A Phase 1, Open-Label Study in Healthy Adults to Evaluate the Safety and Pharmacokinetics of AVYCAZ(R) in Combination With Aztreonam (COMBINE)
Phase: PHASE1
Conditions: Bacterial Infection
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

A Phase I, Open-Label Study in Healthy Adults to Evaluate the 
Safety and Pharmacokinetics of AVYCAZ® in Combination with 
Aztreonam (COMBINE) 
DMID Protocol Number: 17-0107 
DMID Funding Mechanism: UM1AI104681 
IND Sponsor: National Institutes of Health (NIH)/National Institute of Allergy and Infectious 
Diseases (NIAID)/Division of Microbiology and Infectious Diseases (DMID) 
Site Principal Investigator: Jeff Guptill, M.D., MA, MHS 
ARLG Principal Investigator: Thomas Lodise, Pharm.D., Ph.D. 
DMID Clinical Project Manager: Chidi Obasi, MBBS, PhD 
Draft or Version Number:  v3.0 
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STATEMENT OF ASSURANCE 
Each Institution will hold a current Federal Wide Assurance (FWA) issued by the Office of 
Human Research Protections (OHRP) for federally-funded human subject’s research.  Each 
FWA will designate at least one Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) registered with OHRP, for which the research will be reviewed and approved 
by the IRB/IEC and will be subject to continuing review [45 CFR 46.103(b)]. The IRB/IEC 
designated under an FWA may include an institution’s IRB/IEC, an independent IRB/IEC, or an 
IRB/IEC of another institution after establishing a written agreement with that other institution. 
 

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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with Good Clinical Practice (GCP) and as required by 
the following: 
• 
United States Code of Federal Regulations (CFR) 45 CFR Part 46: Protection of Human 
Subjects 
• 
Food and Drug Administration (FDA) Regulations, as applicable: 21 CFR Part 50 (Protection 
of Human Subjects), 21 CFR Part 54 (Financial Disclosure by Clinical Investigators), 21 
CFR Part 56 (Institutional Review Boards), 21 CFR Part 11, and 21 CFR Part 312 
(Investigational New Drug Application) 
• 
International Conference on Harmonisation: Good Clinical Practice (ICH E6); 62 Federal 
Register 25691 (1997); and future revisions 
• 
Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of 
Research, Report of the National Commission for the Protection of Human Subjects of 
Biomedical and Behavioral Research 
• 
National Institutes of Health (NIH) Office of Extramural Research, Research Involving 
Human Subjects, as applicable 
• 
National Institute of Allergy and Infectious Diseases (NIAID) Clinical Terms of Award, as 
applicable 
• 
Applicable Federal, State, and Local Regulations and Guidance 

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SIGNATURE PAGE 
The signature below provides the necessary assurance that this trial will be conducted according 
to all stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable US federal regulations and 
ICH E6 Good Clinical Practice (GCP) guidelines. 
I agree to conduct the study in compliance with GCP and applicable regulatory requirements. 
I agree to conduct the study in accordance with the current protocol and will not make changes to 
the protocol without obtaining the sponsor’s approval and IRB/IEC approval, except when 
necessary to protect the safety, rights, or welfare of subjects. 
Site Investigator Signature:* 
 
Signed: 
 
Date: 
 
 
Jeff Guptill, M.D., MA, MHS 
Associate Professor, Duke Clinical Research Institute 
(DCRI) 
 
 
 
 
 

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TABLE OF CONTENTS 
STATEMENT OF ASSURANCE ...................................................................................................2 
STATEMENT OF COMPLIANCE .................................................................................................3 
SIGNATURE PAGE .......................................................................................................................4 
TABLE OF CONTENTS .................................................................................................................5 
LIST OF TABLES .........................................................................................................................10 
LIST OF FIGURES .......................................................................................................................11 
LIST OF ABBREVIATIONS ........................................................................................................12 
PROTOCOL SUMMARY .............................................................................................................18 
 
KEY ROLES.........................................................................................................................21 
 
BACKGROUND AND SCIENTIFIC RATIONALE ..........................................................23 
 
Background .................................................................................................................23 
 
Scientific Rationale .....................................................................................................25 
2.2.1 Purpose of Study ............................................................................................25 
2.2.2 Study Population ............................................................................................26 
 
Potential Risks and Benefits .......................................................................................26 
2.3.1 Potential Risks ...............................................................................................27 
2.3.2 Potential Benefits ...........................................................................................30 
 
STUDY DESIGN, OBJECTIVES AND ENDPOINTS OR OUTCOME MEASURES .....31 
 
Study Design Description ...........................................................................................31 
 
Study Objectives .........................................................................................................32 
3.2.1 Primary ...........................................................................................................32 
3.2.2 Secondary .......................................................................................................32 
3.2.3 Exploratory ....................................................................................................32 
 
Study Endpoints or Outcome Measures .....................................................................32 
3.3.1 Primary ...........................................................................................................32 
3.3.2 Secondary .......................................................................................................32 
3.3.3 Exploratory ....................................................................................................33 
 
STUDY INTERVENTION/STUDY PRODUCT ................................................................34 

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Study Product Description ..........................................................................................34 
4.1.1 Formulation, Packaging, and Labeling ..........................................................35 
4.1.2 Product Storage and Stability .........................................................................36 
 
Acquisition/Distribution .............................................................................................37 
 
Dosage/Regimen, Preparation, Dispensing and Administration of Study 
Intervention/Study Product .......................................................................................38 
 
Accountability Procedures for the Study Intervention/Study Product(s) ...................39 
 
SELECTION OF SUBJECTS AND STUDY ENROLLMENT AND WITHDRAWAL ....40 
 
Eligibility Criteria .......................................................................................................40 
5.1.1 Subject Inclusion Criteria...............................................................................40 
5.1.2 Subject Exclusion Criteria .............................................................................41 
 
Withdrawal from the Study, Discontinuation of Study Product, or Study Termination
 ..................................................................................................................................43 
5.2.1 Withdrawal from the Study or Discontinuation of the Study Product ...........43 
5.2.2 Subject Replacement ......................................................................................44 
5.2.3 Study Termination .........................................................................................44 
 
STUDY PROCEDURES ......................................................................................................45 
 
Screening (Days -30 to Day -2) ..................................................................................45 
 
Enrollment (Day -1) ....................................................................................................46 
 
Planned Study Visits (Days 1 – 8) ..............................................................................47 
6.3.1 Treatment (Day 1) ..........................................................................................47 
6.3.2 Treatment (Day 2) ..........................................................................................47 
6.3.3 Treatment (Day 4, 6) ......................................................................................48 
6.3.4 Treatment (Day 3, 5, 7) ..................................................................................48 
6.3.5 Discharge (Day 8) ..........................................................................................48 
6.3.6 Final Study Visit (Day 11 +3) ........................................................................49 
 
Early Termination Visit ..............................................................................................50 
 
Unscheduled Study Visits ...........................................................................................50 
 
Protocol Deviations ....................................................................................................51 
 
DESCRIPTION OF CLINICAL AND LABORATORY EVALUATIONS .......................52 

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Clinical Evaluations ....................................................................................................52 
7.1.1 Research Procedures ......................................................................................52 
7.1.2 Assessment of Concomitant Medications/Treatments other than Study 
Product ...........................................................................................................53 
7.1.3 Assessment of Subject Compliance with the Study Visit Schedule ..............53 
 
Laboratory Evaluations ...............................................................................................54 
7.2.1 Clinical Laboratory Evaluations ....................................................................54 
7.2.2 Research Assays .............................................................................................55 
 
ASSESSMENT OF SAFETY ...............................................................................................58 
 
Assessing and Recording Safety Parameters ..............................................................58 
8.1.1 Adverse Events (AEs) ....................................................................................58 
8.1.2 Serious Adverse Events (SAEs) .....................................................................60 
 
Specification of Safety Parameters .............................................................................61 
8.2.1 Solicited Events .............................................................................................61 
8.2.2 Unsolicited Events .........................................................................................61 
 
Reporting Procedures ..................................................................................................61 
8.3.1 Reporting Serious Adverse Events ................................................................61 
8.3.2 Regulatory Reporting for Studies Conducted Under DMID-Sponsored IND
 ........................................................................................................................62 
8.3.3 Reporting of Pregnancy .................................................................................62 
 
Type and Duration of Follow-up of Subjects after Adverse Events ...........................63 
 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings......................................................................................63 
 
Halting Rules ..............................................................................................................63 
8.6.1 Study Halting Criteria ....................................................................................63 
8.6.2 Individual Halting Criteria .............................................................................64 
 
Safety Oversight .........................................................................................................64 
8.7.1 Independent Safety Monitor (ISM) ................................................................64 
8.7.2 Safety Monitoring Committee (SMC) ...........................................................64 
 
HUMAN SUBJECTS PROTECTION .................................................................................66 
 
Institutional Review Board/Independent Ethics Committee ......................................66 

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Informed Consent Process ..........................................................................................66 
 
Exclusion of Women, Minorities, and Children (Special Populations) ......................68 
 
Subject Confidentiality ...............................................................................................68 
 
Certificate of Confidentiality ......................................................................................69 
 
Costs, Subject Compensation, and Research Related Injuries ...................................69 
 
STATISTICAL CONSIDERATIONS .................................................................................70 
 Study Hypotheses .......................................................................................................70 
 Sample Size Considerations .......................................................................................70 
 Treatment Assignment Procedures .............................................................................70 
 Final Analysis Plan .....................................................................................................71 
10.4.1 Safety 71 
10.4.2 Pharmacokinetic Analyses .............................................................................72 
10.4.3 Initial Exploratory Analysis ...........................................................................72 
10.4.4 Non-compartmental pharmacokinetic analysis ..............................................72 
10.4.5 Population Pharmacokinetic Analysis ...........................................................72 
10.4.6 Monte Carlo Simulation .................................................................................73 
10.4.7 Exposure-response relationship analysis .......................................................73 
 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ..............74 
 
QUALITY CONTROL AND QUALITY ASSURANCE ...................................................75 
 
DATA HANDLING AND RECORD KEEPING ................................................................76 
 Data Management Responsibilities ............................................................................76 
 Data Coordinating Center/Biostatistician Responsibilities ........................................76 
 Data Capture Methods ................................................................................................76 
 Types of Data ..............................................................................................................77 
 Study Records Retention ............................................................................................77 
 
CLINICAL MONITORING .................................................................................................78 
 
PUBLICATION POLICY ....................................................................................................79 
 
LITERATURE REFERENCES ............................................................................................80 
 
APPENDICES ......................................................................................................................84 
 
Schedule of Events............................................................................85 

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Toxicity Table ...................................................................................87 
 
 

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LIST OF TABLES 
Table 1: Treatment Cohorts (8 subjects/cohort) ............................................................................38 
 
 

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LIST OF FIGURES 
Figure 1: Chemical structure of ceftazidime pentahydrate ............................................................34 
Figure 2: Chemical structure of avibactam sodium .......................................................................34 
Figure 3: Chemical structure of ATM injection ............................................................................35 
 
 
 

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LIST OF ABBREVIATIONS 
α 
Alpha 
AE 
Adverse Event/Adverse Experience 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Transaminase 
AM 
Ante Meridiem 
AST 
Aspartate Aminotransferase 
ARLG 
Antibacterial Resistance Leadership Group 
ATM 
Aztreonam 
AUC 
Area Under the Curve 
AUC(0-Tau) 
Area under the plasma concentration-time curve during the 
dosing interval on Day 1 
AUC0-Tau,ss 
Area under the plasma concentration-time curve during the 
dosing interval at steady state  
AV 
Atrioventricular 
AVI 
Avibactam 
BMI 
Body Mass Index 
BPM 
Beats Per Minute 
BUN 
Blood Urea Nitrogen 
°C 
Degrees Celsius 
Cmax 
Maximum Plasma Concentration 
Css,max 
Maximum Plasma Concentration at Steady State 
Css,max(tss,max) 
Time to Maximum Plasma Concentration at Steady State 
Css,min 
Minimum Plasma Concentration at Steady State 
C(tmax) 
Time to Maximum Plasma Concentration 

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CAZ 
Ceftazidime 
CFR 
Code of Federal Regulations 
CFU 
Colony Forming Unit 
CI 
Continuous Infusion 
cIAI 
Complicated Intraabdominal Infection 
Cl 
Chloride 
CL 
Systemic Plasma Clearance 
cm 
Centimeters 
CRF 
Case Report Form 
CROMS 
Clinical Research Operations and Management Support 
CS 
Clinically Significant 
cUTI 
Complicated Urinary Tract Infection 
DCRI 
Duke Clinical Research Institute 
DEPRU 
Duke Early Phase Research Unit 
DHHS 
Department of Health and Human Services 
dL 
Deciliter  
DMID 
Division of Microbiology and Infectious Diseases, NIAID, 
NIH, DHHS 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ESBL 
Extended-spectrum β-lactamases 
°F 
Degrees Fahrenheit 
FDA 
Food and Drug Administration 
FEV1 
Forced Expiratory Volume in 1 Second 
FWA 
Federal Wide Assurance 
g 
Gram 

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GCP 
Good Clinical Practice 
GNB 
Gram Negative Bacteria 
HBsAg 
Hepatitis B Surface Antigen 
HCO3 
Bicarbonate 
HCV 
Hepatitis C Virus 
hCG 
Human Chorionic Gonadotropin 
HEENT 
Head, Eye, Ear, Nose, Throat 
HFIM 
Hollow Fiber Infection Model 
HLT 
High Level Term 
HIV 
Human Immunodeficiency Virus 
hpf 
High Power Field 
IATA 
International Air Transport Association 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IDS 
Investigational Drug Services 
IEC 
Independent or Institutional Ethics Committee 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
IV 
Intravenous 
K/CUMM 
Liters/mm3 
K 
Potassium 
kg 
Kilogram 
KPC 
Klebsiella pneumoniae Carbapenemase 
L 
Liters 

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LCE 
Leukocyte Esterase 
LDH 
Lactate Dehydrogenase 
LFT 
Liver Function Test 
LLC 
Limited Liability Company 
m2 
Meters Squared 
MBL 
Metallo-β-Lactamase 
MD 
Maryland 
M.D. 
Medical Doctor 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mEq 
Milliequivalent 
mL 
Milliliter 
MM 
Medical Monitor 
mmHg 
Millimeter of Mercury 
MOP 
Manual of Procedures 
msec 
Millisecond 
Na 
Sodium 
NC 
North Carolina 
NCA 
Non-compartmental Analysis 
NCS 
Not Clinically Significant 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH, 
DHHS 
NIH 
National Institutes of Health 
OER 
Office of Extramural Research 
OHRP 
Office of Human Research Protection 

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PD 
Pharmacodynamic 
pH 
Potential of Hydrogen 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PMC 
Pharmacometrics Center 
PR 
Period on ECG extending from beginning of the P wave (the 
onset of atrial depolarization) until the beginning of the QRS 
complex 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
PubMed 
Public/Publisher MEDLINE 
PVC 
Premature Ventricular Contraction 
QA 
Quality Assurance 
QC 
Quality Control 
QT 
Period on ECG extending from the beginning of the QRS 
complex to the end of the T wave 
QTc 
QT interval, corrected for Heart Rate 
QTcF 
QT duration corrected for heart rate by Fridericia’s formula 
RAUC(0-Tau) 
Accumulation ratio for AUC(0-Tau)  
RBC 
Red Blood Cell 
RCmax 
Accumulation ratio for Cmax 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SDCC 
Statistical and Data Coordinating Center 
SMC 
Safety Monitoring Committee 
tmax 
Time for Maximum Concentration of Drug 
U 
Units 

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ULN 
Upper Limit of Normal 
USA 
United States of America 
US 
United States 
USP 
United States Pharmacopeia 
Vss 
Volume of Distribution at Steady-State 
Vz 
Volume of Distribution at the Terminal Phase 
WBC 
White Blood Cell 
w/v 
Weight/Volume 
 
 
 

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PROTOCOL SUMMARY 
Title: 
A Phase I, Open-Label Study in Healthy Adults to Evaluate the 
Safety and Pharmacokinetics of AVYCAZ® in Combination with 
Aztreonam (COMBINE) 
Design of the Study: 
This is a Phase I, open-label, single center study in 48 healthy 
adult male and female subjects to investigate the safety and 
pharmacokinetics of ceftazidime-avibactam (AVYCAZ) 
combined with aztreonam (ATM), AVYCAZ alone, and ATM 
alone. Cohorts 1-4 are the single drug administration treatment 
cohorts and will include AVYCAZ per label dosing, AVYCAZ 
as a continuous infusion (CI), ATM per label dosing, and ATM 
as a CI.  Cohorts 5 and 6 are the two AVYCAZ and ATM 
combination drug administration treatment cohorts.  Study safety 
will be monitored using assessments of adverse events (AE’s), 
vital signs, and clinical laboratory safety tests. Serial blood and 
urine samples will be collected for pharmacokinetic (PK) 
evaluation. 
Study Phase: 
1 
Study Population: 
Forty-eight (48) healthy, adult male and female subjects ages 18-
45.  The study will be conducted in the United States. 
Number of Sites: 
1 
Description of Study 
Product or Intervention: 
Eight (8) subjects/cohort.   
• 
Cohort 1:  AVYCAZ 2.5 g IV as a 2-hour infusion every 
8 hours for 7 days  
• 
Cohort 2:  AVYCAZ 2.5 g IV as a 2-hour infusion x 1, then 
0.32 g per hour IV daily as a CI (7.5 g/day) for 7 days 
• 
Cohort 3:  ATM 2 g IV as a 2-hour infusion every 6 hours for 
7 days 
• 
Cohort 4:  ATM 2 g IV as a 2-hour infusion x 1, then 0.33 g 
per hour IV daily as a CI (8 g/day) for 7 days  

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• 
Cohort 5:  AVYCAZ 2.5 g IV as a 2-hour infusion every 
8 hours for 7 days and ATM 1.5 g IV as a 2-hour infusion 
every 6 hours for 7 days 
• 
Cohort 6:  AVYCAZ 2.5 g IV as a 2-hour infusion every 8 
hours for 7 days and ATM 2 g as a 2-hour infusion every 6 
hours for 7 days 
Study Objectives: 
 
Primary:  
• 
Describe the safety of two dosing regimens of AVYCAZ 
combined with ATM relative to AVYCAZ alone and ATM 
alone in healthy adult subjects. 
Secondary: 
• 
Characterize the PK profiles of two dosing regimens of 
AVYCAZ combined with ATM, AVYCAZ alone, and ATM 
alone at the population level in healthy adult subjects. 
• 
Characterize the PK profiles of two dosing regimens of 
AVYCAZ combined with ATM, AVYCAZ alone, and ATM 
alone following initiation of dosing on Day 1 in healthy adult 
subjects. 
• 
Characterize the PK profiles of two dosing regimens of 
AVYCAZ combined with ATM, AVYCAZ alone, and ATM 
alone following multiple daily dosing in healthy adult 
subjects. 
Exploratory: 
• 
Predict the distribution of plasma concentration-time profiles 
observed with two dosing regimens AVYCAZ combined 
with ATM, AVYCAZ alone, and ATM alone in healthy adult 
subjects via simulations. 
• 
Predict the distribution of cumulative urine amount-time 
profiles observed with two dosing regimens AVYCAZ 
combined with ATM, AVYCAZ alone, and ATM alone in 
healthy adult subjects via simulations. 
• 
Examine the associations between the plasma concentration-
time profiles of AVYCAZ combined with ATM, AVYCAZ 

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alone, and ATM alone and occurrence of ALT or AST 
elevations. 
Duration of Individual 
Subject Participation: 
Up to 44 days (Screening: within 30 days of Day 1 of study 
product administration; study product administration: 7 days; 
outpatient follow-up visit: Day 11 +3 days post Day 1 of study 
product administration). 
Estimated Time to Last 
Subject/Last Study Day: 
The study will run between approximately 12-15 months. 
 
