A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Intravenous Ertapenem in Combination With Zidebactam (WCK 6777) In Healthy Adult Subjects
Phase: PHASE1
Conditions: Bacterial Infection
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

DMID Protocol 21-0013 
Version 5.0 
WCK 6777 [Ertapenem-Zidebactam (ERT-ZID)] 
                             
15 June 2023 
 
 
DMID/NIAID/NIH 
CONFIDENTIAL 
 
 
 
1 
A PHASE I, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED, DOSE ESCALATION STUDY TO EVALUATE 
THE SAFETY, TOLERABILITY, AND PHARMACOKINETICS 
OF INTRAVENOUS ERTAPENEM IN COMBINATION WITH 
ZIDEBACTAM (WCK 6777) IN HEALTHY ADULT SUBJECTS 
 
DMID Protocol Number: 21-0013 
 
 
DMID Funding Mechanism: Phase 1 Clinical Trial Units 
 
 
Pharmaceutical Support: Wockhardt Bio AG 
 
 
IND Sponsor: Division of Microbiology and Infectious Diseases (DMID), 
National Institute of Allergy and Infectious Diseases (NIAID),  
National Institutes of Health (NIH) 
 
 
Site Principal Investigator: Martin Kankam, MD, PhD, MPH, FAPCR 
 
 
DMID Clinical Project Manager: Maureen Mehigan, RN 
 
Version Number: 5.0 
 
 
15 June 2023 
 

DMID Protocol 21-0013 
Version 5.0 
WCK 6777 [Ertapenem-Zidebactam (ERT-ZID)] 
                             
15 June 2023 
 
 
DMID/NIAID/NIH 
CONFIDENTIAL 
 
 
 
2 
STATEMENT OF COMPLIANCE 
The clinical trial will be carried out in accordance with Good Clinical Practice (GCP) and as 
required by the following: 
• United States (U.S.) Code of Federal Regulations (CFR) applicable to clinical trials 
(45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 54, 21 CFR Part 56, and 21 CFR Part 312). 
• International Council for Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use E6(R2) Good Clinical Practice (ICH E6 GCP): Integrated 
Addendum to ICH E6(R1) Guidance for Industry, published in the Federal Register (83 
Federal Register 8882 (2018)), including the latest finalized National Institutes of Health 
(NIH) Clinical Terms of Award, as applicable. 
Compliance with these standards provides public assurance that the rights, safety, and well-being 
of the subjects are protected and, consistent with principles that originate in the Declaration of 
Helsinki. 
All key personnel (all individuals responsible for the design and conduct of the trial) have 
completed Human Subjects Protection Training. 
 
 

DMID Protocol 21-0013 
Version 5.0 
WCK 6777 [Ertapenem-Zidebactam (ERT-ZID)] 
                             
15 June 2023 
 
 
DMID/NIAID/NIH 
CONFIDENTIAL 
 
 
 
3 
SIGNATURE PAGE 
The signature below constitutes the approval of the protocol and its attachments and provides the 
necessary assurances that the trial will be conducted according to all stipulations of the protocol, 
including all statements regarding confidentiality, and according to local legal and regulatory 
requirements as well as applicable U.S. federal regulations and ICH guidelines. 
 
 
 
Site Investigator: 
 
 
Martin Kankam, MD, PhD, MPH, FAPCR 
_________________________________________________ 
Name/Title (Print) 
 
 
Signature: 
 
_________________________________________________ 
 
Date:  
 
_________________________________________________ 
 
 

DMID Protocol 21-0013 
Version 5.0 
WCK 6777 [Ertapenem-Zidebactam (ERT-ZID)] 
                             
15 June 2023 
 
 
DMID/NIAID/NIH 
CONFIDENTIAL 
 
 
 
4 
TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE .................................................................................................2 
SIGNATURE PAGE .......................................................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF ABBREVIATIONS ........................................................................................................10 
PROTOCOL SUMMARY .............................................................................................................16 
1 
Key Roles ..............................................................................................................................22 
2 
Background Information and Scientific Rationale ...............................................................23 
2.1 
Background Information ...........................................................................................23 
2.2 
Ertapenem and Zidebactam (WCK 6777).................................................................24 
2.2.1 Zidebactam (WCK 5107) .........................................................................25 
2.2.1.1 Physicochemical properties ..........................................................25 
2.2.1.2 Mechanism of Action ...................................................................26 
2.2.1.3 Antibacterial activity ....................................................................26 
2.2.1.4 In Vitro Drug Interaction Studies .................................................26 
2.2.1.5 Genetic Toxicity ...........................................................................26 
2.2.1.6 Preclinical In Vivo Safety Profile .................................................27 
2.2.2 Ertapenem .................................................................................................27 
2.2.2.1 Physicochemical Properties ..........................................................27 
2.2.2.2 Mechanism of Action ...................................................................27 
2.2.2.3 Antibacterial Activity ...................................................................28 
2.2.2.4 In Vitro Drug Interaction Studies .................................................28 
2.2.2.5 Genetic Toxicity ...........................................................................28 
2.2.2.6 Preclinical and Clinical Safety Profile ..........................................28 
2.2.2.7 Clinical Indication ........................................................................29 
2.2.3 WCK 6777 (Combination of ERT and ZID) ............................................29 
2.2.3.1 Mechanism of Action ...................................................................29 
2.2.3.2 Antibacterial activity – In Vitro ....................................................29 
2.2.3.3 Antibacterial activity – In Vivo .....................................................30 
2.2.3.4 Safety Pharmacology – In Vitro ...................................................30 
2.2.3.5 Preclinical Safety – In Vivo ..........................................................31 
2.3 
Clinical Experience ...................................................................................................31 
2.3.1 Human Studies with Zidebactam .............................................................31 
2.3.1.1 Safety and Tolerability .................................................................31 
2.3.1.2 Pharmacokinetics ..........................................................................32 
2.3.2 Human Studies with Ertapenem ...............................................................33 
2.3.2.1 Safety and Tolerability .................................................................33 
2.3.2.2 Pharmacokinetics ..........................................................................34 

DMID Protocol 21-0013 
Version 5.0 
WCK 6777 [Ertapenem-Zidebactam (ERT-ZID)] 
                             
15 June 2023 
 
 
DMID/NIAID/NIH 
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2.3.3 Human Studies with WCK 6777 ..............................................................34 
2.4 
Rationale ...................................................................................................................34 
2.4.1 Study Rationale ........................................................................................34 
2.4.2 Rationale for Dose Selection ....................................................................35 
2.5 
Identified and Potential Risks and Benefits Associated with the Study ...................35 
2.5.1 Risks with ZID .........................................................................................35 
2.5.2 Risks with ERT ........................................................................................36 
2.5.3 Risks with WCK 6777 ..............................................................................36 
2.5.4 Venipuncture and IV Catheter Risks ........................................................36 
2.5.5 Additional Risks .......................................................................................37 
2.6 
Known Potential Benefits .........................................................................................37 
2.7 
Risk/Benefit Ratio .....................................................................................................37 
3 
Objectives and Outcome Measures .......................................................................................39 
3.1 
Study Objectives .......................................................................................................39 
3.2 
Study Outcome Measures .........................................................................................39 
4 
Study Design .........................................................................................................................40 
4.1 
Sub-studies ................................................................................................................43 
5 
Study Enrollment and Withdrawal .......................................................................................44 
5.1 
Subject Inclusion Criteria .........................................................................................44 
5.2 
Subject Exclusion Criteria ........................................................................................45 
5.3 
Treatment Assignment Procedures ...........................................................................46 
5.3.1 Enrollment and Randomization Procedures .............................................46 
5.3.2 Masking Procedures .................................................................................47 
5.3.3 Reasons for Withdrawal and Discontinuation of Study Drug 
Administration ..........................................................................................48 
5.3.4 Handling of Withdrawals and Discontinuation of Study Drug 
Administration ..........................................................................................48 
5.3.5 Lost to Follow-up .....................................................................................49 
5.3.6 Termination of Study ................................................................................49 
6 
Study Intervention/investigational products .........................................................................50 
6.1 
Description of Study Products ..................................................................................50 
6.1.1 Zidebactam for Injection, 1 g/vial ............................................................50 
6.1.2 Ertapenem Sodium for Injection, 1 g/vial (ERT) .....................................50 
6.1.3 WCK 6777 (ERT-ZID) ............................................................................50 
6.1.4 Placebo .....................................................................................................51 
6.1.5 Acquisition ...............................................................................................51 
6.1.6 Formulation, Packaging, and Labeling .....................................................51 
6.1.7 Product Storage and Stability ...................................................................52 
6.1.7.1 Stability in Storage Prior to Reconstitution ..................................52 

DMID Protocol 21-0013 
Version 5.0 
WCK 6777 [Ertapenem-Zidebactam (ERT-ZID)] 
                             
15 June 2023 
 
 
DMID/NIAID/NIH 
CONFIDENTIAL 
 
 
 
6 
6.1.7.2 Stability of ERT or ZID after Reconstitution in Sterile Water for 
Injection ........................................................................................53 
6.1.7.3 Stability of ERT or ZID after Dilution in 0.9% Sodium Chloride
 ......................................................................................................53 
6.1.7.4 Photostability ................................................................................53 
6.2 
Dosage, Preparation, and Administration of Study Intervention/ Investigational 
Products.....................................................................................................................54 
6.3 
Modification of the Study Intervention/ Investigational Products ............................54 
6.3.1 Overdose ...................................................................................................54 
6.4 
Accountability Procedures for the Study Intervention/ Investigational Products .....55 
6.5 
Assessment of Subject Compliance with the Study Intervention/ Investigational 
Products.....................................................................................................................56 
6.6 
Prior and  Concomitant Medications/Treatments .....................................................56 
6.7 
Subject Restrictions  and Precautions .......................................................................57 
6.7.1 Smoking ....................................................................................................57 
6.7.2 Physical Activity ......................................................................................57 
6.7.3 Food and Fluid intake ...............................................................................57 
6.7.4 Alcohol, Marijuana and Illicit Drugs .......................................................58 
7 
Study Schedule .....................................................................................................................59 
7.1 
Recruitment ...............................................................................................................59 
7.2 
Screening Visit (Day -28 to Day -2) .........................................................................59 
7.3 
Baseline / Check-in (Day -1) ....................................................................................60 
7.4 
Inpatient Treatment Period (Days 1 to 8) .................................................................61 
7.4.1 DAY 1 ......................................................................................................61 
7.4.2 DAY 2 ......................................................................................................62 
7.4.3 DAY 3 ......................................................................................................63 
7.4.4 DAY 4 ......................................................................................................64 
7.4.5 DAY 5 ......................................................................................................65 
7.4.6 DAY 6 ......................................................................................................66 
7.4.7 DAY 7 ......................................................................................................66 
7.4.8 DAY 8 ......................................................................................................68 
7.5 
Outpatient Follow-up Period / Last Visit (Day 11 + 3 days) ....................................68 
7.6 
Early Termination (if needed) ...................................................................................69 
7.7 
Unscheduled Visit (if needed) ..................................................................................69 
8 
Clinical Procedures / Evaluations .........................................................................................70 
8.1 
Clinical Procedures and Evaluations ........................................................................70 
8.1.1 Informed Consent .....................................................................................70 
8.1.2 Demographics ...........................................................................................70 
8.1.3 Inclusion/Exclusion Criteria .....................................................................70 

DMID Protocol 21-0013 
Version 5.0 
WCK 6777 [Ertapenem-Zidebactam (ERT-ZID)] 
                             
15 June 2023 
 
 
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8.1.4 Medical History ........................................................................................70 
8.1.5 Physical Examination ...............................................................................71 
8.1.6 Vital Signs ................................................................................................71 
8.1.6.1 Screening to Predose on Day 1 .....................................................71 
8.1.6.2 Post Dosing on Day 1 through Day 11 (+ 3days) or ET ...............72 
8.1.7 12-lead Standard Electrocardiogram (ECG) ............................................72 
8.2 
Laboratory Evaluations .............................................................................................72 
8.2.1 Clinical Laboratory Evaluations (Hematology, Coagulation, 
Chemistry and Urinalysis) ........................................................................72 
8.2.2 Viral Serology Testing .............................................................................73 
8.2.3 Pregnancy Testing ....................................................................................73 
8.2.4 Serum FSH Testing ..................................................................................74 
8.2.5 Urine Toxicology Screening ....................................................................74 
8.2.6 Urine Alcohol and Cotinine Testing ........................................................74 
8.3 
Blood and Urine Sampling and Bioanalytical Assays for Pharmacokinetics (PK) ..74 
8.3.1 Blood Sampling for Plasma Total and Free ERT and ZID Assay ............74 
8.3.2 Collection of Urine for Total ERT and ZID Assay ..................................75 
8.3.3 Specimen Preparation, Handling and Shipping ........................................75 
8.3.3.1 Instructions for Specimens Preparation, Handling, and Storage ..75 
8.3.3.2 Specimen Shipment ......................................................................76 
8.4 
Disposition of Plasma and Urine Samples ................................................................77 
9 
Assessment of Safety ............................................................................................................78 
9.1 
Specification of Safety Parameters ...........................................................................78 
9.2 
Methods and Timing for Assessing, Recording and Analyzing Safety Parameters .78 
9.2.1 Adverse Events .........................................................................................78 
9.2.2 Severity of Events ....................................................................................79 
9.2.3 Relationship to Study Products ................................................................79 
9.2.4 Reporting Adverse Events ........................................................................80 
9.2.5 Serious Adverse Events ............................................................................80 
9.2.6 Procedures to be Followed in the Event of Abnormal Laboratory Test 
Values or Abnormal Clinical Findings .....................................................81 
9.3 
Reporting Procedures ................................................................................................81 
9.3.1 Serious Adverse Events ............................................................................81 
9.3.2 SUSAR Regulatory Reporting for Studies Conducted under DMID 
Sponsored IND .........................................................................................82 
9.3.3 Other Adverse Events (if applicable) .......................................................83 
9.3.3.1 Reporting of Overdose ..................................................................83 
9.3.3.2 Reporting of Pregnancy ................................................................83 
9.4 
Type and Duration of Follow-up of Subjects after Adverse Events .........................84 

DMID Protocol 21-0013 
Version 5.0 
WCK 6777 [Ertapenem-Zidebactam (ERT-ZID)] 
                             
15 June 2023 
 
 
DMID/NIAID/NIH 
CONFIDENTIAL 
 
 
 
8 
9.5 
Halting Rules ............................................................................................................84 
9.5.1 Study Halting Criteria ..............................................................................84 
9.5.2 Individual Subject Halting Criteria ..........................................................84 
9.5.3 Dose Escalation Halting Criteria ..............................................................85 
9.6 
Safety Oversight........................................................................................................86 
9.6.1 Safety Monitoring Committee (SMC) ......................................................86 
10 
Clinical Monitoring...............................................................................................................87 
10.1 
Site Monitoring Plan .................................................................................................87 
11 
Statistical Considerations ......................................................................................................88 
11.1 
Study Hypotheses......................................................................................................88 
11.2 
Sample Size Considerations ......................................................................................88 
11.3 
Safety Review ...........................................................................................................88 
11.4 
Final Analysis Plan ...................................................................................................88 
11.4.1 Analysis Populations ................................................................................89 
11.4.2 Demographics and Baseline Characteristics ............................................89 
11.4.3 Safety Analysis .........................................................................................89 
11.4.3.1 Adverse and Serious Adverse Events ...........................................89 
11.4.3.2 Additional Safety Analyses ..........................................................90 
11.4.3.3 Tolerability Assessment ................................................................90 
11.4.4 PK Analysis ..............................................................................................90 
11.4.5 Plasma PK parameters: .............................................................................91 
11.4.6 Urine PK parameters: ...............................................................................92 
11.4.7 Missing Values and Outliers ....................................................................92 
11.4.8 Multiple Comparisons / Multiplicity ........................................................93 
11.4.9 Interim Reports .........................................................................................93 
12 
Source Documents and Access to Source Data/Documents .................................................94 
13 
Quality Control and Quality Assurance ................................................................................95 
14 
Ethics/Protection of Human Subjects ...................................................................................96 
14.1 
Ethical Standard ........................................................................................................96 
14.2 
Institutional Review Board .......................................................................................96 
14.3 
Informed Consent Process ........................................................................................96 
14.4 
Exclusion of Women, Minorities and Children (Special Populations) .....................97 
14.5 
Subject Confidentiality .............................................................................................98 
14.6 
Certificate of Confidentiality ....................................................................................98 
14.7 
Study Discontinuation ...............................................................................................99 
15 
Data Handling and Record Keeping ...................................................................................100 
15.1 
Data Management Responsibilities.........................................................................100 
15.2 
Data Capture Methods ............................................................................................100 
15.3 
Types of Data ..........................................................................................................100 

DMID Protocol 21-0013 
Version 5.0 
WCK 6777 [Ertapenem-Zidebactam (ERT-ZID)] 
                             
15 June 2023 
 
 
DMID/NIAID/NIH 
CONFIDENTIAL 
 
 
 
9 
15.4 
Timing/Reports .......................................................................................................101 
15.5 
Study Records Retention .........................................................................................101 
15.6 
Protocol Deviations .................................................................................................101 
16 
Publication Policy ...............................................................................................................102 
17 
Literature References ..........................................................................................................103 
18 
Appendices..........................................................................................................................106 
Appendix A: Schedule of Study Procedures and Evaluations .....................................................107 
Appendix B: Adverse Events Toxicity Grading Criteria .............................................................109 
Appendix C: Blood Volume Withdrawn During the Trial ..........................................................119 
 
 
 
LIST OF TABLES 
Table 1 Study Treatment Cohort................................................................................................... 40 
Table 2 Toxicity Grading Tables – CLINICAL AEs .................................................................. 110 
Table 3 Toxicity Grading Tables – LABORATORY AEs ......................................................... 114 
Table 4 Toxicity Grading Tables – ECG .................................................................................... 118 
Table 5: Laboratory Samples and Estimated Total Blood Volume (mL) ................................... 119 
 
 
LIST OF FIGURES 
Figure 1 Description Schematic of Study Design ......................................................................... 21 
 

DMID Protocol 21-0013 
Version 5.0 
WCK 6777 [Ertapenem-Zidebactam (ERT-ZID)] 
                             
15 June 2023 
 
 
DMID/NIAID/NIH 
CONFIDENTIAL 
 
 
 
10 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
Ae, urine 
Amount of unchanged drug excreted in urine during each collection 
interval 
Ae,urine(0-24) 
Cumulative amount of unchanged drug excreted in urine from zero 
(predose) to 24 hours 
Ae,urine(0-36) 
Cumulative amount of unchanged drug excreted in urine from zero 
(predose) to 36 hours 
ALT 
Alanine Aminotransferase 
AP 
Alkaline Phosphatase 
APTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Concentration – Time Curve 
AUC (0-t) 
Area under the concentration - time curve from time zero to time t 
AUC(0-24) 
Area under the concentration – time curve from time zero to 24 h 
AUC(0-∞) 
Area under the concentration - time curve from time zero to infinity 
AUC(0-last) 
Area under the concentration - time curve from time zero to the last 
concentration above the lower limit of quantitation 
AUC(0-tau) 
Area under the concentration – time curve to the end of the dosing interval  
β-HCG 
Beta Human Chorionic Gonadotropin 
BL 
β-lactamase 
BLI 
β-lactamase inhibitor 
BMI 
Body Mass Index 
BP 
Blood Pressure 
bpm 
Beats per Minute 
BUN 
Blood Urea Nitrogen 
CAP 
Community-acquired Pneumonia 
CBC 
Complete Blood Count 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CHEM 
Chemistry Panel 
CI 
Confidence Interval 

DMID Protocol 21-0013 
Version 5.0 
WCK 6777 [Ertapenem-Zidebactam (ERT-ZID)] 
                             
15 June 2023 
 
 
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11 
cIAI 
Complicated Intra-abdominal Infections 
Cavg 
Calculated average concentration during the dosing interval 
Cmax 
Maximum Concentration 
Cmin 
Minimum Concentration 
CLCR 
Creatinine Clearance 
CLr(0-24) 
Renal clearance to 24 h after initial dose 
CLr, ss 
Renal clearance following multiple dosing 
CLT 
Total Clearance 
CMS 
Clinical Materials Services 
ConMed(s) 
Concomitant Medication(s) 
COAG 
Coagulation 
CPM 
Clinical Project Manager 
CRE 
Carbapenem-Resistant Enterobacterales 
CROMS 
Clinical Research Operations and Management Support 
CSR 
Clinical Study Report 
CTU 
Clinical Trial Unit 
cUTI 
Complicated Urinary Tract Infection 
DBP 
Diastolic Blood Pressure 
DVC 
Dynport Vaccine Company, LLC, a GDIT company 
dL 
Deciliter 
DMID 
Division of Microbiology and Infectious Diseases, NIAID, NIH 
eCRF 
Electronic Case Report Form 
EC 
Ethics Committee 
ECG  
Electrocardiogram 
EDC 
Electronic Data Capture 
ERT 
Ertapenem 
ESBL 
Extended-Spectrum β-lactamases 
ET 
Early Termination 
fe,urine(0-24) 
Fraction of dose excreted unchanged in urine from zero (predose) to 24 
hours 

DMID Protocol 21-0013 
Version 5.0 
WCK 6777 [Ertapenem-Zidebactam (ERT-ZID)] 
                             
15 June 2023 
 
 
DMID/NIAID/NIH 
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fe,urine(0-36) 
Fraction of dose excreted unchanged in urine from zero (predose) to 36 
hours 
FEP 
Cefepime 
FDA 
Food and Drug Administration 
FH 
Family History 
FSH 
Follicle-Stimulating Hormone 
FWA 
Federalwide Assurance 
g 
Gram(s) 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
eGFR 
Estimated GFR 
h 
Hour(s) 
HBsAg 
Hepatitis B Surface Antigen 
Hct 
Hematocrit 
HCV 
Hepatitis C Virus 
HEENT 
Head, Eyes, Ears, Nose, and Throat 
HEM 
Hematology Panel 
Hgb 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 
HLGT 
High Level Group Term 
HPF 
High-Powered Field 
HR 
Heart Rate 
IATA 
International Air Transport Association 
IB 
Investigator’s Brochure 
IC50 
Half Maximal Inhibitory Concentration 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization 
IMP 
Imipenemase  
IND 
Investigational New Drug  
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 

DMID Protocol 21-0013 
Version 5.0 
WCK 6777 [Ertapenem-Zidebactam (ERT-ZID)] 
                             
15 June 2023 
 
 
DMID/NIAID/NIH 
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13 
IUD 
Intrauterine Device 
IV 
Intravenous(ly) 
kg 
Kilogram(s) 
LC-MS/MS 
Liquid Chromatography with Tandem Mass Spectrometry 
LLN 
Lower Limit of Normal 
MAD 
Multiple Ascending Dose 
MBL 
Metallo-β-lactamases 
MDR 
Multiple Drug Resistant 
MedDRA 
Medical Dictionary for Regulatory Activities 
µg 
Microgram(s) 
mg 
Milligram(s) 
MH 
Medical History 
MIC 
Minimum Inhibitory Concentration 
min 
Minute(s) 
mL 
Milliliter(s) 
MM 
Medical Monitor 
mmHg 
Millimeters of Mercury 
mmol 
Millimole(s) 
MO 
Medical Officer 
MOP 
Manual of Procedures 
msec 
Milliseconds(s) 
N 
Number (typically refers to the total number of subjects) 
n 
Number (typically refers to a subset of the total number of subjects) 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH 
NIH 
National Institutes of Health 
NOAEL 
No Observable Adverse Effect Level 
NSAID 
Nonsteroidal Anti-Inflammatory Drug 
OAT 
Organic Anion Transporter  
OPAT 
Out-Patient Parenteral Antibiotic Therapy 
OER 
Office of Extramural Research, NIH 
OTC 
Over the Counter 

DMID Protocol 21-0013 
Version 5.0 
WCK 6777 [Ertapenem-Zidebactam (ERT-ZID)] 
                             
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PD 
Pharmacodynamic(s) 
PE 
Physical Examination 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
POC 
Point of Contact 
Protime 
Prothrombin time 
PVG 
Pharmacovigilance Group 
QID 
Four times a day 
QTc 
Corrected QT Interval of the ECG 
QTcF  
Corrected QT interval of the ECG using Fridericia’s Formula 
RAUC 
Accumulation ratio for AUC 
RBC 
Red Blood Cell 
RCAUC 
Accumulation ratio for AUC 
RCmax 
Accumulation ratio for Cmax 
RP 
Research Pharmacist 
RR 
Respiratory Rate 
SAD 
Single Ascending Dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SDCC 
Statistical and Data Coordinating Center 
sec 
Second(s) 
SMC 
Safety Monitoring Committee 
SOC 
System Organ Class 
T 
Temperature 
t1/2 
Terminal Elimination Half-life 
Tmax 
Time of Maximum Concentration 
Tmin 
Time of Minimum Concentration 
TEAE 
Treatment-emergent Adverse Event 
TID 
Three times a day 

DMID Protocol 21-0013 
Version 5.0 
WCK 6777 [Ertapenem-Zidebactam (ERT-ZID)] 
                             
15 June 2023 
 
 
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TLF 
Tables, Listing and Figures 
UA 
Urinalysis 
ULN 
Upper Limit of Normal 
US 
United States 
Vd 
Volume of Distribution 
VS 
Vital Signs 
Vd,ss 
Volume of distribution at steady state  
WBC 
White Blood Cell 
WCK 5107 
Zidebactam 
WCK 5222 
Combination of Cefepime with Zidebactam 
WCK 6777 
Combination of Ertapenem with Zidebactam 
WHO 
World Health Organization 
ZID 
Zidebactam 
 
 

DMID Protocol 21-0013 
Version 5.0 
WCK 6777 [Ertapenem-Zidebactam (ERT-ZID)] 
                             
15 June 2023 
 
 
DMID/NIAID/NIH 
CONFIDENTIAL 
 
 
 
16 
PROTOCOL SUMMARY 
Title: 
A Phase I, Randomized, Double-blind, Placebo-controlled, Dose 
Escalation Study to Evaluate the Safety, Tolerability, and 
Pharmacokinetics of Intravenous Ertapenem in Combination with 
Zidebactam (WCK 6777) in Healthy Adult Subjects 
Phase: 
1 
Population: 
Approximately 52 evaluable healthy male or female subjects 18 to 
45 years of age (both inclusive) at the time of dosing 
Number of Sites: 
One (Altasciences Clinical Kansas, Inc.)  
Study Duration:  
Approximately 11 months from study activation to last subject last 
visit 
Subject Participation 
Duration: 
Each subject will participate in the study for up to 42 days. The trial 
will consist of a Screening Period of up to 27 days as outpatient  
(Day -28 to Day -2); a Check-in/Baseline/Enrollment Day (Day -1); 
a Treatment Period of minimum of 7 nights/8 days (Days 1 to 8) as 
inpatient, with daily dosing on Days 1 to 7 and discharge on Day 8; 
and an out-patient Follow-up Period of 3 to 6 days (Days 9 to 14) 
with one site visit on Day 11 (+3 days) (Final Visit). 
Description of 
Agents: 
WCK 6777 is the designation for the combined preparation 
containing Ertapenem (ERT) and Zidebactam (ZID; WCK 5107) in 
equal amounts, ranging from 2 g (1 g of each compound) to 6 g (3 g 
of each compound). 
 
ERT is an approved antibacterial drug that belongs to the class of 
carbapenem antibiotics. ERT is provided as lyophilized powder of 
ERT sodium in a glass vial containing ERT 1 g/vial. The doses to be 
used range from 1 g to 3 g per injection daily for 7 days, depending 
on the study cohort. Sterile Water for Injection, USP will be used to 
reconstitute the drug and sterile 0.9% Sodium Chloride, USP to 
further dilute the reconstituted solution to the desired volume for IV 
infusion, which is 100  mL for the ERT 1-g combination with 1-g 
ZID, as the 2-g WCK 6777 (1-g ERT + 1-g ZID), and 250 mL either 

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for the 2-g or 3-g standalone ERT or for the combination with 2-g or 
3-g ZID, respectively as the 4-g WCK 6777 (2-g ERT + 2-g ZID) or 
the 6-g WCK 6777 (3-g ERT + 3-g ZID). ERT will be administered 
by IV infusion over a period from 30 min to 2 hours, depending on 
the drug amount delivered following study design. 
 
