) who have received 
required training and are authorized to enter data or make corrections to CRFs. The CRA will be 
responsible for ensuring that only the appropriate parties are making entries in the CRFs and that the 
data is accurate and complete. 
The CRA will ensure that the site staff is instructed on how to complete the CRFs correctly. 
4.7 CRF Guidelines 
In addition to checking CRF pages against source documents, the CRA must review all data for 
completion and plausibility. If the quality of completion of CRFs is inadequate, this must be discussed 
with the Investigator and appropriate site staff. 
Monitors will not be able to enter data into the CRF and will have access to the PDF versions for 
query/note generation and associated operational tasks only. 
Following the review and source verification of CRFs, the CRA should indicate the CRF as ‘monitored’ by 
initialing and dating each monitored page of the CRF. 
4.8 Source Document Requirements

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Data entered onto CRFs must be verified against original source documents to confirm accurate, 
complete and legible reporting of valid data. Original source documents may be the electronic medical 
record at the site, or copies of select medical record documents maintained in a shadow chart, or a 
combination of both. Sites will use an inclusion/exclusion criteria checklist copied from the CRF when a 
study coordinator approaches a patient to determine eligibility for the trial and to ensure all the 
required presentation data are captured and documented. This checklist will be considered a source 
document for the required presentation data. Medical history may also be obtained on this Worksheet 
but must be verified with the subject’s official medical record. If the subject does not have an 
established medical record at the study facility to verify against, it should be noted by the study site 
personnel in the study documents that the information was derived from a patient interview and is non-
verifiable.
Additional source documents required by the study include but are not limited to: 
♦ Study required specimen collection dates, times, and method of collection, 
♦ Medication records including prior and prescribed antibiotics, 
♦ Laboratory tests, 
♦ Chest X-ray results, 
♦ Prior non-drug therapies and procedures, 
♦ Documentation of the Initial and Final Diagnoses, and 
♦ Disposition of the patient 
4.8.1 CRF as Source Document
 
The only CRF that will be considered as source data will be the NCT03100760 case report forms for 
Cohort A and Cohort B. It is the clinical site’s option to use these CRFs as a source documents.
4.9 Source Document Verification (SDV) 
Source Document Verification will include 100% verification of all data recorded for all patients enrolled 
in the study.
Each site is required to maintain records of each subject's case history. Case histories include the CRFs 
and supporting data including, for example, signed and dated consent forms and medical records 
including, for example, past medical history, progress notes of the physician, laboratory results, the 

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individual's hospital chart(s), and the nurses' notes. Any significant deficiencies will be reported to the 
Study Manager and documented by the CRA in the Monitoring Visit Report. 
4.9.1 Adverse Event/Serious Adverse Event Reporting 
This study is a non-interventional study. The only study related procedure the patient will experience is 
the urea breath test. Adverse events will be collected up until 48 hours post administration of the study 
drug and any noted adverse events from this time period will be followed till resolution. 
A patient may experience an adverse event related to the urea breath test, which is defined as but not 
limited to coughing, dizziness, feeling faint or fainting. If a patient were to experience an adverse event, 
this must be recorded in the CRF. If the adverse event is deemed to be serious, the event must be 
reported by the site investigator or his/her designate to the safety monitor (Dr. Mark Schuyler of 
UNMHSC) and the study PI (Dr. Justin Baca of UNMHSC-EM) as soon as possible.  In addition, notification 
shall be given in writing to the FDA and the site’s IRB per the IRB’s internal procedures. 
Serious is defined as either: 
♦ Death, 
♦ Life-Threatening, 
♦ Unanticipated Hospitalization (initial or prolonged), 
♦ Disability, 
♦ Congenital Anomaly, or 
♦ Requiring Intervention to Prevent Permanent Impairment or Damage. 
4.10 Subject Screening and Enrollment 
All screened subjects will be listed on the Subject Screening and Enrollment Log. The log will be sent by 
the site research coordinator or his/her designate to the NCT03100760 Study Manager weekly either by 
fax or e-mail attachment. 
4.11 Regulatory Binder 
The CRO CRA will review the Regulatory Binder for completeness and/or additions during Monitoring 
Visits. The CRA should collect original signed protocol signature pages and the Investigator Agreement 
form, leaving copies of these documents in the site’s Regulatory Binder.
In addition, if there has been a change in site personnel and/or personnel responsibilities, the CRA 
should collect a copy of the updated Delegation Log (Signature and Responsibilities) for NCT03100760’s 
Master files. 