 

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KEY ROLES 
Antibacterial Resistance 
Leadership Group 
(ARLG) Lead Principal 
Investigator: 
Thomas Lodise, PharmD, PhD 
Professor, Pharmacy Practice 
Albany College of Pharmacy and Health Sciences 
Telephone: 1 (518) 694-7292 
Thomas.Lodise@acphs.edu  
ARLG Co-Investigator 
J Nicholas O’Donnell, PharmD, MSc 
Assistant Professor, Pharmacy Practice 
Albany College of Pharmacy and Health Sciences 
Telephone:  1 (518) 694-7203 
Nick.Odonnell@acphs.edu  
ARLG Project Leader 
Smitha Zaharoff, PhD 
Clinical Trials Project Leader 
Duke Clinical Research Institute (DCRI) 
Telephone: 1 (919) 668-8607 
smitha.zaharoff@duke.edu  
Study Site Principal 
Investigator: 
Jeffrey Guptill, M.D 
Associate Professor 
Duke University 
Telephone:  1 (919) 668-6373 
jeffrey.guptill@duke.edu  
Study Site: 
Duke Early Phase Research Unit (DEPRU) 
40 Medicine Circle 
Room 14214, Red Zone, Duke South 
Durham, NC  27710 
 
Debbie Freeman 
Nurse Manager, Operations 
Telephone:  1 (919) 684-1780   
debra.h.freeman@duke.edu  
DMID Clinical Project 
Manager: 
Chidi Obasi, MBBS, PhD 
5601 Fishers Lane, 7E17 
Rockville MD 20852 
Telephone: 1 (301) 761-6899 
chidi.obasi@nih.gov  

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Safety and 
Pharmacovigilance 
Contractor: 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support 
(CROMS) 
6500 Rock Spring Dr., Suite 650 
Bethesda, MD 20817 
SAE Hot Line: 1-800-537-9979 (US) 
SAE Fax: 1-800-275-7619 (US) 
SAE Email: PVG@dmidcroms.com  
Pharmacokinetic Analysis 
Group 
DCRI Pharmacometrics Center 
300 West Morgan Street, Suite 800 
Durham, NC 27701 
DCRI-PMC@duke.edu  
Statistical and Data 
Coordinating Center: 
The Emmes Company 
401 N. Washington St. Suite 700 
Rockville, MD  20850 
Study Agent Repository: 
Duke Investigational Drug Services (IDS) 
Duke University Hospital 
pharmacy-grp_ids@dm.duke.edu  
DMID Clinical Materials 
Services: 
Fisher BioServices  
c/o DMID Clinical Materials Services (CMS) 
20439 Seneca Meadows Parkway 
Germantown, MD 20876 
Telephone: 1 (240) 477-1350 
Fax: 1 (240) 477-1360 
DMID.CMS@ThermoFisher.com 
Laboratory: 
Keystone Bioanalytical, Inc. 
501 Dickerson Rd 
North Wales, PA 19454 

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BACKGROUND AND SCIENTIFIC RATIONALE 
 
Background  
Treatment of patients with serious infections due to highly resistant Gram-negative bacteria 
(GNB) remains problematic and is a major public health concern.  Not only is there increased 
resistance among frequently encountered GNB like Pseudomonas aeruginosa and Klebsiella 
pneumoniae, but there is also a rise in the number of multidrug-resistant strains [1-3].  This 
change is driven in large part by the increasing prevalence and complexity of a variety of β-
lactamases [4]. The most important of these are the extended-spectrum β-lactamases (ESBLs) 
and carbapenemases, such as Klebsiella pneumoniae carbapenemase (KPC) [1,3,4]. The metallo-
β-lactamases (MBLs), which have the ability to hydrolyze all β-lactams except aztreonam 
(ATM), have emerged recently as problematic carbapenemases [5-10].  While there has been an 
impressive drug development response to combat ESBL- and KPC-producing GNB infections, 
none of the recently approved antibiotics have reliable activity against MBL-producing GNB 
[11,12].  Several antibiotics with activity against MBL-producing GNB are being developed, but 
none are anticipated to be available until at least 2021 [11,13]. 
Previous studies have demonstrated that while ATM is not hydrolyzed by MBLs, many MBL-
bearing GNB co-harbor ESBLs that hydrolyze ATM [6,7,9,13,15].  Combination with avibactam 
(AVI), a beta-lactamase inhibitor, protects ATM from hydrolysis by ESBLs and KPCs and 
results in effective killing of bacteria harboring a broad range of beta-lactamase enzymes [5-
8,10,13,15].  The ATM-AVI combination is currently being tested in clinical trials; however, it 
will be several years before this new treatment option will be considered for approval by the 
Food and Drug Administration (FDA) for treating patients infected with MBL-producing GNB.   
This underscores the exigency of redeploying our existing agents in innovative ways to meet the 
needs of patients today [14]. 
One strategy that may serve as a “bridge” treatment for MBL-producing GNB infections is 
ceftazidime-avibactam (AVYCAZ®) combined with ATM [5,13,16,17].  In the combination of 
ATM with AVYCAZ, AVI inhibits the ESBL and KPC beta-lactamases that are often present in 
MBL-producing GNB, allowing ATM, which is unaffected by MBLs, to effectively bind to 
bacterial penicillin binding proteins.  Limited data to date suggest that AVYCAZ combined with 
ATM is a promising treatment for patients with MBL-producing GNB infections [5,10,13,17].  
In a MBL-producing K. pneumoniae time-kill assay, AVYCAZ combined with ATM resulted in 
a ≥ 3-log10-colony forming unit (CFU)/mL decrease compared to AVYCAZ alone [13].  In a 
murine neutropenic thigh infection model with the same strain, an almost 4-log10-CFU/mL 
greater reduction was noted with AVYCAZ combined with ATM vs. AVYCAZ alone [13].  
Although the precise mechanism of improved bacterial killing activity with AVYCAZ combined 
with ATM is not completely understood, it is likely attributable to maximal saturation of the 

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diverse penicillin binding proteins present in GNB, flooding of periplasm with β-lactams, and 
maximal binding of available β-lactamases [5,14]. 
The combination of AVYCAZ with ATM has been employed clinically.  To date, four published 
case reports have documented successful use of this combination in 14 patients with serious 
infections due to MBL-producing GNB [5,13,16,17]. Patients have received this combination for 
infections due to MBL-bearing strains of Klebsiella pneumoniae, Enterobacter cloacae, 
Pseudomonas aeruginosa, and Stenotrophomonas maltophilia.  While there are theoretical safety 
concerns with dual beta-lactam use, no adverse events (AEs) were attributed to receipt of 
AVYCAZ combined with ATM across the published patient reports [5,13,14, 16,17].  This is 
notable as at least two of the patients described in these case reports received AVYCAZ 
combined with ATM for greater than one month [13,17]. 
Although AVYCAZ combined with ATM has been shown to be efficacious against MBL-
producing GNB in pre-clinical studies and clinical case reports, optimal dosing remains 
unknown. Hollow fiber infection model (HFIM) studies using E. coli ARLG-1013 (blaNDM-1, 
blaCTX-M, blaCMY, blaTEM) and K. pneumoniae ARLG-1002 (blaNDM-1, blaCTXM-15, blaDHA, blaSHV, 
blaTEM were conducted to identify AVYCAZ combined with ATM regimens that result in 
maximal bacterial kill and resistance suppression [23].  In these HFIM experiments, a number of 
FDA-approved ATM 6-8 grams (g)/day regimens were evaluated in combination with FDA-
approved AVYCAZ dosing (2.5 g IV as a 2-hour infusion every 8 hours) and continuous 
infusion (CI) AVYCAZ (7.5 g IV daily) [18,19].  It was anticipated that administration of 
AVYCAZ as a CI combined with ATM would outperform FDA-approved AVYCAZ dosing 
combined with ATM.  Continuous infusion administration maximizes the pharmacokinetics/ 
pharmacodynamics (PK/PD) of AVYCAZ and it was anticipated that this would result in 
enhanced bacterial killing and resistance suppression [20-22]. Since it is not practical for all 
institutions to infuse AVYCAZ as a CI, HFIM experiments were also conducted to identify the 
optimal dosing of AVYCAZ combined with ATM using FDA-approved dosing regimens of each 
antibiotic. In these HFIM experiments, maximal daily dose of AVYCAZ combined with 8g/day 
ATM regimens were found to be optimal.  Specifically, the two combination regimens that 
showed maximal bacterial killing and resistance suppression over 7 days were: 
• 
AVYCAZ 2.5 g IV as a 2-hour infusion every 8 hours combined with ATM 2 g IV as a 2-
hour infusion every six hours, and 
• 
AVYCAZ combined with ATM, each administered as a CI (AVYCAZ 7.5 g/day CI 
combined with ATM 8g/day CI) [23]. 
While the initial intent was to examine the two optimal AVYCAZ with ATM regimens identified 
in the HFIM experiments, two subjects who received ATM 8g/day CI alone in cohort 4 
experienced grade 3 AST/ALT elevations.  Despite having AST/ALT elevations >10 ULN, the 
two subjects were asymptomatic and there were no clinical findings suggestive of liver necrosis 

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or jaundice.  There were also no elevations in ALP and bilirubin and there were no clinically 
significant elevations in all other serum chemistries and blood counts.  The two subjects’ in 
cohort 4 continued to experience elevations in AST/ALT for 1 to 2 days after discontinuation of 
ATM but the AST/ALT values then trended down 2 to 4 days after study product 
discontinuation.  For both subjects, AST/ALT values returned to baseline within 25 days after 
discontinuation of ATM.  Please note that for both subjects, daily AST/ALT monitoring was not 
performed as subjects had been discharged from the study unit and only returned for two 
additional AE follow up visits 5-9 and 25 days after discontinuation of ATM.          
Asymptomatic serum aminotransferase elevations are common during high dose, intravenous 
ATM therapy (10% to 38%) [24].  Liver enzyme elevations occur slightly more commonly 
during aztreonam therapy than with other comparative antibiotics. As observed in the two 
subjects in cohort 4 with grade 3 AST/ALT elevations, aztreonam induced liver injury appears to 
be transient, mild and asymptomatic, marked only by serum enzyme elevations. Data indicate 
that aztreonam is an unlikely cause of clinically apparent liver injury (likelihood score of E) and 
no individual case of frank liver injury and jaundice attributable to aztreonam have been 
reported.   
In response to the occurrence of two grade 3 AEs that were related to study product and of the 
same type [High Level Term (HLT)], the study was halted and a Safety Monitoring Committee 
(SMC) meeting was convened.  The SMC recommended to continue the study but reduce the 
dose of ATM in cohort 5 to ATM 1.5 g IV as a 2-hour infusion every 6 hours (ATM 6 g/daily) 
and to administer it in combination with AVYCAZ 2.5 g IV as a 2-hour infusion every 8 hours.    
The HFIM study indicated that this was an effective combination regimen and SMC 
recommended administering it in cohort 5.  Furthermore, the SMC recommended that a SMC 
meeting be convened after completion of cohort 5.  If no halting rules are met and there are no 
other safety concerns, the SMC recommended administering ATM 2 g IV as a 2-hour infusion 
every 6 hours (ATM 8 g/daily) in combination with AVYCAZ 2.5 g IV as a 2-hour infusion 
every 8 hours in cohort 6.  The SMC was in favor of escalating the ATM dose in cohort 6 if no 
halting rules are met as the HFIM experiments showed increased bacterial killing with 8 g/day vs 
6 g/day combination regimens.  Since the safety of ATM CI was not established in this study, the 
SMC was opposed to administering ATM as a CI in any subsequent cohorts.  As an additional 
safeguard, the SMC also recommended that more intensive Liver Function Test (LFT) 
monitoring be performed.    
 
Scientific Rationale 
2.2.1 Purpose of Study 
Before uniform adoption of AVYCAZ with ATM combination regimens that were found to be 
effective in the aforementioned HFIM studies into clinical practice, it is important to establish 

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the safety and PK of these regimens in humans [23]. This is critically important as two subjects 
in the ATM 8g/daily CI treatment cohort (cohort 4) experienced asymptomatic grade 3 
AST/ALT elevations.  Therefore, this phase 1 study in healthy adults will evaluate the safety and 
PK of AVYCAZ combined with ATM.  AVYCAZ and ATM are both currently approved as 
standalone products for the treatment of patients with various infections due to GNB. Both 
antibiotics are generally safe and well-tolerated, although mild-to-moderate asymptomatic serum 
aminotransferase elevations are common with ATM [18, 19, 24].  These elevations are usually 
self-limiting and do not require ATM discontinuation [18, 24].  Although AVYCAZ and ATM 
appear to be safe and well-tolerated, there are no available data on safety when these antibiotics 
are used in combination. It is unclear if AVYCAZ combined with ATM will further exacerbate 
liver enzyme elevations or lead to other AEs due to the potential of cumulative toxicity from 
dual-β-lactam treatment [14].  There are also no published PK data of these antibiotics when 
administered concurrently, and it is therefore unknown if use of these agents in combination will 
lead to an altered PK profile of each agent due to inhibition of renal or other compensatory 
clearance mechanisms. Therefore, it is important to assess the safety and pharmacokinetic profile 
of AVYCAZ combined with ATM relative to its standalone counterparts before widespread 
adoption into clinical practice.   
2.2.2 Study Population 
The study will be conducted using healthy volunteers to observe the safety and PK of 
combination regimens of AVYCAZ with ATM that were found to be effective in previous HFIM 
experiments [23].  Safety and PK of combination regimes will be compared to the AVYCAZ and 
ATM dosing regimens given alone [23].  This is a single center study being conducted in the 
United States.  The study site will determine the most efficient procedures to identify potentially 
eligible subjects from the general public for the study.  Women of child-bearing potential will 
not be excluded from the study.  In addition, special populations, e.g., non-English speakers, 
illiterate or non-writing individuals will not be excluded from this study. 
Children and vulnerable populations will be excluded from this study as there is insufficient 
safety data and this is the first time AVYCAZ combined with ATM will be administered in a 
systematic manner and as there is insufficient safety data to support the inclusion of these 
vulnerable populations. 
 
Potential Risks and Benefits 
AVYCAZ and ATM are both currently FDA-approved and the package inserts are the primary 
source of risk information for AVYCAZ and ATM [18,19]. 

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2.3.1 Potential Risks 
2.3.1.1 AVYCAZ 
Hypersensitivity Reactions:  Serious and occasionally fatal hypersensitivity (anaphylactic) 
reactions and serious skin reactions have been reported in patients receiving beta-lactam 
antibacterial drugs.  Before therapy with AVYCAZ is instituted, careful inquiry about previous 
hypersensitivity reactions to other cephalosporins, penicillins, or carbapenems should be made.  
Exercise caution if this product is to be given to a penicillin or other beta-lactam-allergic patient 
because cross-sensitivity among beta-lactam antibacterial drugs has been established.  
Discontinue the drug if an allergic reaction to AVYCAZ occurs. 
Clostridium difficle-Associated Diarrhea: Clostridium difficile-associated diarrhea has been 
reported for nearly all antibiotics, including AVYCAZ, and may range in severity from mild 
diarrhea to fatal colitis.  The diarrhea may start during or after the AVYCAZ is administered.  
C. difficle occurs naturally in the colon.  Treatment with antibiotic drugs alters the normal flora 
(microorganisms that live in the colon) and may permit overgrowth of C. difficle. 
Central Nervous System Reactions:  Seizures, non-convulsive status epilepticus, encephalopathy, 
coma, asterixis, neuromuscular excitability, and myoclonia have been reported in patients treated 
with ceftazidime, particularly in the setting of renal impairment.  
Nervous System:  headache, dizziness 
Gastrointestinal:  abdominal pain, nausea, vomiting, diarrhea 
The following selected adverse reactions were reported in AVYCAZ treated patients at a rate of 
less than 1% in the Phase 3 clinical trials and are not described elsewhere in the labeling. 
• 
Blood and lymphatic disorders - thrombocytopenia 
• 
General disorders and administration site conditions - injection site phlebitis 
• 
Infections and infestations - candidiasis 
• 
Investigations - increased aspartate aminotransferase (AST), increased alanine 
aminotransferase (ALT), increased gamma-glutamyltransferase 
• 
Metabolism and nutrition disorders - hypokalemia 
• 
Nervous system disorders - dysgeusia 
• 
Renal and urinary disorders - acute renal failure, renal impairment, nephrolithiasis 
• 
Skin and subcutaneous tissue disorders - rash, rash maculo-papular, urticaria, pruritus 
• 
Psychiatric disorders - anxiety 

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Additionally, adverse reactions reported with ceftazidime alone that were not reported in 
AVYCAZ treated patients in the Phase 3 clinical trials are listed below: 
• 
Blood and lymphatic disorders - agranulocytosis, hemolytic anemia, leukopenia, 
lymphocytosis, neutropenia, thrombocytosis, eosinophilia 
• 
General disorders and administration site conditions - infusion site inflammation, injection 
site hematoma, injection site thrombosis 
• 
Hepatobiliary disorders - jaundice 
• 
Investigations - increased blood lactate dehydrogenase, prolonged prothrombin time (PT) 
• 
Nervous system disorders - paresthesia 
• 
Renal and urinary disorders - tubulointerstitial nephritis 
• 
Reproductive and breast disorders - vaginal inflammation 
• 
Skin and subcutaneous tissue disorders - angioedema, erythema multiforme, Stevens-Johnson 
syndrome, toxic epidermal necrolysis 
Laboratory Changes:  Seroconversion from a negative to a positive direct Coombs test result at 
any time up to the last visit occurred in 31/240 (12.9%) of patients receiving AVYCAZ plus 
metronidazole with initial negative Coombs test and at least one follow-up test and in 7/235 
(3.0%) of patients receiving meropenem in the Phase 3 cIAI trial. 
Seroconversion from a negative to a positive direct Coombs test result at any time up to the last 
visit occurred in 7/216 (3.2%) of patients receiving AVYCAZ with initial negative Coombs test 
and at least one follow-up test and 2/214 (0.9%) of patients receiving doripenem in the Phase 3 
cUTI trial. No adverse reactions representing hemolytic anemia were reported in any treatment 
group. 
Ceftazidime is excreted in human milk in low concentrations. It is not known whether AVI is 
excreted into human milk, although AVI was shown to be excreted in the milk of rats. No 
information is available on the effects of CAZ and AVI on the breast-fed child or on milk 
production. 
2.3.1.2 Aztreonam  
Asymptomatic serum aminotransferase elevations have been reported with ATM therapy (10% 
to 38%) [24].  The enzyme abnormalities are usually mild-to-moderate, asymptomatic, self-
limited and not requiring drug discontinuation.  Instances of marked aminotransferase elevations 
within 3 to 5 days of starting ATM have been reported, but these cases were without jaundice 
and resolved over time once the drug was stopped.  ATM is an unlikely cause of clinically 