ZID is a synthetic compound that belongs to a novel class of bicyclic 
diazabicyclooctane (DBO) with dual functions as β-lactamase 
inhibitor and β-lactam enhancer. It is under investigation as an 
antibacterial agent in combination with cefepime (WCK 5222). ZID 
dihydrate is provided in lyophilized powder in a glass vial containing 
1 g/vial. The doses to be used range from 1 g to 3 g per infusion 
daily for 7 days depending on the study cohort. Sterile Water for 
Injection, USP will be used to reconstitute the drug and sterile 0.9% 
Sodium Chloride, USP to further dilute it to the desired volume for 
IV infusion, which is 100 mL for the ZID 1-g combination with 
ERT, as the 2 g WCK 6777 (1 g ZID + 1 g ERT), and 250 mL either 
for the 2 g or 3 g standalone ZID or for the combination with 2 g or 
3 g ERT, respectively for the 4 g WCK 6777 (2 g ZID + 2 g ERT) or 
the 6 g WCK 6777 (3 g ZID + 3 g ERT). ZID will be administered 
by IV infusion over a period from 30 min to 2 h, depending on the 
drug amount delivered following study design. 
Objectives: 
Primary 
Assess the safety and tolerability of three dose-escalating regimens 
of WCK 6777 (ERT and ZID combination) and two-dose escalating 
regimens of standalone ERT or ZID following single daily doses for 
7 days in healthy adult subjects 
Secondary 
Characterize the PK profiles in plasma (total & free) and in urine of 
three dose-escalating regimens of WCK 6777 (ERT and ZID 
combination) and two dose-escalating regimens of standalone ERT 
or ZID following a single initial dose on Day 1 and after single daily 
doses for 7 days in healthy adult subjects 
Outcome Measures:  
Primary 
Type, incidence, severity, and relatedness to study drug of all 
treatment-emergent adverse events (AEs) and serious adverse events 

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(SAEs) in each treatment cohort from the first dose through the 
follow-up period 
Secondary  
PK parameter estimates and calculated exposure measures in plasma 
(total and free) and urine for ERT and ZID, when given alone and in 
combination following a single initial dose on Day 1 and after single 
daily dose administration for 7 days 
Description of Study 
Design: 
This is a Phase 1, single center study to investigate the safety, 
tolerability, and pharmacokinetics (PK) of three dose-level groups of 
WCK 6777 (ERT and ZID combination), and two dose-level groups 
of ERT alone and ZID (WCK 5107) alone in 52 healthy adult male 
and female subjects aged 18 to 45 years old (both inclusive). 
Seven treatment cohorts will be evaluated in this study (Table 1 and 
Figure 1). WCK 6777 will be evaluated in three cohorts - Cohorts 1, 
4 and 7- of 8 subjects each (6 study drug combinations and 2 
placebos); ERT will be evaluated alone in two cohorts – Cohorts 2 
and 5- of 8 subject each (6 ERT and 2 placebos); and ZID will be 
evaluated in two cohorts, Cohorts 3 and 6, of 6 subjects each (all 
ZID). The study will be placebo-controlled and double-blinded in all 
cohorts except Cohorts 3 and 6. No placebo subjects are included in 
standalone ZID cohorts, since adequate safety data for higher doses 
of ZID alone in comparison with placebo are available from 
completed Phase 1 studies of WCK 5107 (ZID) alone and the ZID-
only arms of WCK 5222 (cefepime + ZID) studies. 
In each cohort, either study drugs alone or their combination will be 
administered by a single intravenous infusion (IV) of 100 mL daily 
for 7 consecutive days in Cohort 1 or 250 mL daily for 7 consecutive 
days in Cohorts 2 to 7. For each treatment cohort, however, the dose 
will be progressively escalated from 1 g/daily to 2 g/daily and to 
3 g/daily, and the duration of infusion time increased from 30 min to 
1 h and to 2 h over the course of the study. In Cohort 1, WCK 6777 
2 g (ERT 1 g/daily combined with ZID 1 g/daily) will be 
administered in 30 (±5) minutes (min); in Cohort 2 (ERT 2 g/daily), 
Cohort 3 (ZID 2 g/daily), and Cohort 4 (WCK 6777 4 g [ERT 
2 g/daily combined with ZID 2 g/daily]) the study drug(s) will be 
administered in 60 (±10) min, and in Cohort 5 (ERT 3 g/daily), 

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Cohort 6 (ZID 3 g daily) and Cohort 7 (WCK 6777 6 g [ERT 3 
g/daily combined with ZID 3 g/daily]), the study drug(s) will be 
administered in 120 (±10) min. (See Table 1). 
Study enrollment will proceed from Cohort 1 to Cohort 7 starting 
with the lowest dose and escalating to the next higher dose. 
Individual dose Cohorts 2 and 3 and 5 and 6 will run in parallel. For 
each combination treatment cohort (Cohorts 1, 4 and 7), two sentinel 
subjects will receive study treatments (one WCK 6777 and one 
placebo; drug/ placebo ratio 1:1) and followed for safety for 
approximately 24 h prior to dosing of the remaining 6 subjects in the 
cohort. If no halting rules have been met 24 hours after start of 
dosing, dosing of sentinel subjects will continue for the remainder of 
the study and the additional 6 subjects in the cohort will be dosed (5 
will receive WCK 6777 and 1 will receive placebo; drug/placebo 
ratio 5:1).  Sentinels will not be employed in the single treatment 
cohorts. 
Blood (plasma) and urine samples will be collected for measuring 
drug concentrations for PK analysis for 24 h after starting the first IV 
infusion on Day 1, and for 24 h after starting the last IV infusion on 
Day 7. Plasma concentrations of study drugs will also be measured 
before and 12 h after dosing on Days 2 to 6. Total and free drug 
concentrations of ERT and ZID will be measured in plasma and total 
drug concentration of ERT and ZID in the urine by validated LC-
MS/MS assays. 
Safety data will be monitored from the time of infusion on Day 1 to 
the last visit (Day 11+3 days) and will consist of: daily assessments 
of treatment-emergent AEs, vital signs and symptom-directed 
physical examination (PE);  clinical laboratory safety tests (Day -1, 
Days 2, 4, 6 and Day 8 (prior to the discharge from the study site]), 
and 12-lead ECGs, and a complete PE on the last visit 
(Day 11 +3 days). AEs will be assessed by the study clinicians for 
severity or seriousness, and relatedness to study drug(s) and include 
outcome and duration. 
The decision for dose escalation from combination Cohort 1 (1 g 
ERT + 1 g ZID) to the next planned higher single dose Cohorts 2 
(2 g ERT) and 3 (2 g ZID), and from combination Cohort 4 (2 g ERT 

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+ 2 g ZID) to single dose Cohorts 5 (3 g ERT) and 6 (3 g ERT) will 
be based on unblinded review of cumulative interim safety data to 
Day 11 (+3 days) of each combination cohort by the Safety 
Monitoring Committee (SMC). The recommendation to continue to 
combination Cohort 4 and to combination Cohort 7 (3 g ERT + 3 g 
ZID) will be made by the study team (DMID Medical Officer [MO] 
and Medical Monitor [MM] and Site PI) after review of blinded 
safety data in Cohorts 2 and 3 and Cohorts 5 and 6, respectively, to 
determine if halting rules are met. The SMC will review all interim 
safety data, not only those that meet pre-specified halting rules. after 
completion of Cohort 1 and Cohorts 1-4, and all final safety data 
after database lock. 
If no halting criteria are met, the decision to continue dose escalation 
will be made and announced by DMID. If halting criteria are met, an 
ad hoc meeting of the SMC will convene to review the unblinded 
data and make recommendations about dose escalation and the 
continuation of the trial. 
The SMC will also review the aggregate data in the first 4 cohorts, 
before dosing the remaining cohorts, and the cumulative safety data 
at the end of the trial after the database lock. 
Estimated Time to 
Complete Enrollment 
Up to 10 months (from dosing of first subject to final visit of last 
subject). 
 
 

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Figure 1 Description Schematic of Study Design  
 
 

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1 
KEY ROLES 
Site Principal Investigator: 
Martin Kankam, MD, PhD, MPH, FAPCR  
Altasciences Clinical Kansas, Inc. 
10103 Metcalf Avenue 
Overland Park, KS 66212 
Office: 913-696-1601 
Email: mkankam@altasciences.com 
DMID Clinical Project Manager: 
Maureen Mehigan, RN 
DMID/NIAID/NIH/HHS 
5601 Fishers Lane, Room 7E19  
Bethesda, MD 20892-9826 
Office: 240-627-3317 
Email: mmehigan@niaid.nih.gov  
Statistical and Data Coordinating 
Center (SDCC): 
The Emmes Company, LLC 
401 N. Washington Street, Suite 700 
Rockville, MD 20850 
Phone: 301-251-1161 
Fax: 301-576-3558 
Email: phase1@emmes.com  
Bioanalytical Laboratory: 
KCAS Bioanalytical and Biomarker Services 
Test Materials Management 
10830 South Clay Blair Boulevard 
Olathe, KS 66061 
Phone: 913-248-3106 
Fax: 913-248-3106 
Email: TMM@kcasbio.com 

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2 
BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
2.1 
Background Information 
Antibiotics were one of the significant medical discoveries in the 20th century and they save 
200,000 American lives annually, extend life expectancy, and facilitate major advances in 
medicine and surgery [1]. Despite best efforts, our ability to use antibiotics safely and effectively 
has been compromised by the emergence of antibiotic resistance. Antimicrobial resistance is an 
ongoing public-health problem of critical importance and is considered as one of the top ten 
threats to global health by the World Health Organization (WHO) [2]. Among the various 
emerging resistant bacterial pathogens, carbapenem-resistant bacteria are particularly worrisome 
given that carbapenems have long been considered the most reliable last-resort treatment for 
infections caused by Gram-negative pathogens. Carbapenem resistance predominately manifests 
in various Gram-negative organisms including Enterobacterales, which have been recognized as 
an urgent threat by both the CDC and WHO that require aggressive action [3, 4]. While a variety 
of mechanisms contribute to carbapenem resistance among Enterobacterales, it is driven in a 
large part by the increasing prevalence and complexity of a variety of β-lactamases. The most 
important of these are the class A serine carbapenemases, such as KPC, class B metallo-β-
lactamases (MBLs), such as Verona integron Metallo β-lactamase (VIM), imipenemase (IMP) 
and New Delhi Metallo β-lactamase (NDM) and class D carbapenemases, such as OXA-48 types 
[5]. 
 
Evidence shows that the only way to stay ahead of the resistance curve is to follow the best 
infection control practices, use antibiotics prudently, and bring new agents to the market [6]. 
There has been an impressive antibiotic drug development response in recent years to combat the 
rise in antibiotic resistant pathogens and several intravenous (IV) antibiotics with activity against 
certain carbapenem- resistant Enterobacterales (CREs) encountered in clinical practice have been 
approved by both the FDA and EMA [7, 8]. While these recently approved agents are welcomed 
additions to our antibiotic armamentarium, nearly all are required to be administered by IV, 
multiple times-a-day with infusion times ranging from 1 to 3 hours. The dosing and 
administration requirements of these newer agents are associated with some logistical challenges, 
but they are largely manageable in hospitalized patients. However, infections due to CREs are of 
substantial concern across all clinical settings, including the community setting, and none of 
newer agents with enhanced CRE activity are conducive for outpatient use. Plazomicin is the 
only recently approved agent against CREs that is dosed once daily but it lacks comprehensive 
coverage of CREs (such as strains producing NDM due to co-expression of 16S rRNA methyl 
transferases) and does not possess a safety profile commensurate for outpatient parenteral 

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antimicrobial therapies (OPAT) [9]. Among epidemiologic studies that identified the occurrence 
of community-onset CRE infections, the prevalence ranged from 8 to 30% globally and from 5 to 
11% in the United States [10]. 
 
The rise in community-onset CRE infections highlights the critical need for effective OPAT [11]. 
OPAT has the potential to be the ‘standard-of-care’ for the management of many infections 
requiring IV antimicrobial therapy like CRE infections. For some conditions, initiation of OPAT 
in the outpatient or emergency department setting may allow avoidance of hospitalization 
entirely [12]. Avoidable hospitalizations impose a significant burden on already stressed health-
care systems which could be mitigated to a large extent if an effective OPAT is available. The 
availability of an effective OPAT also facilitates early discharge of clinically stable patients. 
Data shows that patients often remain in the hospital after their acute infection resolves, and it is 
possible to discharge these patients with OPAT without compromising the clinical outcomes 
[13]. Beyond the potential cost benefits, early discharge of suitable patients with OPAT has been 
shown to improve patient satisfaction, reduce healthcare-associated infections, and allow 
resources to be reallocated to increase patient care throughput. A potential OPAT solution for 
patients with CRE infections in development is the combination of ERT with ZID (WCK 6777, 
ERT-ZID), which will be evaluated in this study as a once-daily intravenous infusion (IV) 
administered over 0.5 to 2 hours. 
2.2 
Ertapenem and Zidebactam (WCK 6777) 
WCK 6777 is the code name for Wockhardt’s proprietary combination of ertapenem (ERT) and 
zidebactam (ZID). 
 
ERT is a once-daily IV carbapenem antibiotic that is FDA-approved for multiple indications in 
the United States. It is a well-established OPAT drug with robust activity against infections due 
to extended-spectrum β-lactamase (ESBL) producing-Enterobacterales [14]. However, ERT has 
no activity against CRE. Moreover, strains harboring multiple ESBLs and AmpC and decreased 
expression of porins also tend to show reduced susceptibility to ERT owing to hampered uptake 
of ERT [15]. ZID is a novel diazabicyclooctane (DBO) [16]. In addition to β-lactamase 
inhibition like other DBOs, such as avibactam and relebactam, ZID forms a strong covalent 
interaction with the penicillin binding protein 2 (PBP2) present in all the clinically important, 
carbapenem-resistant Gram-negative pathogens [17-19]. This feature, termed as β-lactam 
enhancer action, is maximized when ZID is combined with β-lactams like ERT and cefepime 
that bind to PBPs other than PBP2. The antibacterial effects of the PBP-optimized ZID/β-lactam 
combinations are (1) enhanced microbiologic activity against MBL-expressing Gram-negative 
bacteria albeit ZID lacks β-lactamase inhibitory activity against MBLs [20] and (2) substantial 
reductions in % f T>MIC requirements for the partner β-lactam [21-22]. Both these advantages 

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were demonstrated in vitro and in vivo with ZID combined with cefepime (FEP) (WCK 5222, 
Wockhardt’s three times a day [TID] drug) [21, 23]. WCK 5222 is active against Gram-negative 
organisms expressing all four Ambler classes of β- lactamases and has pharmacokinetic/ 
pharmacodynamics (PK/PD) susceptibility breakpoint of 64 µg/mL as compared to 8 µg/mL for 
cefepime alone [23-26]. Presently, cefepime/ZID is pending evaluation in Phase 3 trials for 
complicated urinary tract infections (cUTI) and ventilated-nosocomial pneumonia. 
 
This proposed Phase 1 healthy subject study is aimed to evaluate the safety, tolerability, and 
pharmacokinetics (PK) of the once-daily IV combination of ERT with ZID (WCK 6777). To 
date, pre-clinical animal PK/PD studies that simulated clinical exposure profiles of ERT 2 g and 
ZID 2 g, IV once- daily demonstrated bactericidal activity against KPC-, OXA-48, and MBL-
producing Enterobacterales with ERT/ZID MIC values up to 8 µg/mL [27]. Although the FDA-
approved dosing regimen for ERT in human is 1 g IV daily [28], the safety of IV ERT doses up 
to 3 g once-daily have been evaluated in Phase 1 and 2 studies [29]. Clinical studies with ZID 
have established safety for a single highest dose of 3 g and total divided daily dose of 6 g/day 
[30, 31], with some clinical studies characterizing the PK of ZID in pulmonary tissues of healthy 
subjects [32] as well as in plasma of subjects with impaired renal function [33] 
(ClinicalTrials.gov Identifiers: NCT02532140, NCT02674347, NCT02707107, NCT03630094, 
NCT02942810, NCT03554304). However, no human safety and PK data are available with these 
agents when they are used in combination as a once-daily dosing regimen. Therefore, the 
proposed Phase 1 studies will assess the safety, tolerability, and PK of escalating regimens of 
ERT in combination with ZID to determine its suitability for continued clinical development. 
2.2.1 
Zidebactam (WCK 5107)  
2.2.1.1 
Physicochemical properties  
Zidebactam dihydrate (CAS No. 1996664-59-5) is a proprietary New Chemical Entity (NCE) of 
Wockhardt coded as WCK 5107. It is a bicyclo-acyl-hydrazide (DBO pharmacophore) 
chemically identified as (2S, 5R)-7-Oxo-6-sulphooxy-2-[N'-((R)-piperidin-3-carbonyl)-
hydrazinocarbonyl]-1, 6-diaza-bicyclo [3.2.1] octane dihydrate. The structure and absolute 
stereochemistry of ZID has been confirmed though various instrumental methods of analysis 
such as elemental analysis, NMR spectrometry, mass spectrometry, and single crystal X-ray 
analysis. ZID has a molecular formula of C13H21N5O7S.2H2O and a molecular weight of 
427.45 daltons (includes two water molecules). ZID exists as pale yellow to white crystalline 
powder. It is slightly hygroscopic and is freely soluble in water and insoluble in dichloromethane 
[34]. 

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2.2.1.2 
Mechanism of Action 
ZID has a novel, dual mechanism of action, involving broad-spectrum inhibition of various 
serine β-lactamases including Class A, C and certain Class D β-lactamases, and as β-lactam 
enhancer due to selective, high-affinity binding (IC50 0.01 to 0.26 μM ) to Gram-negative PBP2, 
(a key enzyme involved in cell wall synthesis and maintenance of the rod shape), of in all the 
four clinically significant Gram-negative pathogens, namely, E. coli, K. pneumoniae, 
P. aeruginosa and A. baumannii [17-19, 34]. 
2.2.1.3 
Antibacterial activity 
By virtue of strong affinity towards Gram-negative PBP2 and also pan-β-lactamase stability, ZID 
exhibits antibacterial activity against certain pathogens on standalone basis. For example, ZID 
MIC50/90 for Enterobacterales and P. aeruginosa were 0.12/>64 µg/mL and 0.5/>64 µg/mL, 
respectively. It should be noted that though standalone ZID shows impressive in vitro activity, it 
does not translate into adequate in vivo efficacy due to single PBP2 binding action [20, 34]. 
2.2.1.4 
In Vitro Drug Interaction Studies 
• CYP450 Studies: ZID up to a 500 μM (equivalent to 195.7 μg/mL) did not induce CYP1A2 
or CYP3A4 enzyme activity and mRNA levels. Hence ZID is unlikely to cause CYP 
mediated drug-drug interactions (DDI) [34]. 
ZID is not an inhibitor of all key human CYP450 isoforms (CYP1A2, CYP2C8, and 
CYP2C9 CYP3A4) up to 2,000 μM (782.5 μg/mL) and it did not inhibit CYP2C19, and 
CYP2D6 up to tested concentration of 300 μM (117.4 μg/mL) [34]. 
• Transporter Studies: ZID is unlikely to cause clinical DDIs involving the human 
transporters due to non-inhibitory potential towards P-gp, BCRP, OATP1B1, OATP1B3, 
OAT1, OAT3, and OCT2 human transporters. Additionally, ZID does not have inhibitory 
activity towards human transporters like MRP4, OCT1 and BSEP [34]. 
ZID substrate potential for renal transporters (OAT1, OAT2, OCT2, MRP4) was studied 
in vitro both in the presence and absence of ERT. ZID did not show substrate potential for 
OAT1, OAT2, OCT2, or MRP4 [34]. 
2.2.1.5 
Genetic Toxicity 
Zidebactam was evaluated through a battery of in-vitro (bacterial reverse mutation assay and 
chromosomal aberration in human lymphocytes) and in-vivo (mouse micronucleus test) 
genotoxicity tests. In mouse micronucleus test, the exposure in terms of AUC at NOAEL dose 
(1302 mg/kg) was 1194.5 to 1441.2 mg·h/L. This exposure is about 3.5 to 4 times of clinical 
exposure obtained at the intended clinical dose of Zidebactam 2 g daily in WCK 6777. 
Zidebactam did not show clastogenic potential in both in-vitro and in-vivo genotoxicity studies. 

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Further studies are needed to assess the risk of mutagenicity.  Thus, considering the available 
data and shorter therapeutic duration envisaged of up to 14 days, the risk of carcinogenicity is 
low. [34]. 
2.2.1.6 
Preclinical In Vivo Safety Profile 
In preclinical safety assessment, ZID was found to be safe for vital organ systems based on their 
extensive evaluation in safety pharmacology studies for cardiovascular, gastrointestinal, 
respiratory and central nervous systems. The IV No Observed Adverse Effect Level (NOAEL) 
doses, based on a 28-day repeat dose toxicity study in rat and dog are 800 and 750 mg/kg/day, 
respectively and the corresponding exposure in terms of 24-hour (h) area under the plasma drug 
concentration -time curves (AUCs) are 1950 and 1962 mg·h/L, respectively. On the basis of ZID 
NOAEL dose exposures in dog (750 mg/kg/day) and rat (800 mg/kg/day) and anticipated ZID 
clinical exposure of 360 mg·h/L at 2 g/day, a safety window of approximately 5.4 times is 
envisaged [34]. 
 
In a 13-week repeat-dose intravenous toxicity study of ZID in Beagle dogs, the NOAEL and 
Low Observed Adverse Effect Level (LOAEL) were 250 and 500 mg/kg, respectively. Based on 
the body surface area, these doses in Beagle dog correspond to per day administration of 9.7 g 
and 19.4 g of ZID for a 70 kg human, respectively [34]. 
2.2.2 
Ertapenem 
2.2.2.1 
Physicochemical Properties 
ERT is generally available as ertapenem sodium (CAS No. 153773-82-1), and chemically 
identified as [4R-[3(3S*,5S*),4α,5β,6β(R*)]]-3-[[5-[[(3-carboxyphenyl)amino] carbonyl]-3-
pyrrolidinyl]thio]-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0] hept-2-ene-2-
carboxylic acid monosodium salt. It has a molecular formula C22H24N3O7SNa and a molecular 
weight of 497.50 daltons. ERT sodium is a white to off-white hygroscopic, weakly crystalline 
powder. It is soluble in water and 0.9% sodium chloride solution, practically insoluble in ethanol, 
and insoluble in isopropyl acetate and tetrahydrofuran [28]. 
2.2.2.2 
Mechanism of Action 
ERT rapidly binds to PBPs of Enterobacterales with greater affinity towards PBP3 and PBP2. 
Such a rapid rate of PBP binding of ERT is an enabling feature as it would be able to induce 
elongation even in the presence of inactivating enzymes. In a Pseudomonas PBP binding study, 
ERT showed high-affinity binding to all the essential PBPs, such as PBP2, PBP3 and PBP1a/b in 
P. aeruginosa [34]. 

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2.2.2.3 
Antibacterial Activity 
ERT is a broad-spectrum, carbapenem antibiotic with coverage spectrum encompassing Gram-
negative (including ESBL-expressing strains), Gram-positive and anaerobic pathogens. ERT has 
potent in vitro activity against β-lactamase-expressing Enterobacterales including those that 
produce class A ESBLs and class C enzymes. ERT is not effective against Enterobacterales 
expressing ERT-hydrolyzing β-lactamases, such as KPC, MBL and Class D- OXA-
carbapenemases. ERT also has limited activity against Pseudomonas aeruginosa owing to its 
vulnerability to pseudomonal efflux and poor uptake [34]. 
2.2.2.4 
In Vitro Drug Interaction Studies 
• CYP450 Studies: In vitro studies in human liver microsomes indicate that ERT does not 
inhibit metabolism mediated by any of the following cytochrome p450 (CYP) isoforms: 
1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 [34]. 
 
• Transporter Studies: In vitro studies have established that ERT does not inhibit  
P-glycoprotein mediated efflux nor it is a substrate of the same efflux pump [21].  
 
ERT in presence and absence of ZID was assessed for its renal transporter substrate 
potential against OAT1, OAT3, OCT2 and MRP4 transporters at higher concentration. 
The results of transporter substrate study indicate that ertapenem is a substrate of OAT3 
transporter; it is likely to be a substrate of OAT1 and MRP4 and non-substrate of OCT2 
transporter. The substrate activity of ERT remained unaffected in presence of ZID 
(1000 µM) [34]. 
2.2.2.5 
Genetic Toxicity 
 No long-term studies in animals have been performed to evaluate the carcinogenic potential of 
ertapenem. Ertapenem was not genotoxic in in vitro or in vivo assays, including: an alkaline 
elution/rat hepatocyte assay, a chromosomal aberration assay in Chinese hamster ovary cells, a 
TK6 human lymphoblastoid cell mutagenesis assay and a mouse micronucleus cells, a TK6 
human lymphoblastoid cell mutagenesis assay and a mouse micronucleus assay [28, 34]. 
2.2.2.6 
Preclinical and Clinical Safety Profile 
The safety of ERT is well established through a range of preclinical studies in rodents and non-
rodents and clinical studies. ERT was approved for marketing in 2001 [28]. Safety and 
tolerability of ERT even at doses higher than the currently approved 1 g/day has been well 
established in clinical studies conducted by Merck. In Phase 1, the maximum dose of ERT 
studied was 3 g/day with no serious adverse events (AEs). In Phase 2 trials, higher ERT dose of 

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1.5 g and 2 g were also evaluated; for which the pattern and frequency of AEs were similar to 
those who received 1 g of ERT [29, 34]. 
2.2.2.7 
Clinical Indication 
In the U.S., ERT is indicated as a once-a-day parenteral carbapenem antibiotic in adults and 
pediatric patients (3 months of age and older) for the treatment of the following moderate to 
severe infections caused by susceptible bacteria: complicated urinary tract infections (cUTI) 
including pyelonephritis, community-acquired pneumonia (CAP), complicated intra-abdominal 
infection (cIAI) and complicated skin and skin-structure infections including diabetic foot 
infections without osteomyelitis, acute pelvic infections including postpartum endomyometritis, 
septic abortion and post-surgical gynecologic infections. ERT is also indicated in adults for the 
prophylaxis of surgical site infection following elective colorectal surgery [28, 34]. 
2.2.3 
WCK 6777 (Combination of ERT and ZID)  
WCK 6777 is a combination of equal amounts of ERT, a carbapenem antibiotic, and ZID, a  
non-β-lactam entity which acts as a β-lactam enhancer. It is being developed as once-a day 
parenteral therapy for the treatment of Gram-negative infections. The indications described for 
ERT would be targeted for WCK 6777 in clinical settings. 
2.2.3.1 
Mechanism of Action 
In Gram-negatives, WCK 6777 operates on the basis of β-lactam enhancer mechanism of action. 
ZID binds to Gram-negative PBP2 and ERT being a potent PBP3 and PBP2 binding agent 
(additional binding to PBP1a/b in Enterobacterales), the combination exerts bactericidal action 
against MDR pathogens through complementary binding of multiple PBPs. This mechanism of 
action obviates the need of β-lactamase inhibition leading to the activity against pathogens 
expressing ZID non-inhibitable β-lactamases, such as MBLs. ERT-ZID combination is further 
benefitted by ZID’s ability to inhibit several class A (including KPC) and class C β-lactamases 
[34]. 
2.2.3.2 
Antibacterial activity – In Vitro 
The MIC50/90 of ERT-ZID against KPC-, OXA-48/181- and MBL-expressing Enterobacterales 
were 0.25/2, 1/2, and 0.5/4 µg/mL, respectively. For these set of organisms, the MIC90 of 
standalone ERT or ZID was >128 µg/mL.  ERT-ZID combination was also active against 
P. aeruginosa with MIC50 of 4 µg/mL and MIC90 of 8 µg/mL. Time-kill studies demonstrated 
synergistic bactericidal action to the extent of 1 to 2 log10 kill upon 4-hour (h) exposure of  
ERT-ZID against wild type, ERT-resistant Enterobacterales and efflux hyper-expressing and 
OprD-down regulated P. aeruginosa. 

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Time-kill studies have shown that ERT’s affinity to bind PBP3 in combination with PBP2 
binding when combined with ZID, elicits potent synergistic bactericidality as a result of the 
inhibition of multiple essential PBPs. Thus, ZID enhances the pharmacodynamic action of ERT 
leading to activity against ERT-resistant MDR strains. With this augmented pharmacodynamic 
effect, the duration of the pharmacodynamic relevant exposures of ERT is significantly lowered, 
enhancing the therapeutic coverage of pathogens including those that express ERT-impacting 
resistance mechanisms. WCK 6777 also evokes a bactericidal response against P. aeruginosa as 
a result of PBP3 and PBP2 binding by ERT and ZID, respectively. Such PBP-mediated 
bactericidal action overcomes ERT-impacting resistance mechanisms such as efflux and ERT-
hydrolysing β-lactamases that likely hamper the in vitro activity of ERT against P. aeruginosa. 
The inclusion of P. aeruginosa within the therapeutic scope of WCK 6777 would broaden its 
therapeutic utility as a step-down de-escalation therapy for several TID and QID combination 
products used for treatment of P. aeruginosa causing nosocomial infections [34]. 
2.2.3.3 
Antibacterial activity – In Vivo 
In vivo efficacy of ERT-ZID was assessed in a translational standard neutropenic mouse lung 
infection. ERT, ZID and ERT-ZID were tested at human-simulated regimens (HSR) in uranyl 
nitrate-treated, neutropenic mice which produced free plasma exposures of respective drugs 
mimicking the human free plasma exposures from once-daily administered 2 g of ERT and 2 g 
ZID. Against 24 carbapenem-resistant Enterobacterales which comprised of KPC or OXA-48-
like or NDM-expressing strains, ERT or ZID HSR was ineffective while ERT-ZID HSR showed 
a consistent 1 to 2.5 log10 kill. A similar study was undertaken independently at Centre for Anti-
infective Research and Development, Hartford Hospitals, wherein ERT/ZID HSR evoked 
>1 log10 CFU reduction (exceeding translational endpoint of 1 log10 kill) in 18/21 of KPC or 
OXA-48-like or NDM Enterobacterales and stasis to 0.5 log10 kill was observed in the remaining 
isolates [27, 34]. 
2.2.3.4 
Safety Pharmacology – In Vitro 
• hERG inhibition assay - At the highest tested concentration (1461 μM), there was a 
10% inhibition of hERG current. The IC50 for ZID could be greater than 1461 μM 
(571.5 μg/mL). This concentration of ZID is 3.8-fold higher than the intended clinical 
Cmax of ZID at dose of 2 g [34]. 
 