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The CRA should follow up with the site coordinator to ensure timely processing and submission of any 
amendments to the protocol, informed consent, or other study related documents. The Site Regulatory 
Binder should thus be checked on a regular basis to ensure the filing of appropriate approval 
documents. 
4.12 Data Query Process 
Queries for CRFs can be issued by a CRA. CRA queries are based on the on-site CRF review and use a 
paper query form. These queries should be answered by the site staff, source verified and closed by the 
CRA. 
4.12.1 Query Tracking 
Queries generated from CRFs will be tracked by the NCT03100760 Study Manager. The CRA will follow-
up with the site to ensure queries are followed-up and closed in a timely manner.
4.12.2 Query Status 
There are five categories of query status for the CRFs, and these can be tracked by the CRA and the 
Study Manager for each site or for all sites. CRAs are able to generate manual queries, perform SDV and 
close queries. The five categories are: 
♦ Open – Site: Queries with this status should be sent to the site for review or action. 
♦ Open – CRO: Queries are set to this status after the site user responds to a query by adding a 
comment, and the query is thus routed back to CRO for review or action. 
♦ Accept As Is: Queries are set to this status by CRO personnel if the site has indicated that the data 
value will not be changed, since it is accurate and in accord with source documents, despite the 
validation failure. The query is considered closed and will no longer display on the form. 
♦ Obsolete: Queries are set to this status by CRO personnel if CRO personnel deem that the query has 
been generated in error. The query is considered closed and will no longer display on the form. 
♦ Data Changed: This status is assigned to the query when data on the CRF is changed such that the 
query conditions are no longer violated. The query is considered closed. 

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4.13 Protocol Deviations/Violations 
Protocol non-compliance will be documented in the Monitoring Visit Report. Significant protocol 
violations will be communicated to the Study Manager in a timely manner. UNMHSC-EM will review 
sites with frequent protocol deviations/violations and if the situation cannot be resolved, the site may 
be terminated from the study. 

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4.14 Site Supplies
Initial shipment of supplies will occur after the site receives approval from their IRB, supplemental IDE 
approval is granted and an initiation visit has been scheduled. The Investigator or designated study site 
personnel verifying the receipt of the supplies must complete the Clinical Supplies Received Log and 
send it to the Study Manager. Sites will contact the Study Manager when resupply of supplies is 
required.
4.14.1 Accountability 
The CRA will perform accountability of the supplies at each monitoring visit. Verification of the supplies 
includes the following: 
♦ Confirm that the Clinical Supplies Received Log is on file at the site. 
♦ Confirm that the Clinical Supplies Received Log and supply inventory are in agreement. 
♦ Confirm that the Clinical Supplies Received Log was faxed/e-mailed to the Study Manager after each 
receipt of supplies. 
4.15 Monitoring Visit Reports 
The Monitoring Visit Report must be prepared by the CRA who conducted the Monitoring Visit and 
submitted to the Study Manager in a timely manner (suggested within 10 working days) from the date of 
the Visit. The final Monitoring Visit Report shall be submitted to the Sponsor representative by the Study 
Manager no longer than 15 working days after the date of the visit. 
4.16 Follow-up Communications and Activities 
The CRA will send a detailed follow-up letter to the site in a timely manner (suggested within 10 working 
days) following the visit. This letter will highlight the activities of the Monitoring Visit, any protocol 
deviations/violations noted, and suggested corrective actions/pending items. Outstanding regulatory 
issues will also be discussed along with suggested resolution of the issue(s). If any significant CRF or 
other problem is identified during monitoring, these must be reported to the Study Manager via e-mail 
and/or telephone as soon as possible.
5 Site Closure Activities 
5.1 Timing 
The Site Closure Visit will be scheduled after all CRFs have been completed including all post-discharge 
follow-up visits, and all data queries have been resolved and closed. 
5.2 Pre-Visit Communication

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Prior to the Site Closure Visit the CRA will confirm with the Study Manager that the site is suitable for 
closure. The CRA should review the previous visit report, interim communications and regulatory 
tracking log, noting any outstanding actions. The visit should be arranged with the Principal Investigator 
and any other appropriate study site personnel by sending a visit confirmation letter. The confirmation 
letter should request any follow-up issues/documents required for resolution at the visit. Prior to the 
closure visit, the CRA should confirm that all CRF pages are complete. The CRA should also confirm with 
the Study Manager that all queries have been resolved. 
5.3 Site Closure Visit Activities 
During the visit, activities will include, but are not limited to, the following: 
♦ Review and verify all subject CRFs have been completed, 
♦ Resolve all outstanding data discrepancies and queries, 
♦ Confirm the Principal Investigator has provided their signature for the CRFs, 
♦ Perform final reconciliation of all supplies accountability records and coordinate return of the supplies 
or destruction of the supplies, 
♦ Review the Regulatory Binder for completion and ensure all regulatory documents have been 
submitted to the NCT03100760 Master File, 
♦ Confirm the End of Study Financial Disclosure Forms have been submitted to the NCT03100760 
Master File, 
♦ Confirm provisions for study document storage, 
♦ Review and retrieve a copy of the study closure notification to the IRB/EC, 
♦ Inform investigator of responsibilities (including record retention, inspections, financial disclosure, 
and publication policy)
Request that the investigator prepare, sign, and submit a final study report to the IRB/EC and remit a 
copy for the NCT03100760 Master File. 
5.4 Follow-up Communications
The CRA will send a follow-up letter to the site in a timely manner (suggested within 10 days of the visit) 
following the visit. This letter will highlight the activities of the Termination Visit, protocol deviations/ 
violations noted, and suggested corrective actions. Outstanding regulatory issues will also be 
documented. 
5.5 Site Closure Visit Report 

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The Site Closure Visit Report must be prepared by the CRA who conducted the Visit and submitted to 
the NCT03100760 Study Manager in a timely manner (suggested within 10 working days) from the date 
of the Visit. The final Visit Report shall be submitted to the Sponsor representative by the Study 
Manager no longer than 15 working days after the date of the visit.