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apparent liver injury and no individual cases of frank liver injury and jaundice attributable to 
ATM have been reported. 
Local reactions such as phlebitis/thrombophlebitis following intravenous (IV) administration; 
and discomfort/swelling at the injection site following intramuscular administration occurred at 
rates of approximately 1.9% and 2.4% respectively. 
Systemic reactions (considered to be related to therapy or of uncertain etiology) occurring at an 
incidence of 1% to 1.3% include diarrhea, nausea and/or vomiting, and rash.  Reactions 
occurring at an incidence of less than 1% are listed within each body system in order of 
decreasing severity: 
• 
Hypersensitivity - anaphylaxis, angioedema, bronchospasm 
• 
Renal - Prolonged serum levels of ATM may occur in patients with transient or persistent 
renal insufficiency. 
• 
Hematologic - pancytopenia, neutropenia, thrombocytopenia, anemia, eosinophilia, 
leukocytosis, thrombocytosis 
• 
Gastrointestinal - abdominal cramps; rare cases of Clostridium difficile-associated diarrhea, 
including pseudomembranous colitis, or gastrointestinal bleeding have been reported.   
• 
Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment. 
• 
Dermatologic - toxic epidermal necrolysis, purpura, erythema multiforme, exfoliative 
dermatitis, urticaria, petechiae, pruritus, diaphoresis 
• 
Cardiovascular - hypotension, transient electrocardiogram (ECG) changes (ventricular 
bigeminy and premature ventricular contraction (PVC), flushing 
• 
Respiratory - wheezing, dyspnea, chest pain 
• 
Hepatobiliary - hepatitis, jaundice 
• 
Nervous System - seizure, confusion, vertigo, paresthesia, insomnia, dizziness 
• 
Musculoskeletal - muscular aches 
• 
Special Senses - tinnitus, diplopia, mouth ulcer, altered taste, numb tongue, sneezing, nasal 
congestion, halitosis 
• 
Other - vaginal candidiasis, vaginitis, breast tenderness 
• 
Body as a Whole - weakness, headache, fever, malaise 

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Laboratory Changes:  Adverse laboratory changes without regard to drug relationship that were 
reported during clinical trials were: 
• 
Hepatic - elevations of AST, Serum Glutamic Oxaloacetic Transaminase, ALT, Serum 
Glutamic-Pyruvic Transaminase, and alkaline phosphatase (ALP); signs or symptoms of 
hepatobiliary dysfunction occurred in less than 1% of recipients 
• 
Hematologic - increases in prothrombin and partial thromboplastin times, positive Coombs 
test. 
• 
Renal - increases in serum creatinine. 
In pregnant women, ATM crosses the placenta and enters the fetal circulation.  ATM is excreted 
in human milk in concentrations that are less than 1% of concentrations determined in 
simultaneously obtained maternal serum. 
2.3.1.3 AVYCAZ Combined with ATM 
The risks associated with AVYCAZ combined with ATM are expected to be similar to those 
associated with AVYCAZ alone and ATM alone.  However, there is a theoretical risk for 
increased adverse reactions with AVYCAZ combined with ATM relative to that observed with 
receipt of AVYCAZ alone and ATM alone due to the potential of cumulative or additive toxicity 
from receiving two beta-lactams simultaneously relative to receiving just one beta-lactam [14].  
To date, published reports have described the use of AVYCAZ combined with ATM in 14 
patients [5,13,16,17].  No adverse reactions were attributed to receipt of AVYCAZ combined 
with ATM in these reports.  Four of the 14 patients (28.6%) were reported to have died but none 
of the deaths were considered related to the patient’s infection or receipt of the AVYCAZ 
combined with ATM. 
2.3.1.4 Risks of Drawing Blood and Intravenous Infusions 
Risks associated with drawing blood from the subjects’ arm or administering IV fluids include 
momentary discomfort and/or bruising.  Infection, excess bleeding, clotting, or fainting are also 
possible, although unlikely. 
2.3.2 Potential Benefits 
There are no benefits to healthy subjects for their inclusion in this protocol.  However, data from 
this study may be helpful in determining safe treatment doses in patients with serious antibiotic 
resistant GNB infections. 

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STUDY DESIGN, OBJECTIVES AND ENDPOINTS OR 
OUTCOME MEASURES 
 
Study Design Description 
This is a Phase I, open-label, single center study in 48 healthy adult male and female subjects age 
18-45 years old (6 cohorts of 8 subjects) to investigate the safety and PK of AVYCAZ combined 
with ATM, AVYCAZ alone, and ATM alone. 
Following subject screening, eligible subjects will be assigned into one of the dosing cohorts. 
Subjects will be admitted to the study site on Day -1 for evaluations to confirm they continue to 
meet eligibility criteria, after which they will be admitted to the study site for dosing and 
observation.  Subjects will stay for a minimum of 7 nights and 8 days.  Cohorts 1-4 will be 
completed prior to Cohorts 5 and 6. 
Six dosing cohorts will be evaluated (see Section 4.3).  Four treatment cohorts are single agent 
dosing cohorts and will include AVYCAZ per label dosing, AVYCAZ as a CI, ATM per label 
dosing, and ATM as a CI.  Single drug treatment cohorts are being conducted to collect baseline 
safety and pharmacokinetic data.  The remaining two cohorts are two AVYCAZ combined with 
ATM regimens that were found to be effective in the aforementioned HFIM studies (see 
Section 2.1).  In the treatment cohorts in which the antibiotics are administered as a CI, an initial 
loading dose will be administered prior to starting the CI.  Since the maximum concentration of 
antibiotic (Cmax) is lower and the time for maximum concentration of drug (tmax) is delayed with 
CI, the initial loading dose is included to shorten the time it takes to achieve critical PK/PD 
associated with maximal response [20,25,26].  The use of initial loading doses is also congruent 
with clinical practice guideline recommendations to use PK/PD data to optimize dosing early in 
the course of therapy for patients with serious, life threatening infections [27, 28]. 
Study safety will be closely monitored using daily assessments of AE’s, vital signs and clinical 
laboratory safety tests.  Clinical laboratory safety tests will be collected on Day -1, Days 2, 4, 6 
and Day 8 (prior to discharge from the study site).  LFTs will be obtained daily beginning on 
Day 4 until a subject completes dosing.  The Final Visit (Day 11 + 3) will be scheduled with 
each subject for a final safety evaluation and collection of clinical laboratory safety tests. 
Plasma and urine concentrations of AVYCAZ and ATM will be quantified, when each antibiotic 
is given alone (AVYCAZ or ATM), and in combination (AVYCAZ combined with ATM) 
following the first dose and after multiple administrations.   
 
The study will run between approximately 12-15 months. 

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Study Objectives 
3.2.1 Primary 
• 
Describe the safety of two dosing regimens of AVYCAZ combined with ATM relative to 
AVYCAZ alone, and ATM alone in healthy adult subjects. 
3.2.2 Secondary 
• 
Characterize the PK profiles of two dosing regimens of AVYCAZ combined with ATM, 
AVYCAZ alone, and ATM alone at the population level in healthy adult subjects. 
• 
Characterize the PK profiles of two dosing regimens of AVYCAZ combined with ATM, 
AVYCAZ alone, and ATM alone following initiation of dosing on day 1 in healthy adult 
subjects. 
• 
Characterize the PK profiles of two dosing regimens of AVYCAZ combined with ATM, 
AVYCAZ alone, and ATM alone following multiple daily dosing in healthy adult subjects. 
3.2.3 Exploratory  
• 
Predict the distribution of plasma concentration-time profiles observed with two dosing 
regimens AVYCAZ combined with ATM, AVYCAZ alone, and ATM alone in healthy adult 
subjects via simulations. 
• 
Predict the distribution of urine cumulative urine amount-time profiles observed with two 
dosing regimens AVYCAZ combined with ATM, AVYCAZ alone, and ATM alone in 
healthy adult subjects via simulations. 
• 
Examine the associations between the plasma concentration-time profiles of AVYCAZ 
combined with ATM, AVYCAZ alone, and ATM alone and occurrence of ALT or AST 
elevations. 
 
Study Endpoints or Outcome Measures 
3.3.1 Primary  
• 
Number of subjects in each treatment cohort with at least one Grade 2 or higher treatment-
emergent AE from first dose through follow-up period. 
3.3.2 Secondary  
• 
Incidence and severity of all treatment-emergent AEs in each treatment cohort from first dose 
through follow-up period. 

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• 
Population mean PK parameter estimates and the magnitude of the associated 
inter-individual variability for AVYCAZ and ATM, when given alone and in combination. 
• 
Individual post-hoc PK parameter estimates and calculated exposure measures in plasma for 
AVYCAZ and ATM, when given alone and in combination following initial dosing on  
Day 1. 
• 
Individual post-hoc PK parameters estimates and calculated exposure measures in urine for 
AVYCAZ and ATM, when given alone and in combination following initial dosing on  
Day 1. 
• 
Individual post-hoc PK parameter estimates and calculated exposure measures in plasma for 
AVYCAZ and ATM, when given alone and in combination following multiple daily dosing. 
• 
Individual post-hoc PK parameters estimates and calculated exposure measures in urine for 
AVYCAZ and ATM, when given alone and in combination following multiple daily dosing.  
3.3.3 Exploratory  
• 
Distribution of simulated plasma concentration-time profiles associated with each treatment 
cohort. 
• 
Distribution of simulated urine concentration-time profiles associated with each treatment 
cohort. 
• 
Occurrence of ALT or AST elevations ≥ 3 times upper limit of normal (ULN) from first dose 
of study product through follow-up period. 
• 
Occurrence of ALT or AST elevations ≥ 5 times ULN from first dose of study product 
through follow-up period. 
• 
Changes in ALT or AST from first dose of study product through follow-up period. 

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STUDY INTERVENTION/STUDY PRODUCT 
 
Study Product Description 
AVYCAZ: 
AVYCAZ is an antibacterial combination product for intravenous administration consisting of 
the semisynthetic cephalosporin ceftazidime pentahydrate and the beta-lactamase inhibitor 
avibactam sodium at a fixed ratio of 4:1 [19]. 
• 
Ceftazidime 
Ceftazidime is a semisynthetic, beta-lactam antibacterial drug. It is the pentahydrate of 
(6R,7R,Z)-7-(2-(2-aminothiazol-4-yl)-2-(2-carboxypropan-2-yloxyimino)acetamido)-8-oxo-3-
(pyridinium-1-ylmethyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate.  Its molecular 
weight is 636.6.  The empirical formula is C22H32N6O12S2. 
Figure 1: Chemical Structure of Ceftazidime Pentahydrate 
 
• 
Avibactam 
Avibactam sodium chemical name is sodium [(2S,5R)-2-carbamoyl-7-oxo-1,6-
diazabicyclo[3.2.1]octan-6-yl] sulfate.  Its molecular weight is 287.23. The empirical formula is 
C7H10N3O6SNa. 
Figure 2: Chemical Structure of Avibactam Sodium 
 

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AZACTAM® (aztreonam for injection, USP): 
AZACTAM® (aztreonam for injection, USP) injection contains the active ingredient ATM, a 
monobactam. It was originally isolated from Chromobacterium violaceum. It is a synthetic 
bactericidal antibiotic [18]. 
The monobactams, having a unique monocyclic beta-lactam nucleus, are structurally different 
from other beta-lactam antibiotics (e.g., penicillins, cephalosporins, cephamycins). The sulfonic 
acid substituent in the 1-position of the ring activates the beta-lactam moiety; an aminothiazolyl 
oxime side chain in the 3-position and a methyl group in the 4-position confer the specific 
antibacterial spectrum and beta-lactamase stability. Aztreonam is designated chemically as (Z)-
2-[[[(2-amino-4-thiazolyl)[[(2S,3S)-2-methyl-4-oxo-1-sulfo-3-
azetidinyl]carbamoyl]methylene]amino]oxy]-2-methylpropionic acid. 
Figure 3: Chemical Structure of ATM Injection 
 
4.1.1 Formulation, Packaging, and Labeling 
AVYCAZ (ceftazidime-avibactam) 
AVYCAZ 2.5 grams (2 grams ceftazidime and 0.5 grams avibactam) for injection is a white to 
yellow sterile powder for constitution consisting of ceftazidime pentahydrate and avibactam 
sodium packaged in glass vials.  The formulation also contains sodium carbonate [19]. 
Each AVYCAZ 2.5 grams single-dose vial contains ceftazidime 2 grams (equivalent to 2.635 
grams sterile ceftazidime pentahydrate/sodium carbonate) and avibactam 0.5 grams (equivalent 
to 0.551 grams sterile avibactam sodium). The sodium carbonate content of the mixture is 239.6 
mg/vial.  The total sodium content of the mixture is approximately 146 mg (6.4 mEq)/vial. 
AZACTAM® (aztreonam for injection, USP) 
AZACTAM (aztreonam for injection, USP) is a sterile, non-pyrogenic, sodium-free, white 
powder containing approximately 780 mg arginine per gram of ATM.  Following constitution, 
the product is for intramuscular or intravenous use.  Aqueous solutions of the product have a pH 
in the range of 4.5 to 7.5.   

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The study product vials will be labeled according to manufacturer or regulatory specifications.  
The dispensed study product (IV bags) will be labeled with the cautionary statement “For 
Investigational Use Only.” 
4.1.2 Product Storage and Stability 
AVYCAZ (ceftazidime-avibactam) 
Storage of AVYCAZ vials: 
• 
AVYCAZ vials should be stored at 20° to 25°C (68° to 77°F); excursions permitted between 
15°C and 30°C (59°F and 86°F) [See USP Controlled Room Temperature]. Protect from 
light. Store in carton until time of use [19]. 
Stability of AVYCAZ: 
• 
Upon constitution with appropriate diluent, the constituted AVYCAZ solution may be held at 
room temperature for no longer than 30 minutes prior to transfer and dilution in a suitable 
infusion bag. 
• 
Following dilution of the constituted solutions with the appropriate diluents, AVYCAZ 
solutions in the infusion bags are stable for 12 hours when stored at room temperature. 
• 
Following dilution of the constituted solutions with the appropriate diluents, AVYCAZ 
solutions in the infusion bags may also be refrigerated at 2 to 8°C (36 to 46°F) for up to 
24 hours; and then should be used within 12 hours of subsequent storage at room 
temperature. 
AZACTAM® (aztreonam for injection, USP): 
Storage of AZACTAM® (aztreonam for injection, USP): 
• 
Store AZACTAM® vials in original packages at room temperature; avoid excessive heat 
(above 40°C (104° F)). 
Stability of Intravenous AZACTAM®: 
• 
AZACTAM solutions for intravenous infusion at concentrations not exceeding 2% weight/ 
volume (w/v) must be used within 48 hours following constitution if kept at controlled room 
temperature 15° to 30°C (59° to 86°F) or within 7 days if refrigerated (2° to 8°C/ 36° to 
46°F). 

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Acquisition/Distribution 
AVYCAZ (ceftazidime-avibactam) 
AVYCAZ vials manufactured by Allergan will be purchased by the study site’s Investigational 
Pharmacy. 
AZACTAM® (aztreonam for injection, USP): 
AZACTAM® vials manufactured by Bristol-Myers Squibb will be obtained by the DMID 
Clinical Materials Services (CMS) and shipped to the following address at Fisher BioServices 
for storage and site distribution: 
DMID-CMS 
20439 Seneca Meadows Parkway 
Germantown, MD 20876 
Tel: 1 (240) 477-1350 
Fax: 1 (240) 477-1360 
E-mail: DMID.CMS@ThermoFisher.com 
AZACTAM® will be shipped to Duke IDS upon request by the study site and approval by 
DMID. 
Sterile Water for Injection (WFI), USP 
The sterile water for injection (WFI), USP is nonpyrogenic and contains no bacteriostatic, 
antimicrobial agent, or added buffer.  Each gram of ATM should be initially reconstituted with at 
least 3 mL WFI, USP.  Single-dose container WFI will be purchased by the study sites 
Investigational Pharmacy. 
0.9% Sodium Chloride, USP (Normal Saline) 
0.9% Sodium Chloride Injection, USP is a sterile, nonpyrogenic, isotonic solution of sodium 
chloride and water for injection.  Each mL contains 9 mg of sodium chloride and contains no 
preservatives, bacteriostatic, antimicrobial agent, or added buffer.  The solution is clear in 
appearance and may contain hydrochloric acid and/or sodium hydroxide for pH adjustment (pH 
5.3 [4.5 to 7.0]).  Normal saline in single use and IV bags will be purchased by the 
Investigational Pharmacy for dilution of AVYCAZ, preparation of IV administration bags for 
both study products and flushing of IV lines.  The appropriate size IV bag will be determined by 
the Investigational Pharmacy to ensure the correct amount of study product is being infused. 

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Dosage/Regimen, Preparation, Dispensing and Administration of Study 
Intervention/Study Product 
Both AVYCAZ and ATM will be prepared in separate IV bags according to the products’ IV 
infusion directions in the package insert. Complete instructions for dosage, preparation, labeling, 
storage, stability, and administration is detailed in protocol-specific Manual of Procedures 
(MOP).  Dosing will be completed the morning of Day 7 for all cohorts. 
For cohorts 5 and 6, both drugs will be administered either via a double lumen catheter 
connected to separate ports, or via a single lumen Y-site injection port.  Stability data in both the 
AVYCAZ and ATM package insert and protocol-specific Y-site stability studies support CI 
administration outlined in Table 1. 
The infusion times listed in the table below are approximate (refer to the MOP for infusion time 
windows).  Dose modifications will not be permitted. 
Table 1: Treatment Cohorts (8 subjects/cohort) 
Cohort 1: 
AVYCAZ 2.5 g IV as a 2-hour infusion every 8 hours for 7 days  
(19 total doses) 
Cohort 2: 
AVYCAZ 2.5 g IV as a 2-hour infusion x 1, then 0.32 g per hour IV daily as a 
CI (7.5 g/day) for 7 days (20 total doses, IV bag changes every 8 hours for CI) 
Cohort 3: 
ATM 2 g IV as a 2-hour infusion every 6 hours for 7 days  
(25 total doses) 
Cohort 4: 
ATM 2 g IV as a 2-hour infusion x 1, then 0.33 g per hour IV daily as a CI 
(8 g/day) for 7 days (14 total doses, IV bag changes every 12 hours for CI) 
Cohort 5: 
AVYCAZ 2.5 g IV as a 2-hour infusion every 8 hours for 7 days and ATM 
1.5 g IV as a 2-hour infusion every 6 hours for 7 days  
(AVYCAZ 19 total doses; ATM 25 total doses) 
Cohort 6*: 
AVYCAZ 2.5 g IV as a 2-hour infusion  every 8 hours for 7 days and ATM 2 g 
IV as a 2-hour infusion  every 6 hours for 7 days  
(AVYCAZ 19 total doses; ATM 25 total doses) 
*A SMC meeting will be convened after completion of cohort 5 to assess whether the study may 
proceed to cohort 6.   
 