• Receptor binding and enzyme assays - ZID did not cause ≥ 50% inhibition of any of 
the enzymes or receptors at concentration of 500 µM (1.3-fold of clinical Cmax of ZID 
2 g), demonstrating lack of secondary pharmacodynamic targets [34]. 

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2.2.3.5 
Preclinical Safety – In Vivo 
ERT-ZID up to the highest dose studied (1,200 + 1,000 mg/kg) in rats did not affect any of the 
respiratory functions or neurobehavioral parameters in a head-out plethysmography and a 
functional observational battery test, respectively. The maximum concentration (Cmax) of ERT 
and ZID at these doses was about 3.9 and 5.3 times higher than the intended therapeutic Cmax 
levels, respectively. Further, in a 28-day repeat dose toxicity study in rats, ERT-ZID (800 + 800 
and 1600 + 1600 mg/kg/day) did not show any clinical signs of systemic toxicity. The no-
observed-adverse-effect-level (NOAEL) of ERT-ZID for this study was adjudged as 
1600+1600 mg/kg/day. The corresponding plasma AUC of ERT and ZID, 3700 and 
4540 mg·h/L, were about 3.6 and 12.6 times higher the expected therapeutic exposures, 
respectively, indicating a broad safety margin. US FDA has granted a waiver for the 28-days 
study in non-rodent species in light of adequate data on preclinical and clinical safety available 
for both ERT and ZID. [34]. 
2.3 
Clinical Experience 
2.3.1 
Human Studies with Zidebactam 
ZID has been studied in Phase 1 human trial as WCK 5107 and is also being developed in 
combination with cefepime (FEP) as WCK 5222 (q8h) and is slated to enter Phase 3 clinical 
studies. 
 
ZID has been administered to 91 healthy adult human volunteers in two Phase 1 double-blind, 
placebo-controlled single ascending dose (SAD) and multiple-ascending dose (MAD) studies 
conducted in the U.S. in healthy volunteers (W-5107-101; NCT02532140, and W-5107-102; 
NCT02674347). Doses ranged from 0.25 g to 3 g daily in the SAD study and 3 g (1 g q8 h) to 
6 g (2 g q8 h) in the MAD study. In addition, 1 g (approximately 200 μCi) of [14C]-ZID has 
been administered to 8 healthy adult male volunteers in a Metabolism and Excretion study [30, 
31, 34]. 
2.3.1.1 
Safety and Tolerability 
In the SAD study (W-5107-101), there were no deaths, serious adverse events (SAEs) or 
discontinuations due to AEs. No subjects on placebo reported any TEAEs. The majority of 
TEAEs were mild. One subject in the 1 g ZID cohort reported urticaria, and 1 subject in the 2 g 
cohort reported headache. In the cross-over cohorts, 5 subjects reported TEAEs that were 
considered treatment related, one with oral hypoesthesia (1 g dose ZID), 1 vulvovaginal mycotic 
infection (2 g FEP), 1 headache (1 g ZID+2 g FEP), 1 headache (2 g ZID+2 g FEP) and 1 
vaginal discharge (2 g ZID+2 g FEP) [34]. 

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In the MAD study (W-5107-102), there were no deaths, serious adverse events (SAEs) or 
discontinuations due to AEs. All TEAEs were mild in severity. Three subjects (37.5%) in 
Cohort 1 reported TEAEs, 2 due to the procedure (infusion site extravasation and 1 infusion site 
erythema), and 1 each myalgia, headache and vulvovaginal discomfort. In Cohort 2, there were 
3 TEAEs of headache, and 2 of vessel puncture site hematoma. In the Placebo Cohort, 2 subjects 
reported headache, 2 infusion site erythema and 2 vessel puncture site pain. In the metabolism 
and excretion study (Q-5107-103), all AEs were mild in severity and were assessed as related to 
ZID. Overall, 3 subjects (37.5%) reported 5 TEAEs (3 AEs of diarrhea, 2 AEs of infrequent 
bowel movements) [34]. 
 
No deaths, serious adverse events (SAEs) or discontinuations due to AEs were reported during 
the study. No subjects on placebo reported any AEs [34]. 
 
Clinical safety of ZID is also supported through WCK 5222 (FEP-ZID) Phase 1 studies, in which 
233 healthy volunteers were dosed with Zidebactam or cefepime/ZID, with ZID doses ranging 
from 3 g (1 g q8h) to 6 g (2 g q8h) daily for 7 to 10 days and FEP 6 g (2 g q8 h) daily. 
(ClinicalTrials.gov Identifiers: NCT02532140, NCT02707107, NCT03554304, NCT03630094, 
NCT02942810). These studies included a thorough QT study, which did not report QT 
prolongation or any cardiovascular AEs. No safety concerns were observed in any study. Both 
cefepime and ZID, at high doses, were well tolerated with a safety profile consistent with the  
β-lactam class [30-34]. 
2.3.1.2 
Pharmacokinetics 
ZID pharmacokinetics (PK), safety and tolerability have been investigated in Phase 1 clinical 
studies (W-5107-101 and W-5107-102). Intravenous ZID was assessed through single ascending 
dose (SAD) and multiple ascending dose (MAD) regimens in healthy adult (>18 years) human 
subjects. These randomized, double-blinded, placebo-controlled studies involved single 
escalating IV doses (0.25 to 3 g) and multiple IV doses (1 and 2 g, q8h for 7 days), administered 
as a 1 h infusion. In single ascending dose studies, ZID showed a linear PK; Geometric mean 
AUC(0- inf) ranged from 44.3 to 458 mg·h/L and Cmax ranged from 16.5 to 174 µg/mL. ZID 
elimination half-life (1.8 to 2.4 h) was appeared to be independent of dose. The observed median 
Tmax coincided with the respective cohort infusion duration within the 0.25 g to 3 g dose range. 
Renal clearance (4.85 L/h to 6.77 L/h) approximated the plasma clearance and appeared to be 
independent of the administered dose. In repeat dose study, exposure parameters were similar for 
each dosing interval within each dosing day. The plasma exposures of ZID were linear and 
comparable on Day 1 and Day 7. The majority (>80%) of the administered dose of ZID in the 
SAD study was excreted as unchanged drug within the first 0 to 6 h of the collection interval, 

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with the complete dose recovered within 24 h post-dose. In the MAD study, the majority of the 
administered q8h doses of ZID were excreted as unchanged drug within each dosing interval 
(0 to 8 h, 8 to 16 h, and 16 to 24 h collection intervals), with near complete dose recovery within 
24 h post AM dosing on Day 1 (92% to 95%), and within 48 h post AM dosing on Day 7 (95% 
to 99%) [34]. 
 
In addition, 1 g (approximately 200 μCi) of [14C]-ZID has been administered to 8 healthy adult 
male volunteers in a Metabolism and Excretion study conducted in U.S. In this study maximum 
plasma ZID concentrations were observed at the end of infusion for all subjects, after which 
plasma concentrations of ZID appeared to decline in a generally monophasic manner, with 
arithmetic mean t1/2 of approximately 2 hours. The primary route of elimination of total 
radioactivity was in urine, with 94.6% of the dose recovered. Excretion of total radioactivity in 
feces was negligible (0.235%). An arithmetic mean of 102% of the administered dose was 
excreted as unchanged ZID in urine, with the majority being recovered within the first 12 hours 
after start of infusion [34]. 
2.3.2 
Human Studies with Ertapenem 
2.3.2.1 
Safety and Tolerability 
ERT is an antibiotic approved by the FDA for human use by prescription in 2001. Extensive 
safety data (mostly post-marketing) is available for standalone ERT, which should be taken into 
account for an ongoing safety assessment of the ERT-ZID combination in clinical studies, both 
of assessment of causality of adverse events, as well as expectedness of any Serious Adverse 
Events (SAE). Clinical trials enrolled 1,954 patients treated with ERT. Most adverse experiences 
reported in these clinical trials were described as mild to moderate in severity. ERT was 
discontinued due to adverse experiences in 4.7% of patients. The most common drug-related 
adverse experiences in patients treated with ERT were diarrhea (5.5%), infused vein 
complication (3.7%), nausea (3.1%), headache (2.2%), and vaginitis in females (2.1%). Merck-
conducted clinical studies involving higher ertapenem doses of 1.5 g, 2 g or 3 g daily were 
administered to approximately 150 subjects [28, 29]. In these studies, ERT 2 g was well-
tolerated with minimal adverse events (AEs) of diarrhea, nausea, vomiting, somnolence and 
headache of mild to moderate severity, and asymptomatic increases in hepatic transaminases and 
platelet counts that were reversible and not clinically significant. The infusion duration of the 3 g 
IV dose initially was 1 h, but this was changed to 2 h due to the apparent association of nausea 
with the more rapid infusion rate. In Phase 2 studies, the pattern and frequency of AEs in patients 
who received 1.5 g or 2 g of ERT were similar to that of 1 g ERT [28, 29, 34]. A complete list of 
TEAEs reported in clinical trials with ERT as well as post-marketing studies is available in the 
Prescribing Information for Ertapenem Sodium for Injection, and in the IB [28, 34, 37]. 

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2.3.2.2 
Pharmacokinetics 
The single- and multiple-dose pharmacokinetics of ERT at doses up to 3 g were examined in 
healthy young men and women volunteers. Plasma and urine samples collected were analyzed 
using reversed-phase high-performance liquid chromatography with UV detection. ERT is highly 
bound to plasma protein. The protein binding changes from ∼95% bound at concentrations of 
<50 μg/ml to ∼92% bound at concentrations of 150 μg/ml (concentration at the end of a 30-min 
infusion following the 1-g dose). The nonlinear protein binding of ERT resulted in a slightly less 
than dose proportional increase in the area under the curve from 0 h to infinity (AUC0-∞) of 
total ERT. The single-dose AUC0-∞ of unbound ERT was nearly dose proportional over the 
dose range of 0.5 to 2 g. The mean concentration of ERT in plasma ranged from ∼145 to 
175 μg/mL at the end of a 30-min infusion, from ∼30 to 34 μg/mL at 6 h, and from ∼9 to 
11 μg/mL at 12 h. The mean plasma t1/2 ranged from 3.8 to 4.4 h. About 45% of the plasma 
clearance (CLp) was via renal clearance. The remainder of the CLp was primarily via the 
formation of the β-lactam ring-opened metabolite that was excreted in urine. There were no 
clinically significant differences between the pharmacokinetics of ERT in men and women. ERT 
does not accumulate after multiple once-daily dosing [35]. 
2.3.3 
Human Studies with WCK 6777 
WCK 6777 has not been studied in humans. This is the first in human study to investigate the 
safety and PK of ERT and ZID in combination. 
2.4 
Rationale  
2.4.1 
Study Rationale 
The aim of the clinical development program for WCK 6777 is to allow a full assessment of 
safety and efficacy as well as ensuring that the product is rapidly made available to fulfill an 
unmet medical need in the treatment of infections due to multi-drug resistant (MDR) bacteria. 
  
A Phase 1 study is required given that human safety and PK data are not available for ERT and 
ZID administered in combination. The following observations support conduct of this study: (a) 
Non-clinical mechanism of action (MOA) and PK/PD studies establish ERT/ZID 2 g/2 g QD as a 
potential treatment of patients with CRE infections; (b) Multiple Phase 1 studies conducted for 
ZID alone or in combination with FEP demonstrated safety and tolerability of ZID at multiple 
daily doses up to 6 g (2 g q8h) administered over 7 to 10 days; (c) Higher IV ERT doses of 2 g 
and 3 g QD have been studied in previous phase 1 and 2 studies (n = 101) [28,29]; (d) The 
preclinical toxicity studies of WCK 6777 in rats and dogs employing doses that generated 

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exposures higher than the clinical exposures reported for ERT 2 g and ZID 2 g suggest that the 
combination would be safe and tolerable. 
2.4.2 
Rationale for Dose Selection 
In vivo PK/PD studies involving neutropenic mouse lung infection models have demonstrated 
that the ERT-ZID combination exerts significant bactericidal action against KPC, OXA-48-like 
and MBL-expressing Enterobacterales at mouse exposures that correspond to 2 g q24h unbound 
clinical exposures of ERT and 2 g q24h unbound exposures of ZID obtained when dosed 
individually [34]. 
 
The IV No Observed Adverse Effect Level (NOAEL) doses, based on a 28-day repeat dose 
toxicity study for ZID in rat and dog, are 800 and 750 mg/kg/day, respectively, and the 
corresponding exposure in terms of 24-hour (h) area under the plasma drug concentration-time 
curves (AUCs) are 1950 and 1962 µg·h/mL, respectively. On the basis of ZID NOAEL dose 
exposures in dog (750 mg/kg/day) and rat (800 mg/kg/day) and anticipated ZID clinical exposure 
of 360 µg·h/mL at 2 g/day, a safety window of approximately 5.4 times is estimated [34]. 
 
Extrapolation of the dog IV NOAEL dose of 750 mg/kg to a human dose (based on body surface 
area) would lead to a human equivalent dose for ZID of 416 mg/kg, corresponding to 29 g for a 
70 kg human. Likewise, considering the NOAEL dose (800 mg/kg) in rat, the human equivalent 
dose for ZID would be 64 mg/kg, corresponding to 9 g for a 70 kg human [34]. 
2.5 
Identified and Potential Risks and Benefits Associated with the Study 
2.5.1 
Risks with ZID 
ZID alone has been administered to 91 healthy adult human volunteers in two Phase 1 studies 
[SAD and MAD] conducted in the U.S. In addition, 1 g (approximately 200 μCi) of [14C]-ZID 
has been administered to 8 healthy adult male volunteers in a Metabolism and Excretion study 
conducted in U.S. 
 
Overall, there were no SAEs or AEs that led to discontinuation of participants. The most 
common AE reported was headache, and it was mild in the majority of subjects, with one subject 
reporting moderate headache. Infusion site erythema and infusion site pain have also been 
reported as side effects, both considered related to the placement of an IV catheter than a 
reaction associated with the study drug. 

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2.5.2 
Risks with ERT 
Extensive safety data (mostly post-marketing) is available for standalone ERT. The latter should 
be taken into account for an ongoing safety assessment of the ERT-ZID combination in clinical 
studies, both for the assessment of causality of adverse events, as well as expectedness of any 
SAEs. 
 
Most adverse experiences reported in clinical studies with ERT, including those involving higher 
ertapenem doses of 1.5 g, 2 g or 3 g daily, were described as mild to moderate in severity. ERT 
was discontinued due to adverse experiences in 4.7% of patients. The most common drug-related 
adverse experiences in patients treated with ERT were diarrhea (5.5%), infused vein 
complication (3.7%), nausea (3.1%), headache (2.2%), and vaginitis in females (2.1%). The 
infusion duration of the 3 g IV dose initially was 1 h, but this was changed to 2 h due to the 
apparent association of nausea with the more rapid infusion rate. In Phase 2 studies, the pattern 
and frequency of AEs in patients who received 1.5 g or 2 g of ERT were similar to that of 1 g 
ERT [28, 29]. The safety profile of ERT is expected to be similar to that described during its 
clinical use when administered alone; however, as for all drug studies, there may be unexpected 
AEs with ERT that have not been observed to date. 
2.5.3 
Risks with WCK 6777 
The ERT-ZID combination has not been tested in humans. Preclinical data suggest that there are 
no significant system organ effects and the doses to be used in the study are below NOAEL for 
both drugs in rats and dogs. The safety profile of WCK 6777 is expected to be similar to that 
described for each drug alone [34]; however, as for all drug studies, there may be unexpected 
AEs with WCK 6777 that have not been observed with ERT or ZID alone to date. 
2.5.4 
Venipuncture and IV Catheter Risks 
Venipuncture: Venipuncture causes transient discomfort and may cause fainting. Bruising at the 
site of venipuncture may occur but can be prevented or lessened by applying pressure for several 
minutes. Infection at the site is possible but highly unlikely as aseptic technique will be used. 
 
IV catheter placement: An indwelling catheter may be placed in an arm vein (preferably 
antecubital) for frequent blood drawing for PK measurements on Days 1 to Day 8 and another 
one in a vein on the opposite arm for IV infusion of the study drugs. The catheter may cause 
phlebitis with signs of redness and warmth at or near the IV insertion site, and thrombophlebitis 
with a hard area palpable near the IV insertion site. These risks are minimal as the IV catheters, 
when used, are only used briefly after dosing. Careful inspection of the catheter site, including 
visualization of blood return, withdrawal of the catheter if needed, and change every 72 to 96 h 

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will minimize this risk. There is a risk of infection; however, this is a small risk as aseptic 
technique will be used. 
2.5.5 
Additional Risks 
ECG: Possible side effects from ECG patches include a rash or minor irritation of the skin. 
 
Blood draws: The amount of blood drawn is about 24 mL at Screening Visit, 15 mL on Day -1, 
371 mL during the inpatient period (Days 1 to 8), 15 mL at Day 11 (last visit), and 425 mL 
during the entire trial. Additionally, small amounts of blood loss may occur if an IV catheter is 
used or additional blood samples are collected (for repeat laboratory testing, TEAE evaluation, 
etc.). Overall, the amount of blood that may be drawn during the trial is within the amount that 
are considered safe to be drawn during short or extended periods, respectively, and not excessive 
for the safety and PK assessment requirements of Phase 1 trials. However, there is a small risk 
that some subjects may develop mild symptoms of hypovolemia or anemia during the trial. 
These are reversible with specific treatments (e.g., fluid replacement, good nutrition, vitamins or 
iron supplementation). 
2.6 
Known Potential Benefits 
The trial has no direct benefit for healthy participants. Knowledge gained in the trial could be of 
future benefit to public health and to individuals with infections, who might benefit if the study 
drug combination is licensed. The medical benefit would be to patients in the future from a 
potential new addition to the drugs available for the treatment of serious, antibiotic-resistant 
nosocomial and community acquired infections with increase efficacy and lower toxicity than 
available drug regiments. An additional benefit to future patients would be the ability to 
administer effective therapy for these infections in an out-patient setting, thus decreasing the 
need for hospitalization and associated costs. 
 
Subjects will be promptly notified of any clinical test results that would have an impact on their 
health. Screening evaluations may detect previously unknown abnormalities that could be 
clinically significant. This could benefit a subject, as it may lead to earlier diagnostic evaluation 
and treatment of an underlying disorder. 
2.7 
Risk/Benefit Ratio 
This ratio cannot be calculated by available data. Since high dose safety has been established for 
ERT and ZID individually, the risk for an SAE occurring in a subject treated with single or daily 
doses of each study drug separately in doses 1 to 3 g is considered to be very low. On the other 
hand, the risk of WCK 6777 (combined ERT and ZID) is not known. Preclinical studies have 
shown no potential DDIs through effects on enzymes and transporters.  Selection of the 

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combined human doses by appropriate methods for estimating human exposures from animal 
studies, suggest that the maximum exposure in humans will be at levels several-fold lower than 
NOAELs in rats and dogs. Data collected in the preclinical and clinical development of ZID and 
ERT/ZID to date, support further clinical development. Subject selection is based on carefully 
considered eligibility criteria. Subjects will be treated in an inpatient unit and closely monitored 
during the trial, so that appropriate emergency care can be provided immediately if an acute 
event occurs. As an additional measure of risk mitigation, each WCK 6777 cohort involves 
sentinel dosing in two subjects and remaining subjects will be dosed if no halting rules have been 
met after 24 hours of dosing to sentinel subjects. 
  
There is no medical benefit to healthy study volunteers from participation in this clinical trial.  

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3 
OBJECTIVES AND OUTCOME MEASURES 
3.1 
Study Objectives 
Primary 
• Assess the safety and tolerability of three dose-escalating regimens of WCK 6777 (ERT 
and ZID combination) and two dose-escalating regimens of standalone ERT or ZID 
following single daily doses for 7 days in healthy adult subjects 
Secondary  
• Characterize the PK profiles in plasma (total and free) and in urine of three dose-
escalating regimens of WCK 6777 (ERT and ZID combination) and the two dose-
escalating regimens of standalone ERT or ZID following single daily doses for 7 days in 
healthy adult subjects 
3.2 
Study Outcome Measures 
Primary 
• Type, incidence, severity, and relatedness to study drug of all treatment-emergent adverse 
events AEs and serious adverse events (SAEs) in each treatment cohort from the first 
dose through the follow-up period 
Secondary  
• PK parameter estimates and calculated exposure measures in plasma (total and free) and 
urine for ERT and ZID, when given alone and in combination following a single initial 
dose on Day 1 and after single daily dose administration for 7 days 

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4 
STUDY DESIGN 
This is a Phase 1, single center study to investigate the safety, tolerability, and pharmacokinetics 
(PK) of three dose-escalating regimens of WCK 6777 (ERT+ZID), and two dose-escalating 
regimens of ERT alone and ZID (WCK 5107) alone in 52 healthy adult male and female subjects 
aged 18 to 45 years old. 
Seven treatment cohorts will be evaluated in this study (Table 1). WCK 6777 (ERT+ZID) will be 
evaluated in three cohorts - Cohorts 1, 4 and 7 - of 8 subjects each (6 study drug combination and 
2 placebos); ERT will be evaluated in two cohorts - Cohorts 2 and 5 - of 8 subject each (6 ERT 
and 2 placebo); and ZID will be evaluated in two cohorts - Cohorts 3 and 6 - of 6 subjects each 
(all 6 ZID). The study will be placebo-controlled and double-blinded in all cohorts except 
Cohorts 3 and 6. No placebo subjects are included in standalone ZID cohorts, since adequate 
safety data for higher doses of ZID are available [34]. 
In each cohort, ERT and ZID will be administered either alone or in combination by a single 
intravenous infusion (IV) of 100 mL daily for 7 consecutive days in Cohort 1 and 250 mL in 
Cohorts 2 to 7. The dose will be progressively escalated from 2 g to 3 g/daily for each study drug 
individually, and from 2 g to 4 g to 6 g for WCK 6777 [ERT+ZID]) and, depending on the 
cohort, the duration of infusion time will increase from 30 min to 1 h to 2 h over the course of 
the study. Thus, in Cohort 1, 2 g WCK 6777 (ERT 1 g combined with ZID 1 g), the infusion 
solution (100 mL) will be administered in 30 (±5) minutes; in Cohort 2 (ERT 2 g/daily), 
Cohort 3 (ZID 2 g/daily) and Cohort 4 (4 g WCK 6777; ERT 2 g combined with ZID 2 g), the 
infusion solution (250 mL) will be administered in 60 (±10) minutes; and in Cohort 5 (ERT 
3 g/daily) , Cohort 6 (ZID 3 g daily) and Cohort 7 (6 g WCK 6777; ERT 3 g combined with ZID 
3 g), the infusion solution (250 mL) will be administered in 120 (±10) minutes. 
 Table 1 Study Treatment Cohort 
Cohort No. 
Study Drug-Dose 
Infusion time - frequency 
Subjects 
Cohort 1 
WCK 6777 2 g 
(ERT 1 g + ZID 1 g)  
or placebo 
30 (±5) minutes - once daily-for 
7 days, 100 mL per dose 
8 (6 drug combination, 2 placebo) 
Cohort 2 
ERT 2 g 
or placebo 
60 (±10) minutes - once daily-for 
7 days, 250 mL per dose 
8 (6 drug, 2 placebo) 
Cohort 3 
ZID 2 g 
60 (±10) minutes - once daily-for 
7 days, 250 mL per dose 
6 (all drug) 
Cohort 4 
WCK 6777 4 g 
(ERT 2 g + ZID 2 g) 
 or placebo 
60 (±10) minutes - once daily-for 
7 days, 250 mL per dose 
8 (6 drug combination, 2 placebo) 
Cohort 5 
ERT 3 g  
or placebo 
120 (±10) minutes - once daily-for 
7 days, 250 mL per dose 
8 (6 drug, 2 placebo) 

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 Table 1 Study Treatment Cohort 
Cohort No. 
Study Drug-Dose 
Infusion time - frequency 
Subjects 
Cohort 6 
ZID 3 g 
120 (±10) minutes - once daily-for 
7 days, 250 mL per dose 
6 (all drug) 
Cohort 7 
WCK 6777 6 g 
(ERT 3 g + ZID 3 g) 
or placebo 
120 (±10) minutes - once daily-for 
7 days, 250 mL per dose 
8 (6 drug combination, 2 placebo) 
 
The treatment regimen for the first combination cohort (Cohort 1), WCK 6777 2 g (ERT 1 g with 
ZID 1 g daily; 30-minute infusion), was selected because there are no human safety and PK data 
available with these agents in combination. The second combination cohort (Cohort 4) will 
evaluate the safety and PK of the anticipated therapeutic combination regimen of WCK 6777 4 g 
(ERT 2 g with ZID 2 g daily; 1-h infusion). The third combination-treatment cohort (Cohort 7) 
will evaluate the safety and PK of higher daily doses of WCK 6777 6 g (ERT 3 g + ZID 3 g 
daily; 2-h infusion). The primary purpose of the ERT 3 g with ZID 3 g combination treatment 
cohort is to ensure maximal flexibility in the clinical development program in the event there is a 
need to evaluate more intensive combination daily dosing regimens and different infusion 
strategies in future clinical trials. Moreover, 3 + 3 g/daily combination regimen will provide 
critical information on dose proportionality, PK linearity, and plasma protein binding linearity. 
As it is well-established that healthy subjects do not fully reflect the real-world inter-subject 
variability observed in patients [36], the higher daily dosing regimen will also provide data on 
the safety, tolerability, and PK of upper range exposures likely to be encountered in clinical 
practice with ERT 2 g + ZID 2 g. To mitigate the risk of higher osmolality-linked infusion 
reactions, the volume of each infusion in the 2-g and 3-g dose standalone and combined groups 
(Cohorts 2-7) will be increased to 250 mL. The duration of infusions in the 2-g and 3-g cohorts 
were chosen to mitigate infusion duration-related AEs (nausea, vomiting) with ERT doses >2 g 
[29]. In four of the seven cohorts (Cohorts 2, 3, 5 and 6), single 2 g and 3 g ERT or ZID 
infusions will be administered. ERT 1 g daily and ZID 1 g daily will not be evaluated as single 
drug treatment cohorts as there are sufficient safety, tolerability, and PK data with these 
standalone regimens [28, 29, 34]. 
In all cohorts, 6 subjects will receive study drug product. Two additional subjects will receive 
placebo in the 2 g/daily and 3 g/daily ERT single treatment cohorts and in ERT-ZID combination 
cohorts to maximize interpretation of the safety and tolerability of the observed results. The 
single drug treatment cohorts are being conducted to collect the baseline safety and 
pharmacokinetic data. Specifically, the single-treatment arms of ERT and ZID are necessary to 
assess for the presence of any PK interactions between the two constituents and to deduce the 
role of each, in the event of any safety or tolerability signals in the combination cohorts. In 
conjunction with the escalating dose combination regimens, the single treatment drug cohorts 

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will also provide information on dose-PK proportionality, which is necessary for building robust 
individual population PK models for ERT and ZID, which, when supplemented with PK/PD 
studies, will help justify the dose regimen for advanced clinical trials. 
Study enrollment will proceed from Cohort 1 to the last Cohort 7 starting with the lowest dose 
and escalating to the next higher dose. Enrollment of single drug Cohorts 2 and 3, and 5 and 6 
will be conducted in parallel and completed before enrollment of combination Cohorts 4 and 7, 
respectively. Placebo subjects will be enrolled in WCK 6777 cohorts (Cohorts 1, 4 and 7) and in 
the ERT alone cohorts (Cohorts 2 and 5), but not in the ZID cohorts (Cohorts 3 and 6). Sentinel 
subjects will be enrolled in the WCK 6777 cohorts but not in the ERT and ZID standalone 
cohorts. For each WCK 6777 cohort (Cohorts 1, 4 and 7), two sentinel subjects will receive 
study drug product on the first day of treatment, one active drug combination and the other 
placebo (normal saline) (active drug/placebo ratio, 1:1) and followed for approximately 24 hours. 
If no halting rules are met after 24 hours of dosing, dosing of sentinel subjects will continue for 
the remainder of the study, and the additional 6 subjects in the cohort will be dosed (5 will 
receive the study drug combination and 1 will receive placebo (active/placebo ratio, 5:1). 
Alternate subjects may be admitted in all cohorts at check-in and, if they are not used on the 
following dosing day, they may be used on another dosing day in the same cohort or in a future 
cohort if they continue to meet eligibility criteria. 
Blood (plasma) and urine samples will be collected for measuring drug concentrations of ERT 
and ZID and for PK analysis in all cohorts before dosing, for 24 h after starting the first IV 
infusion on Day 1, and for 24 h after starting the last IV infusion on Day 7. In addition, blood 
(plasma) will be collected before dosing and 12 hours after dosing on Days 2 to 6 for the 
measurement of concentrations of ERT and ZID. Total and free drug concentration will be 
measured in plasma and total drug concentration in the urine for ERT and ZID by validated LC-
MS/MS assays. The plasma and urine PK profiles for each study drug in the single dose ZID and 
ERT cohorts and the WCK 6777 cohorts will be analyzed by non-compartmental methods 
(NCA). 
Safety data will be monitored from the time of infusion on Day 1 to the last visit, Day 11 
(+3 days), and changes will be compared to the pre-dosing baseline (Day -1). Evaluations will 
consist of: assessments of TEAEs (Day 1 to Day 11), symptom-directed (focused) physical 
examination (PE) as needed (Days 1 to 7) and complete PE (Days 8 and 11); vital signs (Day 1 
to 8, Day 11);  Clinical laboratory safety tests (Days 2, 4, 6, 8 and 11); and 12-lead ECGs (Days 8 
and 11). AEs will be assessed by study clinicians for severity or seriousness and relatedness and 
will include outcome and duration. 
Dose escalation from combination Cohort 1 (1 g ERT + 1 g ZID) to higher single dose Cohorts 2 
(2 g ERT) and 3 (2 g ZID), and from combination Cohort 4 (2 g ERT + 2 g ZID) to higher single 
dose Cohorts 5 (3 g ERT) and 6 (3 g ZID) will be based on the SMC review of unblinded 
cumulative interim safety data collected through study Day 11 (+3 days) in each combination 

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treatment cohort. (See Section 9.5.3). The recommendation to continue to the next planned 
combination cohorts (i.e., Cohort 4 and Cohort 7 [3 g ERT + 3 g ZID]), will be made by the 
study team (DMID MO and MM and the site PI) after review of blinded safety data in Cohorts 2 
and 3 and Cohorts 5 and 6, respectively. The SDCC will provide a report of number of subjects 
meeting dose escalation halting criteria. The decision to continue dose escalation to the next 
single or combination dose cohorts will be made by DMID after review of the SMC or the study 
team recommendation. If the decision is to continue dose escalation, the next in line cohort(s) 
will enroll.  
If halting criteria are met, an ad hoc meeting of the Safety Monitoring Committee (SMC) will 
convene to review blinded data (or unblinded in a closed meeting) and make recommendation 
about dose escalation (See Section 9.5.1). The SMC will also convene in ad hoc meetings per 
DMID request to review a potential safety concern identified by either the Site PI or the DMID 
MM.  
Finally, in scheduled meetings, the SMC will review unblinded aggregate data in the first 
4 cohorts, before dosing will continue in the remaining cohorts (Cohorts 5, 6 and 7), and 
cumulative safety data at the end of the trial after database lock (See Section 9.6.1). 
4.1 
Sub-studies 
No sub-studies are planned. 