 

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Accountability Procedures for the Study Intervention/Study Product(s) 
AVYCAZ will be purchased by the study site’s Investigational Pharmacy. ATM will be obtained 
by the DMID CMS and shipped to Duke IDS upon request by the study site and approval by 
DMID. Once received, AVYCAZ and ATM will be stored in and dispensed by the 
Investigational Pharmacy. Unused product will be destroyed and documented per institutional 
procedures. 
The FDA requires accounting for the disposition of all study products. The Investigator is 
responsible for ensuring that a current record of product disposition is maintained and product is 
dispensed only at an official study site by authorized personnel as required by applicable 
regulations and guidelines. Records of study product disposition, as required by federal law, 
consist of the date received at the Investigational Pharmacy, lot number(s), each subject assigned 
study number, date, lot number(s) and quantity administered to each subject and final disposition 
for unused study product.  
The Investigational Pharmacist will be responsible for maintaining accurate records of the 
shipment and dispensing of the study product. The pharmacy records must be available for 
inspection by the Division of Microbiology and Infectious Diseases (DMID) monitoring 
contractors and is subject to inspection by a regulatory agency (e.g., FDA) at any time. An 
assigned Study Monitor will review the pharmacy records. 

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SELECTION OF SUBJECTS AND STUDY ENROLLMENT 
AND WITHDRAWAL 
Subject inclusion and exclusion criteria must be confirmed by a study clinician licensed to make 
medical diagnoses. 
No exemptions are granted on subject Inclusion/Exclusion Criteria in DMID-sponsored studies. 
Questions about eligibility will be directed toward the DMID Medical Officer. 
The study site will determine the most efficient procedures to identify potentially eligible 
subjects from the general public for the study.   
 
Eligibility Criteria 
5.1.1 Subject Inclusion Criteria 
A subject must meet all the following criteria to be considered eligible for inclusion in this study: 
1. Provide a signed and dated written informed consent. 
2. Be able to understand and willing to comply with study procedures, restrictions, and 
requirements, as determined by the Principal Investigator (PI). 
3. Male and female volunteers aged 18 to 45 years inclusive.  
4. Suitable veins for cannulation or repeated venipuncture. 
5. Subject must be in good general health as judged by the investigator as determined by 
medical history, vital signs1, body mass index (BMI) and body weight2, clinical laboratory 
values3, and physical examination (PE). 
 
1 Oral temp <38.0°C/100.4°F; pulse 50 to 100 bpm; systolic blood pressure 90 to 140 mm Hg, and diastolic blood 
pressure 55 to 90 mmHg. 
2 BMI between 19-33 kg/m2 and body weight ≥ 50 kg 
3 Clinical chemistry, hematology, coagulation and urinalysis results within the clinical laboratory reference ranges; 
clinical laboratory values outside these ranges, if considered by the site investigator to be clinically insignificant, are 
also acceptable 

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6. Sexually active female subjects must be of non-childbearing potential4 or must use a highly 
effective method of birth control5. 
7. Sexually active male subjects must be vasectomized or agree to use barrier contraception 
(condom with spermicide) from first dose of study product until 30 days following the last 
dose of study product. 
8. Nonsmokers defined as abstinence from cigarette smoking or use of nicotine-containing 
products for 6 months prior to enrollment into the study. 
5.1.2 Subject Exclusion Criteria 
A subject must not meet any of the following criteria to be considered eligible for inclusion in 
this study: 
1. History of any clinically significant (CS) disease or disorder, medical/surgical procedure, or 
trauma within 4 weeks prior to the first administration of study product(s)6. 
2. History or presence of gastrointestinal, hepatic, or renal disease, or any other condition 
known to interfere with absorption, distribution, metabolism, or excretion of drugs. 
3. Known history of a clinically important allergy/hypersensitivity to AVI, any monobactam, 
any beta-lactam and/or L-arginine. 
4. Receipt of probenecid or furosemide within 14 days prior to study enrollment 
5. Receipt of any antibiotics within 14 days prior to study enrollment. 
6. Receipt of prescription medications (except birth control pills or hormone replacement in 
females) within 14 days prior to study enrollment, unless in the opinion of site investigator 
the medication will not interfere with the study procedures or impact subject safety. 
 
4 Non-childbearing potential is defined as being post-menopausal for at least 18 months or surgically sterile via 
hysterectomy, bilateral oophorectomy, or tubal sterilization. 
5 Sexually active female subjects of childbearing potential must avoid becoming pregnant by using one of the 
following acceptable methods of birth control for 30 days prior to study product dosing and must be maintained for 
30 days after last dose of study product: 
- 
Intrauterine contraceptive device; OR 
- 
Approved hormonal contraceptives (such as birth control pills, skin patches, Implanon®, Nexplanon®, 
DepoProvera®, or NuvaRing®); OR 
Birth control must be captured on the appropriate data collection form. 
6 In the opinion of the PI, may either put the volunteer at risk because of participation in the study, or influence the 
results or the volunteer's ability to participate in the study. 

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7.   Receipt of non-antibiotic medications that interacts with OAT37 within 14 days prior to 
study enrollment. 
8.   Receipt of herbal and dietary supplements (including St. John’s Wort) within 14 days prior 
to study enrollment. 
9.   ALT or AST laboratory value above the ULN as defined in the toxicity table in Appendix 
B. 
10. Prolonged QTcF (> 450 msec) or shortened QTcF (< 340 msec) or family history of long QT 
syndrome.  Any clinically important abnormalities in rhythm, conduction, or morphology of 
resting ECG.8 
11. Any positive result on screening for human immunodeficiency virus (HIV) serum hepatitis B 
surface antigen (HBsAg) and hepatitis C virus (HCV) antibody. 
12. Creatinine clearance equal or less than 80 mL/minute (measured by Cockcroft-Gault  
method) [23]. 
13. History of Clostridium difficile infection in past 90 days. 
14. Known or suspected history of drug or alcohol abuse within the last 5 years, as judged by the 
PI.  
15. Positive screen for drugs of abuse, cotinine (nicotine), or alcohol at screening and at 
admission to the study site prior to the first administration of the study products(s). 
16. Received a new chemical entity (compound not approved for marketing) or participated in a 
study that included drug treatment within 1 month of the first dose of study product(s) for 
study.9 
Note:  subjects consented and screened, but not dosed in this study or a previous Phase I 
study will not be excluded. 
17. Previous participation in the present study. 
18. Involvement in the planning and/or conduct of the study. 
 
7 Adefovir, Anagliptin,  Baricitinib, Cefaclor, Cimetidine, Ciprofloxacin (Systemic), Clofarabine, Eluxadoline, 
Empagliflozin, Furosemide, Ketoprofen, Methotrexate, Mycophenolate, PEMEtrexed, Penicillin G 
(Parenteral/Aqueous), Penicillin G Benzathine, Penicillin G Procaine, Penicillin V Benzathine, Penicillin V 
Potassium, Zidovudine 
8 Abnormalities that may interfere with interpretation of QTc interval changes per the medical judgment of the PI. 
9 Period of exclusion begins at the time of the last visit of the prior study. 

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19. Any ongoing/recent (during screening) medical complaints that may interfere with analysis 
of study data or are considered unlikely to comply with study procedures, restrictions, and 
requirements.10 
20. Known history of past or current epilepsy or seizure disorders, excluding febrile seizures of 
childhood. 
 
Withdrawal from the Study, Discontinuation of Study Product, or 
Study Termination  
5.2.1 Withdrawal from the Study or Discontinuation of the Study Product  
Subjects may voluntarily withdraw their consent for study participation at any time without 
penalty or loss of benefits to which they are otherwise entitled.   
An investigator may also withdraw a subject from receiving the study product for any reason. If 
the subject agrees, follow-up safety evaluations will be conducted.  If a subject withdraws or is 
withdrawn prior to completion of the study, the reason for this decision must be recorded in the 
case report forms (CRFs).  
The reasons, might include, but are not limited to the following: 
• 
Subject withdraws consent 
• 
Subject no longer meets eligibility criteria 
• 
Subject meets individual halting criteria (see Section 8.6.2) 
• 
Subject becomes noncompliant 
• 
Medical disease or condition or new clinical finding(s) for which continued participation, in 
the opinion of the investigator might compromise the safety of the subject, interfere with the 
subject’s successful completion of this study, or interfere with the evaluation of responses 
• 
Subject lost to follow-up 
The investigator should be explicit regarding study follow-up (e.g. safety follow-up) that might 
be carried out despite the fact the subject will not receive further study product.  If the subject 
consents, every attempt will be made to follow all AEs through resolution.  The procedures that 
collect safety data for the purposes of research must be inclusive in the original informed consent 
 
10 Judgment by the PI that the subject should not participate in the study. 

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or the investigator may seek subsequent informed consent using an IRB/IEC-approved consent 
form with the revised procedures. 
Every attempt should be made to complete a physical examination and all Day 8 procedures for 
all subjects who withdraw from the study or discontinue study product. 
The investigator will inform the subject that any data already collected will be retained and 
analyzed even if the subject withdraws from this study.  
5.2.2 Subject Replacement 
Subjects who are enrolled but drop out before receiving study product(s) will be replaced.  If two 
or more subjects in a dosing cohort have an incomplete PK profile, subjects will be replaced in 
that dosing cohort to ensure there are at least seven subjects with complete PK profiles in each 
dosing cohort.  A subject will be considered to have a complete PK profile if  ≥70% of plasma 
PK samples are collected.  For participants who have incomplete PK profiles, their available PK 
data will be considered in the PK analyses. 
5.2.3 Study Termination  
If the study is prematurely terminated by the sponsor, any regulatory authority, or the 
investigator for any reason, the investigator will promptly inform the study subjects and assure 
appropriate therapy or follow-up for the subjects, as necessary (see Section 6.4 and 8.3). The 
investigator will provide a detailed written explanation of the termination to the IRB/IEC. 

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STUDY PROCEDURES 
The study schedule is outlined below and in the Schedule of Events (Appendix A).  Protocol 
waivers or exemptions are not allowed. Therefore, adherence to the study design requirements, 
including those specified in the Schedule of Events, is required. 
Amendments or changes to the protocol require the approval of the sponsor and the Institution 
Review Board (IRB). 
 
Screening (Days -30 to Day -2) 
The study site will determine the most efficient procedures to identify potentially eligible 
subjects for the study. Subjects will report to the study site between Days -30 to Day -2. The 
study will be explained to each potential subject.  A signed and dated IRB-approved informed 
consent form (ICF) must be properly obtained from each subject before any study-specific test or 
evaluation is administered.  Approximately 75 subjects will be screened to enroll 48 evaluable 
subjects.  Individuals who agree to participate and sign the informed consent will undergo the 
following procedures [also see Schedule of Events (Appendix A)].   
• 
Obtain informed consent 
• 
Review and obtain medical history, concomitant medication(s), demographics, height, and 
weight.  Ensure review of any history of hypersensitivity to drugs with a similar chemical 
structure or class to ATM, AVI or CAZ. 
• 
Complete physical examination 
• 
Vital signs:  Systolic and diastolic blood pressures (mmHg), pulse rate (BPM), respiratory 
rate, and body temperature (oral measurement) 
• 
12-lead ECG in triplicate (mean value of ECGs will be used to determine study eligibility) 
• 
Clinical chemistry:  sodium (Na), potassium (K), chloride (Cl), bicarbonate (HCO3), blood 
urea nitrogen (BUN), serum creatinine, glucose, albumin, total protein, total bilirubin, ALT, 
AST, ALP and lactate dehydrogenase (LDH) 
• 
Hematology:  Hemoglobin, hematocrit, white blood cell count (WBC), WBC differential, red 
blood cell count (RBC), platelets  
• 
Coagulation:  PT and Partial thromboplastin time (PTT) 
• 
Viral serology:  HIV, HBsAg, HCV antibody 
• 
Coombs test 

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• 
Urinalysis: dipstick urinalysis, including protein, glucose, ketones, bilirubin, blood, nitrites, 
leukocyte esterase (LCE), urobilinogen, specific gravity, and pH. 
NOTE: The administration of ceftazidime may result in a false-positive reaction for glucose 
in the urine with certain methods.  The clinical laboratory equipment will measure glucose 
via glucose oxidase reactions, which is not affected by ceftazidime administration. [17] 
• 
Urine drug screening 
• 
Pregnancy testing (females of child bearing potential only): Serum human chorionic 
gonadotropin (hCG) 
• 
Alcohol Screen Breathalyzer 
• 
Cotinine Test 
 
Enrollment (Day -1) 
Subjects will report to the study site on Day -1 for the procedures listed below and in the 
Schedule of Events (Appendix A).  Once eligibility has been confirmed, subjects will be enrolled 
into the study and assigned to a treatment cohort. Assessments at Day -1 will serve as baseline 
values.  Subjects will remain at the study site until discharge on Day 8 or until withdrawal from 
the study (see Section 5.2). 
• 
Complete physical examination, height and weight, concomitant medication review and 
review for changes in medical history 
• 
Vital signs:  Systolic and diastolic blood pressures (mmHg), pulse rate (BPM), respiratory 
rate, and body temperature (oral measurement) 
• 
Single 12-lead ECG 
• 
Clinical chemistry:  Na, K, Cl, HCO3, BUN, serum creatinine, glucose, albumin, total 
protein, total bilirubin, ALT, AST, ALP and LDH 
• 
Hematology:  Hemoglobin, hematocrit, WBC, WBC differential, RBC, platelets 
• 
Coagulation:  PT and PTT 
• 
Urinalysis and urine drug screening 
• 
Pregnancy testing (females of child bearing potential only): Serum hCG if not already 
performed within 48 hours of Day -1. Results must be available prior to administration of 
study product. 

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• 
Alcohol Screen Breathalyzer 
• 
Cotinine Test 
 
Planned Study Visits (Days 1 – 8) 
6.3.1 Treatment (Day 1) 
The following procedures will be completed as listed below and in the Schedule of Events 
(Appendix A): 
• 
Symptom directed physical exam 
• 
Vital signs will be obtained prior to dosing on Day 1 and 1 hour after starting AM dose 
• 
Monitoring for AEs will begin after the first dose of study product 
• 
Review for any new medication 
• 
Study product administration as outlined in Section 4 
• 
Plasma and urine PK as outlined in Sections 7.2.2. 
6.3.2 Treatment (Day 2) 
The following procedures will be completed as listed below and in the Schedule of Events 
(Appendix A): 
• 
Symptom directed physical exam 
• 
Vital signs will be obtained in the morning 
• 
Monitor for AEs. 
• 
Review for any new medication 
• 
Study product administration as outlined in Section 4. 
• 
Clinical chemistry:  Na, K, Cl, HCO3, BUN, serum creatinine, glucose, albumin, total 
protein, total bilirubin, ALT, AST, ALP and LDH 
• 
Hematology:  hemoglobin, hematocrit, WBC, WBC differential, RBC, platelets 
• 
Coagulation:  PT and PTT 

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6.3.3 Treatment (Day 4, 6) 
The following procedures will be completed as listed below and in the Schedule of Events 
(Appendix A): 
• 
Symptom directed physical exam 
• 
Vital signs will be obtained in the morning 
• 
Monitor for AEs. 
• 
Review for any new medication 
• 
Study product administration as outlined in Section 4. 
• 
Clinical chemistry:  Na, K, Cl, HCO3, BUN, serum creatinine, glucose, albumin, total 
protein, total bilirubin, ALT, AST, ALP and LDH 
• 
Hematology:  hemoglobin, hematocrit, WBC, WBC differential, RBC, platelets 
• 
Coagulation:  PT and PTT 
• 
Day 4 only: Urinalysis 
• 
Day 6 only: Urine PK as outlined in Section 7.2.2.2 
6.3.4 Treatment (Day 3, 5, 7) 
The following procedures will be completed as listed below and in the Schedule of Events 
(Appendix A): 
• 
Symptom directed physical exam 
• 
Vital signs will be obtained in the morning 
• 
Monitor for AEs 
• 
Review for any new medication 
• 
Study product administration as outlined in Section 4. 
• 
Plasma PK as outlined in Section 7.2.2.1 
• 
Day 5 and 7 only: LFTs: ALT, AST, ALP, and total bilirubin 
6.3.5 Discharge (Day 8) 
The following procedures will be completed as listed below and in the Schedule of Events 
(Appendix A): 

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• 
Complete physical examination, concomitant medication review and review for changes in 
medical history 
• 
Vital signs will be obtained in the morning 
• 
Single 12-lead ECG 
• 
Assessment of AEs 
• 
Clinical chemistry:  Na, K, Cl, HCO3, BUN, serum creatinine, glucose, albumin, total 
protein, total bilirubin, ALT, AST, ALP and LDH 
• 
Hematology:  Hemoglobin, hematocrit, WBC, WBC differential, RBC, platelets 
• 
Coagulation:  PT and PTT 
• 
Coombs Test 
• 
Urinalysis 
• 
Plasma PK as outlined in Section 7.2.2.1 
• 
Schedule Day 11 Final Study Visit 
6.3.6 Final Study Visit (Day 11 +3) 
Subjects will report to the study site on Day 11 + 3 for the final study visit and completion of the 
assessments as listed below and in the Schedule of Events (Appendix A): 
• 
Complete physical examination and concomitant medication review 
• 
Vital signs 
• 
Single 12-lead ECG 
• 
Assessment of AEs 
• 
Clinical chemistry:  Na, K, Cl, HCO3, BUN, serum creatinine, glucose, albumin, total 
protein, total bilirubin, ALT, AST, ALP and LDH 
• 
Hematology:  Hemoglobin, hematocrit, WBC, WBC differential, RBC, platelets 
• 
Coagulation:  PT and PTT 
• 
Urinalysis 

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Early Termination Visit  
• 
In circumstances where a subject discontinues the study early, an early termination visit will 
be performed. Every attempt should be made to complete a physical examination and all 
other Day 8 procedures for all subjects who withdraw from the study or discontinue study 
product.  The reason(s) for early termination should be reflected in the source documentation 
and the Study Termination electronic case report form (eCRF).  Complete physical 
examination, concomitant medication review and review for changes in medical history 
• 
Vital signs 
• 
Single 12-lead EGC 
• 
Assessment of AEs 
• 
Clinical chemistry:  Na, K, Cl, HCO3, BUN, serum creatinine, glucose, albumin, total 
protein, total bilirubin, ALT, AST, ALP and LDH 
• 
Hematology:  Hemoglobin, hematocrit, WBC, WBC differential, RBC, platelets  
• 
Coagulation:  PT and PTT 
• 
Coombs Test 
• 
Urinalysis 
• 
Sample for a single plasma PK level 
 
Unscheduled Study Visits 
The PI may decide a subject requires an unscheduled visit outside the normal schedule. At a 
minimum this visit will include a physical exam, clinical chemistry, hematology, coagulation 
test, and AE assessment.  However the following may be included based on the judgement of  
the PI. 
• 
Complete physical examination, concomitant medication review and review for changes in 
medical history 
• 
Vital signs 
• 
Single 12-lead ECG 
• 
Assessment of AEs 
• 
Clinical chemistry:  Na, K, Cl, HCO3, BUN, serum creatinine, glucose, albumin, total 
protein, total bilirubin, ALT, AST, ALP and LDH 

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• 
Hematology:  Hemoglobin, hematocrit, WBC, WBC differential, RBC, platelets 
• 
Coagulation:  PT and PTT 
• 
Coombs Test 
• 
Urinalysis 
• 
Sample for a single plasma PK level (optional) 
Unscheduled study visits will be assigned a trailing alpha letter after the study day number.  For 
example, if a subject has an unscheduled study day that occurs between study day 1 and study 
day 2, the study visit day would be numbered as study day 1S. 
 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or protocol-
specific MOP requirements.  The noncompliance may be either on the part of the subject, the site 
PI, or the site personnel.  As a result of deviations, corrective actions are to be developed by the 
site and implemented promptly. 
These practices are consistent with ICH E6: 
4.5 
Compliance with Protocol, Sections 4.5.1, 4.5.2, and 4.5.3 
5.1 
Quality Assurance (QA) and Quality Control (QC), Section 5.1.1 
5.20 
Noncompliance, Sections 5.20.1, and 5.20.2. 
It is the responsibility of the site PI and personnel to use continuous vigilance to identify and 
report deviations within five working days of identification of the protocol deviation, or within 
five working days of the scheduled protocol-required activity.  All deviations must be promptly 
reported to DMID per the Statistical and Data Coordinating Center (SDCC) protocol deviation 
reporting procedures. 
All protocol deviations, as defined above, must be addressed in study subject data collection 
forms.  A completed copy of the DMID Protocol Deviation Form must be maintained in the 
Regulatory File, as well as in the subject’s chart.  Protocol deviations must be sent to the local 
IRB/IEC per their guidelines.  The site PI and personnel are responsible for knowing and 
adhering to their IRB requirements. 