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5 
STUDY ENROLLMENT AND WITHDRAWAL 
Only subjects who meet all inclusion criteria and no exclusion criteria will be eligible for 
enrollment into the trial. 
5.1 
Subject Inclusion Criteria 
All must be answered YES for the subject to be eligible for study participation: 
1. Provide a signed and dated written informed consent and agrees to comply with the study 
procedures and length of confinement to the research site. 
2. Be able to understand and willing to comply with study procedures, restrictions, and 
requirements, as determined by the Site Principal Investigator (PI) or authorized 
clinician(s) (listed on FDA Form 1572).  
3. Adults 18 to 45 years of age inclusive, including non-pregnant, non-lactating females. 
4. Have suitable veins for cannulation or repeated venipuncture. 
5. Be in good general health at the time of enrollment. 
• Note 1: Determined by medical history (MH), medication use, physical examination 
(PE), vital signs (VS), clinical laboratory tests including estimated creatinine 
clearance (CLCR) ≥80 mL/min by the Cockcroft-Gault method, and 12-lead ECG 
within reference ranges at Screening and Day-1 (See Sections 8.1 and 8.2 and 
Appendix B, Table 2, Table 3, and Table 4). 
• Note 2: Exceptions to BP, HR and laboratory test values being with normal ranges 
are: 
o Subjects with baseline HR ≥ 45 to 50 bpm may be accepted if otherwise healthy 
adults with known history of asymptomatic bradycardia.  
o Subjects with baseline SBP up to 140 mmHg and DBP up to 90 mmHg may be 
accepted if otherwise healthy.  
o A laboratory value that is Grade 1 will be allowed if not considered to be 
clinically significant by the investigator, with the exception of ALT, AST, AP, 
total and direct bilirubin, BUN, serum creatinine, CLCR, and urine protein.  
6. Sexually active females must be of non-childbearing potential or must use a highly 
effective method of birth control from screening to 30 days following the last dose of 
study product. 
• 
Note 1: A female is considered of childbearing potential unless post-menopausal 
(defined as history of ≥1 year of spontaneous amenorrhea and a FSH level >40 IU/L), 
or permanently surgically sterilized. 
• 
Note 2: Highly effective contraceptive methods include: (a) surgical sterilization 
methods, such as tubal ligation, bilateral oophorectomy, salpingectomy, 
hysterectomy, or successful tubal obliteration (e.g., Essure®) with documented 

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radiological confirmation test at least 90 days after the procedure, or (b) long-acting 
reversible contraception, such as progestin-releasing subdermal implants, copper 
intrauterine devices (IUDs), levonorgestrel-releasing IUDs. 
• 
Note 3: A subject who is not sexually active and abstains from sexual intercourse can 
be enrolled and abstinence documented. 
7. Sexually active males must be vasectomized or agree to use barrier contraception and not 
donate sperm from first dose of study product until 30 days following the last dose. 
• 
Note 1: Barrier contraception includes use of condom with spermicide. 
• 
Note 2: A subject who is not sexually active and abstains from sexual intercourse can 
be enrolled and abstinence documented. 
8. Subjects must be willing to avoid excessive physical exercise within 48 h prior to dosing 
until discharge from the clinical trial unit (CTU) on Day 8, and 24 h before the last visit 
(Day 11 + 3 days). 
9. No history of acute febrile or infectious illness for at least 7 days prior to the 
administration of study drug(s). 
5.2 
Subject Exclusion Criteria 
All must be answered NO for the subject to be eligible for study participation: 
1. Known history of a clinically significant food or drug allergy/hypersensitivity including 
known allergy/hypersensitivity to ERT, any β-lactam drugs or other related drugs. 
2. Current seasonal allergies with ongoing symptoms for more than a week prior to dosing 
requiring glucocorticoids and/or frequent use of antihistamines for treatment. 
3. Any history of a chronic condition including renal failure that may increase risk to 
subject or interfere with endpoint assessment, or any unstable chronic disease. 
• Note 1: Unstable chronic disease is defined by need for frequent medical 
interventions that lead to a change in medications and/or required hospitalization, 
surgery or an invasive procedure or emergency department/urgent care visit, as 
determined by the Site PI. 
• Note 2: Any chronic disease, that has been diagnosed within 90 days of screening is 
excluded. 
4. History of any psychiatric condition that has required hospitalization in the last 
12 months or subject is considered psychologically unstable by the investigator. 
5. History of any clinically significant (CS) disease or disorder, medical/surgical procedure, 
or trauma within 4 weeks prior to initiation of administration of study product(s). 
6. History of Clostridium difficile induced diarrhea within 1 year before screening 
7. Known history of past or current epilepsy or seizure disorders, excluding febrile seizures 
of childhood. 
8. Prior exposure to ZID. 

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9. Use of any prohibited prescription or non-prescription medication within 14 days prior to 
the first dose of study drug(s) as described in Section 6.6. 
10. Use of any investigational drug product within 30 days or 5 half-lives (whichever is 
longer) before investigational product administration in this study. 
11. Planned participation in a clinical research study that requires treatment with a study 
drug, blood draws or other invasive assessments during the study period (screening until 
final visit). 
12. Blood or plasma donation of 500 mL within 3 months or more than 100 mL within 
30 days before signing informed consent or planned donation prior to completion of this 
trial. 
13. Positive serum pregnancy test for women at screening and urine pregnancy test at check-
in. 
14. Positive urine alcohol test or urine drug screen test at screening or check-in (Day -1). 
15. Positive test for HIV antibodies, hepatitis B-virus surface antigen (HBsAg), or  
anti-hepatitis C-virus antibodies (anti-HCV) at screening. 
16. History of ≥10 pack-years smoking in the 5-year period before screening, or positive 
urine cotinine screen at check-in. 
• Note 1: Nicotine products include cigarettes, e-cigarettes, pipe, cigar, chewing 
tobacco, nicotine patch. 
•  Note 2: Positive urine cotinine at screening is allowed if negative at check-in  
(Day -1). 
17. History of binge drinking or heavy drinking of alcohol at any time in the 6 months before 
study product administration. 
• Note 1: Binge drinking is defined as 5 or more drinks during single occasion if male, 
or 4 or more if female. 
• Note 2: Heavy drinking of alcohol is defined as consumption of more than 15 units of 
alcohol per week if male, or more than 8 units if female. 
5.3 
Treatment Assignment Procedures 
5.3.1 
Enrollment and Randomization Procedures 
Fifty-two healthy subjects who consent to participate in the trial and meet the eligibility criteria 
will be enrolled following admittance to the CTU and confirmation of eligibility. Subjects will 
be registered using Advantage eClinical®, a web-based application developed by The Emmes 
Company, LLC, the DMID Statistical and Data Coordinating Center (SDCC) for the trial. 
Reasons for screen failure will be entered in Advantage eClinical®. Instructions for using the 
enrollment module are included in the Advantage eClinical® User’s Guide. 
For the drug combination cohorts (Cohorts 1, 4 and 7) and standalone ERT cohorts (Cohorts 2 
and 5), the trial will be double-blinded, placebo controlled, with eight subjects randomized to 
receive either active drug(s) or placebo (normal saline) in an overall 3:1 ratio (6 subjects study 
drug and 2 subjects placebo). For each drug combination dosing cohort, two sentinel subjects 

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will be randomized in a 1:1 fashion to active drug and placebo and will be followed for 24 h. If 
there are no safety events, the remaining 6 subjects in each cohort will be randomized in a 5:1 
ratio to active drug and placebo. Sentinel subjects will not be used for the randomized, 
standalone ERT cohorts and for the ZID cohorts. 
Randomized treatment assignments for these cohorts will be generated centrally at SDCC 
through the Advantage eClinical® application by the unblinded study biostatistician, and a list 
will be transferred to the unblinded study personnel (i.e., research pharmacists and a verifier) at 
the research site prior to start of the study for the purpose of an emergency back-up, which will 
be kept up in a secure place. The research pharmacists will perform dose preparation; the 
unblinded verifier is a member of the pharmacy team who will not participate in dose 
preparation. 
In the standalone ZID cohorts (Cohorts 3 and 6), 6 subjects will be enrolled, and all will receive 
active drug. All subjects will be registered into the Advantage eClinical®. 
5.3.2 
Masking Procedures 
All investigative site personnel, study volunteers, DMID, Wockhardt and DVC personnel will 
remain blinded through database lock, with the exception of an unblinded pharmacist/verifier at 
the research site, an unblinded SDCC biostatistician, and a DMID/CMS manager responsible for 
PK sample storage. 
 
The randomization scheme will be provided to the unblinded research pharmacist at the site, who 
will perform dose preparation, and a pharmacy verifier who will not participate in dose 
preparation. These pharmacy personnel at the site will not be involved in study-related 
assessments or have subject contact for data collection following study drug administration. 
 
The study staff participating in the administration of study product and assessment of the 
subjects will not be aware of the administered contents of the IV infusion in the randomized arms 
of the study. Study drugs will be diluted in normal saline, and they will look identical to placebo 
in the IV infusion bag so the study staff and the subject will not be able to determine whether 
placebo or active drug are being administered. The label on the IV infusion bag will not have 
information that can identify the contents. 
 
Only plasma and urine PK samples collected from subjects who received active drug(s) will be 
sent to the bioanalytical laboratory, KCAS, for testing. To select these samples, an SDCC 
Unblinded Biostatistics Team will determine which volunteers received active drug and will 
provide the list of samples from those volunteers to DMID-CMS. DMID-CMS repository 
employees will identify those samples and ship to KCAS. KCAS personnel are blinded. 
Individual samples are barcoded, and the barcode includes information that can match the 

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sample to the volunteer identification number, aliquot number, treatment cohort and collection 
timepoint. Data from KCAS will be received by the SDCC Unblinded Biostatistics Team and 
entered into the database after the safety analysis was completed by the SDCC Blinded 
Biostatistics team. 
The SMC will receive blinded data in aggregate and presented by cohort. The SMC may review 
unblinded data prepared by an unblinded biostatistician in the closed session only. 
5.3.3 
Reasons for Withdrawal and Discontinuation of Study Drug Administration 
A subject may withdraw from the trial at any time for any reason, without any consequences. 
A subject will be discontinued from the trial if any of the following occur before dosing: 
• Request by the subject to terminate participation. 
• Failure to receive the study drug due to difficulty initiating or maintaining an intravenous 
infusion line. 
A subject may be removed from the trial after dosing for the following reasons; however, 
whenever possible, the subject will be followed for safety per protocol to Day 11 (+ 3 days): 
• Failure to adhere to protocol requirements. 
• Loss to follow-up. 
• Request of primary care provider. 
• Request of the Institutional Review Board (IRB)/Ethics Committee (EC), FDA or DMID. 
• The occurrence of a Serious AE (SAE) or treatment-emergent AE warranting withdrawal. 
• Any other condition that the study site PI judges to unduly increase the risk to the subject. 
5.3.4 
Handling of Withdrawals and Discontinuation of Study Drug Administration 
• Subjects who are withdrawn before dosing or subjects who do not have at least 1 PK 
blood draw should be replaced with a subject assigned to the same cohort and treatment 
as the subject they replaced. 
• Additionally, subjects will be replaced in each dosing cohort to ensure there are at least 
seven subjects with complete PK profiles in each 8 subject dosing cohort or 5 subjects in 
each 6 subject dosing cohort. A Subject will be considered to have a complete PK profile 
if ≥70% of plasma PK samples are collected. (See the SAP for details). 
• Subjects who withdraw after receiving all study doses and completed scheduled 
assessments to Day 8 will not be replaced unless more than 50% of subjects in a cohort 
are withdrawn from the trial. 

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• Replacement of additional withdrawals is at the discretion of the Investigator in 
consultation with the Sponsor. Replacement subjects should be allocated to the same 
treatment as the subject they replaced. 
Generally, subjects who received any amount of the study drug but withdraw from the trial will 
be encouraged to continue follow-up (with subjects’ consent) for safety assessments until Final 
Visit (Day 11+3) and for completion of scheduled plasma PK sample collection following the 
last dose of study drug they received. Subjects withdrawing will be asked to complete safety 
assessments according to the ET schedule (See Section 7.6).  
5.3.5 
Lost to Follow-up 
If subjects fail to appear for a follow-up assessment, extensive effort (i.e., three documented 
contact attempts via phone calls, e-mail, etc., made on separate occasions and followed by a 
certified letter) will be made to locate or recall them, or at least to determine their health status. 
These efforts will be documented in the subjects’ records. 
5.3.6 
Termination of Study 
Although DMID has every intention of completing the trial, it reserves the right to terminate the 
trial at any time for clinical or administrative reasons. In addition, the trial may be terminated or 
suspended at the request of the FDA, SMC or IRB/EC. 
 

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6 
STUDY INTERVENTION/INVESTIGATIONAL 
PRODUCTS 
6.1 
Description of Study Products 
6.1.1 
Zidebactam for Injection, 1 g/vial  
Zidebactam dihydrate (CAS No. 1996664-59-5) is a proprietary New Chemical Entity (NCE) of 
Wockhardt Bio AG. It is an entity from the diazabicyclooctane (DBO) class and exhibits a novel 
mode of action as a β-lactamase inhibitor and β-lactam enhancer. It is chemically identified as 
(2S, 5R)-7-Oxo-6-sulphooxy-2-[N'-((R)-piperidin-3-carbonyl)-hydrazinocarbonyl]-1, 6-diaza-
bicyclo [3.2.1] octane dihydrate. The structure and absolute stereochemistry of ZID have been 
confirmed though various instrumental methods of analysis. ZID is slightly hygroscopic and is 
freely soluble in water and insoluble in dichloromethane. ZID (WCK 5107) drug substance is 
manufactured at Wockhardt Limited, Ankleshwar, Gujarat, India and/or Aragen Life Sciences 
Private Ltd (formerly GVK Biosciences Pvt. Ltd and Inogent Laboratories Private Ltd.), 
Hyderabad, Telangana, India. ZID for Injection 1g/vial drug product is manufactured at 
Wockhardt Limited, Shendra, Aurangabad, India [34]. 
6.1.2 
Ertapenem Sodium for Injection, 1 g/vial (ERT) 
ERT is a sterile, synthetic, parenteral, 1-β methyl-carbapenem that is structurally related to beta-
lactam antibiotics. It is generally available as ertapenem sodium (CAS No. 153773-82-1), and 
chemically identified as [4R-[3(3S*,5S*),4α,5β,6β(R*)]]-3-[[5-[[(3-carboxyphenyl)amino] 
carbonyl]-3-pyrrolidinyl]thio]-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0] hept-2-
ene-2-carboxylic acid monosodium salt. ERT sodium is a white to off-white hygroscopic, weakly 
crystalline powder. It is soluble in water and 0.9% sodium chloride solution, practically insoluble 
in ethanol, and insoluble in isopropyl acetate and tetrahydrofuran [34]. For this study, a U.S. 
FDA- approved generic ERT for injection will be procured from Dr. Reddy’s Laboratories, Inc., 
in the U.S. by Wockhardt (37). 
6.1.3 
WCK 6777 (ERT-ZID) 
It is a combination of ERT and ZID (WCK 5107). For this clinical trial, single use, sterile, 
lyophilized ZID for Injection, 1 g/ vial and ERT Sodium for Injection, 1 g ertapenem/vial will be 
used and supplied separately by Wockhardt. Solutions for injection containing ZID and ERT will 
be reconstituted in the Pharmacy of the clinical research site in the desired drug doses. 

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6.1.4 
Placebo 
0.9% Sodium Chloride Injection, USP will be used as the placebo for this study. 
Sterile Water for Injection, USP is sterile, nonpyrogenic, distilled water for intravenous 
administration after addition of a suitable solute. No antimicrobial or other substance has been 
added. The pH is 5.5 (5.0 to 7.0). The osmolarity is 0 mOsmol/L. It will be used for 
reconstituting ERT and ZID separately or combined (for WCK 6777) prior to dilution with 
sterile 0.9% Sodium Chloride Injection, USP. 
0.9% Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution. Each 100 mL 
contains 900 mg sodium chloride in water for injection. It contains sodium (Na+) 154 mEq/L and 
chloride (Cl–) 154 mEq/L. The osmolarity is 308 mOsmol/L (calc.). The solution may contain 
hydrochloric acid and/or sodium hydroxide for pH adjustment (pH 5.6, range 4.5 to 7.0). This 
solution contains no bacteriostatic, antimicrobial agent or added buffer. It will be used as the 
secondary diluent for ERT and ZID and as the placebo in this study. 
6.1.5 
Acquisition 
ZID for Injection, 1 g/vial will be provided by Wockhardt. ERT Sodium for Injection, 1 g 
ertapenem/vial will be procured by Wockhardt from a US supplier [37]. Upon request by DMID, 
study products will be shipped for clinical labeling to the DMID Clinical Materials Services 
(DMID-CMS) at the address provided in the protocol-specific MOP. 
The study drugs will be shipped from DMID-CMS to the CTU upon request and approval by 
DMID. Details will be provided in the protocol-specific MOP. 
Sterile Water for Injection, USP and 0.9% Sodium Chloride Injection, USP will be purchased by 
the clinical research site from commercial sources. Details will be described in the protocol-
specific MOP. 
Ancillary supplies required for IV administration (including syringes or infusion bag, tubing and 
IV catheter and line-filter) will be supplied by the clinical research site as described in the 
protocol-specific MOP. 
6.1.6 
Formulation, Packaging, and Labeling 
For this Phase 1 clinical study, individual vials of Zidebactam for Injection 1 g / vial and 
Ertapenem Sodium for Injection, 1 g ertapenem/ vial will be used. 
• Zidebactam for Injection, 1 g/vial will be used in this study. The drug product is 
manufactured by Wockhardt Limited, Shendra, Aurangabad, India according to cGMP 
requirements as a sterile, lyophilized powder. Zidebactam for Injection is packed in 
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sealed with aluminum flip-off seal. Product information, packaging and labeling will be 
described in the MOP. 
• Ertapenem Sodium for Injection, 1 g ertapenem/vial is supplied in single dose glass vials 
as a sterile, lyophilized powder. Each vial contains 1.046 grams of ERT sodium, 
equivalent to 1 gram of ERT. The sodium content is approximately 137 mg 
(approximately 6.0 mEq). Each vial of ERT sodium contains the following inactive 
ingredients: 175 mg sodium bicarbonate and sodium hydroxide to adjust pH to 7.5 [37]. 
Commercial source, product information packaging and labeling will be described in the 
MOP. 
• WCK 6777 for Injection (combination of ZID [WCK 5107] and ERT) will be formulated 
for IV infusion at the clinical research pharmacy of the CTU using separate vials of ZID 
for Injection, 1 g/vial and ERT Sodium for Injection, 1 g ertapenem/vial to the desired 
doses. (See Section 6.2)  
• Sterile Water for Injection, USP - Commercial source, product information and 
packaging will be described in the MOP. 
•  0.9% Sodium Chloride Injection, USP - Commercial source, product information and 
packaging of the diluent will be described in the MOP. 
Each product vial and diluent will be labeled in compliance with applicable regulatory 
requirements as described in the MOP and will include FDA-required cautionary statement, 
“Caution – New drug - Limited by United States Federal Law to Investigational Use.”   
6.1.7 
Product Storage and Stability 
6.1.7.1 
Stability in Storage Prior to Reconstitution 
It is recommended that the vials for both drug products should be stored refrigerated at 2°C to 
8°C (35.6°F to 46.4°F) within the packaging until time of preparation for dosing.  
• ZID for Injection, 1 g/vial -  Based on available stability data, the proposed shelf life for 
ZID for Injection, 1 g/vial is 48 months at 2°C to 8°C (35.6°F to 46.4°F). Further stability 
study is on-going up to 60 months at long-term conditions. GMP/ Clinical batch of ZID 
for Injection 1 g/vial (#QV10001 Mfg. date: Dec. 2019), which is intended to be used in 
this WCK 6777 phase 1 study, was found to be stable up to 24 months at accelerated 
conditions (25°C± 2°C / 60% ± 5% RH) and 36 months at long-term conditions (5°C± 
3°C). Extended stability testing is ongoing and proposed “Use by Date” will be based on 
satisfactory stability data and ICH Q1E recommendation. Details will be provided in the 
study-specific MOP. 

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• ERT Sodium for Injection, 1 g ertapenem/vial lyophilized powder should not be stored 
above 25°C (77°F) before reconstitution per product information [37]. For this study, it is 
recommended that lyophilized ERT be stored refrigerated at 2°C to 8°C (35.6°F to 
46.4°F) within the packaging until time of preparation for dosing. The expiration date of 
ERT for Injection 1 g/vial shall be referred from the labelling of the commercial product 
being procured from the US market.  
• Sterile Water for Injection, USP will be stored per manufacturing instructions. Product 
storage and stability will be described in the MOP. 
• The diluent, 0.9% Sodium Chloride Injection, USP, will be stored per manufacturing 
instructions. Product storage and stability will be described in the MOP. 
6.1.7.2 
Stability of ERT or ZID after Reconstitution in Sterile Water for Injection 
The reconstitution of ERT or ZID vial should start within 1 h after removal from refrigeration. 
The reconstituted ERT vials should be immediately diluted in 0.9% Sodium Chloride for the 
preparation of either the ERT standalone infusion solution or the WCK 6777 (ERT+ZID) 
infusion solution.  
Likewise, the reconstituted ZID vials should be immediately diluted in 0.9% Sodium Chloride 
for the preparation of either the ZID standalone infusion solution or the WCK 6777 (ERT+ZID) 
infusion solution.  
6.1.7.3 
Stability of ERT or ZID after Dilution in 0.9% Sodium Chloride 
• ERT or ZID or ERT-ZID infusion solutions in 100 mL (for Cohort 1 - ERT-ZID  1 + 1 g) 
or 250 mL (for remaining Cohorts 2 to 7) were found to be stable for up to 6 hours at 
room temperature (25 ± 2°C) and up to 24 hours at refrigeration (5 ± 3°C). 
In spite of the above-mentioned stability of ERT or ZID or WCK 6777 in 0.9% normal saline, 
to negate the risk of sterility loss uniformly for all the cohorts, the infusion (stored at room 
temperature or refrigerated) should begin within 2 h of preparation. 
6.1.7.4 
Photostability 
• ZID for Injection, 1 g/vial is photostable   
• ERT Sodium for Injection, 1 g ertapenem/vial is photostable 
The clinical supplies storage area at the CTU will be monitored by its staff for temperature 
consistency with the acceptable storage temperature range specified in this protocol or in the 
MOP. Documentation of temperature monitoring will be maintained. 

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6.2 
Dosage, Preparation, and Administration of Study Intervention/ 
Investigational Products 
The site Research Pharmacist (RP) will prepare the study product on the same day as 
administration as instructed in above sections. The study drug will be inspected for damage, 
contamination, discoloration, or particulate matter before use. Any study drug that fails 
inspection will be quarantined at appropriate temperature and labeled ‘Do Not Use’ until further 
notice. The Site Principal Investigator (PI) or responsible person will immediately contact the 
DMID Clinical Project Manager (CPM) and study clinical team for further instructions before 
administering any additional study drug infusions. Based on the information collected, DMID, 
with consultation from Wockhardt, will determine whether the affected study drug can be used. 
If it cannot be used, the CTU will receive specific instructions on how to return it to DMID CMS 
or destroy it on site. 
The site Research Pharmacist will prepare the infusion using aseptic technique under a sterile 
environment (e.g., Biologic Safety Cabinet or laminar flow hood) as described in the protocol-
specific MOP.  
The appropriate number of vials will be removed from storage to prepare the infusion. Each vial 
of ERT Sodium, 1 g ertapenem/vial and/or ZID for Injection, 1 g/vial, depending on the 
treatment cohort, will be reconstituted separately using 5 mL sterile Water for Injection as the 
primary diluent for each ZID 1-g vial and 10 mL sterile Water for Injection as the primary 
diluent for each ERT Sodium, 1-g vial. A 0.9% Sodium Chloride Injection solution will serve as 
the secondary diluent to make up the total volume for IV infusion to 100 mL for Cohort 1 or 
250 mL for Cohorts 2-7. 
The IV administration set must contain a 0.20 µm in-line filter. 
Refer to protocol-specific MOP for detailed information on study product dose and volume 
calculations, documentation of time of placement and removal from refrigeration as well as 
preparation and administration of the study product and handling of infusion interruptions. 
6.3 
Modification of the Study Intervention/ Investigational Products 
6.3.1 
Overdose 
An overdose is defined as a dose greater than the high-dose level evaluated in the trial. 
Intentional overdosing of ERT or ZID is unlikely. 
All overdoses will be reported as a deviation; if the overdose is associated with a TEAE, then the 
TEAE will also be reported. In the event of an overdose, the Investigator will use clinical 
judgment in treating the overdose and contact the DMID Medical Monitor (MM). There is no 
specific information available on the treatment of overdosage with ERT or ZID. 

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Intravenous administration of ERT at a dose of 2 g over 30 min or 3 g over 1h to 2h in healthy 
adult volunteers resulted in an increased incidence of nausea [29]. In clinical trials in adults, 
inadvertent administration of three 1 g doses of ERT in a 24-hour period resulted in diarrhea and 
transient dizziness in one patient [29]. In the event of an overdose, ERT should be discontinued, 
and general supportive treatment given until renal elimination takes place. In case of severe 
overdosage, especially in patients with compromised renal function, hemodialysis will aid in the 
removal of ERT from the body [28]. 
There is no information on overdose with ZID. 
The investigator will refer to the relevant document(s) for detailed information regarding 
warnings, precautions, contraindications, TEAEs, and other significant data pertaining to the 
study drug. Such documentation may include but not be limited to the IB. 
6.4 
Accountability Procedures for the Study Intervention/ 
Investigational Products   
The Site PI is responsible for the distribution and disposition of the study drugs and has ultimate 
responsibility for accountability. The Site PI may delegate this responsibility to the Site RP. If 
delegated, the Site RP will be responsible for maintaining complete records and documentation 
of the study drug’s receipt, accountability, dispensation, temperature monitoring, storage 
conditions, and final disposition. Time of study drug administration to the subject must be 
recorded on the appropriate eCRF. 
All study drugs, whether administered or not, will be documented on the appropriate study drug 
accountability record or dispensing log. Used and unused study drug vials will be retained until 
monitored. Upon completion of the trial and after the final monitoring visit, any remaining 
unused study drugs will either be returned or destroyed appropriately at the CTU as per DMID 
requirements and instructions that will be communicated to the CTU by the DMID CPM. 
Unused study drug vials will be released for disposition per DMID requirements. DMID does not 
require used containers of study product to be maintained at the research pharmacy, except when 
the local institution’s SOP/policy mandates retaining used IV vials. If local SOPs allow 
destruction of used study product containers, the used vials can be destroyed per the site’s SOPs; 
a second staff member must observe the destruction and sign verification (two signatures) that 
the used vials were discarded. 
Any unused solution left in the IV infusion syringe or bag or the IV administration tubing after 
administration to the subject should be discarded as biohazardous waste. If a container of study 
product is unusable due to breakage, or any other reason, this explanation should also be noted 
on the Study Product Accountability Record (e.g., broken – dropped on floor). Details will be 
provided in the MOP. 