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DESCRIPTION OF CLINICAL AND LABORATORY 
EVALUATIONS 
 
Clinical Evaluations 
7.1.1 Research Procedures 
The following will be obtained: 
• 
Complete medical history – subjects will be queried regarding a history of significant 
medical disorders and any allergies.  Specifically querying if the subject has a history of 
hypersensitivity to drugs with a similar chemical structure or class to ATM, AVI or CAZ. 
• 
Complete medications history – subjects will be queried regarding all prescription and over-
the-counter medications and supplements taken within 24 hours and any study products taken 
within 90 days prior to start of study products. 
• 
A complete physical examination should include general appearance, neurological, head, eye, 
ear, nose, throat (HEENT), cardiovascular, lungs, abdomen, musculoskeletal, and skin 
examinations.  The physical examination performed at Day -1 will serve as the baseline for 
clinical assessments.  
• 
A targeted or focused physical examination is symptom directed and includes neurological, 
HEENT, and musculoskeletal examinations and is specifically related to reported AEs during 
the study (e.g., abdomen for AEs of vomiting or diarrhea). 
• 
Height and weight will be measured at Screening and Day -1 to calculate the BMI. 
• 
Vital signs should be collected after resting in supine position.  Vital signs include systolic 
and diastolic blood pressures (mmHg), pulse rate (BPM), respiratory rate, and body 
temperature. 
• 
The PI or his designee will interpret ECGs in real time during inpatient dosing periods and 
within 12 hours for late-night tracings. If a CS abnormality is detected, an appointed 
cardiologist at the study site will immediately interpret the ECG. A licensed physician listed 
on Form FDA 1572 will review the final results. Subjects with CS findings will be referred 
either to the emergency department or to their primary care physician for follow-up. 
An ECG will be recorded in triplicate approximately 2 minutes apart at the Screening visit. 
Single ECGs will be recorded on Days -1, 8, and 11 (+3).  Subjects must be lying supine or 
sitting for 10 minutes before recording the ECG tracings. 

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The ECGs will be printed and evaluated by an appropriately qualified physician at the study 
site. The reader will sign and date the safety ECGs and provide a global interpretation using 
the following categories: 
• 
Normal ECG 
• 
Abnormal ECG-not clinically significant (NCS) 
• 
Abnormal ECG-CS 
• 
Unable to evaluate 
• 
Other -details will be noted in the source document and eCRF 
7.1.2 Assessment of Concomitant Medications/Treatments Other Than Study Product 
Use of concomitant medications (probenecid and furosemide) that are contraindicated in the 
AVYCAZ and ATM package inserts will not be permitted [18,19].  Subjects taking such 
medications will not be eligible for the study.   
Patients who received antibiotics within the 14 days prior to study enrollment will not be eligible 
for the study.  
Patients receiving a non-antibiotic medication that interacts with OAT3 (e.g., Adefovir, 
Anagliptin, Baricitinib, Cefaclor, Cimetidine, Ciprofloxacin (Systemic), Clofarabine, 
Eluxadoline, Empagliflozin, Furosemide, Ketoprofen, Methotrexate, Mycophenolate, 
PEMEtrexed, Penicillin G (Parenteral/Aqueous), Penicillin G Benzathine, Penicillin G Procaine, 
Penicillin V Benzathine, Penicillin V Potassium, Zidovudine) will not be included [30,31]. 
In addition, no prescription (except birth control pills or hormone replacement in females) or 
non-prescription drugs will be permitted, unless in the opinion of site investigator the medication 
will not interfere with the study procedures or impact subject safety.  The use of herbal and 
dietary supplements (including St. John’s Wort) will not be permitted during the study. 
7.1.3 Assessment of Subject Compliance With the Study Visit Schedule 
The Investigational Pharmacist or designee is responsible for the reconstitution and labeling of 
the study products. Study products will be administered via IV infusion by a member of the 
clinical research team who is licensed to administer the study products. Administration will be 
documented on the source document and entered into the eCRF. 
Study product compliance including start and stop time of infusion, volume administered, and 
the occurrence of any infusion interruptions (greater than 10 minutes) will be captured in the 
source documents. 

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Laboratory Evaluations 
Subjects will have up to approximately 135 mL of blood drawn for safety laboratory tests in each 
of the study cohorts.   
Safety laboratory monitoring will include:  hematology, clinical chemistry, LFTs, coagulation, 
viral serology and urinalysis. 
7.2.1 Clinical Laboratory Evaluations 
• 
Clinical chemistry:  Na, K, Cl, HCO3, BUN, serum creatinine, glucose, albumin, total 
protein, total bilirubin, ALT, AST, ALP and LDH 
• 
LFTs: ALT, AST, ALP, and total bilirubin 
• 
Hematology:  Hemoglobin, hematocrit, WBC, WBC differential, RBC, platelets 
• 
Coombs Test 
• 
Coagulation:  PT, PTT 
• 
Serology: HIV, HBsAg, HCV 
• 
Urinalysis:  dipstick urinalysis, including protein, glucose, ketones, bilirubin, blood, nitrites, 
LCE, urobilinogen, specific gravity, and pH.  The administration of ceftazidime may result in 
a false-positive reaction for glucose in the urine with certain methods.  The clinical 
laboratory equipment will measure glucose via glucose oxidase reactions, which is not 
affected by ceftazidime administration. 
• 
Pregnancy testing (females of child bearing potential only): Serum human chorionic 
gonadotropin (hCG).  
• 
Alcohol screen breathalyzer 
• 
Cotinine Test 
• 
Urine drug screen:  amphetamines, barbiturates, benzodiazepines, cocaine metabolites, 
opiates, cannabinoids and phencyclidine 

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7.2.2 Research Assays 
7.2.2.1 Plasma Pharmacokinetic Sample Collection 
Venous plasma samples for pharmacokinetic analyses of AVYCAZ and ATM will be collected 
at the following time points ±5 minutes for pre-dose, during, and end of short infusion samples 
and then ±15 minutes for other samples.  The actual date and time of each blood sample 
collection will be recorded in the subjects’ source document and the eCRF.  The timing of the 
study assessments should allow the blood draw to occur at the exact nominal time. 
Approximately 192 mL of blood will be obtained from each subject for determining plasma 
AVYCAZ and ATM for each dosing regimen.  Blood collected will be processed at the study 
site’s laboratory. 
Cohort 1 (AVYCAZ Q8 hours treatment cohort) 
• 
Day 1: blood samples will be collected pre-dose (10 minutes prior to the start of 1st infusion), 
0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, and 8 hours after the start of the 1st infusion (8 hour sample 
must be collected prior to the start of the 2nd dose of AVYCAZ). 
• 
Day 3: Blood samples will be collected 10 minutes prior to the start of the 1st infusion on 
Day 3. 
• 
Day 5: Blood samples will be collected 10 minutes prior to the start of the 1st infusion on 
Day 5. 
• 
Day 7, blood samples will be collected pre-dose (10 minutes prior to the start of the morning 
infusion on Day 7, which is the last infusion of the study), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 
10, 12, 18, and 24 hours after the start of the Day 7 infusion. 
Cohorts 2, 4 (CI treatment cohort) 
• 
Day 1: blood samples will be collected at pre-dose (10 minutes prior to the start of 
1st infusion), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, and 8 hours after the start of the 1st infusion of 
Day 1.  
• 
Day 3: Blood samples will be collected 10 minutes prior to the start of the 1st infusion on 
Day 3. 
• 
Day 5: Blood samples will be collected 10 minutes prior to the start of the 1st infusion on 
Day 5. 
• 
Day 7: Blood samples will be collected 10 minutes prior to the start of the 1st infusion(s) on 
Day 7 (last infusion(s) of the study), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, 12, 18, and 
24 hours after the start of the Day 7 infusion(s). 

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Cohort 3 (ATM Q6 hours treatment cohort) 
• 
Day 1: blood samples will be collected pre-dose (10 minutes prior to the start of 1st infusion), 
0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6 (6 hour sample must be collected prior to the start of the 2nd dose 
of ATM), 7, and 8 hours after the start of the 1st infusion.  
• 
Day 3: Blood samples will be collected 10 minutes prior to the start of the 1st infusion on 
Day 3. 
• 
Day 5: Blood samples will be collected 10 minutes prior to the start of the 1st infusion on 
Day 5. 
• 
Day 7: blood samples will be collected pre-dose (10 minutes prior to the start of the morning 
infusion on Day 7, which is the last infusion of the study), 0.5, 1, 1.5, 2 , 2.5, 3, 4, 5, 6, 7, 8, 
10, 12, 18, and 24 hours after the start of the Day 7 infusion. 
Cohort 5, 6 (AVYCAZ Q8 hours + ATM Q6 hours treatment cohort) 
• 
Day 1: blood samples will be collected pre-dose (10 minutes prior to the start of 1st infusion), 
0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6 (6 hour sample must be collected prior to the start of the 2nd dose 
of ATM), 7, and 8 hours after the start of the 1st infusion (8 hour sample must be collected 
prior to the start of the 2nd dose of AVYCAZ).  
• 
Day 3: Blood samples will be collected 10 minutes prior to the start of the 1st infusion on 
Day 3. 
• 
Day 5: Blood samples will be collected 10 minutes prior to the start of the 1st infusion on 
Day 5. 
• 
Day 7: blood samples will be collected pre-dose (10 minutes prior to the start of the morning 
infusion on Day 7, which is the last infusion of the study), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 
10, 12, 18, and 24 hours after the start of the Day 7 infusion. 
7.2.2.2 Urine Pharmacokinetic Sample Collection 
Each study subject will have serial urine samples collected on Day 1 and Day 6 to determine 
urine concentrations of AVYCAZ and ATM alone and in combination.  The actual date and time 
of each urine sample collection will be recorded in the subjects’ source document and the eCRF.  
The total volume of urine for each collection interval will be recorded. After measuring total 
volume of urine for each collection interval, aliquots of urine samples will be taken from the 
collected urine sample and transferred into suitably labeled polypropylene cryogenic sample 
storage vials and maintain being chilled before being transferred to freezer. 

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Days 1 and 6: 
Serial urine samples will be collected for all cohorts at the following intervals:  >0 to 4, >4 to 8, 
>8 to 12, and >12 to 24 hours after the start of the morning dose administration(s) of the day. 
7.2.2.3 Laboratory Specimen Preparation, Handling, and Storage 
Plasma and urine PK specimens will be processed and stored in a -80oC freezer until time of 
shipment to Keystone Bioanalytical laboratory for analysis. 
Detailed instructions for the preparation, handling, and storage of plasma and urine PK 
specimens are detailed in the study MOP including aliquots of specimens, temperature 
requirements, where they will be stored, and how they will be labeled. 
7.2.2.4 Laboratory Specimen Shipping 
After the completion of each dosing cohort, both plasma and urine PK samples for all subjects in 
each cohort will be shipped on dry ice to Keystone Bioanalytical laboratory for analysis.  
Samples will be shipped in compliance with the International Air Transport Association (IATA) 
regulations.  Plasma and urine PK samples will be shipped in separate shipping containers.  
Instructions for the shipment of specimens are outlined in the study MOP. 

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ASSESSMENT OF SAFETY 
 
Assessing and Recording Safety Parameters 
This study will assist in determining the safety profile for the combination of AVYCAZ with 
ATM, AVYCAZ alone and ATM alone.  The same safety data will be collected across all 
treatment cohorts.  AVYCAZ and ATM both are approved drugs with established safety profiles.  
However, the AVYCAZ CI regimens examined as part of this study are not FDA approved.  
There is also limited published safety data on ATM alone. 
To ensure a clear comparison of safety between the single dose cohorts and the combination 
dosing cohorts for this study, AEs will be collected for all study cohorts.   
8.1.1 Adverse Events (AEs) 
Monitoring for AEs will begin after starting infusion of the first dose of study product on Day 1 
through the final Study Visit on Day 11 +3.   
ICH E6 defines an AE as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product regardless of its causal relationship to the study 
treatment.  FDA defines an AE as any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of medicinal (investigational) 
product.  The occurrence of an AE may come to the attention of study personnel during study 
visits and interviews of a study recipient presenting for medical care, or upon review by a study 
monitor.  
All AEs, including local (infusion site) and systemic reactions, will be captured on the 
appropriate data collection form and eCRF.  Information to be collected for AEs includes event 
description, date of onset, assessment of severity, relationship to study product and alternate 
etiology (assessed only by those with the training and authority to make a diagnosis and listed on 
the Form FDA 1572 as an investigator), date of resolution, seriousness and outcome.  AEs 
occurring during the trial collection and reporting period will be documented appropriately 
regardless of relationship.  AEs will be followed through resolution, return to pretreatment status 
or stabilization of the condition with the expectation that it will remain chronic. 
Any medical condition that is present at the time that the subject is screened will be considered 
as baseline and not reported as an AE.  However, if the severity of any pre-existing medical 
condition worsens, it should be recorded as an AE. 

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8.1.1.1 Adverse Events Grading 
All AEs (laboratory and clinical symptoms) will be graded for severity (Appendix B) and 
assessed for relationship to study product (see definitions below). AEs characterized as 
intermittent require documentation of onset and duration of each episode.  The start and stop date 
of each reported AE will be recorded on the appropriate data collection form and eCRF. Changes 
in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of intensity. 
Severity of Event:   
AEs will be assessed by the investigator using a protocol-defined grading system (Laboratory 
and Vital Signs Reference Ranges, Eligibility Ranges, and Toxicity Grading information in 
Appendix B).  For events not included in the protocol-defined grading system, the following 
guidelines will be used to quantify severity: 
• 
Mild (Grade 1):  Events that are usually transient (less than 48 hours) and may require only 
minimal or no treatment or therapeutic intervention and generally do not interfere with the 
subject’s usual activities of daily living. 
• 
Moderate (Grade 2):  Events that are usually alleviated with additional specific therapeutic 
intervention (use of non-narcotic pain reliever or over-the-counter medication).  The event 
interferes with usual activities of daily living, causing discomfort but poses no significant or 
permanent risk of harm to the research participant. 
• 
Severe (Grade 3):  Events interrupt usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention (requires prescription 
medication, or IV fluids or medical procedure).  Severe events are usually incapacitating. 
Relationship to Study Product: The assessment of the AE’s relationship to study product will 
be done by the licensed study physician indicated on the Form FDA 1572 and the assessment 
will be part of the documentation process.  Whether the AE is related or not to the study product, 
is not a factor in determining what is or is not recorded in the eCRF in this trial.  If there is any 
doubt as to whether a clinical observation is an AE, the event should be recorded in the eCRF. 
In a clinical trial, the study product must always be suspect.  The relationship to study product 
will be assessed for AEs using the terms related or not related: 
• 
Related – There is a reasonable possibility that the study product caused the AE. Reasonable 
possibility means that there is evidence to suggest a causal relationship between the study 
product and the AE. 
• 
Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event. 

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8.1.2 Serious Adverse Events (SAEs) 
An AE is considered an SAE if, in the view of either the site PI or sponsor, it results in any of the 
following outcomes:  
• 
Death, 
• 
a life-threatening AE11, 
• 
inpatient hospitalization or prolongation of existing hospitalization,  
• 
a persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions, or  
• 
a congenital anomaly/birth defect, 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalizations may be considered serious when, based upon appropriate medical judgment 
they may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
All SAEs will be: 
• 
Assessed for severity and relationship to study product and alternate etiology (if not related 
to study product) by a licensed study physician listed on the Form FDA 1572 or by the 
Institution as the site PI or Sub-Investigator. 
• 
Recorded on the appropriate SAE data collection form and eCRF. 
Followed through resolution or stabilization, even if this extends beyond the study-reporting 
period, by a licensed study physician (for Investigational New Drug Application (IND) studies, a 
physician listed on the Form FDA 1572 as the site PI or Sub-Investigator). 
• 
Reviewed and evaluated by DMID, an Independent Safety Monitor (ISM) (as deemed 
necessary) or SMC (periodic review unless related), and the IRB/IEC. 
 
11 Life-threatening adverse event. An AE is considered “life-threatening” if, in the view of either the site PI or 
sponsor, its occurrence places the patient or subject at immediate risk of death.  It does not include an AE that, had it 
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Specification of Safety Parameters 
8.2.1 Solicited Events 
Solicited events will not be collected as part of this study. 
8.2.2 Unsolicited Events 
Unsolicited events are AEs that occur following administration of study product.  Subjects can 
be queried as needed to evaluate occurrence of any AEs. 
 
Reporting Procedures 
8.3.1 Reporting Serious Adverse Events 
For this study, all AE/SAEs occurring from first dose of study product on Day 1 through Day 
11 + 3 days after last dose of study product(s) will be collected in the eCRF.   
Any AE that meets a protocol-defined serious criterion must be submitted immediately 
(within 24 hours of site awareness) on an SAE form to the DMID Pharmacovigilance 
Group, at the following address: 
 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Dr. Suite 650 
Bethesda, MD 20817, USA 
SAE Hot Line: 1-800-537-9979 (US) or 1-301-897-1709 (outside US) 
SAE FAX Number: 1-800-275-7619 (US) or 1-301-897-1710 (outside US) 
SAE Email Address: PVG@dmidcroms.com 
 
In addition to the SAE form, select SAE data fields must also be entered into the SDCC system 
that must match the data on the SAE Report form. Please see the protocol-specific MOP for 
details regarding this procedure.  
Other supporting documentation of the event may be requested by the DMID Pharmacovigilance 
Group and should be provided as soon as possible.  
The site will send a copy of the SAE report(s) to the ISM when they are provided to the DMID 
Pharmacovigilance Group.  The DMID Medical Monitor (MM) and DMID Clinical Project 
Manager will be notified of the SAE by the DMID Pharmacovigilance Group.  The DMID 
Medical Monitor will review and assess the SAE for regulatory reporting and potential impact on 
study subject safety and protocol conduct. 

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At any time after completion of the study, if the site PI or appropriate sub-investigator becomes 
aware of an SAE that is suspected to be related to study product, the site PI or appropriate sub-
investigator will report the event to the DMID Pharmacovigilance Group. 
8.3.2 Regulatory Reporting for Studies Conducted Under DMID-Sponsored IND 
Following notification from the site PI or appropriate sub-investigator, DMID, as the IND 
sponsor, will report any suspected unexpected serious adverse event (SUSAR).  DMID will 
report an SAE as a SUSAR only if there is evidence to suggest a causal relationship between the 
study intervention and the SAE.  DMID will submit an IND safety report to the FDA and will 
notify all participating site PIs (i.e., all PIs to whom the sponsor is providing drug under its 
IND(s) or under any PI’s IND(s)of potential serious risks from clinical studies or any other 
source, as soon as possible.  DMID will report to the FDA any unexpected fatal or life-
threatening suspected adverse reaction as soon as possible, but in no case later than seven (7) 
calendar days after the sponsor’s initial receipt of the information.  If the event is not fatal or life-
threatening the IND safety report will be submitted within 15 calendar days after the sponsor 
determines that the information qualifies for reporting as specified in 21 CFR Part 312.32.  
Relevant follow up information to an IND safety report will be submitted as soon as the 
information is available.  Upon request from FDA, DMID will submit to the FDA any additional 
data or information that the agency deems necessary, as soon as possible, but in no case later 
than 15 calendar days after receiving the request. 
All SAEs designated as “not related” to study product(s), will be reported to the FDA at least 
annually in a summary format. 
8.3.3 Reporting of Pregnancy 
Female subjects of childbearing age who become pregnant during the study will be discontinued 
from study medication and will be followed for pregnancy outcome.  Pregnancy occurring during 
a clinical investigation, although not considered a SAE, must be reported within the same 
timelines as a SAE. The positive pregnancy test will be recorded in the database within 5 days of 
site awareness, on the Pregnancy Report form.  The report will include pregnancy outcome (e.g., 
any premature terminations, elective or therapeutic, any spontaneous abortions or stillbirths), as 
well as the health status of the mother and child, including date of delivery and infant’s sex and 
weight.  Any subject with a positive pregnancy test, who has received study product(s), will be 
followed through eight (8) weeks post-live delivery or elective or natural termination of the 
pregnancy, whichever occurs first.  If the database is locked at time of pregnancy, a supplemental 
report will be generated and completed after birth, which will be appended to the database.  Any 
occurring AEs or SAEs that occur to the mother or fetus will be recorded in the eCRF in the 
database and on the SAE Report form.  

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The site is responsible for notifying their local IRB of any pregnancies in accordance with local 
policies. 
 
Type and Duration of Follow-up of Subjects after Adverse Events 
Adverse events, including serious AEs, will be assessed and collected from initial recognition of 
the AE occurring from first dose of study product on Day 1 through end of the protocol defined 
follow-up period (Day 11 + 3). 
All AEs and serious AEs occurring from first dose of study product on Day 1 through Day 11 + 
3 days will be followed up through resolution even if duration of follow-up goes beyond the 
protocol-defined follow-up period. 
Resolution of an AE is defined as the return to pre-treatment status or stabilization of the 
condition with the expectation that it will remain chronic. 
 
Procedures to be Followed in the Event of Abnormal Laboratory Test 
Values or Abnormal Clinical Findings 
Mild abnormal laboratory values (Grade 1) that are not, in the investigator's opinion, medically 
significant should not be reported as AEs. Any Grade 2 or higher abnormal laboratory value (see 
Appendix B) will be reported as an AE regardless of the relationship to the study product.  
Laboratory abnormalities reported as AEs will be followed until the abnormality stabilizes or 
normalizes. 
 
Halting Rules 
8.6.1 Study Halting Criteria 
If any of the following events occur, enrollment and dosing for all subject will be suspended 
until the event is assessed by the SMC: 
• 
Any subject develops an SAE related to the study product through the last study visit. 
• 
In cohorts 2, 4, 5, and 6, two (2) or more subjects, in a single treatment cohort, experience a 
Grade 3 (severe) AE (including clinical, ECG, vital signs and laboratory AEs) that is related 
to study product and is of the same type [High Level Term (HLT)]. 
• 
In cohorts 5 and 6, three (3) or more subjects (cumulative) experience a Grade 3 (severe) AE 
(including clinical, ECG, vital, and laboratory AEs) that is related to the study products 
(combination) and is of the same type (HLT). 
• 
Any subject develops anaphylaxis within 24 hours after receiving the study product. 

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8.6.2 Individual Halting Criteria 
Further dosing of study product will be halted for any individual subject if any one of the 
following occurs:  
• 
Any SAE related to the study product. 
• 
Any Grade 3 AE event related to the study product. 
• 
Any other condition that the study site PI judges to unduly increase the risk to the subject. 
 
Safety Oversight 
8.7.1 Independent Safety Monitor (ISM) 
For this clinical trial, DMID will require an Independent Safety Monitor (ISM) to be assigned for 
each study site and the requirement for an ISM will be specified in the protocol. An ISM is a 
physician with relevant expertise whose primary responsibility is to provide to DMID an 
independent safety assessment in a timely fashion. The ISM will review all SAEs in real time 
and other AEs as needed and provide an independent assessment to DMID.   
8.7.2 Safety Monitoring Committee (SMC) 
This clinical study will utilize a SMC, which is an independent group of experts that advises the 
DMID. The primary responsibility of the SMC is to monitor subject safety. The SMC is external 
to the DMID and comprises at least 3 voting members. The SMC will consist of members with 
appropriate phase 1 study expertise to contribute to the interpretation of the data from this trial. 
Its activities will be delineated in an SMC charter that will describe the membership, 
responsibilities, and the scope and frequency of data reviews. The SMC will operate on a 
conflict-free basis independently of the study team. The DMID or the SMC may convene ad hoc 
meetings of the SMC according to protocol criteria or if there are concerns that arise during the 
study. 
As defined in the charter, the SMC will review data at specified times during the course of the 
study for subject and overall study progress, and may conduct ad hoc reviews as appropriate 
when a halting rule is met or for immediate concerns regarding observations during this study. 
The SMC will meet as follows: 
• 
Organization meeting (prior to start of the study). 
• 
Ad-hoc meeting when a halting rule is met or by request of the PI, ISM, or DMID MM if any 
safety concern arises. 
• 
Upon completion of cohort 5, prior to enrolling cohort 6.  

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• 
Final review meeting, to be conducted 6 to 8 months after clinical database lock to review the 
cumulative safety data for the study.  
The data will be provided in a standard summary format. The SMC may be asked to provide 
recommendations in response to questions posed by the DMID. 
Study product(s) administration data, including dose interruptions, modifications, and the 
associated reason(s), will be reported to the SMC. 
The SMC will operate under the rules of a DMID-approved charter. Data reviews may include 
enrollment and demographic information, medical history, concomitant medications, physical 
assessments, dosing compliance, protocol adherence, clinical laboratory values, PK data, and 
SAEs. Additional data may be requested by the SMC, and interim statistical reports may be 
generated as deemed necessary and appropriate by DMID. The SMC will receive data in 
aggregate and stratified by treatment cohort. The objective of the SMC is to make 
recommendations to the sponsors if the study should continue per protocol, be modified and then 
proceed, or be terminated.  After each review/meeting the SMC will make recommendations as 
to the advisability of proceeding with study (as applicable), and to continue, modify, or terminate 
this study. 
The DMID Medical Monitor or Medical Officer is empowered to stop study enrollment and 
administration if halting criteria are met or if any serious safety concerns arise. 

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HUMAN SUBJECTS PROTECTION 
 
Institutional Review Board/Independent Ethics Committee 
Each site PI will obtain IRB approval for this protocol to be conducted at his/her research site(s), 
and send supporting documentation to the DMID before initiating recruitment of subjects.  The 
investigator will submit applicable information to the IRB/IEC on which it relies for the review, 
to conduct the review in accordance with 45 CFR 46, ICH E6 GCP, and as applicable, 21 CFR 
56 (Institutional Review Boards) and 21 CFR 50 (Protection of Human Subjects), other federal, 
state, and local regulations. The IRB/IEC must be registered with OHRP as applicable to the 
research.  DMID must receive the documentation that verifies IRB/IEC-approval for this 
protocol, associated informed consent documents, and upon request any recruitment material and 
handouts or surveys intended for the subjects, prior to the recruitment and enrollment of subjects. 
Any amendments to the protocol or consent materials will be approved by the IRB/IEC before 
they are implemented.  IRB/IEC review and approval will occur at least annually throughout the 
enrollment and follow-up of subjects, and may cease if annual review is no longer required by 
applicable regulations and the IRB/IEC.  The investigator will notify the IRB/IEC of deviations 
from the protocol and reportable SAEs, as applicable to the IRB/IEC policy. 
Each institution engaged in this research will hold a current Federalwide Assurance (FWA) 
issued by the Office of Human Research Protection (OHRP) for federally funded research. 
 
Informed Consent Process 
Informed consent is a process that is initiated prior to an individual agreeing to participate in a 
clinical trial and continuing throughout the individual’s clinical trial participation.  Before any 
study procedures are performed, informed consent will be obtained and documented.  Subjects 
will receive a concise and focused presentation of key information about the clinical trial, 
verbally and with a written consent form. The explanation will be organized and presented in lay 
terminology and language that facilitates understanding why one might or might not want to 
participate. 
An investigator or designee will describe the protocol to potential subjects face-to-face. The key 
information about the purpose of the study, the procedures and experimental aspects of the study, 
risks and discomforts, any expected benefits to the subject, and alternative treatment will be 
presented first to the subject.   
Subjects will also receive an explanation that the trial involves research, and a detailed summary 
of the proposed study procedures and study interventions/products.  This will include aspects of 

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the trial that are experimental, the probability for random assignment to treatment cohort, any 
expected benefits, all possible risks (including a statement that the particular treatment or 
procedure may involve risks to the subject or to the embryo or fetus, if the subject is or may 
become pregnant, that are currently unforeseeable), the expected duration of the subject’s 
participation in the trial, alternative procedures that may be available and the important potential 
benefits and risks of these available alternative procedures.  
Subjects will be informed that they will be notified in a timely manner if information becomes 
available that may be relevant to their willingness to continue participation in the trial. Subjects 
will receive an explanation as to whether any compensation and any medical treatments are 
available if injury occurs, and, if so, what they consist of, or where further information may be 
obtained. Subjects will be informed of the anticipated financial expenses, if any, to the subject 
for participating in the trial, as well as any anticipated prorated payments, if any, to the subject 
for participating in the trial. They will be informed of whom to contact (e.g., the investigator) for 
answers to any questions relating to the research project.  
Information will also include the foreseeable circumstances and/or reasons under which the 
subject’s participation in the trial may be terminated. The subjects will be informed that 
participation is voluntary and that they are free to withdraw from the study for any reason at any 
time without penalty or loss of benefits to which the subject is otherwise entitled.   
The extent of the confidentiality of the subjects’ records will be defined, and subjects will be 
informed that applicable data protection legislation will be followed. Subjects will be informed 
that the monitor(s), auditors(s), IRB, NIAID, and regulatory authority(ies) will be granted direct 
access to the subject’s original medical records for verification of clinical trial procedures and/or 
data without violating the confidentiality of the subject, to the extent permitted by the applicable 
laws and regulations, and that, by signing a written ICF, the subject is authorizing such access.  
Subjects will be informed that records identifying the subject will be kept confidential, and, to 
the extent permitted by the applicable laws and/or regulations, will not be made publicly 
available and, if the results of the trial are published, the subject’s identity will remain 
confidential. Subjects will be informed whether private information collected from this research 
will be used for additional research, even if identifiers are removed.   
Subjects will be allowed sufficient time to consider participation in this research trial, and have 
the opportunity to discuss this trial with their family, friends or legally authorized representative, 
or think about it prior to agreeing to participate. 
Informed consent forms will be IRB-approved and subjects will be asked to read and review the 
ICF. Subjects must sign the ICF prior to starting any study procedures being done specifically for 
this trial. 

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Once signed, a copy of the ICF will be given to the subject(s) for their records.  The subject(s) 
may withdraw consent at any time throughout the course of the trial.  The rights and welfare of 
the subject(s) will be protected by emphasizing to them that the quality of their medical care will 
not be adversely affected if they decline to participate in this study. 
Study personnel may employ recruitment efforts prior to obtaining study consent if a 
patient-specific screening consent is on record or if the IRB has agreed that chart review is 
allowed without a fully executed screening consent.  In cases where there is not a patient-specific 
screening consent on record, site clinical staff may pre-screen via chart review and refer potential 
subjects to the research staff.  Research staff would obtain written consent per the standard 
informed consent process before conducting protocol-specific screening activities. 
New information will be communicated by the site PI to subjects who consent to participate in 
this trial in accordance with IRB requirements.  The informed consent document will be updated 
and subjects will be re-consented per IRB requirements, if necessary.  Subjects will be given a 
copy of all ICFs that they sign. 
 
Exclusion of Women, Minorities, and Children (Special Populations) 
Women of child-bearing potential will not be excluded from the trial.  In addition, special 
populations, e.g., non-English speakers, illiterate or non-writing individuals will not be excluded 
from this study. 
Children and vulnerable populations will be excluded from this study as there is insufficient 
safety data and this is the first time AVYCAZ combined with ATM will be studied in a clinical 
trial. 
 
Subject Confidentiality 
Subject confidentiality is strictly held in trust by the participating investigators, their staff, and 
the sponsor(s) and their agents. This confidentiality includes documentation, investigation data, 
subject’s clinical information, and all other information generated during participation in the 
study. No information concerning the study or the data generated from the study will be released 
to any unauthorized third party without prior written approval of the DMID and the subject. 
Subject confidentiality will be maintained when study results are published or discussed in 
conferences.  The study monitor or other authorized representatives of the sponsor or 
governmental regulatory agencies may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, clinic, or 
hospital) and pharmacy records for the subjects in this study. The clinical study site will permit 
access to such records. 

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All records will be kept locked and all computer entry and networking programs will be carried 
out with coded numbers only and with password protected systems. All non-clinical specimens, 
evaluation forms, reports, and other records that leave the site will be identified only by a coded 
number. 
 
Certificate of Confidentiality 
To protect privacy, a Certificate of Confidentiality will be issued.  With this Certificate, the 
researchers cannot be forced to release information that may identify the research subject, even 
by a court subpoena, in any federal, state, or local civil, criminal, administrative, legislative, or 
other proceedings.  The researchers will use the Certificate to resist any demands for information 
that would identify the subject, except as explained below. 
The Certificate cannot be used to resist a demand for information from personnel of the United 
States Government that is used for auditing or evaluation of federally funded projects, like this 
study, or for information that must be released in order to meet the requirements of the FDA. 
A Certificate of Confidentiality does not prevent the subject from voluntarily releasing 
information about themselves or their involvement in this research.  If any person or agency 
obtains a written consent to receive research information, then the researchers may not use the 
Certificate to withhold that information.   
The Certificate of Confidentiality does not prevent the researchers from reporting without the 
subject’s consent, information that would identify the subject as a participant in the research 
project regarding matters that must be legally reported including child and elder abuse, sexual 
abuse, or wanting to harm themselves or others.   
The release of individual private information for other research will only occur if consent was 
obtained from the individual to whom the information or document pertains. 
 
Costs, Subject Compensation, and Research Related Injuries 
There is no cost to subjects for the research tests, procedures, and study product while taking part 
in this trial.  Subjects may be compensated for their participation in this trial.  Compensation will 
be in accordance with the local IRB’s policies and procedures, and pursuant to IRB approval. 
If it is determined by the site PI that an injury occurred to a subject as a direct result of the tests 
or treatments that are done for this trial, then referrals to appropriate health care facilities will be 
provided to the subject.  Study personnel will try to reduce, control, and treat any complications 
from this trial.  Immediate medical treatment may be provided by the participating site.  No 
financial compensation will be provided to the subject by the NIAID, NIH to the subject for any 
injury suffered due to participation in this trial. 

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STATISTICAL CONSIDERATIONS 
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a Statistical Analysis and PK Plan. The Statistical Analysis and PK Plan 
document may modify the plans outlined in the protocol; however, any major modifications of 
the primary endpoints definitions and/or their analyses will also be reflected in a protocol 
amendment. Additional statistical analyses other than those described in this section may be 
performed if deemed appropriate and included in the plan. 
This is a Phase 1 study of the safety and PK of AVYCAZ with ATM. Each subject will be 
assigned to a cohort as described in Section 4.3 and have PK samples collected at designated 
time points.  For a subject to be considered “completed” they will have received the full seven 
days of scheduled study product(s), as well as completing an in person safety follow up.   
A subject will be considered to have a complete PK profile if ≥70% of plasma PK samples are 
collected.  If two or more subjects in a dosing cohort have an incomplete PK profile, subjects 
will be replaced in that dosing cohort to ensure there at least 7 subjects with complete PK 
profiles in each dosing cohort.  For participants who have incomplete PK profile, their available 
PK data will be considered in the PK analyses. 
 Study Hypotheses 
The aim of this study is to evaluate the safety and PK of combination doses of AVYCAZ with 
ATM. As this is a Phase I study, no hypothesis will be tested. 
 Sample Size Considerations 
This is a Phase I study to investigate the safety and PK of AVYCAZ combined with ATM.  The 
sample size was chosen to obtain reasonable evidence of safety without exposing undue numbers 
of healthy subjects to combination of AVYCAZ with ATM at this phase of clinical evaluation.  
Previous experience in Phase I studies has shown that the sample size being proposed is 
sufficient to fulfil the primary and secondary objectives of the study. 
 Treatment Assignment Procedures 
This is an open-label study and randomization and masking procedures are not required. 