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6.5 
Assessment of Subject Compliance with the Study Intervention/ 
Investigational Products 
Since each dose of study drug(s) will be administered by site personnel, subject compliance is 
not anticipated to be an issue. Complete information regarding any partial or interrupted dosing 
will be documented. Subjects unable to receive the full volume of study drug(s) infusion will be 
withdrawn from data analysis and followed up for safety as described in Section 5.3.3.  
6.6 
Prior and  Concomitant Medications/Treatments 
Medications include the following: prescription drugs, birth control hormonal preparations, non-
prescription medication, herbs, vitamins, nutritional supplements, and illicit and recreational 
substances. 
Medications taken before or after dosing will be reported as Prior Medications or Concomitant 
Medications (ConMeds), respectively. 
Prior prescription medications will be recorded at Screening Visit. All prior medications are 
not allowed during the study period with the exception of oral contraceptives, which are 
permitted throughout the study if already used. 
The following medications are prohibited for the indicated periods prior to dosing: 
• 
Receipt of probenecid or furosemide within 14 days prior to study enrollment. 
• 
Receipt of any antibiotics within 14 days prior to study enrollment. 
• 
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). 
• 
Receipt of the following medications that interact with human OAT3 within 14 days prior 
to study enrollment. 
Note: 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. 
• 
Receipt of herbal and dietary supplements (including St. John’s Wort) within 14 days 
prior to study enrollment. 
• 
Receipt of valproic acid within 14 days prior to study enrollment. 

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Non-prescription medications, herbs, vitamins, and nutritional supplements will not be 
taken within 14 days before dosing and during the trial. Exceptions: vitamins and OTC 
medications, taken for <48 h for the treatment of common symptoms (e.g., headache, 
indigestion, muscle pain), including solitary doses of up to 1,000 mg acetaminophen 
(paracetamol), may be allowed if approved by the Site PI or authorized clinician(s). 
Blood/blood products (RBCs, WBCs, platelets, and plasma) donation of 500 mL within 
3 months or more than 100 mL within 30 days before signing informed consent to this trial is not 
allowed, and it is prohibited during the course of this trial. 
Following dosing, each new ConMed and changes to existing medications will be recorded. 
Subjects will be required not to utilize non-study medications during the trial except those 
deemed necessary by the Site PI or authorized clinician(s).  
Any drug (e.g., non-prescription medications, herbal supplements, vitamins, or prescription 
medications) or vaccines or blood/blood products used by the subject during the trial will be 
recorded in the subject’s source documents and on the appropriate electronic case report form 
(eCRF), and the PI or authorized clinician(s) will note whether the use was medically indicated 
and immediately necessary. Any use of medications not authorized by the Site PI or authorized 
clinician(s) will be recorded as a deviation. 
6.7 
 Subject Restrictions and Precautions 
From signing informed consent until end-of-study, the subjects have to follow the instructions of 
the study site. They have to adhere to the following restrictions during participation in the study. 
6.7.1 
Smoking 
Smoking is prohibited during the in-patient period of the study (Day -1 to discharge on Day 8). 
Subjects will be counseled to avoid smoking during the out-patient follow-up period until the last 
visit (Day 11 + 3 days). 
6.7.2 
Physical Activity 
Subjects will be counseled to refrain from excessive physical exercise starting 2 days before 
dosing until discharge from the CTU on Day 8, and 24 hours before the last visit (Day 11 
+ 3 days).  
6.7.3 
Food and Fluid intake 
Subjects will be provided food and non-caffeinated and non-alcoholic beverages by the CTU 
during the dosing period of the trial. Subjects will fast at least 4 hours prior to blood draw on 
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+ 3 days (last visit)). Subjects will fast for at least 4 h before dosing on Day 1 and 1 h after end 
of infusion. Water can be taken ad lib during those periods of fasting. Food may be eaten 1 h 
after the end of infusion.   
6.7.4 
Alcohol, Marijuana and Illicit Drugs 
Alcohol will not be served during the in-patient period from Day -1 check-in to Day 8. 
Marijuana and illicit drugs are prohibited during the course of the trial. 

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7 
STUDY SCHEDULE 
The Schedule of Study Procedures and Evaluations is included as Appendix A. Clinical and 
Laboratory Procedures are described in Section 8. 
7.1 
Recruitment 
The subject population will be recruited by the CTU utilizing the CTU subject database and IRB-
approved advertisements and social media. IRB-approved, prescreening questionnaires will be 
used to determine if subjects meet study requirements before scheduling screening visits. 
7.2 
Screening Visit (Day -28 to Day -2) 
This will be an out-patient visit to complete the following within 28 days before study drug 
dosing: 
Note: A second screening visit may be scheduled to complete screening tests to accommodate 
subjects’ personal schedule. 
• Obtain informed consent. 
• Assign a study ID number to subjects who consent to participate. 
• Record demographics including age, gender, race, and ethnicity. 
• Obtain contact information. 
• Obtain height (ht) and body weight (wt) and calculate Body Mass Index (BMI; wt [kg] / 
ht [m2]).  
• Take VS. 
• Obtain Medical History (MH). 
• Review history of Prior Medications. 
• Perform complete Physical Examination (PE). 
• Obtain fasting (at least 4 hours) blood and urine samples for screening clinical laboratory 
tests that include a calculation of creatinine clearance (CLCR) by the Cockcroft-Gault 
equation. 
• Obtain blood samples for viral serology (HIV antibody, HBsAg, HCV antibody). 
• Obtain serum for β-HCG pregnancy test from all women. 
• Obtain serum for FSH level only from post-menopausal women. 
• Obtain urine sample for illicit drugs and drugs of abuse (urine drug screen), cotinine and 
alcohol. 
• Obtain a triplicate 12-lead ECG with 10-sec rhythm strip. 
• Counsel on use of contraception (males and females), avoidance of pregnancy (women of 
childbearing potential), avoidance of excessive physical exercise, avoidance of prohibited 
medication, illicit drugs, alcohol, and nicotine products. 

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• Confirm eligibility. 
Subjects who meet the eligibility criteria will be contacted by CTU personnel and asked to return 
on Day -1 to complete check-in assessments and be admitted to the CTU if they continue to meet 
eligibility criteria. Subjects will be reminded to avoid excessive physical exercise, prohibited 
medication, illicit drugs, alcohol and nicotine products, and too fast for at least 4 h before the 
Day -1 visit,  
Subjects who fail screening due to a medical condition or abnormal laboratory tests including 
pregnancy test and positive tests for HIV, HBV and HCV will be informed of the findings and 
counseled to seek medical care for further evaluation and treatment. If subjects test positive for 
HIV antibody, HBsAg, and/or HCV antibody, they will be informed that test results may be 
reported to the local health authorities according to state or local law. 
Subjects who fail screening assessments will not be rescreened unless they had an inter-current, 
short-term medical illness per site PI or authorized study clinician (listed on FDA Form 1572) 
discretion. Subjects who meet eligibility criteria but could not be enrolled within permissible 
window may be rescreened. 
7.3 
Baseline / Check-in (Day -1) 
Subjects meeting all inclusion and no exclusion criteria at Screening Visit will check into the 
CTU on Day -1 and the following procedures will be performed: 
• Review inclusion/exclusion criteria to confirm the subject remains eligible for 
enrollment. 
• Update MH. 
• Update Prior Medications. 
• Obtain VS. 
o Note: Obtain VS before blood draws  
• Obtain body weight. 
• Perform complete PE. 
• Obtain blood and urine samples for clinical laboratory tests that include a calculation of 
CLCR by the Cockcroft-Gault equation. 
• For all women, a urine β-HCG pregnancy test will be done, and negative results 
confirmed before dosing. 
• Obtain urine sample for illicit drugs and drugs of abuse (urine drug screen), cotinine, and 
alcohol. 
• Obtain baseline 12-lead standard ECG with 10-sec rhythm strip. 
• Admit eligible subjects in the CTU. 

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• Assign to study treatment cohort and randomize to active drug or placebo, except for 
Cohorts 3 and 6. 
• Counsel to avoid excessive physical exercise, encourage good hydration. 
7.4 
Inpatient Treatment Period (Days 1 to 8) 
The following assessments will be performed daily before and after dosing on study Days 1 to 7, 
and before discharge from the CTU on Day 8. 
7.4.1 
DAY 1 
2+ hours Before Dosing: 
• Withhold solid food at least 4 h before dosing. 
• Allow access to water and non-carbonated beverages. 
• Review inclusion/exclusion criteria to confirm the subject remains eligible for dosing. 
• Update MH. 
• Review any new medications and update list of prior medications as needed. 
• Perform symptom-directed (focused) PE as needed for evaluation of new symptoms. 
 
About 1 – 2 hours Before Dosing: 
• Insert IV line for study drug infusion into a forearm vein 
• Insert IV catheter for blood collection into a vein in the other arm 
 
About 30 – 60 min Before Dosing: 
• Obtain VS within 30 min before dosing (baseline). 
• Obtain pre-dose blood (plasma) PK sample for total and free study drug within 30 min 
before starting administration of study drug. 
• Obtain pre-dose urine PK sample for study drug concentration within 30- 60 min before 
starting drug administration.  
o Void bladder as close to study drug administration as possible. 
Dosing:  
• Administer study drug as a single IV infusion with an infusion pump in a forearm vein. 
The volume and duration of infusion will vary according to study cohort as follows:  
o For Cohort 1: 100 mL, 30 (±5) minutes; 
o For Cohort 2, Cohort 3 and Cohort 4: 250 mL, 60 (±10) minutes; and 
o For Cohort 5, Cohort 6 and Cohort 7: 250 mL, 120 (±10) minutes. 
After Dosing Initiation: 
• Initiate AE assessments until the end of the study. 
• Perform symptom-directed (focused) PE as needed (for TEAE assessments). 

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• Initiate recording of Concomitant Medications (ConMeds). 
• Withhold solid food until at least 1 h after end of infusion.  
• Provide access to water and non-carbonated beverage. 
• Check infusion site for infusion site reactions during the infusion, at the end-of-infusion 
(+10 min), 1 h (±10 min) after the end of infusion, and as needed for evaluation of local 
symptoms at the infusion site. Replace as needed. (Details will be provided in the MOP.) 
• Check IV blood draw lines and replace as needed. 
• Obtain VS at the end of dosing (+10 min), and 1 h (±5 min) after the end of dosing. 
o Note 1: More frequent monitoring will be at the PI’s or authorized study clinician’s 
discretion based on subject’s clinical status. 
o Note 2: Obtain VS before blood draws.  
• Obtain blood (plasma) PK samples for total and free study drug as follows: 
o From Cohort 1 (infusion duration 0.5 h): within 30 min before dosing, and at 0.25 h 
(±5 min), 0.5 h (±5 min) [immediately at end of infusion], 1 h (±5 min), 2 h (±5 min), 
3 h (±10 min), 4 h (±10 min), 8 h (±15 min), 12 h (±15 min), and 18 h (±15 min) after 
the start of the infusion. 
o From Cohorts 2, 3, and 4 (infusion duration 1 h): within 30 min before dosing, and at 
0.5 h (±5 min), 1 h (±5 min) [immediately at end of infusion], 2 h (±5 min), 3 h 
(±10 min), 4 h (±10 min), 8 h (±15 min), 12 h (±15 min), and 18 h (±15 min) after the 
start of the infusion. 
o  From Cohorts 5, 6 and 7 (infusion duration 2 h): within 30 min before dosing and at 
1 h (±5 min), 2 h (±5 min) [immediately at end of infusion], 3 h (±10 min), 4 h 
(±10 min), 8 h (±15 min), 12 h (±15 min), and 18 h (±15 min) after the start of the 
infusion. 
• Obtain post-dose urine PK samples at the following intervals after the start of the 
infusion: 0 to 4 h (±10 min), 4 to 8 h (±15 min), 8 to 12 h (±15 min), and 12 to 24 h 
(±30 min). 
• Counsel to avoid excessive physical exercise, encourage good hydration. 
7.4.2 
DAY 2  
As for DAY 1 with the exception that frequent plasma and urine PK samples are not collected 
after dosing. 
 
Before Dosing: 
• Check the infusion site for any reactions. 
• Assess the IV lines used for infusion and blood PK draws and replace as needed. 
• Obtain VS within 30 min before dosing. 

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• Obtain blood for safety laboratory testing (Hematology [HEM], Coagulation [COAG], 
and Clinical chemistry [CHEM] that includes a calculation of CLCR by the Cockcroft-
Gault equation 30-60 min before dosing. 
• Collect blood (plasma) PK sample at 24 h (±30 min) after initiation of dosing on Day 1. 
o Note: If collected within 30 min prior to dosing, this sample could also be the “pre-
dose” sample for Day 2. 
• Complete collection of the 12 h to 24 h (±30 min) urine PK sample after dosing on Day 1 
before dosing on Day 2. 
Dosing: 
• Administer study drug at approximately the same time (within 24 h +1h) as on Day 1. 
• The duration of infusion will vary according to study cohort as described on Day 1. 
After Dosing Initiation: 
• Check infusion site for infusion site reactions as on Day 1. 
• Assess the IV lines used for infusion and blood PK draws and replace as needed. 
• Obtain VS at the end of dosing (+10 min), and 1 h (±5 min) after the end of dosing. 
o Note 1: More frequent monitoring will be at the PI’s or authorized study clinician’s 
(listed on FDA Form 1572) discretion based on subject’s clinical status. 
o Note 2: Obtain VS before blood draws  
• Perform AE assessments. 
• Perform symptom-directed (focused) PE as needed for TEAE assessments. 
• Document ConMeds. 
• Provide solid food at least 1 h after the end infusion. 
• Collect blood (plasma) for PK 12 h (± 15 min) after the start of infusion. 
• Counsel to avoid excessive physical exercise, encourage good hydration. 
7.4.3 
DAY 3  
As for DAY 1 with the exception that frequent plasma and urine PK samples are not collected 
after dosing. 
Before Dosing: 
• Check the infusion site for any reactions. 
• Assess the IV lines used for infusion and blood PK draws and replace as needed. 
• Obtain VS within 30 min before dosing. 
o 
Note: Obtain VS before blood draws.  
• Collect pre-dose blood (plasma) PK sample within 30 min before starting administration 
of study drug. 
 
 

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Dosing: 
• Administer study drug at approximately the same time (within 24 h +1h) as on Day 1. 
• The duration of infusion will vary according to study cohort as described on Day 1. 
After Dosing Initiation: 
• Check infusion site(s) for infusion site reactions as on Day 1. 
• Obtain VS at the end of dosing (+10 min), and 1 h (±5 min) after the end of dosing. 
o Note 1: More frequent monitoring will be at the PI’s or authorized study clinician’s 
discretion based on subject’s clinical status. 
o Note 2: Obtain VS before blood draws.  
• Perform AE assessments. 
• Perform symptom-directed (focused) PE as needed for TEAE evaluation of TEAEs. 
• Document ConMeds. 
• Provide solid food at least 1 h after the end infusion. 
• Collect blood (plasma) for PK 12 h (± 15 min) after the start of infusion. 
• Counsel to avoid excessive physical exercise, encourage good hydration. 
7.4.4 DAY 4 
As for DAY 1 with the exception that frequent plasma and urine PK samples are not collected 
after dosing. 
 
Before Dosing: 
• Check the infusion site for any reactions. 
• Assess the IV lines used for infusion and blood PK draws. Replace IV catheters as 
needed. 
• Obtain VS within 30 min before dosing  
o Note: Obtain VS before blood draws  
• Obtain blood for safety laboratory testing (Hematology [HEM], Coagulation [COAG], 
and Clinical chemistry [CHEM] that includes a calculation of CLCR by the Cockcroft-
Gault equation 30-60 min before dosing. 
• Obtain urine for urinalysis. 
• Collect pre-dose blood (plasma) PK sample within 30 min before starting administration 
of study drug. 
Dosing: 
• Administer study drug at approximately the same time (within 24 h +1h) as on Day 1. 
• The duration of infusion will vary according to study cohort as described on Day 1. 
After Dosing Initiation: 
• Check infusion site for infusion site reactions as on Day 1. 

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• Remove IV infusion catheter if it has been in use for 3 to 4 days 
• Obtain VS at the end of dosing (+10 min), and 1 h (±5 min) after the end of dosing. 
o Note 1: More frequent monitoring will be at the PI’s or authorized study clinician’s 
(listed on FDA Form 1572) discretion based on subject’s clinical status. 
o Note 2: Obtain VS before blood draws.  
• Perform AE assessments. 
• Perform symptom-directed (focused) PE as needed for TEAE assessments. 
• Document ConMeds. 
• Provide solid food at least 1 h after the end infusion. 
• Collect blood (plasma) for PK 12 h (± 15 min) after the start of infusion. 
• Counsel to avoid excessive physical exercise, encourage good hydration. 
7.4.5 
DAY 5 
As for DAY 1 with the exception that frequent plasma and urine PK samples are not collected 
after dosing. 
 
Before Dosing: 
• Check the infusion site for any reactions. 
• Assess the IV lines used for infusion and blood PK draws. Replace IV catheters as 
needed. 
• Obtain VS within 30 min before dosing. 
o Note: Obtain VS before blood draws  
• Collect pre-dose blood (plasma) PK sample within 30 min before starting administration 
of study drug. 
Dosing: 
• Administer study drug at approximately the same time (within 24 h +1h) as on Day 1. 
• The duration of infusion will vary according to study cohort as described on Day 1. 
After Dosing Initiation: 
• Check infusion site(s) infusion site reactions as on Day 1. 
• Obtain VS at the end of dosing (+10 min), and 1 h (±5 min) after the end of dosing. 
o Note 1: More frequent monitoring will be at the PI’s or authorized study clinician’s 
(listed on FDA Form 1572) discretion based on subject’s clinical status. 
o Note 2: Obtain VS before blood draws.  
• Perform AE assessments. 
• Perform symptom-directed (focused) PE as needed for TEAE assessments. 
• Document ConMeds. 
• Provide solid food at least 1 h after the end infusion. 

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• Collect blood (plasma) for PK 12 h (± 15 min) after the start of infusion. 
• Counsel to avoid excessive physical exercise, encourage good hydration. 
7.4.6 
DAY 6 
As for DAY 1 with the exception that frequent plasma and urine PK samples are not collected 
after dosing. 
 
Before Dosing: 
• Check the infusion site for any reactions. 
• Assess the IV lines used for infusion and blood PK draws. Replace IV catheters as 
needed. 
• Obtain VS within 30 min before dosing. 
o Note: Obtain VS before blood draws.  
• Obtain blood for safety laboratory testing (Hematology [HEM], Coagulation [COAG], 
and Clinical chemistry [CHEM] that includes a calculation of CLCR by the Cockcroft-
Gault equation 30-60 min before dosing. 
• Collect pre-dose blood plasma PK sample within 30 min before starting administration of 
study drug. 
 
Dosing: 
• Administer study drug at approximately the same time (within 24 h +1h) as on Day 1. 
• The duration of infusion will vary according to study cohort as described on Day 1. 
 
After Dosing Initiation:  
• Check infusion site for infusion site reactions as on Day 1. 
• Obtain VS at the end of dosing (+10 min), and 1 h (±5 min) after the end of dosing.  
o Note 1: More frequent monitoring will be at the PI’s or authorized study clinician’s 
(listed on FDA Form 1572) discretion based on subject’s clinical status. 
o Note 2: Obtain VS before blood draws  
• Perform AE assessments. 
• Perform symptom-directed (focused) PE as needed for evaluation of TEAEs. 
• Document ConMeds. 
• Provide solid food at least 1 h after the end infusion. 
• Collect blood (plasma) for PK 12 h (± 15 min) after the start of infusion. 
• Counsel to avoid excessive physical exercise, encourage good hydration. 
7.4.7 
DAY 7 
All procedures and assessments are as on DAY 1. 

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Before Dosing: 
• Check the infusion site for any reactions. 
• Assess the IV lines used for infusion and blood PK draws and replace as needed.  
• Obtain VS within 30 min before dosing. 
• Note: Obtain VS before blood draws Collect pre-dose blood (plasma) PK sample within 
30 min before starting administration of study drug. 
• Obtain pre-dose urine PK sample within 30-60 min before starting administration of 
study drug.  
o Void bladder as close to study drug administration as possible. 
 
Dosing:  
• Administer study drug at approximately the same time (within 24 h +1h) as on Day 1. 
• The volume and duration of infusion will vary according to study cohort as described on 
Day 1. 
 
After Dosing Initiation: 
• Obtain VS at the end of dosing (+10 min), and 1 h (±5 min) after the end of dosing. 
o Note 1: More frequent monitoring will be at the PI’s or authorized study clinician’s 
(listed on FDA Form 1572) discretion based on subject’s clinical status. 
o Note 2: Obtain VS before blood draws. 
• Obtain blood (plasma) PK samples for total and free study drug as follows: 
o From Cohort 1 (infusion duration 0.5 h):  within 30 min before dosing, and at 0.25 h 
(±5 min), 0.5 h (±5 min) [immediately at end of infusion], 1 h (±5 min), 2 h (±5 min), 
3 h (±10 min), 4 h (±10 min), 8 h (±15 min), 12 h (±15 min), 18 h (±15 min) and 24 h 
(± 30 min) after the start of the infusion. 
o  From Cohorts 2, 3, and 4 (infusion duration 1 h): within 30 min before dosing, and at 
0.5 h (±5 min), 1 h (±5 min) [immediately at end of infusion], 2 h (±5 min), 3 h 
(±10 min), 4 h (±10 min), 8 h (±15 min), 12 h (±15 min), 18 h (±15 min) and 24 h 
(± 30 min) after the start of the infusion. 
o o From Cohorts 5, 6 and 7 (infusion duration 2 h): within 30 min before dosing and at 
1 h (±5 min), 2 h (±5 min) [immediately at end of infusion], 3 h (±10 min), 4 h 
(±10 min), 8 h (±15 min), 12 h (±15 min), 18 h (±15 min) and 24 h (± 30 min) after 
the start of the infusion.  
o Obtain post-dose urine PK samples for study drug concentration and at the following 
intervals after the start of the infusion: 0 to 4h (±10 min), 4h to 8h (±15 min), 8h to 
12h (±15 min), and 12h to 24h (±30 min). 
• Check infusion site for infusion site reactions during the infusion, at the end-of-infusion 
(+10 min), 1 h (±10 min) after the end of infusion, and as needed for evaluation of local 
symptoms at the infusion site.  

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• Remove IV infusion line. 
• Perform AE assessments. 
• Perform symptom-directed (focused) PE as needed for TEAE assessments. 
• Document ConMeds 
• Provide solid food at least 1 h after the end infusion. 
• Counsel to avoid excessive physical exercise, encourage good hydration. 
7.4.8 
DAY 8 
• Check the infusion and blood PK draw sites for any reactions. 
• Obtain 12-lead standard ECG with 10-sec rhythm. 
• Obtain VS. 
•  Obtain blood for safety laboratory testing (Clinical chemistry [CHEM], Hematology 
[HEM] and Coagulation [COAG]) that include a calculation of CLCR by the Cockcroft-
Gault equation) at 24 h (± 1 h) after last dose. 
• Obtain urine for urinalysis. 
• Collect blood (plasma) PK samples for total and free study drug at 24 h (±15 min) after 
initiation of study drug infusion on Day 7. 
• Remove catheter for blood draws. 
• Complete collection of the 12h to 24 h (±30 min) urine PK sample after dosing on Day 7. 
• Perform complete PE. 
• Obtain body weight. 
• Perform AE assessments.  
• Document ConMeds. 
• Counsel on use of contraception (males and females), avoidance of pregnancy (women of 
childbearing potential), avoidance of excessive physical exercise 24 h before last visit 
(Day 11 +3 days), avoidance of prohibited medications, illicit drugs, alcohol, and nicotine 
products. 
• Instruct on the next scheduled visit. 
• Discharge subject from the CTU after review of clinical laboratory tests, ECGs and other 
assessments by PI or authorized study clinician. 
o Note: If the time of discharge is late in the evening, due to the time schedule for 
starting procedures on Day 7 or personal reasons (such as distance from residence), 
the subject may stay in the CTU overnight and be discharged the following morning. 
7.5 
Outpatient Follow-up Period / Last Visit (Day 11 + 3 days)  
• Obtain 12-lead standard ECG with 10-sec rhythm. 
• Obtain VS. 
•  Obtain blood for safety laboratory testing (Hematology [HEM], Coagulation [COAG], 
and Clinical chemistry [CHEM] that includes a calculation of CLCR. 
• Obtain urine for urinalysis. 

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• Perform complete PE. 
• Check the venous infusion and blood draw sites for any reactions. 
• Perform AE assessments.  
• Document ConMeds. 
• Counsel on use of contraception (males and females), avoidance of pregnancy (women of 
childbearing potential and males), and sperm donation (males) for 30 days after last dose. 
• Discharge subject from the study. 
7.6 
Early Termination (if needed) 
• Obtain 12-lead standard ECG with 10-sec rhythm. 
• Obtain VS. 
• Obtain blood for safety laboratory testing (Clinical chemistry [CHEM], Hematology 
[HEM] and Coagulation [COAG]) that include a calculation of CLCR. 
• Collect blood (plasma) PK sample. 
• Remove any IV line present. 
• Obtain urine for urinalysis. 
• Perform complete PE. 
• Check the infusion and blood draw site(s) for any reactions.  
• Perform AE assessments.  
• Document ConMeds. 
• Counsel on use of contraception (males and females), avoidance of pregnancy (women of 
childbearing potential and males), and sperm donation (males) for 30 days after last dose. 
• Discharge subject from the study. 
7.7 
Unscheduled Visit (if needed) 
A subject may return to the clinic for an unscheduled visit at any time after discharge on Day 8. 
The following activities may be performed as needed: 
• Obtain 12-lead standard ECG with 10-sec rhythm. 
• Obtain VS. 
•  Obtain blood for safety laboratory testing (Clinical chemistry [CHEM], Hematology 
[HEM] and Coagulation [COAG]) that include a calculation of CLCR. 
• Collect blood (plasma) PK sample. 
• Obtain urine for urinalysis. 
• Check on the infusion and blood draw site(s) for any reactions. 
• Perform AE assessments. 
• Perform symptom-directed (focused) AE as needed for TEAE assessments. 
• Document ConMeds. 

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8 
CLINICAL PROCEDURES / EVALUATIONS 
8.1 
Clinical Procedures and Evaluations 
8.1.1 
Informed Consent 
The informed consent form (ICF) will be approved by the reviewing IRB/EC and executed 
before performing any study-related activities. 
Informed consent will be obtained for all subjects participating in the trial before performing any 
screening assessments. Subjects may withdraw consent at any time. Participation in the trial may 
be terminated at any time without the subject’s consent as determined by the Investigator. 
8.1.2 
Demographics 
Demographic information (date of birth, gender, ethnicity and race) will be recorded on the 
subject’s source documents and eCRF at Screening Visit. Name, address, phone number, and 
emergency contact information will be documented in the source documents only. 
8.1.3 
Inclusion/Exclusion Criteria 
Eligibility screening of healthy subjects will be completed within 28 days before study drug 
dosing and will be documented on the subject’s source documents and eCRF. Confirmation of 
eligibility will be performed before dosing on Day 1. 
Screening failures and the reason for failure to meet the study eligibility requirements will be 
documented in the source documents and entered into the study database. 
8.1.4 
Medical History 
For subjects enrolled in the trial, the medical history (MH) will be obtained by direct interview 
of the subject and recorded on the subject’s source document and eCRF. The MH will capture 
the subject’s current disease processes, past disease processes, history of hospitalization, history 
of surgery, allergies, and prior medications (see Section 6.6). Subjects will be queried regarding 
a history of significant medical disorders of the head, eyes, ears, nose, throat (HEENT), mouth, 
skin, the cardiovascular, respiratory, gastrointestinal, renal, urological, nervous, hematological, 
lymphatic, endocrine, musculoskeletal and genital/reproductive systems. A history of allergies 
including allergies to medications, medication history, and history of substance and alcohol 
abuse will be obtained. The MH will be obtained at Screening Visit and updated on Day -1 
(Check-in) and before dosing on Day 1. After start of study drug dosing, any worsening of pre-
dosing MH or new symptoms will be evaluated and reported as TEAEs. 

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8.1.5 
Physical Examination 
A complete PE – except genital, breast, and rectal exams – will be performed at the Screening 
Visit, check-in visit (Day -1), Day 8, and Final Visit (Day 11 + 3 days), or ET, and will assess 
general appearance, HEENT, heart, lungs, abdomen, skin, musculoskeletal system, lymph nodes, 
and a standard neurological exam. 
A symptom-directed (focused) PE may be performed before dosing on Day 1, at any time after 
dosing on Days 1 to 7, and at Unscheduled visit for evaluation of TEAEs. 
Height and weight will be measured, and BMI calculated at the Screening Visit, and weight on 
Day -1 and Day 8. A subject may be enrolled if BMI is ≥ 18 to 32 kg/m2 or weight is ≥ 100 lbs. 
Refer to the protocol-specific MOP for further details. The findings of each examination will be 
recorded on the subject’s source documents and eCRF. Any new findings on examination or 
worsening of existing conditions after dosing are to be reported as TEAEs. 
8.1.6 
Vital Signs 
VS should be taken while resting (measured after supine for at least 5 min) and include systolic 
blood pressure (SBP) and diastolic BP (DBP), heart rate (HR), respiratory rate (RR) and oral 
temperature (T). VSs will be measured before any blood draws.  BP and pulse measurement will 
be assessed at rest defined above with a completely automated device.  Normal references ranges 
are shown in Appendix B, Table 2. Please reference the study specific MOP for additional detail 
for VS measurements. 
8.1.6.1 
Screening to Predose on Day 1 
Abnormal VSs that are either due to technical or procedural error or the result of an acute, short-
term condition as assessed by the PI (e.g., stress, anxiety, white coat syndrome) may be repeated 
up to twice more at rest and within at least 5 minutes of each other.  
• If the second measurement is abnormal, it will be reported at the highest grade/value of 
severity of the two measurements and will be used for assessment of eligibility (per 
Inclusion Criterion #5, Note 2).   
• If the second measurement is normal, a third measurement will be taken within at least 5 
minutes.   
• If the third measurement is normal, the subject is eligible. If the third measurement is 
abnormal, the value with the highest grade of severity between the first and the third 
measurements will be reported and will be used for assessment of eligibility (per 
Inclusion Criterion #5, Note 2). 
 