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 Final Analysis Plan 
10.4.1 Safety 
All subjects who receive at least one dose of study product(s) will be included in the safety 
analysis. AEs [i.e., those beginning after the first dose of study product(s)] will be summarized 
using frequency counts and percentages by treatment cohort. Graphical presentations may be 
used, as appropriate. The following summaries will be presented for AEs and SAEs: 
• 
Overall (i.e., regardless of severity or relationship to study product) 
• 
By severity grade (mild, moderate, or severe), 
• 
By relationship to study product, 
• 
By MedDRA level hierarchy (System Organ Class and preferred term). 
Unless otherwise specified, at each level of subject summarization in reporting the incidence of 
the AEs, a subject will be counted once if the subject reported 1 or more events. If more than 1 
occurrence of an event is reported, the event of the worst severity or the worst-case relationship 
assessment will be summarized.  Furthermore, listings of deaths (if any), SAEs, and AEs that 
lead to study discontinuation will be made. The number of volunteers who have any AEs, SAEs, 
AEs that lead to withdrawal, and AEs judged causally related to study product(s) by the PI will 
be summarized.  Shifts in clinical laboratory data will be tabulated. 
For each treatment cohort, the percentage of subjects who experience the following selected 
dichotomous events will be calculated. Subjects will be counted for each event only once, at the 
highest observed grade. Event categories include: 
• 
Premature discontinuation of study product(s) 
• 
Any grade 1 or higher laboratory value 
• 
Any grade 1 or higher sign or symptom 
• 
Any grade 1 or higher AEs 
• 
Any grade 1 or higher occurrence of laboratory values, signs, symptoms and/or diagnosis 
• 
Grade 1 or higher of any specific AE that occurs in at least 10% of subjects for any regimen 
Separate tables and listings of SAEs will be generated. 
Safety laboratory parameters and vital signs will be tabulated for each treatment cohort using 
descriptive statistics. Laboratory values for hematologic, urinalysis, coagulation, and clinical 
chemistry panels will be compared to normal ranges as reported by the reference laboratory. 
Vital signs, physical examinations, clinical laboratory values, and ECG parameters will be 

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presented by treatment cohort. Continuous variables (hematology [including direct Coombs], 
clinical chemistry, coagulation, ECGs, urinalysis, and vital signs) will be summarized using 
descriptive statistics (n, mean, standard deviation, minimum, median, and maximum) by 
treatment, or scheduled time point, as appropriate. Categorical variables (e.g., urinalysis, etc.) 
will be summarized in frequency tables (frequency counts and proportion) by treatment, age 
group, or scheduled time point, as appropriate. Where applicable, data will be summarized for 
the absolute value at each scheduled assessment, and for the corresponding change from 
baseline. 
10.4.2 Pharmacokinetic Analyses 
Pharmacokinetic analyses will be completed by the DCRI Pharmacometrics Center (PMC).  The 
study population and methodology used to evaluate individual agent and combination PK 
parameters will be described in detail in the PK Plan and is reviewed briefly below. 
10.4.3 Initial Exploratory Analysis 
Concentration-time data will be visualized using box and whisker plots, with investigation of any 
outliers for erroneous time or concentration data entry. Individual concentration-time plots will 
be generated on linear and semi-log scales to inform potentially optimal structural model builds 
for analysis. 
10.4.4 Non-Compartmental Pharmacokinetic Analysis 
Non-compartmental analysis (NCA) will be used as the initial approach to generated base PK 
parameter estimates for each individual agent (i.e. CAZ, AVI and ATM). These analyses will be 
conducted using an appropriate statistical package. This descriptive analysis will allow for 
comparison to previously published data on each of the individual agents. The following PK 
parameters will be calculated as appropriate and if possible depending on actual samples 
collected: maximum plasma concentration (Cmax) after the first dose on Day 1, maximum plasma 
concentration at steady state (Css,max), time to Cmax (tmax), time to Css,max (tss,max), minimum plasma 
concentration at the end of the dosing interval on Day 1 [Cmin] and at steady state (Css,min), steady 
state concentration after CI (Css), area under the plasma concentration-time curve during the 
dosing interval on Day 1 [AUC(0-Tau)] and at steady state during the dosing interval [AUC0-Tau,ss], 
systemic plasma clearance (CL), renal clearance (CLR), volume of distribution during terminal 
phase (Vz), dose-normalized exposure parameters after the first and multiple dose, accumulation 
ratio for Cmax (RCmax) and AUC(0-Tau) [RAUC(0-Tau)]. Nominal sampling time will be used in PK 
calculations, unless it is decided that actual times are needed. 
10.4.5 Population Pharmacokinetic Analysis 
Population pharmacokinetic analysis provides a platform to identify patient covariates which can 
help explain a portion of the inter-individual variability in selected PK parameters. The non-

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linear mixed effects modeling software NONMEM® Version 7.2 (ICON Development Solutions, 
Ellicott City, MD) will be used to develop the population PK model for CAZ, AVI and ATM 
concentrations in plasma. Different structural PK models (e.g., 2 and 3 compartment) will be 
fitted to the concentration-time data of each drug. Between-subject variability on model 
parameters and different residual error models will be tested.  Model development will be guided 
by goodness of fit plots, plausibility of parameter estimates, and reduction in inter-individual 
variability for structural and residual error parameters, as well as objective function and 
shrinkage values. 
Upon selection of an appropriate base structural PK model, covariate effects (i.e., age, sex, body 
size descriptors and renal function) will be evaluated using stepwise forward selection followed 
by stepwise backward elimination processes.  Standard model diagnostic plots and procedures 
will be used to evaluate model appropriateness.  Model validation will be performed using visual 
predictive check and bootstrapping. 
10.4.6 Monte Carlo Simulation 
Monte Carlo simulations will be performed using the final population PK model with all 
statistically significant covariate effects. Simulated exposures of treatment cohorts will be 
evaluated. Simulated medians and 90% prediction intervals for each treatment cohort will be 
overlaid on the observed concentration-time data from subjects as a QC check. 
10.4.7 Exposure-Response Relationship Analysis 
Using the final population PK model, EBE PK parameters and dosing information, simulations 
will be performed to predict PK exposure of CAZ, AVI and ATM in study subjects. Multiple 
exposure parameters may be explored. The association between occurrence of ALT or AST 
elevations and PK exposure of CAZ, AVI and ATM will be explored using standard statistical 
correlation methodologies. 

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SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
Each participating site will maintain appropriate medical and research records in compliance 
with ICH E6, Section 4.9 and regulatory and institutional requirements for the protection of 
confidentiality of subjects. Each site will permit authorized representatives of the DMID, its 
designees, and appropriate regulatory agencies to examine (and when required by applicable law, 
to copy) clinical records for the purposes of QA reviews, audits, and evaluation of the study 
safety and progress. These representatives will be permitted access to all source data and source 
documents, which include, but are not limited to, hospital records, clinical and office charts, 
laboratory notes, memoranda, subjects’ memory aid or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions certified 
after verification as being accurate and complete, microfiches, photographic negatives, microfilm 
or magnetic media, x-rays, and subject files and records kept at the pharmacy, at the laboratories, 
and medico-technical departments involved in the clinical trial.  

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QUALITY CONTROL AND QUALITY ASSURANCE 
Following a written DMID-accepted site quality management plan, each participating site(s) and 
its subcontractors are responsible for conducting routine QA and quality control (QC) activities 
to internally monitor study progress and protocol compliance.  The site PI will provide direct 
access to all study-related sites, source data/data collection forms, and reports for the purpose of 
monitoring and auditing by the sponsor, and inspection by local and regulatory authorities.  The 
site PI will ensure all study personnel are appropriately trained and applicable documentations 
are maintained on site. 
The SDCC will implement QC procedures beginning with the data entry system and generate 
data QC checks that will be run on the database.  Any missing data or data anomalies will be 
communicated to the participating site(s) for clarification and resolution. 
 

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DATA HANDLING AND RECORD KEEPING 
 Data Management Responsibilities 
The investigator is responsible to ensure the accuracy, completeness, legibility, and timeliness of 
the data reported.  All source documents should be completed in a neat, legible manner to ensure 
accurate interpretation of data.  Black or blue permanent ink is required to ensure clarity of 
reproduced copies.  When making changes or corrections, cross out the original entry with a 
single line, and initial and date the change.  DO NOT ERASE, OVERWRITE, OR USE 
CORRECTION FLUID OR TAPE ON THE ORIGINAL. 
All source documents and laboratory reports must be reviewed by the clinical team and data 
entry staff, who will ensure that they are accurate and complete.  Adverse events must be graded, 
assessed for severity and causality, and reviewed by the site PI or designee. 
Copies of the eCRF will be provided for use as source data collection forms and maintained for 
recording data for each subject enrolled in the study.  Data reported in the eCRF derived from 
source data collection forms should be consistent or the discrepancies should be explained. 
The sponsor and/or its designee will provide guidance to the site PIs and other study personnel 
on making corrections to the data collection forms and eCRF. 
 Data Coordinating Center/Biostatistician Responsibilities 
Data collection is the responsibility of the study personnel at the participating clinical study site 
under the supervision of the site PI.  During the study, the site PI must maintain complete and 
accurate documentation for the study. 
The Emmes Company will serve as the SDDC for this study and will be responsible for data 
management, quality review, analysis (with the exception of the PK analyses) and reporting of 
the study data. Adverse events and concomitant medications will be coded using the MedDRA 
and World Health Organization Drug dictionaries (WHO DD) respectively.  The DCRI PMC 
will be responsible for all analysis of PK data. 
 Data Capture Methods 
Clinical data (including, but not limited to, AE/SAEs, concomitant medications, medical history, 
physical assessments, and clinical laboratory values) will be collected on data collection forms 
by study personnel then entered into eCRFs via a 21 CFR Part 11-compliant internet data entry 
system provided by the study data coordinating center.  The data system includes password 
protection and internal quality checks, such as automatic range checks, to identify data that 
appear inconsistent, incomplete, or inaccurate.   

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Data will be entered into the eCRF on an ongoing basis and will be reviewed on a continuous 
basis throughout the study. 
 Types of Data 
Data for this trial will be collected in a single database.  The data will include medical history, 
demographics, physical examination, vital signs, ECGs, concomitant medications, study product 
administration, PK collection times, bioanalytical data, PK modelling and safety (e.g., clinical 
laboratory values and AEs/SAEs).  The PK modelling will be completed at the DCRI PMC and a 
copy transferred to the SDDC database. 
 Study Records Retention 
Study records and reports including, but not limited to, eCRFs, source documents, ICFs, 
laboratory test results, and study product disposition records will be retained for 2 years after a 
marketing application is approved for the study product for the indication for which it is being 
investigated; or, if no application is to be filed or if the application is not approved for the study 
product, until 2 years after the investigation is discontinued and the FDA has been notified. 
These documents will be retained for a longer period, however, if required by local regulations.  
No records will be destroyed without the written consent of the sponsor. It is the responsibility of 
the sponsor to inform the site PI when these documents no longer need to be retained. 

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CLINICAL MONITORING 
Site monitoring is conducted to ensure that the human subjects’ protections, study and laboratory 
procedures, study intervention administration, and data collection processes are of high quality 
and meet sponsor, ICH/GCP guidelines and applicable regulations, and that this clinical trial is 
conducted in accordance with the protocol, protocol-specific MOP and applicable sponsor 
standard operating procedures.  DMID, the sponsoring agency, or its designee will conduct site-
monitoring visits as detailed in the clinical monitoring plan. 
Site visits will be made at standard intervals as defined by DMID and may be made more 
frequently as directed by DMID.  Monitoring visits will include, but are not limited to, review of 
regulatory files, accountability records, eCRFs, ICFs, medical and laboratory reports, and 
protocol and GCP compliance.  Site monitors will have access to each participating site, study 
personnel, and all study documentation according to the DMID-approved site monitoring plan.  
Study monitors will meet with site PIs to discuss any problems and actions to be taken, and will 
document site visit findings and discussions. 
 

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PUBLICATION POLICY 
Following completion of the study, the lead PI is expected to publish the results of this research 
in a scientific journal.  All investigators funded by the NIH must submit or have submitted for 
them to the National Library of Medicine’s PubMed Central (http://www.ncbi.nlm.nih.gov/pmc/) 
an electronic version of their final, peer-reviewed manuscripts upon acceptance for publication, 
to be made publicly available no later than 12 months after the official date of publication.  The 
NIH Public Access Policy ensures the public has access to the published results of NIH funded 
research.  It requires investigators to submit final peer-reviewed journal manuscripts that arise 
from NIH funds to the digital archive PubMed Central upon acceptance for publication.  Further, 
the policy stipulates that these papers must be accessible to the public on PubMed Central no 
later than 12 months after publication. 
Refer to: 
• 
NIH Public Access Policy, http://publicaccess.nih.gov/ 
• 
NIH Office of Extramural Research (OER) Grants and Funding, 
http://grants.nih.gov/grants/oer.htm 
As of January 2018, all clinical trials supported by the NIH must be registered on 
ClinicalTrials.gov, no later than 21 days after the enrollment of the first subject. Results of all 
clinical trials supported by the NIH, generally, need to be submitted no later than 12 months 
following the primary completion date. A delay of up to 2 years is available for trials that meet 
certain criteria and have applied for certification of delayed posting. 
As part of the result posting a copy of this protocol (and its amendments) and a copy of the 
Statistical Analysis Plan will be posted on ClincialTrials.gov. 
For this trial the responsible party is DMID which will register the trial and post results.   
The responsible party does not plan to request certification of delayed posting. 
Refer to: 
• 
Public Law 110-85, Section 801, Clinical Trial Databases 
• 
42CFR11 
• 
NIH NOT-OD-16-149 

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LITERATURE REFERENCES 
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accessed 04/29/15. 
2. Weiner LM, Webb AK, Limbago B, et al. Antimicrobial-Resistant Pathogens Associated 
With Healthcare-Associated Infections: Summary of Data Reported to the National 
Healthcare Safety Network at the Centers for Disease Control and Prevention, 2011-2014. 
Infect Control Hosp Epidemiol 2016; 37(11): 1288-301. 
3. CDC 2013. Antibiotic resistant threats in the United States. Available at: 
http://www.cdc.gov/drugresistance/threat-report-2013/. Accessed July 6, 2015. 
4. Jacoby GA, Munoz-Price LS. The new beta-lactamases. N Engl J Med 2005; 352(4): 380-91. 
5. Davido B, Fellous L, Lawrence C, Maxime V, Rottman M, Dinh A. Ceftazidime-Avibactam 
and Aztreonam, an Interesting Strategy To Overcome beta-Lactam Resistance Conferred by 
Metallo-beta-Lactamases in Enterobacteriaceae and Pseudomonas aeruginosa. Antimicrob 
Agents Chemother 2017; 61(9).(pii): e01008-17. doi: 10.1128/AAC.-17. Print 2017 Sep. 
6. Karlowsky JA, Kazmierczak KM, de Jonge BLM, Hackel MA, Sahm DF, Bradford PA. In 
Vitro Activity of Aztreonam-Avibactam against Enterobacteriaceae and Pseudomonas 
aeruginosa Isolated by Clinical Laboratories in 40 Countries from 2012 to 2015. Antimicrob 
Agents Chemother 2017; 61(9).(pii): e00472-17. doi: 10.1128/AAC.-17. Print 2017 Sep. 
7. Kazmierczak KM, Rabine S, Hackel M, et al. Multiyear, Multinational Survey of the 
Incidence and Global Distribution of Metallo-beta-Lactamase-Producing Enterobacteriaceae 
and Pseudomonas aeruginosa. Antimicrob Agents Chemother 2016; 60(2): 1067-78. doi: 
10.128/AAC.02379-15. Print 2016 Feb. 
8. Singh R, Kim A, Tanudra MA, et al. Pharmacokinetics/pharmacodynamics of a beta-lactam 
and beta-lactamase inhibitor combination: a novel approach for aztreonam/avibactam. J 
Antimicrob Chemother 2015; 70(9): 2618-26. doi: 10.1093/jac/dkv132. Epub 2015 May 29. 
9. Walsh TR, Toleman MA, Poirel L, Nordmann P. Metallo-beta-lactamases: the quiet before 
the storm? Clin Microbiol Rev 2005; 18(2): 306-25. 
10. Wenzler E, Deraedt MF, Harrington AT, Danizger LH. Synergistic activity of ceftazidime-
avibactam and aztreonam against serine and metallo-beta-lactamase-producing gram-
negative pathogens. Diagn Microbiol Infect Dis 2017; 88(4): 352-4. doi: 
10.1016/j.diagmicrobio.2017.05.009. Epub May 18. 

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11. Wright H, Bonomo RA, Paterson DL. New agents for the treatment of infections with Gram-
negative bacteria: Restoring the miracle or false dawn? Clin Microbiol Infect 2017 Oct; 
23(10): 704-712. doi: 10.1016/j.cmi.2017.09.001. Epub 2017 Sep 8 
12. IDSA Facts on Antibacterial Resistance.  
http://www.idsociety.org/uploadedFiles/IDSA/Policy_and_Advocacy/Current_Topics_and_I
ssues/Antimicrobial_Resistance/Strengthening_US_Efforts/Background/Antibiotic%20Resist
ance%20Fact%20Sheet.pdf.  accessed 04/29/15. 
13. Marshall S, Hujer AM, Rojas LJ, et al. Can Ceftazidime-Avibactam and Aztreonam 
Overcome beta-Lactam Resistance Conferred by Metallo-beta-Lactamases in 
Enterobacteriaceae? Antimicrob Agents Chemother 2017; 61(4).(pii): e02243-16. doi: 
10.1128/AAC.-16. Print 2017 Apr. 
14. Rahm C, Butterfield JM, Nicasio AM, Lodise TP. Dual beta-lactam therapy for serious 
Gram-negative infections: is it time to revisit? Diagn Microbiol Infect Dis 2014; 80(4): 239-
59. doi: 10.1016/j.diagmicrobio.2014.07.007. Epub  Jul 31. 
15. Monoue ML, Abbo LM, Rosa R, et al. In Vitro Discordance with In Vivo Activity: 
Humanized Exposures of Ceftazidime-Avibactam, Aztreonam, and Tigecycline Alone and in 
Combination against New Delhi Metallo-beta-Lactamase-Producing Klebsiella pneumoniae 
in a Murine Lung Infection Model. Antimicrob Agents Chemother 2017; 61(7).(pii): e00486-
17. doi: 10.1128/AAC.-17. Print 2017 Jul. 
16. Shaw E, Rombauts A, Tubau F, et al. Clinical outcomes after combination treatment with 
ceftazidime/avibactam and aztreonam for NDM-1/OXA-48/CTX-M-15-producing Klebsiella 
pneumoniae infection. J Antimicrob Chemother 2017. 
17. Mojica MF, Ouellette CP, Leber A, et al. Successful Treatment of Bloodstream Infection 
Due to Metallo-β-Lactamase-Producing Stenotrophomonas maltophilia in a Renal Transplant 
Patient. Antimicrob Agents Chemother. 2016;60(9):5130-4. Published 2016 Aug 22. 
doi:10.1128/AAC.00264-16 
18. AZACTAM® (aztreonam for injection, USP), Bristol-Myers Squibb, Package Insert.  
https://packageinserts.bms.com/pi/pi_azactam.pdf. 
19. AVYCAZ® (ceftazidime and avibactam) for Injection, for intravenous use. Package insert. 
https://www.allergan.com/assets/pdf/avycaz_pi 
20. Abdul-Aziz MH, Sulaiman H, Mat-Nor MB, et al. Beta-Lactam Infusion in Severe Sepsis 
(BLISS): a prospective, two-centre, open-labelled randomised controlled trial of continuous 
versus intermittent beta-lactam infusion in critically ill patients with severe sepsis. Intensive 
Care Med 2016; 42(10): 1535-45. 

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21. Ambrose PG, Bhavnani SM, Rubino CM, et al. Pharmacokinetics-pharmacodynamics of 
antimicrobial therapy: it's not just for mice anymore. Clin Infect Dis 2007; 44(1): 79-86. 
22. Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing 
of mice and men. Clin Infect Dis 1998; 26(1): 1-10; quiz 1-2. 
23. Lodise TP, Smith NM, Holden PN, T Berard, O’Donnell N, Bonomo RA, Tsuji BT. Efficacy 
of Ceftazidime-Avibactam in Combination with Aztreonam (COMBINE): Solutions for 
Metallo-β-lactamase producing-Enterobacteriaceae (MBL). Abstract # 1385. Poster 
presentation at IDweek2018™. San Francisco, CA. October 3-7, 2018.  
24. National Library of Medicine and National Institute of Diabetes and Digestive and Kidney 
Diseases.  https://livertox.nlm.nih.gov/Aztreonam.htm. 
25. Roberts JA, Abdul-Aziz MH, Davis JS, Dulhunty JM, Cotta MO, Myburgh J, Bellomo R, 
Lipman J. Continuous versus Intermittent β-Lactam Infusion in Severe Sepsis. A Meta-
analysis of Individual Patient Data from Randomized Trials. Am J Respir Crit Care Med. 
2016 Sep 15;194(6):681-91. doi: 10.1164/rccm.201601-0024OC. PubMed PMID: 26974879. 
26. Roberts JA, Kirkpatrick CM, Roberts MS, Dalley AJ, Lipman J. First-dose and steady-state 
population pharmacokinetics and pharmacodynamics of piperacillin by continuous or 
intermittent dosing in critically ill patients with sepsis. Int J Antimicrob Agents. 2010 
Feb;35(2):156-63. doi: 10.1016/j.ijantimicag.2009.10.008.Epub 2009 Dec 16. PubMed 
PMID: 20018492. 
27. Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, 
Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M,  Marini JJ, 
Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, 
Zimmerman JL, Vincent JL; International Surviving Sepsis Campaign Guidelines 
Committee; American Association of Critical-Care Nurses; American College of Chest 
Physicians; American College of Emergency Physicians; Canadian Critical Care Society; 
European Society of Clinical Microbiology and Infectious  iseases; European Society of 
Intensive Care Medicine; European Respiratory Society; International Sepsis Forum; 
Japanese Association for Acute Medicine; Japanese Society of Intensive Care Medicine; 
Society of Critical Care Medicine; Society of Hospital Medicine; Surgical Infection Society; 
World Federation of Societies of Intensive and Critical Care Medicine. Surviving Sepsis 
Campaign: international guidelines for management of severe sepsis and septic shock: 2008.  
Crit Care Med. 2008 Jan;36(1):296-327. Erratum in: Crit Care Med. 2008 Apr;36(4):1394-6. 
PubMed PMID: 18158437. 
28. Kalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney DA, Palmer LB, Napolitano 
LM, O'Grady NP, Bartlett JG, Carratalà J, El Solh AA, Ewig S, Fey PD, File TM Jr, 

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Restrepo MI, Roberts JA, Waterer GW, Cruse P, Knight SL, Brozek JL. Management of 
Adults With Hospital-acquired and Ventilator-associated Pneumonia:  2016 Clinical Practice 
Guidelines by the Infectious Diseases Society of America and the American Thoracic 
Society. Clin Infect Dis. 2016 Sep 1;63(5):e61-e111. doi: 10.1093/cid/ciw353. Epub 2016 Jul 
14. PubMed PMID: 27418577; PubMed Central  PMCID: PMC4981759. 
29. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976; 16(1): 31-41. 
30. Lexicomp Online, Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2013; 
April 15, 2013, Date accessed: December, 20, 2018. 
31. Ueo, H., et al., Human organic anion transporter hOAT3 is a potent transporter of 
cephalosporin antibiotics, in comparison with hOAT1. Biochem Pharmacol, 2005. 70(7): p. 
1104-13. 
 

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APPENDICES 
 
 

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 Schedule of Events 
Evaluation 
Screening1 
Visit 1 
Enrollment2 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Discharge 
Visit 10 / Final 
Visit 
Unscheduled / Early 
Termination Visit 
 
Day  
-30 to 
Day -2 
Day -1 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 5 
Day 
6 
Day 
7 
Day 
8 
Day 11 
(+3) 
 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Confirmation 
of eligibility 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
Medical 
history & 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Height / 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
Review of 
changes in 
medical history 
 
X 
 
 
 
 
 
 
 
X 
 
X 
Concomitant 
medications 
X 
X 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X 
X 
X 
Physical 
examination 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
Symptom 
directed 
physical 
examination 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Vital signs4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG5 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
Assessment of 
adverse events6 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assignment to 
treatment 
cohort7 
 
X 
 
 
 
 
 
 
 
 
 
 
Study product 
administration 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Clinical 
chemistry8 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
LFTs9 
 
 
 
 
 
 
X 
 
X 
 
 
 
Hematology10 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Coagulation 
test11 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Viral 
serology12 
X 
 
 
 
 
 
 
 
 
 
 
 
Coombs test 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Urinalysis13 
X 
X 
 
 
 
X 
 
 
 
X 
X 
X 

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Evaluation 
Screening1 
Visit 1 
Enrollment2 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Discharge 
Visit 10 / Final 
Visit 
Unscheduled / Early 
Termination Visit 
 
Day  
-30 to 
Day -2 
Day -1 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 5 
Day 
6 
Day 
7 
Day 
8 
Day 11 
(+3) 
 
Serum hCG 
pregnancy 
test14 
X 
X 
 
 
 
 
 
 
 
 
 
 
Alcohol Screen 
breathalyzer 
X 
X 
 
 
 
 
 
 
 
 
 
 
Urine cotinine 
test 
X 
X 
 
 
 
 
 
 
 
 
 
 
Urine drug 
screen15 
X 
X 
 
 
 
 
 
 
 
 
 
 
Plasma PK16 
 
 
X 
 
X 
 
X 
 
X 
X 
 
X17 
Urine PK18 
 
 
X 
 
 
 
 
X 
 
 
 
 
1. 
Screening evaluations must be completed within 30 days prior to enrollment 
2. 
All baseline procedures should be done before study intervention 
3. 
Review for any new medication only 
4. 
Vital Signs:  collected after 10 minutes of resting in supine position and include systolic and diastolic blood pressures (mmHg), pulse rate 
(BPM), respiratory rate, and body temperature (oral measurement).  Day 1 - prior to dosing on Day 1 and 1 hour after starting AM dose.  
Days 2-8 will be obtained each morning 
5. 
Subjects must be lying supine or sitting for 10 minutes prior to ECG.  ECG will be done in triplicate 2 minutes apart at Screening only.  
Single ECGs will be recorded on Days -1, 8, and 11 (+3) 
6. 
Monitoring for adverse events will begin after the first dose of study product 
7. 
Assignment to dosing cohort:  Must occur after all inclusion and exclusion criteria have been confirmed 
8. 
Clinical Chemistry: sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, albumin, total protein, total bilirubin, ALT, AST, 
ALP and LDH 
9. 
Liver function tests (LFTs): ALT, AST, ALP, and total bilirubin 
10. Hematology: Hemoglobin, hematocrit, WBC, WBC differential, RBC, platelets 
11. Coagulation: PT and PTT 
12. Viral serology:  HIV, HBsAg, HCV antibody 
13. Urinalysis: Dipstick urinalysis, including protein, glucose, ketones, bilirubin, blood, nitrites, LCE, urobilinogen, specific gravity, and pH 
14. Serum pregnancy test on Day-1 must be completed within 48 hours prior dosing.  Results must be obtained prior to study product(s) 
administration 
15. Urine drug screen for: amphetamines, barbiturates, benzodiazepines, cocaine metabolites, opiates, cannabinoids and phencyclidine 
16. Plasma PK collection times:  See Section 7.2.2.1 
17. Unscheduled visit – plasma PK collection is optional 
18. Urine PK collection times:  See Section 7.2.2.2 
 
 

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Toxicity Table 
Clinical Adverse Events 
CARDIOVASCULAR 
TOXICITY 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Arrhythmia 
 
Asymptomatic; 
transient signs; no 
medical intervention 
required  
Recurrent/persistent; 
symptomatic medical 
intervention required  
Hemorrhage, Blood Loss  
Estimated blood 
loss <100 mL  
Estimated blood loss 
≥100 mL, no 
transfusion required 
Transfusion required 
QTc (Fridericia’s correction)1 
 
or QTcb (Bazett’s)1 
Asymptomatic, QTc 
interval 450-479 
msec OR Increase 
in interval  
20-30 msec above 
baseline 
Asymptomatic, QTc 
interval 480-499 msec 
OR Increase in interval 
31-50 msec above 
baseline 
Asymptomatic, QTc interval ≥ 
500 msec OR Increase in 
interval ≥ 51 msec above 
baseline 
PR Interval (prolonged)1 
PR interval  
0.21-0.25 sec 
PR interval >0.25 
Type II 2nd degree AV block 
OR Ventricular pause >3.0 sec 
RESPIRATORY 
TOXICITY 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Cough 
Transient; no 
treatment  
Persistent cough  
Interferes with daily activities 
Bronchospasm, Acute 
Transient; no 
treatment;  
71% - 80% FEV1 
of predicted peak 
flow  
Requires medical 
intervention; 
normalizes with 
bronchodilator; FEV1 
60% - 70% (of 
predicted peak flow)  
No normalization with 
bronchodilator; FEV1 < 60% 
of predicted peak flow 
Dyspnea   
Does not interfere 
with usual and 
social activities 
Interferes with usual 
and social activities; no 
treatment 
Prevents daily and usual social 
activity OR requires treatment 
GASTROINTESTINAL 
TOXICITY 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Nausea  
No interference 
with activity 
Some interference with 
activity 
Prevents daily activities 
Vomiting  
No interference 
with activity OR  
1 - 2 episodes/24 
hours 
Some interference with 
activity OR  
>2 episodes/24 hours 
Prevents daily activity OR 
requires IV hydration OR 
requires medical intervention 
Diarrhea  
2 - 3 loose or 
watery stools or 
<400 g24 hours 
4 - 5 loose or watery 
stools or 400 - 800 
g/24 hours 
6 or more loose or watery 
stools or >800g24 hours OR 
requires IV hydration OR 
requires medical intervention 
 
1 Inclusion dependent upon protocol requirements. 

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LOCAL REACTIONS 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Pain 
Does not interfere 
with activity 
Repeated use of non-
narcotic pain reliever 
>24 hours OR 
interferes with activity 
Any use of narcotic pain 
reliever OR prevents daily 
activity 
Tenderness 
Discomfort only to 
touch 
Discomfort with 
movement 
Significant discomfort at rest 
Erythema/Redness2 
2.5 - 5 cm 
5.1 - 10 cm 
>10 cm 
Induration/Swelling3 
2.5 - 5 cm and does 
not interfere with 
activity 
5.1 - 10 cm OR 
interferes with activity 
>10 cm OR prevents daily 
activity 
SYSTEMIC REACTIONS 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Allergic Reaction  
Pruritus without 
rash  
Localized urticaria OR 
requires oral therapy 
Generalized urticaria; 
angioedema OR anaphylaxis 
OR requires epinephrine 
Headache  
No interference 
with activity 
Repeated use of non-
narcotic pain reliever 
>24 hours OR some 
interference with 
activity 
Significant; any use of 
narcotic pain reliever OR 
prevents daily activity OR 
requires triptans  
Fatigue  
No interference 
with activity 
Some interference with 
activity 
Significant; prevents daily 
activity 
Myalgia 
No interference 
with activity 
Some interference with 
activity 
Significant; prevents daily 
activity 
All Other conditions 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Illness or clinical adverse 
event (as defined according to 
applicable regulations) 
No interference 
with activity 
Some interference with 
activity not requiring 
medical intervention 
Prevents daily activity and 
requires medical intervention 
 
 
2 In addition to grading the measured local reaction at the greatest single diameter, the measurement should be 
recorded as a continuous variable. 
3 Induration/Swelling should be evaluated and graded using the functional scale as well as the actual measurement.  

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Laboratory and Vital Signs Reference Ranges, Eligibility Ranges, and Toxicity Grading 
Blood, Serum, or Plasma Chemistries1 
Reference 
Range2 
Eligibility 
Range3 
LO/HI/N4 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Sodium (mEq/L) 
135 - 145 
135 - 145 
LO 
132 - <LLN 
130 - 131 
<130 
HI 
>ULN - 148 
149 - 150 
>150 
Potassium (mEq/L) 
3.5 – 5.0 
3.5 – 5.0 
HI 
>ULN - 5.2 
5.3 - 5.4 
>5.4 
LO 
>LLN - 3.1 
<3.1 - 3.0 
<3.0 
Blood Urea Nitrogen (BUN, mg/dL) 
7 - 20 
7 - 20 
HI 
21 - 26 
27 - 31 
>31 
Creatinine (mg/dL) 
0.5 - 1.2 
0.5 – 1.2 
HI 
>ULN - 1.7 
1.8 - 2.0 
>2.0 
Glucose (mg/dL) 
<70 
<70 
LO 
65 - 69 
55 - 64 
<55 
70 - 99 
70 - 99 
HI5 
>ULN - 120 
121 - 130 
>130 
70 - 140 
70 - 140 
HI6 
141 - 159 
160 - 200 
>200 
Total Protein (g/dL) 
5.8 - 7.8 
5.8 - 7.8 
LO 
5.2 - <LLN 
4.8 - 5.1 
<4.8 
Bilirubin, serum total (mg/dL)  
0.4 - 1.5 
0.4 - 1.5 
HI 
1.6 - 2.0 
2.1 - 2.5 
>2.5 
ALT (U/L) 
Female: 14-54 
Female: 14-54 
HI 
>ULN - 105 
106 - 175 
>175 
Male: 17-63 
Male: 17-63 
AST (U/L) 
15 - 41 
15 - 41 
HI 
42 - 105 
106 - 175 
>175 
Alkaline phosphatase (U/L) 
24 - 110 
24 - 110 
HI 
111 - 240 
241 - 360 
>360 
 
 
1 Depending upon the lab used, references ranges, eligibility ranges and grading may be split out by sex and/or age. 
2 Reference range of site laboratory 
3 Laboratory values acceptable for eligibility for enrollment 
4 High, Low, Not Graded 
5 Fasting 
6 Non-fasting 

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Hematology 
Reference 
Range7 
Eligibility 
Range8 
LO/HI/N9 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Hemoglobin (Females) (g/dL) 
Hemoglobin (Males) (g/dL) 
12.0-15.5 
12.0-15.5 
LO 
11.0 - 11.9 
9.5 - 10.9 
<9.5 
13.7-17.3 
13.7-17.3 
LO 
12.0 – 13.6 
10.0 - 11.9 
<10.0 
White Blood Cell Count (WBC, K/CUMM) 
3.2-9.8 
3.2-9.8 
HI 
9.9 – 14.99 
15.00 - 20.00 
>20.00 
LO 
2.50 - 3.19 
1.50 - 2.49 
<1.50 
Lymphocytes (K/CUMM) 
0.6-4.2 
0.6-4.2 
LO 
0.50 – 0.59 
0.40 - 0.49 
<0.4 
Neutrophils (K/CUMM) 
2.0-8.6 
2.0-8.6 
LO 
1.50 – 1.99 
1.00 - 1.49 
<1.00 
Eosinophils (K/CUMM) 
0.0-0.7 
0.0-0.7 
HI 
>ULN - 0.74 
0.75 - 1.50 
>1.50 
Platelets (K/CUMM) 
150-450 
150-450 
LO 
120 - 149 
100 - 119 
<100 
Coagulation 
 
 
 
 
 
 
Prothrombin time (PT, seconds) 
9.5-13.1 
9.5-13.1 
HI 
>ULN - 14.4 
14.5 - 15.7 
>15.7 
Partial thromboplastin time (PTT or aPTT, seconds) 
26.8-37.1 
26.8-37.1 
HI 
>ULN - 42.1 
42.2 - 50.0 
>50.0 
Urine*  
 
 
 
 
 
 
Protein (dipstick) 
0 
0 
HI 
1+ 
2+ 
>2+ 
Glucose (dipstick) 
0 
0 
HI 
1+ 
2+ 
>2+ 
 
Vital Signs 
Mild  
(Grade 1)10 
Moderate  
(Grade 2) 
Severe  
(Grade 3) 
Fever (°F)  
100.4 - 101.1 
101.2 - 102.0 
≥102.1 
 
7 Reference range of site laboratory 
8 Laboratory values acceptable for eligibility for enrollment 
9 High, Low, Not Graded 
10 If initial bound of Grade 1 has gap from reference range or eligibility range, calculations based on NEJM reference ranges 

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Vital Signs 
Mild  
(Grade 1)10 
Moderate  
(Grade 2) 
Severe  
(Grade 3) 
Tachycardia - beats per minute11 
101 - 115 
116 - 130 
>130 or ventricular 
dysrhythmias 
Bradycardia - beats per minute12 
50 – 54 or 45 – 49 
if baseline 50-59 bpm 
45 – 49 or 40 - 44 
if baseline 50-59 bpm 
< 45 or <40 
if baseline 50-59 bpm 
Hypertension (systolic) - mm Hg13 
141 - 150 
151 - 160 
>160 
Hypertension (diastolic) - mm Hg 
91 - 95 
96 - 100 
>100 
Hypotension (systolic) - mm Hg 
85 - 89 
80 - 84 
<80 
Tachypnea - breaths per minute 
23 - 25 
26 - 30 
>30 
 
 
11 Expanded heart rate limits can be considered with normal ECGs. 
12 Expanded heart rate limits can be considered with normal ECGs. 
13 Assuming subject is awake, resting, and supine; for AE, 3 measurements on the same arm with concordant results.