 

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8.1.6.2 
Post Dosing on Day 1 through Day 11 (+ 3days) or ET 
Any time after the start of the dose infusion, any abnormalities that occur either due to technical 
or procedural error or the result of an acute, short-term condition as assessed by the PI (e.g., 
stress, anxiety, white coat syndrome) may be repeated twice more at rest and within at least 5 
minutes of each other. 
• If the second VS is abnormal, then the highest severity grade between the first and second 
measurements will be used for assessment of TEAE per Appendix B, Table 2.  
• If the second VS is normal, then a third repeat is to be taken at least after 5 minutes of 
rest.   
• If the third value is abnormal, the highest grade of severity between the first and third 
measurements will be used for assessment of TEAE per Appendix B, Table 2.  
8.1.7 
12-lead Standard Electrocardiogram (ECG) 
Triplicate 12-lead standard ECG and 10-sec rhythm strip will be obtained at the Screening Visit, 
2 minutes apart. Single ECGs will be recorded on Day -1, Day 8 and Day 11 (+3 days), or ET. 
ECGs will be performed after the subject rests quietly in a supine position for at least 10 min. 
The ECGs will be reviewed by the PI or authorized study clinician (listed on FDA Form 1572). 
ECGs will be analyzed for PR, QRS, and QT intervals, and for morphological abnormalities. The 
QT interval will be corrected by the Fridericia (QTcF) formula and recorded. To be eligible for 
participation, the QTcF interval must be within protocol reference range criteria at Screening and 
Day -1 and there must be no clinically significant ECG abnormalities. ECG PR and QTcF 
intervals after dosing will be reported as TEAEs if they meet toxicity grading criteria (See 
Appendix B, Table 4). If a question regarding ECG interpretation arises, the study investigators 
will have the ECG reviewed by a cardiologist. 
8.2 
Laboratory Evaluations 
Venipuncture schedule and blood volumes are shown in Appendix A and Appendix C, 
respectively.  
8.2.1 
Clinical Laboratory Evaluations (Hematology, Coagulation, Chemistry and 
Urinalysis) 
Blood and urine samples for clinical laboratory tests will be collected at the Screening Visit and 
on Day -1 to determine eligibility. For subjects eligible to enroll, measurements on Day-1 will be 
considered “baseline”. Blood (serum) for clinical laboratory tests (HEM, COAG, and CHEM), 
will also be collected on Days 2, 4 and 6 before dosing, and on Day 8 (24 h ± 1 h after last dose), 
and on Day 11 (+3 days), or ET. Urine for UA will also be collected on Day 4 before dosing, and 

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on Days 8, 11 (+3), or ET. Subjects must be fasting at least for 4 h before any blood draw for 
clinical laboratory assessments. These tests will include: 
• HEM: Hgb, Hct, RBC, platelet count, and WBC count with absolute differential count. 
• COAG: INR with prothrombin time, alpha partial thromboplastin time. 
• CHEM: electrolytes (sodium, potassium, chloride, total carbon dioxide [CO2]), creatinine 
with estimation of CLCR by the Cockcroft-Gault method, blood urea nitrogen (BUN), 
calcium, glucose (fasting), total bilirubin, direct bilirubin, alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), alkaline phosphatase (AP), lactic 
dehydrogenase (LDH), total protein, and albumin. 
• UA: Routine dipstick testing of clean-catch urine for occult blood, protein, glucose, 
ketones, nitrate, bilirubin, leucocyte esterase, specific gravity, and pH. 
o If urine dipstick is abnormal for blood, protein, glucose and leukocyte esterase, urine 
microscopy will be performed (for WBC, RBC, bacteria and other cell counts), and the 
results will supersede those of the dipstick UA. 
Clinical laboratory tests at the Screening Visit and Day -1 should be in the normal reference 
range with exceptions. (See Section 5.2, Inclusion Criteria #5 and Appendix B, Table 3). 
Calculated CLCR should be ≥80 mL/min (estimated by the Cockcroft-Gault method). 
Screening laboratory values that are outside the range of eligibility but are thought to be due to 
an acute condition or due to collection or laboratory error may be repeated once, preferably 
within 24 h or as soon as subject is available. 
Laboratory values will be transferred to Advantage eClinical®. 
Abnormal safety laboratory values after dosing will be graded per Appendix B, Table 3. If the 
subject was enrolled at check-in (Day -1) with baseline values within the Grade 1 range in some 
laboratory tests, as allowed by the protocol (per Section 5.3.1, Inclusion Criteria #5 and 
Appendix B, Table 3), abnormal values in the same tests after starting study dosing will only be 
considered TEAEs if they deteriorate to a higher grade. 
8.2.2 
Viral Serology Testing 
Serological testing for HIV antibody, HBsAg, and HCV antibody will be performed only at 
Screening Visit. These tests must be negative for study eligibility. 
8.2.3 
Pregnancy Testing 
In all women, a serum β-HCG pregnancy test will be done at the Screening Visit and a urine 
pregnancy test will be done upon check in on Day -1 and results must be negative for dosing 
with study drug(s). 

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8.2.4 
Serum FSH Testing 
A serum FSH level for confirmation of post-menopausal status in female subjects will be 
measured at the initial Screening Visit only. 
8.2.5 
Urine Toxicology Screening 
A urine toxicology screen will be performed at Screening Visit and on Day -1 to detect the 
presence of amphetamines, cocaine (and metabolite), barbiturates, benzodiazepines, opiates, 
cannabinoids (THC), tricyclic antidepressants (TCAs), and phencyclidine. Results must be 
negative for study eligibility. Urine creatinine will be measured as part of the profile to assess 
quality of collected sample. 
8.2.6 
Urine Alcohol and Cotinine Testing  
Detection of urine alcohol and cotinine, for recent alcohol and tobacco products consumption, 
respectively, will be performed at the Screening Visit, and on Day -1. Results must be negative 
for study eligibility. 
8.3 
Blood and Urine Sampling and Bioanalytical Assays for 
Pharmacokinetics (PK) 
The LC-MS/MS bioanalytical assay methods for total and free ERT and ZID quantitation in 
plasma and total ERT and ZID quantitation in urine will be transferred and validated at the 
bioanalytical lab, KCAS, before subject enrollment starts for determination of plasma and urine 
concentrations of ERT and ZID. 
8.3.1 
Blood Sampling for Plasma Total and Free ERT and ZID Assay 
Blood (plasma) samples for assay of total and free ERT and ZID concentration measurement 
(plasma PK samples) will be collected at the following timepoints: 
• On Day 1 and Day 7, samples will be collected at the following timepoints: 
o From Cohort 1 (infusion duration 0.5 h):  within 30 min before dosing, and at 0.25 h 
(±5 min), 0.5 h (±5 min) [immediately at end of infusion], 1 h (±5 min), 2 h (±5 min), 
3 h (±10 min), 4 h (±10 min), 8 h (±15 min), 12 h (±15 min), 18 h (±15 min) and 24 h 
(± 30 min) after the start of the infusion. 
o  From Cohorts 2, 3, and 4 (infusion duration 1 h): within 30 min before dosing, and at 
0.5 h (±5 min), 1 h (±5 min) [immediately at end of infusion], 2 h (±5 min), 3 h 
(±10 min), 4 h (±10 min), 8 h (±15 min), 12 h (±15 min), 18 h (±15 min) and 24 h 
(± 30 min) after the start of the infusion. 

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o From Cohorts 5, 6 and 7 (infusion duration 2 h): within 30 min before dosing and at 
1 h (±5 min), 2 h (±5 min) [immediately at end of infusion], 3 h (±10 min), 4 h 
(±10 min), 8 h (±15 min), 12 h (±15 min), 18 h (±15 min) and 24 h (± 30 min) after 
the start of the infusion. 
• On Days 2, 3, 4, 5, and 6 within 30 min before dosing and at 12 h (±15 min) after the 
start of the infusion. 
o Note 1: On these days, the pre-dosing PK sample will be collected 24 h (± 30 min) 
after the start of infusion on the previous day. 
o Note 2:  On Day 2, the pre-dosing PK sample can be the same as the 24 h (± 30 min) 
sample after the start of infusion on Day 1. 
Blood samples will be obtained promptly after each corresponding VS assessment before dosing 
on Days 1 to 7. 
Sample collections will be scheduled for the nominal time point and actual collection times 
recorded in source documents. 
Details for collecting blood (plasma) samples for PK analysis and for protein binding estimation 
will be described in the MOP. 
8.3.2 
Collection of Urine for Total ERT and ZID Assay 
Timed urine samples for assay of total ERT and ZID concentration measurement (urine PK 
samples) will be collected at the following periods: 
• On Day 1, before the start of infusion, and at the following intervals after the start of the 
infusion: 0 to 4h (± 10 min), 4 to 8h (± 15 min), 8 to 12h (± 15 min), and 12 to 24h  
(± 30 min). 
• On Day 7, before the start of infusion, and at the following intervals after the start of the 
infusion: 0 to 4h (± 10 min), 4 to 8h (± 15 min), 8 to 12h (± 15 min), and 12 to 24h  
(± 30 min). 
8.3.3 
Specimen Preparation, Handling and Shipping 
8.3.3.1 
Instructions for Specimens Preparation, Handling, and Storage 
Plasma and urine samples collected from subjects treated with ZID, ERT or WCK (6777 
ERT+ZID) need to be processed at 2°C to 8°C (35.6°F to 46.4°F) to avoid degradation. In 
addition, a stabilizing buffer (0.1 M MES) will be added to plasma and urine samples for total 
drug concentration measurements of ERT and ZID, but not to samples for free plasma 
concentration measurements. Details regarding the specimen preparation, handling, and storage 
of bioanalytical samples for the measurement of plasma total and free study drug concentration 
and urine total study drug concentration will be described in the protocol-specific MOP. 

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8.3.3.2 
Specimen Shipment 
Specimen shipment will occur at intervals during the trial following all applicable International 
Air Transport Association (IATA) requirements and according to the specifics for storage 
temperature and documentation as detailed in the central clinical laboratory manual and protocol-
specific MOP, as appropriate. 
All specimens for clinical screening and safety laboratory evaluations will be transported from 
the CTU to the local clinical laboratory. 
Plasma (total and free) and urine (total) PK samples will be collected from all subjects and 
aliquots will be prepared according to protocol-specific MOP. In order to perform bioanalytical 
assays within the stability period of PK samples, primary aliquots of plasma and urine PK 
samples designated by the SDCC (Emmes) picklist will be shipped to the bioanalytical lab, 
KCAS, Inc., directly from the CTU within 3-4 business days after Day 8 collection in each 
cohort and back-up samples will be shipped after Day 11 to the DMID CMS for storage. Details 
will be provided in the study-specific MOP. Methods for maintaining the blind at the 
bioanalytical lab will be described in the Statistical Analysis Plan (SAP). 
Primary aliquots of plasma and urine samples will be provided by the CTU to the bioanalytical 
lab, KCAS Inc., at:  
Test Materials Management (TMM) 
KCAS Bioanalytical and Biomarker Services  
10830 South Clay Blair Boulevard 
Olathe, KS, 66061 
Office: 913-248-3006 
Fax: 913-248-3106  
Email: TMM@kcasbio.com  
Back-up aliquots of plasma and urine PK samples for storage will be shipped from the CTU to 
DMID-CMS at: 
Fisher BioServices 
c/o DMID Clinical Materials Services (CMS) 
20439 Seneca Meadows Parkway 
Germantown, MD 20876 
Phone: 240-477-1350  
Fax: 240-477-1360 
Email: DMID.CMS@thermofisher.com  
Further information will be provided in the study-specific MOP.  

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8.4 
Disposition of Plasma and Urine Samples 
Blood (plasma or serum) and urine samples collected for clinical laboratory testing and PK 
assays will not be used for purposes other than those described. No genetic testing will be done 
on collected blood samples.  
Clinical laboratory samples (Table 5) will be destroyed after tests are completed and results are 
reviewed according to standard practices of the Site Clinical Lab. 
Plasma and urine PK samples used for measurement of the concentration of study drugs at 
KCAS, the bioanalytical lab, will be disposed of per sponsor (DMID) guidance.  

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9 
ASSESSMENT OF SAFETY 
Regulatory requirements including FDA regulations and ICH Guidelines for GCP set forth safety 
monitoring and reporting responsibilities of sponsors and investigators to ensure the safety and 
protection of human subjects participating in clinical trials. 
Responsibilities: 
Investigators participating in this clinical trial are responsible for and will: 
• Evaluate subject safety including assessment of treatment-emergent adverse events 
(TEAEs) for seriousness, severity, and causality (relatedness to study drug). 
• Notify DMID of treatment-emergent serious AEs (SAEs) within 24 h of site awareness. 
• Provide detailed written reports, including necessary documentation requested by DMID or 
IRB/EC, promptly following immediate initial reports of SAEs. 
• Inform the IRB/EC of SAEs and TEAEs as required by applicable regulatory requirements. 
9.1 
 Specification of Safety Parameters 
Safety will be assessed by the timing, frequency, causality, and severity of: 
1. Systemic and infusion site TEAEs and SAEs occurring from time of first dose with study 
drug(s) through Final Visit (Day 11 + 3 days), or ET. 
2. Clinical laboratory TEAEs occurring from time of first dose with study drug(s) through 
Final Visit (Day 11 + 3 days), or ET. 
3. 12-lead standard ECGs performed on Day 8 and on the Final Visit (Day 11 + 3 days), or 
ET. 
4. Physical examinations (PE) and VS measurements performed from time of first dose with 
study drug(s) through Final Visit (Day 11 + 3 days), or ET. 
9.2 
Methods and Timing for Assessing, Recording and Analyzing Safety 
Parameters 
9.2.1 
Adverse Events 
Definitions 
ICH E6 defines an AE as any untoward medical occurrence in a subject or clinical investigation 
subject who was administered a pharmaceutical product, regardless of its causal relationship to the 
product. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with use of the product, and are 
described as treatment-emergent AEs (TEAEs). The occurrence of a TEAE may come to the 

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attention of study personnel during study visits and interviews, or by a subject presenting for 
medical care. 
Expected safety information for ERT and ZID are described in detail in the product information for 
Ertapenem Sodium for Injection [28, 37] and the IB [34]. The severity and frequency of events 
listed in these sources and in the ERT product information will be taken into account for both the 
assessment of causality of AEs, as well as expectedness of any SAEs. 
Any systemic medical condition, and the last VS and ECG measurement and clinical safety lab test 
value that are recorded prior to dosing on Day 1 will be considered a baseline finding for the 
purpose of data analysis. Baseline comprises PE, lab and ECG assessments performed on Day -1 
and VS and focused PE performed on Day 1 prior to initiation of IV infusion of study drug. 
However, if the condition increases in severity or frequency after study drug administration at any 
time during the trial, it will be recorded as a TEAE. 
Any medical condition that is reported after screening but before study drug administration will be 
evaluated and reported as MH update. 
All TEAEs will be graded for severity according to Appendix B, Table 3 and Table 4 and for 
relationship to the study drug. 
9.2.2 
Severity of Events 
Intensity of TEAEs will be graded as follows, unless otherwise specified in Appendix B: 
Mild (Grade 1): Require minimal or no treatment; do not interfere with the subject’s daily 
activities. 
Moderate (Grade 2): Result in a low level of inconvenience or concern with therapeutic 
measures; may cause some interference with functioning. 
Severe (Grade 3): Interrupt a subject’s usual daily activity and may require systemic drug therapy 
or other treatment; are usually incapacitating. 
9.2.3 
Relationship to Study Products 
TEAEs and treatment-emergent SAEs will be assessed by the investigator to determine 
relationship to the study drug, using the following two terms. In a clinical trial, the study drug must 
always be suspect. 
• Related: There is a reasonable possibility that the study drug caused the treatment-
emergent AE/SAE. 
• Not Related: There is not a reasonable possibility that the study drug caused the treatment-
emergent AE/SAE. 
The investigator will provide an assessment of association or relationship of each treatment-
emergent AE/SAE to the study drug based on: 

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• Temporal relationship of the TEAE/SAE to study drug dosing. 
• Whether an alternative etiology has been identified. 
• Biological plausibility. 
• Existing therapy and/or ConMeds. 
9.2.4 
Reporting Adverse Events 
All AEs will be captured on the appropriate subject’s source document and eCRF. Information 
collected for TEAEs includes event description, time of onset, investigator assessment of severity 
and relationship to the study drug, date of resolution of the event, seriousness, and outcome. 
All AEs will be documented from the time of starting study drug administration through the time 
of Final Visit (Day 11 + 3 days), or ET. All AEs including abnormal safety laboratory test results 
will be followed to resolution or until considered stable in the clinical judgment of the study 
investigator. Evaluation of AEs may require unscheduled visits and clinical and laboratory 
investigations, according to the clinical judgment of the Site PI or authorized study clinicians 
(listed on FDA Form 1572). 
9.2.5 
Serious Adverse Events 
A SAE is any treatment-emergent AE that meets at least one of the following criteria: 
• Death. 
• Life-threatening AE*. 
• Inpatient hospitalization or prolongation of existing hospitalization. 
• Persistent or significant disability or incapacity, or substantial disruption of the ability to 
conduct normal life function. 
• Congenital anomaly/birth defect. 
• Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the 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. 
*A treatment-emergent SAE is considered “life-threatening” if, in the view of either the 
investigator or DMID, its occurrence places the subject at immediate risk of death. It does 
not include a TEAE that, had it occurred in a more severe form, might have caused death. 
SAEs will be: 
• Assessed for severity and relationship to study product and alternate etiology by an 
authorized study physician (listed on FDA Form 1572). 

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• Recorded on the appropriate SAE eCRF. 
• Followed through resolution. 
• Reviewed and evaluated by the SMC (periodic review unless related), DMID, and the IRB. 
9.2.6 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings 
A licensed study clinician (listed on FDA Form 1572) will determine seriousness, severity, and 
causality of abnormal laboratory values; provide a medical evaluation of TEAEs; and classify 
TEAEs as clinically significant (CS) or not clinically significant (NCS) based upon medical 
judgment. 
Abnormal laboratory values or clinical findings for all enrolled subjects after dosing will be 
assessed using the toxicity scales in Appendix B, Table 3. Abnormal values assessed as Grade 1 in 
severity and noted at screening or baseline but allowed for enrollment per Section 5.1, Inclusion 
Criteria #5 will only be considered TEAEs if they increase in severity to Grade 2 or higher. For 
abnormalities noted from the time of study drug dosing, any Grade 1 or higher laboratory 
abnormality listed on the toxicity in Appendix B, Table 3will be entered in the database as a 
TEAE. Gross blood in urine that is confirmed due to menses is not a TEAE (but is for all other 
reasons). Abnormal laboratory values, performed as part of HEM, COAG, CHEM, or UA but not 
listed in this toxicity table will be evaluated by the study clinicians, recorded in the source 
document and, if clinically significant, considered TEAEs and graded according to the criteria in 
Section 9.2.1. 
Protocol-specific laboratory normal range values in effect at the time of protocol submission for 
evaluation of TEAEs are included in Appendix B, Table 3.  
9.3 
Reporting Procedures 
9.3.1 
Serious Adverse Events 
SAEs will be followed until resolution even if this extends beyond the study-reporting period. 
Resolution of an SAE is defined as the return to pretreatment status or stabilization of the 
condition with the expectation that it will remain chronic. 
All SAEs will be: 
• Recorded on the appropriate SAE report form and sent to DMID Pharmacovigilance Group 
(PVG). 
• Entered into the appropriate subject source document and eCRF in Advantage eClinical®. 
• Reported to the IRB. 
• Reviewed and followed to resolution or stability by an authorized study physician (listed on 
FDA Form 1572). 

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• Collected on each subject until Day 11 + 3 days (Final Visit), or ET Visit. 
Any AE that meets a protocol-defined serious criterion will be submitted immediately 
(within 24 h of site awareness) on an SAE report form to DMID PVG at the following 
address: 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Drive, 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 report form, selected SAE data fields will also be entered into Advantage 
eClinical®. Please see the protocol-specific MOP for details regarding this procedure. 
Other supporting documentation of the SAE may be requested by DMID PVG and will be 
provided as soon as possible. 
The DMID Medical Monitor (MM) and DMID CPM will be notified of the SAE by the DMID 
PVG. The DMID MM will review and assess the SAE for regulatory reporting and potential 
impact on subject safety and protocol conduct. 
At any time after completion of the trial, if the Site PI or authorized study clinician (listed on FDA 
Form 1572) becomes aware of an SAE that is suspected to be related to study drug, the Site PI or 
authorized study clinician will report the event to the DMID PVG. 
9.3.2 
SUSAR Regulatory Reporting for Studies Conducted under DMID Sponsored 
IND 
Following notification from the investigator, DMID, the Investigational New Drug (IND) sponsor, 
is responsible for making the determination of which SAEs are Suspected unexpected serious 
adverse reactions or SUSARs. A SUSAR, as defined in 21 CFR 312.32, is any SAE where a causal 
relationship with the study product is at least reasonably possible but that adverse event is not 
listed in the IB, Package Insert, and/or Summary of Product Characteristics. 
 
All SUSARs will be reported to the FDA as IND Safety Reports per 21 CFR 312.32 as soon as 
possible but not exceeding 7 calendar days for unexpected fatal or life-threatening events, and not 
exceeding 15 calendar days for other qualifying events. IND Safety Reports will also be provided 
to the IRB. 
 
The DMID Medical Monitor and Clinical Project Manager will be notified of the SAE and 
potential SUSAR by the DMID Pharmacovigilance Group. The DMID Medical Monitor will 

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review and assess SUSARs for regulatory reporting and potential impact on study subjects’ safety 
and protocol conduct. 
DMID will submit an IND safety report to the FDA and will notify all participating site Principal 
Investigators of potential serious risks from clinical studies or any other source, as soon as 
possible. 
All SAEs designated as “not related” to study product(s), will be reported to the FDA and to the 
national regulatory authorities at least annually in a summary format (e.g., IND Annual Report). 
9.3.3 
Other Adverse Events (if applicable) 
9.3.3.1 
Reporting of Overdose 
An overdose is defined as a dose greater than the high-dose level evaluated in the trial as described 
in Section 6.3.1. All overdoses will be reported; if the overdose is associated with a TEAE, then 
the TEAE will also be reported. In the event of an overdose of study drug, the investigator will use 
clinical judgment in treating the overdose and contact the DMID MM. There is no specific antidote 
in case of ERT or ZID or WCK 6777 (ERT plus ZID) overdose. The same measures as 
recommended for other antibiotics belonging to the class of carbapenem antibiotics (treatment 
cessation, supportive treatment, adequate hydration, and hemodialysis in case of severe 
overdosage) should be considered until further clinical data are available for the study drug(s). The 
investigator will refer to the relevant document(s) for detailed information regarding warnings, 
precautions, contraindications, TEAEs, and other significant data pertaining to each study drug. 
Such documentation may include but not be limited to Prescription Information for Ertapenem 
Sodium for Injection (ERT) (28, 37), and the 2022 WCK 6777 Investigator Brochure (34). 
9.3.3.2 
Reporting of Pregnancy 
Pregnancies that occur in female subjects during the trial will be reported via Advantage eClinical® 
on a pregnancy report form. With the subject’s permission, all protocol-required venous blood 
samples will be obtained, and the subject will continue to be followed for safety until 
Day 11 + 3 days (Final Visit). Efforts will be made to follow all pregnancies reported during the 
trial to pregnancy outcome, as described in the protocol-specific MOP (e.g., delivery, spontaneous 
abortion, or therapeutic abortion), pending the subject’s permission. 
A female subject who participates in the trial and becomes pregnant will be asked to inform study 
personnel of a pregnancy occurring within 30 days after Final Visit. For all reported pregnancies, 
subjects will be asked to provide pregnancy outcome upon delivery or pregnancy termination to 
the CTU. 
Serious adverse outcomes of pregnancy affecting the mother and/or fetus or neonate (e.g., 
spontaneous abortion, congenital anomaly(ies) in fetus or child, late fetal death, or reports of 
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significant disability/incapacity or resulting in or prolonging hospitalization) will be documented 
in a SAE form and reported to the CROMS PVG within 24 hours of clinical site awareness of the 
events. 
9.4 
Type and Duration of Follow-up of Subjects after Adverse Events 
Treatment-emergent SAEs and AEs will be followed until resolution or until considered stable in 
the clinical judgment of the investigator. Resolution of an AE is defined as the return to 
pretreatment status or stabilization of the condition in the clinical judgment of the study 
investigator, with the expectation that it will remain chronic. 
Follow-up procedures, evaluations, and outcomes will be recorded in the subject's source 
document and eCRF. 
9.5 
Halting Rules 
9.5.1 
Study Halting Criteria 
• One subject experiences an SAE regardless of the relationship to study product, with the 
exception of accidental injury. from the time of first dose through the last visit (Day 11 +3).  
• Two or more subjects, in the same cohort, experience Grade 3 (severe) AEs (Systemic or 
Laboratory) through the last visit (Day 11+3) regardless of the relationship to study product 
that are coded in the same High Level Term (HLT) per MedDRA classification. 
• In combination treatment cohorts (Cohorts 1, 4 and 7), three or more subjects (cumulative) 
experience Grade 3 (severe) AEs (Systemic or Laboratory) regardless of the relationship to 
study product with the exception of accidental injury that are coded in the same High Level 
Group Term (HLGT) per MedDRA classification. 
o Note: For Grade 3 TEAEs in the situations above, VS abnormalities will be 
considered part of a systemic disorder or an organ-specific condition, as described in 
Appendix B: Adverse Events Toxicity Grading Criteria, in order to be included among 
the Study Halting Criteria. 
If the predefined criteria for the halting rules are met, the SMC will review the study data and 
provide guidance on how to proceed. 
A halted study will resume upon recommendation by the Sponsor (DMID). 
9.5.2 
Individual Subject Halting Criteria 
A subject will be discontinued from further dosing if any of the following criteria are met: 
• A subject experiences a SAE, regardless of the relationship to the study product. 
• A subject develops anaphylaxis within 24 hours after receiving the study product(s). 

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• A subject experiences a suspected drug-related hypersensitivity AE Grade 2 or higher 
during the infusion. In that case, the infusion must be stopped, and that subject will not 
continue with dosing. 
• A subject experiences a Grade 3 AE event (laboratory or systemic) if not resolved within 
24 hours of dosing. 
• If in the opinion of the site PI or authorized study clinician (listed on FDA Form 1572), 
further dosing would not be in the best interest of the subject. 
9.5.3 
Dose Escalation Halting Criteria 
Administration of drug product(s) in the next higher dose cohort should not occur unless all 
participants in the previous dose cohort(s) have received the study products and safety data from 
those participants are reviewed in accordance with the protocol (See Section 4 and Section 9.6.1). 
For dose escalation from the combination Cohort 1 (1 g ERT + 1 g ZID) to higher single dose 
Cohorts 2 (2 g ERT) and 3 (2 g ZID), and from the combination Cohort 4 (2 g ERT + 2 g ZID) to 
higher single dose Cohorts 5 (3 g ERT) and 6 (3 g ZID), the study will proceed to the next planned 
dose level upon recommendation by the SMC following review of cumulative interim safety data 
after completion of Cohort 1 or Cohort 4, respectively. The recommendation to continue to the 
next planned combination treatment cohorts (i.e., Cohort 4 and Cohort 7 [3 g ERT +3 g ZID]) will 
be made by the study team (DMID MO and MM and the site PI) after review of blinded safety data 
in Cohorts 2 and 3 and Cohorts 5 and 6, respectively. For dose escalation to single or combination 
cohorts, the SDCC confirms and notifies the SMC and/or study team (DMID MM, DMID MO and 
study PI) as needed that none of the following criteria were met: 
• Three or more subjects in the same cohort experience an AE, grade 2 or higher (Systemic 
or Laboratory), regardless of the relationship to study the study product with the exception 
of accidental injury in the same system organ Preferred Term (PT) per MedDRA 
classification. 
• Two or more subjects in the same cohort experience at least one Grade 3 AE and at least 
one Grade 2 AE, regardless of the relationship to study product with the exception of 
accidental injury, in the same HLT per MedDRA classification. 
If any of the above criteria is met, escalation to the next planned dose cohort will not proceed until 
all available study data have been reviewed by the SMC. If, following review by the SMC, this is 
deemed acceptable to restart the study, the study will resume with DMID (sponsor) agreement. 

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9.6 
Safety Oversight 
9.6.1 
Safety Monitoring Committee (SMC) 
Safety oversight will be conducted by a SMC, which is an independent group of experts that 
monitors subject safety and advises DMID. SMC members will be separate and independent of 
study personnel participating in the trial and will not have scientific, financial, or other conflicts of 
interest related to the trial. The SMC will consist of a minimum of three members with appropriate 
expertise to contribute to the interpretation of the data from the trial. 
The SMC will meet as follows: 
• Organizational meeting (before study initiation). 
• Ad hoc meeting. 
o When study halting criteria are met following review by the study team (DMID MO 
and MM and the site PI). 
o At the request of DMID to review a potential safety concern identified by either the Site 
PI or DMID MM. 
• Scheduled meeting. 
o The SMC will review cumulative interim safety data after completion of all subjects in 
Cohort 1. 
o The SMC will review cumulative, interim safety data when available after completion 
of all subjects in Cohorts 1 to 4. 
o The SMC will review final safety data in all cohorts when available after database lock. 
Procedures for SMC reviews/meetings will be defined in the SMC charter. The SMC will review 
safety data and provide recommendations to DMID, NIAID on resumption or stopping of a 
temporary halted trial. 

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10 
CLINICAL MONITORING 
10.1 
Site Monitoring Plan 
Site monitoring will be conducted to ensure that human subject protections, study and laboratory 
procedures, study intervention administration, and data collection processes are of high quality and 
meet DMID, GCP/ICH, and regulatory guidelines, when appropriate. Site visits may be conducted 
by an authorized representative of DMID or other regulatory agencies to inspect study data, 
subjects’ medical records, and eCRFs in accordance with ICH guidelines, GCP, and the respective 
local and national government regulations and guidelines. 
The investigator will permit authorized representatives of DMID and the respective local and 
national health authorities to inspect facilities and records relevant to the trial, if needed. 
A separate monitoring plan developed by DMID will describe protocol-specific items to be 
monitored. 
Site visits will be made at standard intervals defined by DMID and may be made more frequently 
as directed by DMID. Monitoring visits will include, but not be limited to, review of regulatory 
files, accountability records, subjects’ source documents, eCRFs, ICFs, clinical and laboratory 
reports, and protocol and GCP compliance. Site monitors will have access to the CTU, study 
personnel, and all study documentation according to the DMID-approved site monitoring plan. 
Study monitors will meet with the Site PI to discuss any problems and actions to be taken and 
document visit findings and discussions. 
 

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11 
STATISTICAL CONSIDERATIONS 
11.1 
Study Hypotheses 
The objectives of the study are to obtain safety data and plasma and urine PK data for 3 escalating 
doses of WCK 6777 (combination of ERT with ZID) and 2 escalating doses of ERT alone and ZID 
alone. There are no formal hypotheses being tested in this Phase 1 trial. 
11.2 
Sample Size Considerations 
The sample size of 52 subjects assigned into 7 treatment cohorts with 8 subjects per cohort (6 
subjects randomized to receive active drug(s) and 2 placebo), with the exception of Cohorts 3 and 
6, where 6 subjects will receive active ZID only, was chosen to obtain reasonable evidence of 
safety without exposing undue numbers of healthy subjects to ERT combined with ZID, ERT 
alone, and ZID alone at this phase of clinical evaluation. Previous experience in Phase 1 studies 
has shown that the sample size being proposed is sufficient to fulfill the primary and secondary 
objectives of the study. Power calculations have not been performed. 
It is expected there will be 7 evaluable subjects in each cohort with 8 subjects each (ERT 
standalone Cohorts 2 and 5 and WCK 6777 cohorts 1, 4 and 7), and 5 subjects in each ZID 
standalone cohort (Cohorts 3 and 6). 
11.3 
 Safety Review 
An SMC will be appointed to oversee the safe conduct of the trial. A scheduled SMC meeting will 
be held to review safety data from Cohorts 1 to 4 and decide on continuation of the study to 
Cohorts 5 to 7. If the study is continued, a final SMC meeting will be held to review cumulative 
data and to make recommendations about the safety profile and safety monitoring of the clinical 
trial. The decision to continue the study after Cohort 1, Cohorts 2 and 3, and Cohorts 5 and 6 will 
be made by DMID based on review of safety data and summary provided by the site PI. If criteria 
for halting the trial (as listed in Section 9.5.1) are met, an ad hoc SMC meeting will be held to 
review all available safety data and to make recommendations about the dosing of all further 
subjects in the trial. Blinded data will be presented at the open SMC meeting. An unblinded 
statistician may present unblinded data in a closed session of an SMC meeting. 
11.4 
Final Analysis Plan 
The ICH Guidance E9 (Statistical Principles for Clinical Trials) will be followed for all statistical 
content. Summaries of frequencies and percentages will be presented for categorical data, and 
summary statistics such as median, mean, standard deviation (SD), minimum and maximum values 
will be presented for continuous data by Dose Cohort. Details of the statistical methods and 
models used for plasma and urine PK analyses, including dose proportionality, and safety data 
analyses and presentations will be described in the Statistical Analysis Plan (SAP) and 

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accompanying Tables, Listings and Figures (TLF) templates. The SAP will be prepared and 
finalized by the SDCC before analysis of the safety and PK data. A final analysis containing safety 
data and PK data from all study cohorts will be performed by the SDCC after final data lock and 
included in the clinical study report (CSR). Any change from originally planned statistical analyses 
will be reported in the CSR. 
11.4.1 
Analysis Populations 
The safety population will include all subjects who received any amount of study drug(s). 
The PK analysis population will consist of all subjects who received at least a single dose of study 
drug and have at least one quantifiable post-dosing plasma drug concentration measured. The PK 
Analysis Subset is defined as the subset of the PK Analysis Population that received the intended 
doses of study drug(s) and have adequate data that permit estimation of PK parameters. For the PK 
analysis and estimates of exposure parameters, 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. Subjects will be analyzed 
by dose as treated. 
If any subjects are found to be noncompliant with respect to dosing or have incomplete data, a 
decision to include them in the analysis will be made by criteria that would be described in the 
Statistical Analysis Plan. 
11.4.2 
Demographics and Baseline Characteristics 
Subject demographics and baseline characteristics will be summarized. The number of subjects 
who enroll in the trial, and the number and percentage of subjects who complete each assessment, 
will be presented. The percentage of subjects who withdraw from the trial or discontinue the study 
drug, and reasons for withdrawal or discontinuation, will be summarized. 
11.4.3 
Safety Analysis 
11.4.3.1 
Adverse and Serious Adverse Events 
Treatment-emergent AEs (TEAEs) and Serious AEs (SAEs) will be coded using the latest version 
of the Medical Dictionary for Regulatory Activities® (MedDRA). All AEs occurring after study 
drug dosing will be summarized using frequency counts and percentages. The following 
summaries will be presented for TEAEs and SAEs: 
• Overall (i.e., regardless of severity or relationship to treatment). 
• By severity grade (mild, moderate, or severe). 
• By relationship to study drug. 

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• By MedDRA level hierarchy (system organ class [SOC], higher level group term [HLGT] 
and preferred term [PT]). 
Unless otherwise specified, at each level of subject summarization in reporting the incidence of 
TEAEs, a subject will be counted once if the subject reported one or more TEAEs. If more than 
one occurrence of a TEAE is reported, the TEAE of the worst severity or the worst-case 
relationship assessment will be summarized. 
11.4.3.2 
Additional Safety Analyses 
Descriptive summary statistics (mean, SD, median, minimum, and maximum) for all clinical 
laboratory data, 12-lead standard ECG parameters, and VS at admission and each applicable post-
dosing visit, including changes from baseline values, will be calculated and presented by treatment 
cohort. Baseline values will be the last values recorded before administration of study drug. For 
change-from-baseline summaries, subjects with an undefined change from baseline, due to missing 
data, will be excluded. Clinical significance of abnormalities, as assessed by the study PI or 
authorized study clinicians, will be indicated. The number and percentage of subjects who meet 
toxicity criteria for clinical laboratory, VS and 12-lead ECG investigations will be listed and 
tabulated by treatment cohort. 
11.4.3.3 
Tolerability Assessment 
Tolerability to study product will be summarized by dose cohort and include number and incidence 
of subjects who: 1) discontinued study drug due to an AE, 2) chose to withdraw from the study due 
to an AE at any time from start of dosing until end of study, or 3) were withdrawn from the study 
by the investigator due to an adverse event at any time from start of dosing until end of study. 
11.4.4 
PK Analysis 
Plasma (total and free) and urine concentrations of ERT and ZID on Day 1 and Day 7 will be 
summarized using descriptive statistics (n, mean, SD, CV%, median, minimum, and maximum) for 
each treatment cohort, study day and nominal timepoint. Plasma (total and free) study drug 
concentrations observed before dosing on Days 2, 3, 4, 5, 6 and 7 and 24 h after dosing on Day 7 
(trough concentrations) and 12 h (± 15 min) after start of infusion on Days 1 to 7 will be 
summarized similarly for each treatment cohort and study day. 
Plasma (total and free) and urine PK parameters will be estimated separately for ERT and ZID by 
noncompartmental analysis (NCA) methods using Phoenix® WinNonlin® version 8.0 or higher and 
presented by treatment cohort.  PK parameters and linearity index and dose-normalized exposure 
parameters (AUC(0-tau)/Dose and Cmax/Dose) after the first dose and multiple doses will be analyzed 
and presented. 
Graphical presentations of plasma concentration vs. time profiles will be provided for ERT and 
ZID and will include individual subject and mean concentration profiles. Semi-log concentration 

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profiles will be provided for individual subjects. Graphical presentation of mean and individual 
trough study drug concentrations and study drug concentrations collected 12 h after dosing through 
Day 7 will be displayed. 
% Protein binding for ERT and ZID will be calculated and presented by treatment cohort at all 
collected timepoints the results will be tabulated and presented graphically. 
11.4.5 
Plasma PK parameters: 
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. 
The following single-dose plasma PK parameters will be computed (if estimable) from the plasma 
total and free concentration-time data over the 24-hour following Dose 1 for each study drug: 
• Cmax:  observed maximum concentration 
• Tmax: Time of maximum concentration (h) 
• Cmin:  observed minimum concentration at the end of the dosing interval 
• AUC(0-t):  area under the plasma concentration -time curve to the last time with a 
concentration greater than or equal to the validated limit of quantitation of the assay 
• AUC(0-∞):  area under the plasma concentration-time curve to infinity 
• AUC(0-24):  area under the plasma concentration - time curve extrapolated to 24 h after 
dosing 
• AUC(0-last): Area under the plasma concentration - time curve from time zero to the last 
concentration above the lower limit of quantitation   
• AUC(0-tau):  area under the plasma concentration - time curve to the end of the dosing 
interval 
• t1/2:  Terminal half-life 
• CLT:  Total clearance 
• Ke: terminal phase elimination rate constant 
• Vd:  Volume of distribution 
• Dose-normalized exposure parameters (AUC(0-tau)/Dose and Cmax/Dose) 
The following multiple-dose plasma PK parameters will be computed (if estimable) from the drug 
total and free concentration-time data over the 24-hour dosing interval following Dose 7 for each 
study drug. 
• Cmax,ss: observed maximum concentration at steady state 
• Cmin,ss: observed minimum concentration at the end of the dosing interval at steady state 
• Cavg: calculated average concentration during the dosing interval 
• Tmax,ss: Time of maximum concentration (Cmax) at steady state 

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• Tmin: Time to minimum concentration (Cmin) 
• AUC(0-24),ss:  area under the plasma concentration - time curve extrapolated to 24 h after 
dosing 
• AUC(0-tau),ss: Area under the plasma concentration - time curve to the end of the dosing 
interval at steady state  
• t1/2: Terminal half-life (Day 7 only) 
• CLT: Total clearance 
• Vd,ss: Volume of distribution at steady state 
• Linearity Index: AUC(0-tau),ss (Day 7) / AUC(0-∞) (Day 1) 
• RAUC : Accumulation ratio for AUC estimated as AUC(0-tau) (Day 7) / AUC(0-24) (Day 1) 
• RCmax: Accumulation ratio for Cmax estimated as Cmax (Day 7) / Cmax (Day 1). 
• Dose-normalized exposure parameters (AUC(0-tau)/Dose and Cmax/Dose) 
11.4.6 
Urine PK parameters: 
The results of urine PK parameters for each individual study drug in each cohort will be listed by 
subject at each dose, and summarized with descriptive statistics (n, mean, SD, coefficient of 
variation, median, minimum, maximum, geometric mean and geometric SD) at each collection 
period. When evaluable, estimated urine PK parameters will include: 
• Ae,urine:  Amount of unchanged drug excreted in urine during each collection interval 
following Dose 1 and Dose 7 (i.e., at 0-4, 4-8, 8-12, 12-24 h after initiation of infusion) 
• Ae,urine(0-24):  Cumulative amount of unchanged drug excreted in urine from zero (predose) 
to 24 h following Dose 1 
• Ae,urine(0-24),ss: Cumulative amount of unchanged drug excreted in urine from zero 
(predose) to 24 h after Dose 7  
• fe,urine: Fraction (%) of dose excreted unchanged in urine during each collection interval 
following Dose 1 and Dose 7 (i.e., at 0-4, 4-8, 8-12, 12-24 h after initiation of infusion) 
• fe,urine(0-24): Fraction (%) of dose excreted unchanged in urine from zero (predose) to 24 h 
after Dose 1 
• fe,urine(0-24),ss: Fraction (%) of dose excreted unchanged in urine from zero (predose) to 
24 h following Dose 7 
• CLr(0-24): Renal clearance (L/h) following Dose 1 
• CLr,ss: Renal clearance following Dose 7 
11.4.7 
Missing Values and Outliers 
All attempts will be made to collect all data per protocol. No imputation will be performed for 
missing values. Rules for identifying outliers will be described in the SAP. Outliers will not be 

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excluded from the primary analyses. Outliers identified during the PK analysis will be discussed in 
the analysis report. 
11.4.8 
Multiple Comparisons / Multiplicity 
This is a small Phase 1 Study with multiple endpoints. Because analyses of endpoints are 
descriptive rather than hypothesis tests, no adjustments for multiplicity testing are planned. 
11.4.9 
Interim Reports 
Interim cumulative safety data will be presented to the SMC after completion of Cohort 1 and 
Cohort 4.  
Blinded safety and tolerability data will be periodically reviewed by DMID and the site PI or 
authorized study clinician (listed on FDA Form 1572) to assess whether rules for halting 
progression to the next study cohort have been met. An ad hoc SMC meeting will review safety 
data if halting criteria have been met. The SMC will receive data in aggregate. The SMC may 
request to receive data by study product vs. placebo in a closed session. The SMC may also request 
that the blind be broken for individual subjects, as needed, to assess safety issues. 

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12 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
The CTU will maintain appropriate medical and/or research records for the trial, in compliance 
with ICH E6 GCP, Section 4.9, and regulatory and institutional requirements for the protection of 
confidentiality of subjects. As part of participating in a DMID-sponsored, DMID-affiliated, or 
manufacturer-sponsored trial, the CTU will permit authorized representatives of DMID, to include 
The Emmes Company, LLC (the SDCC), DynPort Vaccine Company, LLC (DVC), and regulatory 
agencies to review (and, when required by applicable law, to copy) clinical records for the 
purposes of quality assurance reviews, audits, and evaluation of the study safety and progress. 
Forms for use as source documents will be derived from eCRFs and will be provided by the SDCC 
and CTU. Additional source data are all information, original records of clinical findings, 
observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of 
the trial. Examples of these original documents and data records include, but are not limited to, 
hospital records, clinical and office charts, laboratory notes, memoranda, 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, ECG print-outs, and subject files and records kept at the pharmacy, 
laboratories, and medico-technical departments involved in the trial. 
 
 
 

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13 
QUALITY CONTROL AND QUALITY ASSURANCE 
Following a written DMID-accepted site quality management plan, the CTU is responsible for 
conducting routine quality assurance and quality control activities to internally monitor study 
progress and protocol compliance. The Site PI will provide direct access to the CTU, source 
data/documents, and reports for monitoring and auditing by DMID, 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 quality control procedures beginning with the data entry system and 
generate data quality control checks that will be run on the database. Any missing data or data 
anomalies will be communicated to the CTU for clarification and resolution. 

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14 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
14.1 
Ethical Standard 
The Site PI will ensure that the trial is conducted in full conformity with principles of the Belmont 
Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research of the 
National Commission for the Protection of Human Subjects of Biomedical and Behavioral 
Research (April 18, 1979) and codified in 45 CFR 46, 21 CFR 50 and 56, and ICH E6; 62 Federal 
Regulations 25692 (1997), if applicable. The Site PI’s institution will hold a current Federal Wide 
Assurance (FWA) issued by the Office of Human Research Protection for federally funded 
research. 
14.2 
Institutional Review Board 
The CTU will provide for the review and approval of this protocol and associated ICFs by an 
appropriate IRB/EC listed on the FWA. Any amendments to the protocol or consent materials will 
also be approved before they are used, unless change is for the safety of the subject. Only those 
IRB members who are independent of the investigators and DMID will provide an opinion on 
study-related matters. Verification of IRB approval of the protocol and the written ICF will be 
transmitted by the investigator or designee before shipment of the study drug. No deviations from 
or changes to the protocol will be initiated without prior approval of an appropriate amendment 
unless change is for the safety of the subject. 
14.3 
Informed Consent Process 
The written consent document will embody the elements of informed consent as described in the 
Declaration of Helsinki and will adhere to the ICH Harmonized Tripartite Guideline for GCP. 
Informed consent will be obtained before any protocol-specified procedures or interventions are 
carried out, and in accordance with 21 CFR 50.25 and 45 CFR 46. Information will be presented 
both orally and in written form. 
An investigator or designee will describe the protocol to potential subjects face-to-face. The ICF 
may be read to the subjects, but, in any event, the investigator shall give the subjects ample 
opportunity to inquire about details of the trial and ask any questions before signing the ICF. 
Study staff will inform subjects that the trial involves research, and explain the purpose of the trial, 
those aspects of the trial that are experimental, 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, the procedures of the research study, 
including all invasive procedures, and the probability for assignment to treatment cohorts. 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. They will also be 

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informed of alternative procedures that may be available, and the important potential benefits and 
risks of these available alternative procedures. 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. Subjects will be informed that 
participation is voluntary and that they are free to withdraw from the trial for any reason at any 
time without penalty or loss of benefits to which the subject is otherwise entitled. 
Neither the investigator, nor the trial staff, will coerce or unduly influence a subject to participate 
or continue to participate in the trial. 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), auditor(s), IRB, DMID, 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 subject’s confidentiality, to the extent 
permitted by 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. 
ICFs will be in a language fully comprehensible to the prospective subjects. Informed consent shall 
be documented using a written consent form approved by the IRB and signed and dated by the 
subject and the person who conducted the informed consent discussion. The signature confirms 
that the consent is based on information that has been provided and all questions have been 
answered to the prospective subject’s satisfaction. Each subject’s signed ICF will be kept on file 
by the investigator for possible inspection by regulatory authorities and/or DMID and regulatory 
compliance persons. The subject will receive a copy of the signed and dated written ICF and any 
other written information provided to the subjects and will receive copies of any signed and dated 
ICF updates and any amendments to the written information provided to subjects. 
14.4 
Exclusion of Women, Minorities and Children (Special Populations) 
Children aged < 18 years will be excluded from participation because insufficient data are 
available in adults to judge potential risk in children, and as a Phase 1 trial, there is no known 
benefit.   
Neither women nor minorities will be routinely excluded from participation in the trial. Subjects 
will be recruited without regard to gender or race. It is expected that race and gender distributions 
in the trial will approximate the proportion to their numbers within the community. 

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Women of childbearing potential will be included but will be repeatedly counseled to use effective 
measures (Section 5.1) to avoid becoming pregnant from the time of screening to 30 days 
following the last dose of study product, because the effects of the study drugs on the unborn fetus 
are not known. 
14.5 
Subject Confidentiality  
Subject confidentiality is held strictly in trust by the participating investigators, their staff, and 
DMID and its agents. This confidentiality is extended to cover testing of biological samples, and 
also clinical information related to participating subjects. 
The study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the trial or data will be released to any unauthorized third 
party without prior written approval from DMID. This information and data will not be used by the 
Site PI or other study personnel for any purpose other than conducting the trial. These restrictions 
do not apply to: (1) information which becomes publicly available through no fault of the Site PI 
or other study personnel; (2) information which is necessary to disclose in confidence to an IRB 
solely for the evaluation of the trial; (3) information which is necessary to disclose in order to 
provide appropriate medical care to a subject; or (4) study results which may be published as 
described in Section 16. 
The study monitors or other authorized representatives of DMID may inspect all documents and 
records required to be maintained by the Site Investigator, including, but not limited to, medical 
records (office, clinic or hospital) and pharmacy records for the subjects in the trial. The CTU will 
permit access to such records. 
14.6 
Certificate of Confidentiality 
To protect privacy, we have received a Certificate of Confidentiality. 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 Federal 
Food and Drug Administration (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. 

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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 or specimens for other research will only occur if 
consent was obtained from the individual to whom the information, document, or biospecimen 
pertains, or for the purposes of other research that is in compliance with applicable Federal 
regulations governing the protection of human subjects in research. 
14.7 
Study Discontinuation 
DMID has the right to terminate the trial or the CTU’s participation at any time. Reasons for 
terminating the trial may include, but are not limited to: 
• Incidence or severity of TEAEs indicates a potential health hazard. 
• Data recording is inaccurate or incomplete. 
• Investigator does not adhere to the protocol or applicable regulatory guidelines in 
conducting the trial. 
If the trial is discontinued, subjects who have signed the ICF and received the study drug will 
continue to be followed for safety for the duration of the trial. No further study treatments will be 
administered to other subjects. 
. 

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15 
DATA HANDLING AND RECORD KEEPING 
The Site PI is responsible to ensure the accuracy, completeness, legibility, and timeliness of 
reported data. All data collection forms will be completed legibly to ensure accurate interpretation 
of data. Black or blue 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. 
Data collection forms will be provided by the SDCC and the CTU will use them to develop the 
CTU’s source documents to record and maintain data for each subject enrolled in the trial. Data 
reported in the eCRF derived from source documents will be consistent with the source documents 
or the discrepancies will be explained. 
DMID and/or its designee will provide guidance to investigators and other study personnel on 
making corrections to the data collection forms, source documents and eCRFs. 
15.1 
Data Management Responsibilities 
All source documents and laboratory reports will be reviewed by the clinical team and data entry 
staff, who will ensure that they are accurate and complete. TEAEs will be graded, assessed for 
severity and causality, and clinical significance as needed, and reviewed by the Site PI or designee. 
Data collection is the responsibility of the clinical trial staff at the CTU under the supervision of 
the Site PI. During the trial, the investigator will maintain complete and accurate documentation 
for the trial. 
The Emmes Company, LLC will serve as the SDCC for the trial, and will be responsible for data 
management, quality review, analysis, and reporting of the study data. 
15.2 
Data Capture Methods 
Clinical data (including, but not limited to treatment-emergent AE/SAEs, ConMeds, MH, PE, 
clinical laboratory data, and ECG data [ECG intervals and interpretations]) will be collected on 
data collection forms by study personnel then entered into eCRFs via a 21 CFR 11-compliant 
Internet Data Entry System provided by the SDCC. The data system includes password protection 
and internal quality checks (e.g., automatic range checks) to identify data that appear inconsistent, 
incomplete, or inaccurate. Clinical data will be entered directly from the source documents by 
CTU study personnel. 
15.3 
Types of Data 
Data for the trial will include clinical and laboratory safety assessments, 12-lead standard ECG 
interval measurements and interpretations, plasma and urine study drug concentrations at each 
specified timepoint and PK parameters for each dose of individual study drugs (ERT and ZID) and 
of WCK 6777 (combination ERT and ZID). 

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15.4 
Timing/Reports 
A final CSR will be prepared after all safety, 12-lead standard ECG, and plasma and urine PK data 
are available. 
15.5 
Study Records Retention 
Study files and ICFs will be maintained for at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region, or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the study drug. 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 DMID, if applicable. It is DMID’s responsibility to inform the investigator when these 
documents no longer need to be retained. 
15.6 
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 
investigator, or the CTU staff. Corrective actions for protocol deviations are to be developed by the 
CTU and implemented promptly. 
These practices are consistent with ICH E6: 
4.5 Compliance with Protocol, Sections 4.5.1, 4.5.2, and 4.5.3 
5.1 Quality Assurance and Quality Control, Section 5.1.1 
5.20 Noncompliance, Sections 5.20.1, and 5.20.2. 
It is the responsibility of the Site PI/study staff to use continuous vigilance to identify and report 
deviations within 5 working days of identification of the protocol deviation, or within 5 working 
days of the scheduled protocol-required activity. All deviations will be promptly reported to DMID 
via SDCC’s Advantage eClinical®. 
All protocol deviations, as defined above, will be addressed in subject data collection forms. A 
completed copy of the DMID Protocol Deviation Form will be maintained in the regulatory file, as 
well as in the subject's source document. Protocol deviations will be sent to the local IRB/EC per 
their guidelines. The Site PI/study staff is responsible for knowing and adhering to their IRB 
requirements. 

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16 
PUBLICATION POLICY 
Following completion of the study, the lead Principal Investigator 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/NIAID/NIH, which will 
register the trial and post results. 
 
Refer to: 
• Public Law 110-85, Section 801, Clinical Trial Databases 
• 42CFR11 
• NIH NOT-OD-16-149 
 
 

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17 
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17. Moya B, Barcelo IM, Bhagwat S, et al. Potent β-Lactam Enhancer Activity of Zidebactam 
and WCK 5153 against Acinetobacter baumannii, Including Carbapenemase-Producing 
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doi:10.1128/AAC.01238-17. 
18. Moya B, Barcelo IM, Bhagwat S, et al. WCK 5107 (Zidebactam) and WCK 5153 Are Novel 
Inhibitors of PBP2 Showing Potent "β-Lactam Enhancer" Activity against Pseudomonas 
aeruginosa, Including Multidrug-Resistant Metallo-β-Lactamase-Producing High-Risk 
Clones. Antimicrob Agents Chemother. 2017;61(6):e02529-16. doi:10.1128/AAC.02529-16 
19. Moya B, Barcelo IM, Cabot G, et al. In Vitro and In Vivo Activities of β-Lactams in 
Combination with the Novel β-Lactam Enhancers Zidebactam and WCK 5153 against 
Multidrug-Resistant Metallo-β-Lactamase-Producing Klebsiella pneumoniae. Antimicrob 
Agents Chemother. 2019;63(5):e00128-19. doi:10.1128/AAC.00128-19 
20. Moya B, Bhagwat S, Cabot G, Bou G, Patel M, Oliver A. Effective inhibition of PBPs by 
cefepime and zidebactam in the presence of VIM-1 drives potent bactericidal activity 
against MBL-expressing Pseudomonas aeruginosa. J Antimicrob Chemother. 
2020;75(6):1474-1478. doi:10.1093/jac/dkaa036 
21. Bhagwat SS, Periasamy H, Takalkar SS, Palwe SR, Khande HN, Patel MV. The Novel β-
Lactam Enhancer Zidebactam Augments the In Vivo Pharmacodynamic Activity of 
Cefepime in a Neutropenic Mouse Lung Acinetobacter baumannii Infection Model. 
Antimicrob Agents Chemother. 2019;63(4):e02146-18. doi:10.1128/AAC.02146-18 
22. Lepak AJ, Zhao M, Andes DR. WCK 5222 (Cefepime/Zidebactam) Pharmacodynamic 
Target Analysis against Metallo-β-lactamase producing Enterobacteriaceae in the 
Neutropenic Mouse Pneumonia Model [published online ahead of print, 2019 Oct 7]. 
Antimicrob Agents Chemother. 2019;63(12):e01648-19. doi:10.1128/AAC.01648-19 
23. Avery LM, Abdelraouf K, Nicolau DP. Assessment of the In Vivo Efficacy of WCK 5222 
(Cefepime-Zidebactam) against Carbapenem-Resistant Acinetobacter baumannii in the 
Neutropenic Murine Lung Infection Model. Antimicrob Agents Chemother. 
2018;62(11):e00948-18. doi:10.1128/AAC.00948-18 
24. Monogue ML, Tabor-Rennie J, Abdelraouf K, Nicolau DP. In Vivo Efficacy of WCK 5222 
(Cefepime-Zidebactam) against Multidrug-Resistant Pseudomonas aeruginosa in the 
Neutropenic Murine Thigh Infection Model. Antimicrob Agents Chemother. 
2019;63(7):e00233-19. doi:10.1128/AAC.00233-19 
25. Kidd JM, Abdelraouf K, Nicolau DP. Efficacy of human-simulated bronchopulmonary 
exposures of cefepime, zidebactam and the combination (WCK 5222) against MDR 
Pseudomonas aeruginosa in a neutropenic murine pneumonia model. J Antimicrob 
Chemother. 2020;75(1):149-155. doi:10.1093/jac/dkz414 
26. Almarzoky Abuhussain SS, Avery LM, Abdelraouf K, Nicolau DP. In Vivo Efficacy of 
Humanized WCK 5222 (Cefepime-Zidebactam) Exposures against Carbapenem-Resistant 
Acinetobacter baumannii in the Neutropenic Thigh Model. Antimicrob Agents Chemother. 
2018;63(1):e01931-18. doi:10.1128/AAC.01931-18 
27. Gethers M, Chen I, Abdelraouf K, Nicolau DP. In vivo efficacy of WCK 6777 
(ertapenem/zidebactam) against carbapenemase-producing Klebsiella pneumoniae in the 
neutropenic murine pneumonia model [published online ahead of print, 2022 Apr 12]. J 
Antimicrob Chemother. 2022;dkac110. doi:10.1093/jac/dkac110 
28. INVANZ® (ertapenem sodium injection. Prescribing information, Merck Sharpe and Dohme 
LLC. Available from:  

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https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021337s038lbl. pdf   
29. Teppler H, Gesser RM, Friedland IR, et al. Safety and tolerability of ertapenem. J 
Antimicrob Chemother. 2004;53 Suppl 2:ii75-ii81. doi:10.1093/jac/dkh209 
30. Bhatia A, Chugh R, Friedland D. Zidebactam Phase 1 Single Ascending Dose and Crossover 
Study in Healthy Subjects. Poster 2236,  ID Week, 26th – 30th October, New Orleans, LA, 
USA., 2016. 
31. Chugh R, Lakdavala F, Friedland D, Bhatia A. Safety and pharmacokinetics of multiple 
ascending doses of WCK 5107 (Zidebactam) and WCK 5222 (Cefepime and zidebactam). 
Poster 1301, 27th European Congress of Clinical Microbiology and Infectious Diseases 
(ECCMID), April 22nd - 25th, Vienna, 2017. 
32. Rodvold KA, Gotfried MH, Chugh R, et al. Plasma and Intrapulmonary Concentrations of 
Cefepime and Zidebactam following Intravenous Administration of WCK 5222 to Healthy 
Adult Subjects. Antimicrob Agents Chemother. 2018;62(8):e00682-18. 
doi:10.1128/AAC.00682-18 
33. Preston RA, Mamikonyan G, DeGraff S, et al. Single-Center Evaluation of the 
Pharmacokinetics of WCK 5222 (Cefepime-Zidebactam Combination) in Subjects with 
Renal Impairment. Antimicrob Agents Chemother. 2018;63(1):e01484-18. 
doi:10.1128/AAC.01484-18. 
34. Investigator’s Brochure, WCK 6777 [Ertapenem-Zidebactam (ERT-ZID)], Edition: 7.0, 11 
November 2022, Wockhardt 
35. Majumdar AK, Musson DG, Birk KL, et al. Pharmacokinetics of ertapenem in healthy 
young volunteers. Antimicrob Agents Chemother. 2002;46(11):3506-3511. 
doi:10.1128/AAC.46.11.3506-3511.2002 
36. Ambrose PG, Bhavnani SM, Ellis-Grosse EJ, Drusano GL. Pharmacokinetic-
pharmacodynamic considerations in the design of hospital-acquired or ventilator-associated 
bacterial pneumonia studies: look before you leap! Clin Infect Dis. 2010;51 Suppl 1:S103-
S110. doi:10.1086/653057 
37. Ertapenem Sodium (ertapenem injection). Prescribing information, Dr. Reddy's 
Laboratories, Inc. Available from: 
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=32d9f095-ca39-7e22-6264-
b54f2daaee57 
 

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18 
APPENDICES

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APPENDIX A: SCHEDULE OF STUDY PROCEDURES AND EVALUATIONS 
Evaluation (↓) 
Screening 1 
Check-in/ 
Enrollment 
In-patient Treatment 
Out-
patient 
follow-
up 
Unscheduled / 
Early 
Termination 
Visit (V) -> 
1 
2 
 
 
 
 
 
 
 
 
3 
Study Day (D) -> 
-28 to -2 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
11 (+3) 
Informed consent 
X 
Confirmation of eligibility criteria 
X 
X 2 
X 2 
Medical History 
X 
 
 
Demographics 
X 
 
 
Height, Weight and BMI 3  
X 
Weight 
 
X 2 
 
X 
MH update 
X 2 
X 2 
 
 
 
 
 
 
 
 
 
Prior and Concomitant medications 4 
X 
X 
X 4 
X 4 X 4 
X 4 X 4 
X 4 
X 4 X 4 
X 4 
X 4 
Physical examination (PE) 
X 
X 
X 
X 
X 
Symptom directed (focused) PE 5  
X 
X 
X 
X 
X 
X 
X 
Vital signs 6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 7 
X 
X 
X 
X 
X 
Clinical Laboratory testing (HEM, CHEM, and 
COAG) 8 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 9 
X 
X 
 
X 
 
X 
X 
X 
Viral serology 10 
X 
Serum HCG pregnancy test (all females) and FSH 
(post-menopausal females only) 11 
X 
 
Urine pregnancy test (all females) 11 
 
X 
Urine drug screen 12 
X 
X 
Urine alcohol test 
X 
X 
Urine cotinine test 
X 
X 
Admission of eligible subjects /Assignment to 
treatment cohort / Randomization 13 
X 
 
 
 
 
 
 
 
 
 
 
Study drug administration 14 
X 
X
X 
X
X 
X
X 
 
 
 
Assessment of adverse events 15 
X 
X
X 
X
X 
X
X 
X 
X 
X 
Assessment of infusion and blood drawing sites 16 
X
X
X
X
X
X
X
X
X 
X
Plasma PK 17 
X 17 
X 17 X 17 
X 17 
X 17 
X 17 
X 17 
X 17 
 
X 18 
Urine PK 19 
X 19 
 
X 19 
Discharge from in-patient site 
 
 
   X 
Final visit / Discharge from study 
 
 
     X 
Counseling 
X 
X 
X
X 
X 
X 
X 
X 
X
X 
X 
X 
 
1. Screening evaluations must be completed within 28 days prior to administration of study drug(s). 
2. Confirmation of eligibility for admission and enrollment and randomization on Day -1, and for dosing on Day 1 after completion of all baseline procedures before study intervention  
• Baselines are: Complete PE, weight, Clinical labs and ECG on Day-1; VS (within 30 min before dosing on Day 1), MH and Prior Medications updates, and Focused PE (as needed for new 
symptoms) predose on Day 1 
3. BMI ≥18-32 kg/m2 and Weight ≥ 100 lbs (At Screening). Weight also measured on Day 8.   
4. Concomitant medications include any new medications taken only after initiation of first dose on Day 1. 
5. Symptoms directed (focused) PE for evaluation of new symptoms prior to dosing on Day 1, and for evaluation of TEAEs after dosing on Day 1 to the end of the study, or ET  
6. Vital Signs: collected after 5 minutes of resting in supine position and include SBP, DBP, HR and T (oral measurement). Recorded at Screening, Day -1, Days 1 to 7 (within 30 min prior to 
dosing, at the end of infusion (+10 min) and 1 hour (±5 min) after the end of infusion), Day 8, and Day 11 (+3), or ET.  
7. 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). 
8. Clinical Laboratory testing for Hematology (HEM: Hemoglobin, hematocrit, RBC, WBC with WBC differential count, and platelet count), Clinical Chemistry (CHEM: sodium, potassium, chloride, 
bicarbonate, BUN, creatinine, estimated CLCR (by the Cockcroft-Gault method), calcium, glucose, albumin, total protein, total bilirubin, direct bilirubin, ALT, AST, ALP and LDH) and Coagulation 
(COAG: PT and AP). – Lab values on Day -1 are considered baseline. 
9. Urinalysis: Dipstick urinalysis, including protein, glucose, ketones, bilirubin, occult blood, nitrite, leukocyte esterase, specific gravity, and pH. If dipstick UA is abnormal for blood, protein, glucose 
and leukocyte esterase, a microscopic UA will be done (for WBC, RBC, bacteria, and other cell counts), and results will supersede those of the dipstick UA. Lab values on Day -1 are considered 
baseline. 
10. Viral serology: HIV antibody, HBsAg, HCV antibody 
11. Serum pregnancy at Screening and Urine pregnancy test on Day-1 from all females; FSH at Screening only from post-menopausal females. 
12. Urine drug screen panel for: amphetamines, barbiturates, benzodiazepines, cocaine metabolites, cannabinoids (THC), opiates, phencyclidine, and tri-cyclic antidepressants – At Screening and Day -1  
13. Assignment to dosing cohort and randomization: Must occur after all inclusion and exclusion criteria have been confirmed on Day -1 and subject was admitted to the in-patient site.  
14. Study drug or placebo administered IV according to cohort and randomization assignment. Withhold solid food at least 4 h before starting the infusion and 1 h after completion of infusion. Oral 
liquids are allowed.   
15. Monitoring for treatment-emergent AEs and SAEs will begin upon initiation of the first dose of study product(s) and continue until the last visit, or ET. 
16. Assess and replace IV catheters no more frequently than every 72 to 96 h or as clinically indicated. 
 
  

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17. Plasma PK collection times:   
DAY 1 and DAY 7:  
o 
  For the 30 min infusion (Cohort 1): Predose (within 30 min; t=0) and at 0.25 h (±5 min), 0.5 h (±5 min) (immediately at end of infusion), 1 h (±5 min), 2 h (±5 min), 3 (±10 min),                  
4 h (±10 min), 8 h (±15 min), 12 h (±15 min), 18 (±15 min) and 24 h (±30 min) after start of infusion 
o 
For the 60 min infusion (Cohorts 2, 3 and 4): Predose (within 30 min; t=0) and at 0.5 h (±5 min), 1 h (±5 min) (immediately at end of infusion), 2 h (±5 min), 3 h (±10 min), 4 h (±10 min),  
8 h (±15 min), 12 h (±15 min), 18 h (±15 min) and 24 h (±30 min) after start of infusion 
o 
For the 120 min infusion (Cohorts 5, 6 and 7): Predose (within 30 min; t=0) and at 1 h (±5 min), 2 h (±5 min) (immediately end of infusion), 3 h (±10 min), 4 h (±10 min), 8 h (±15 min),   
12 h (±15 min), 18 (±15 min) and 24 (±30 min) after start of infusion 
DAY 2 to DAY 6:  
o 
Predose (within 30 min) and 12 (±5 min) h after start of infusion. 
18. Unscheduled visit – plasma PK collection is optional 
19. Urine PK collection times 
DAY 1 and DAY 7:  
o 
Before the start of infusion (within 60 min), and at the following intervals after the start of the infusion: 0 to 4 h (±10 min), 4 to 8 h (±15 min), 8 to 12 h (±15 min), and 12 to 24 h (±30 min),   

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APPENDIX B: ADVERSE EVENTS TOXICITY GRADING CRITERIA 
ABBREVIATIONS: Abbreviations utilized in the Tables: 
ADL = Activities of Daily Living 
 
CTU = Clinical Trial Unit 
ULN = Upper Limit of Normal 
IV    = Intravenous 
ESTIMATING SEVERITY GRADE 
For abnormalities NOT found elsewhere in the Toxicity Tables, use the scale below to 
estimate grade of severity: 
GRADE 1 
Mild 
Events require minimal or no treatment; do not interfere with the 
subject’s daily activities.  
GRADE 2 
Moderate 
Events result in a low level of inconvenience or concern with 
therapeutic measures; may cause some interference with 
functioning.  
GRADE 3 
Severe 
Events interrupt a subject’s usual daily activity and may require 
systemic drug therapy or other treatment; are usually 
incapacitating.  
SERIOUS OR LIFE-THREATENING AEs 
Clinical events considered to be serious or life-threatening include, but are not limited to 
seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular coagulation, diffuse 
petechiae, paralysis, acute psychosis, and severe depression. 
COMMENTS REGARDING THE USE OF THESE TABLES 
• Standardized and commonly used toxicity tables (Division of AIDS, National Cancer 
Institute [NCI] Common Toxicity Criteria [CTC], and World Health Organization 
[WHO]) have been adapted for use by the Division of Microbiology and Infectious 
Diseases (DMID) and modified to better meet the needs of subjects in DMID trials. 
• For parameters not included in the following Toxicity Tables, the CTU will refer to the 
“Guide for Estimating Severity Grade” located above. 
• Criteria are generally grouped by body system. 
Some protocols may have additional protocol specific grading criteria, which will supersede 
the use of these tables for specified criteria. 
 

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Note 1:   No recent hot or cold beverages or smoking. A protocol should select either 0C or 0F for inclusion. 
Note 2:  Assume awake and in supine position for 5 min at rest. Abnormal HR and BP on first measurement due to a 
technical (procedural) error may be repeated twice more with the subject resting between measurements for 
at least 5 min (See Section 8.1.6 Vital Signs). 
Note 3:   Exceptions to screening BP and HR reference range are: 
(a) Subjects with baseline HR ≥ 45 to 50 bpm may be accepted if otherwise healthy adults with known history 
of asymptomatic bradycardia. 
(b) Subjects with baseline SBP up to 140 mmHg and DBP up to 90 mmHg may be accepted if otherwise 
healthy.  
Note 4:   Isolated/individual abnormalities of VS would not be considered toward halting criteria. Abnormalities of 
VS will be described as “increased X” or “decreased X” (X = HR, BP, RR, temperature) if asymptomatic, 
transient and not associated with a systemic or organ-specific disorder and coded by MedDRA within the 
System Organ Class (SOC) “Investigations.” These abnormalities will be graded per criteria in this table, 
but not considered in determining whether study stopping criteria have been met. On the other hand, 
abnormalities of VS that are either secondary to systemic or organ-specific clinical syndrome or primary 
disorders will be coded in the appropriate SOC (e.g., “cardiac disorders”, “respiratory disorders”, 
“immunological disorders”, etc.). These abnormalities will be considered in determining whether stopping 
criteria have been met. 
 
 
 
 
 
 
Table 2 Toxicity Grading Tables – CLINICAL AEs 
Clinical AEs 
Reference range 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
VITAL SIGNS 1 
Fever - °C 
Fever - °F 
36.1 - 37.2 1 
97.0 - 99.0 1 
37.3 - 38.4 
 99.1 - 101.1 
38.5 - 38.9 
101.2 - 102.0 
>38.9 
>102.0 
Tachycardia - bpm 
50 - 100 2,3,4,5 
101 - 115 
116 - 130 
>130 or ventricular 
dysrhythmias 
Bradycardia – bpm 
45 - 49 
40 - 44 
<40 
Hypertension (systolic) 
- mmHg 
130/89 2,3,4,5 
131 - 150 
151 - 160 
>160 
Hypertension (diastolic) 
- mmHg 
90 - 95 
96 - 100 
>100 
Hypotension (systolic) - 
mmHg 
85 - 88 
80 - 84 
 <80 
Tachypnea – breaths 
per min 
10 - 20 2,3,4,5 
21 - 25 
26 - 30 
>30 

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Table 2 Toxicity Grading Tables – CLINICAL AEs 
Clinical AEs 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
CARDIOVASCULAR DISORDERS 
Arrhythmia (except 
Sinus tachycardia) 
 
Asymptomatic or transient 
signs; no medical intervention 
required. 
Recurrent and/or persistent signs; 
symptomatic medical intervention 
required. 
Hemorrhage 
Estimated blood loss 
<100 mL. 
Estimated blood loss >100 mL; 
no transfusion required. 
Blood transfusion required. 
RESPIRATORY DISORDERS 
Cough  
Transient cough; no treatment 
required. 
Persistent cough; treatment 
required. 
Interferes with daily activities. 
Bronchospasm, Acute 
Transient bronchospasm; no 
treatment required; FEV1 71-
80% of predicted peak flow. 
Requires treatment; 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 usual and social 
activities OR requires treatment. 
EAR AND LABYRINTH DISORDERS  
Tinnitus 
Mild symptoms: intervention 
not indicated. 
Moderate symptoms; limiting 
instrumental ADL. 
Severe symptoms; limiting self-
care ADL. 
Vertigo  
Mild symptoms. 
Moderate symptoms; limiting 
instrumental ADL. 
Severe symptoms; limiting self-
care ADL. 
GASTROINTESTINAL DISORDERS 
Nausea  
No interference with normal 
activity. 
Some interference with normal 
activity. 
Prevents daily activities. 
Vomiting  
No interference with activity 
OR 1-2 episodes in a 24-h 
period. 
Some interference with activity 
OR >2 episodes in a 24-h 
period. 
Prevents daily activity OR 
requires medical intervention. 
Diarrhea  
2-3 loose OR watery stools in 
a 24-h period. 
4-5 loose OR watery stools in a 
24-h period. 
6 or more loose or watery stools 
in a 24-h period OR requires IV 
hydration OR requires medical 
intervention. 
Oral Discomfort / 
Dysphagia 
Mild discomfort; no difficulty 
swallowing. 
Some limits on eating 
/drinking. 
Eating/talking very limited; 
unable to swallow solid foods. 
NEUROLOGICAL DISORDERS 
Dizziness 
Mild unsteadiness or 
sensation of movement 
Moderate unsteadiness or 
sensation of movement; 
limiting instrumental activities 
of daily life (ADL) 
Severe unsteadiness or 
sensation of movement; 
limiting self-care ADL; medical 
intervention required 
Headache  
Mild pain; No interference 
with activity. 
Moderate pain; repeated use of 
non-narcotic pain reliever for 
more than 24 h OR some 
interference with activity. 
Significant pain; any use of 
narcotic pain reliever OR prevents 
daily activity OR requires 
triptans. 

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Table 2 Toxicity Grading Tables – CLINICAL AEs 
Clinical AEs 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Hypersomnia 
Mild increased need for sleep 
Moderate increased need for 
sleep 
Severe increased need for sleep 
including excessive daytime 
sleepiness 
Seizure 
Brief partial seizure and no 
loss of consciousness 
Brief generalized seizure 
New onset seizures (partial or 
generalized); multiple seizures 
despite medical intervention 
Somnolence 
Mild but more than usual 
drowsiness or sleepiness 
Moderate sedation; limiting 
instrumental ADL 
Obtundation or stupor 
Syncope 
- 
- 
Fainting; orthostatic collapse 
Tremor 
Mild symptoms 
Moderate symptoms; limiting 
instrumental ADL 
Severe symptoms; limiting self-
care 
Other 
Asymptomatic or mild 
symptoms; clinical or 
diagnostic observations only; 
intervention not indicated 
Moderate; minimal, local or 
noninvasive intervention 
indicated, limiting age-
appropriate instrumental ADL 
Severe or medically significant 
but not immediately life 
threatening; hospitalization or 
prolongation of existing 
hospitalization indicated;  
limiting self-care 
PSYCHIATRIC DISORDERS 
Altered Mental Status: Includes agitation, confusion, disorientation, decreased mental acuity, changed mental status, 
somnolence, stupor 
Agitation 
Mild mood alteration 
Moderate mood alteration 
Severe agitation; hospitalization 
not indicated 
Confusion 
Mild disorientation 
Moderate disorientation; 
limiting instrumental ADL 
Severe disorientation; limiting 
self-care 
Insomnia 
Mild difficulty falling asleep, 
staying asleep or waking up 
early 
Moderate difficulty falling 
asleep, staying asleep or 
waking up early 
Severe difficulty in falling asleep, 
staying asleep or waking up early; 
medical intervention required 
Psychiatric disorders - 
Other, specify 
Asymptomatic or mild 
symptoms; clinical or 
diagnostic observations only; 
intervention not indicated 
Moderate; minimal, local or 
noninvasive intervention 
indicated; limiting age-
appropriate instrumental ADL 
Severe or medically significant 
but not immediately life-
threatening; limiting self-care; 
psychiatric intervention required 
LOCAL IV CATHETER REACTION 
IV site reaction 
Not applicable. 
Erythema with associated 
symptoms (e.g., edema, pain, 
induration, phlebitis). 
Ulceration or necrosis; severe 
tissue damage; operative 
intervention indicated. 

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Table 2 Toxicity Grading Tables – CLINICAL AEs 
Clinical AEs 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
SYSTEMIC REACTIONS 
Anaphylaxis ** 
-- 
-- 
Symptomatic bronchospasm, with 
or without urticaria; parenteral 
intervention indicated; allergy-
related edema or angioedema; 
hypotension. 
**Definition: A disorder characterized by an acute inflammatory reaction resulting from the release of histamine and histamine-
like substances from mast cells, causing a hypersensitivity immune response. Clinically, it presents with breathing difficulty, 
dizziness, hypotension, cyanosis, and loss of consciousness, and may lead to death. 
Allergic Reaction  
Pruritus without rash. 
Localized urticaria OR requires 
oral therapy. 
Generalized urticaria OR 
angioedema OR anaphylaxis OR 
requires epinephrine 
Hypersensitivity 
(including drug fever) 
Transient flushing or rash; 
temperature 38.0 – 38.4°C 
(100.4 – 101.1°F). 
Rash; flushing; urticaria; 
dyspnea; temperature 38.5 – 
38.9°C (101.2 – 102.0°F). 
Symptomatic bronchospasm 
with or without urticaria; 
parenteral medication indicated; 
allergy-related edema or 
angioedema; hypotension; 
temperature >38.9°C (>102.0°F).  
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. 
SKIN 
Mucocutaneous 
Erythema, pruritus. 
Diffuse, maculo-papular rash, 
dry desquamation. 
Vesiculation OR moist 
desquamation OR ulceration. 
Pruritus 
No or minimal interference 
with usual social and 
functional activities.  
Greater than minimal 
interference with usual social 
and functional activities.  
Inability to perform usual social 
and functional daily activities. 
ALL OTHER CONDITIONS 
Illness or clinical AE 
(as defined according 
to applicable 
regulations) 
Require minimal or no 
treatment; does not interfere 
with the subject’s daily 
activities. 
Result in a low level of 
inconvenience or concern with 
therapeutic measures; may 
cause some interference with 
functioning. 
Interrupt a subject’s usual daily 
activity and may require systemic 
drug therapy or other treatment; 
are usually incapacitating. 
 
 
 

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Table 3 Toxicity Grading Tables – LABORATORY AEs 
Laboratory AEs 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Blood, serum, or plasma * 
HEMATOLOGY 
Hemoglobin decrease,  
Female, 18Y – g/dL 
9.5 – 11.4 
7.9 – 9.4 
<7.9 
Hemoglobin decrease,  
Female, >18Y – g/dL 
9.7 – 11.6 
8.1 – 9.6 
<8.1 
Hemoglobin decrease,  
Male, 18Y – g/dL 
10.0 – 11.9 
8.0 – 9.9 
<8.0 
Hemoglobin decrease,  
Male, >18Y – g/dL 
11.2 – 13.1 
9.2 – 11.1 
<9.2 
WBC increase  
18Y – x103/ µL 
13.1 – 15.0 
15.1 – 20.0 
>20.0 
WBC increase  
>18Y – x103/ µL 
10.9 – 15.0 
15.1 – 20.0 
>20.0 
WBC decrease 
18Y – x103/ µL 
3.0 – 4.4 
1.5 – 2.9 
<1.5 
WBC decrease 
>18Y – x103/ µL  
2.3 – 3.7 
1.1 – 2.2 
<1.1 
Neutrophils decrease  
18Y – cells/ µL 
1,200 – 1,799 
750 – 1,199 
<750  
Neutrophils decrease  
>18Y – cells/ µL 
1,000 – 1,499 
750 – 999 
<750  
Lymphocytes decrease  
18Y– cells/ µL 
850 – 1,199 
400 – 849 
<400 
Lymphocytes decrease  
>18Y – cells/ µL 
500 - 849 
300 - 499 
<300 
Monocytes increase –  
18Y – cells/ µL 
901 – 2,000 
2,001 – 3,000 
>3,000 
Monocytes increase  
>18Y – cells/ µL 
951 – 2,000 
2,001 – 3,000 
>3,000 
Eosinophils increase  
>6Y– cells/ µL 
501 – 750 
751 – 1,000 
>1,000 
Basophils increase  
>6Y– cells/ µL 
201 – 500 
501 – 800 
>800 
Platelets decrease – x103/ µL 
90 – <140 
55 – <90 
<55 
COAGULATION 
PT INR 
>1.1 – 1.8 
>1.8 – 2.1 
>2.1 
Prothrombin Time - sec 
>11.5 – 15.0 
>15.0 – 18.6 
>18.6 
Activated Partial Thromboplastin Time 
(APTT) - sec 
>32 – 54 
>54 – 75 
>75 
CHEMISTRY 
Sodium decrease – mmol/L 
130 - 134 
124 –129 
<124 
Sodium increase – mmol/L 
147 - 150 
 151 – 156 
>156 
Potassium increase, 
19Y - mmol;/L 
5.2 – 6.0 
6.1 – 6.5 
>6.5 
Potassium increase,  
5.4 – 6.0 
6.1 – 6.5 
>6.5 

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Table 3 Toxicity Grading Tables – LABORATORY AEs 
Laboratory AEs 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
>19Y - mmol/L 
Potassium decrease,  
19Y – mmol/L 
3.2 – 3.7 
2.6 – 3.1 
<2.6 
Potassium decrease,   
>19Y - mmol/L 
3.0 – 3.4  
2.5 – 2.9 
<2.5 
Carbon dioxide increase – mmol/L 
33 – 36 
37 – 40 
>40 
Carbon dioxide decrease – mmol/L 
17 – 19 
14 – 16 
<14 
Calcium increase,  
Male,  4 -19Y – mg/dL   
10.5 – 11.2 
11.3 – 12.3 
>12.3 
Calcium increase,  
Male, 20 - 49Y – mg/dL 
10.4 – 11.4 
11.5 – 12.5 
>12.5 
Calcium increase,  
Female, 4 -19Y – mg/dL 
10.5 – 11.4 
11.5 – 12.5 
>12.5 
Calcium increase,  
Female 20 - 49Y – mg/dL 
10.3 – 11.4 
11.5 – 12.5 
>12.5 
Calcium decrease,  
Male, 4 -19Y – mg/dL 
8.1 – 8.8 
7.3 – 8.0 
<7.3 
Calcium decrease,  
Male, 20 - 49Y – mg/dL 
8.1 – 8.5 
7.3 – 8.0 
<7.3 
Calcium decrease,  
Female, 4 -19Y – mg/dL 
8.1 – 8.8 
7.3 – 8.0 
<7.3 
Calcium decrease, 
Female, 20-49Y – mg/dL 
8.1 – 8.5 
7.3 – 8.0 
<7.3 
Blood urea nitrogen (BUN) increase,  
19Y - mg/dL 
21 – 58 
59 – 120 
>120 
Blood urea nitrogen (BUN) increase, 
>19Y- mg/dL  
26 – 58 
59 – 120 
>120 
Glucose decrease, fasting – mg/dL 
47 – 64 
40 – 46 
<40 
Glucose increase, fasting – mg/dL 
100 – 160 
161 – 250 
>250 
Glucose increase, non-fasting – mg/dL 
140 – 200 
201 – 250 
>250 
Creatinine increase,  
Male, 18 - 29Y – mg/dL 
1.25 – 1.62 
1.63 – 2.24 
>2.24 
Creatinine increase,  
Male, 30 – 39 Y – mg/dL 
1.27 – 1.64 
1.65 – 2.27 
>2.27 
Creatinine increase,  
Male, 40 - 49Y – mg/dL 
1.30 – 1.68 
1.69 – 2.32 
>2.32 
Creatinine increase,  
Female, 18 - 29Y – mg/dL 
0.97 – 1.25  
1.26 – 1.73 
>1.73 
Creatinine increase,  
Female, 30 - 39Y – mg/dL 
0.98 – 1.26 
1.27 – 1.75 
>1.75 
Creatinine increase,  
Female, 40 - 49Y – mg/dL 
1.00 – 1.29 
1.30 – 1.78 
>1.78 
Direct bilirubin 
0.3 – 0.6 
0.7 – 1.2 
>1.2 
Total bilirubin (serum) increase 
(with other LFTs in the normal range), 
19Y – mg/dL 
1.2 – 1.7 
1.8 – 2.5 
>2.5 
Total bilirubin (serum) increase  
1.3 – 1.8 
1.9 – 2.6 
>2.6 

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Table 3 Toxicity Grading Tables – LABORATORY AEs 
Laboratory AEs 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
(with other LFTs in the normal range), 
>19Y – mg/dL 
Total bilirubin (serum) increase 
(accompanied by a >3 x ULN increase 
in ALT or AST), 19Y – mg/dL 
1.2 – 2.0 
2.1 – 2.8 
>2.8 
Total bilirubin (serum) increase  
(accompanied by a >3 x ULN increase 
in ALT or AST), >19Y – mg/dL 
1.3 – 2.1 
2.2 – 3.0 
>3.0 
Total protein decrease, 
19Y – g/dL 
5.3 – 6.2 
4.5 – 5.2 
<4.5 
Total protein decrease, 
>19Y – g/dL 
5.1 – 6.0 
4.3 – 5.0 
<4.3 
Albumin, decrease - g/dL 
3.0 – 3.5 
2.0– 2.9 
<2.0 
AST increase,  
19Y – U/L 
33 – 64 
65 – 96 
>96 
AST increase,  
20-49Y – U/L 
41 – 80 
81 – 120 
>120 
ALT increase,   
Male, 19Y – U/L 
47 – 92 
93 – 138 
>138 
ALT increase,   
Male, >19Y – U/L 
47 – 92 
93 – 138 
>138 
ALT increase,   
Female, 19Y – U/L 
33 – 64 
65 – 96 
>96 
ALT increase,   
Female, >19Y – U/L 
30 – 58 
59 – 87 
>87 
Alkaline phosphatase (AP) increase, 
Male, 19Y – U/L 
170 – 338 
339 – 507 
>507 
Alkaline phosphatase (AP) increase,  
Male, ≤49Y – U/L 
131 – 260 
261 – 345 
>345 
Alkaline phosphatase (AP) increase,   
Female, 19Y – U/L 
129 – 256 
257 – 384 
>384 
Alkaline phosphatase (AP) increase,   
Female, ≤49Y – U/L 
126 – 250 
251 – 375 
>375 
Urine  
URINALYSIS by Dipstick 
Protein 
1+ 
2+ 
>2+ 
Blood (occult) 
1+ 
2+ 
>2+ 
Glucose 
1+ 
2+ 
>2+ 
Leukocyte esterase 
1+ 
2+ 
>2+ 
URINE MICROSCOPY 
Red blood cells (RBC) per HPF 
3 – 10 
11 – 40 
>40 and/or gross blood 
WBC (microscopic) – WBC per HPF 
6 – 10 
11 – 40 
>40 and/or symptomatic 
urogenital infection 
Bacteria (microscopic) 
few 
moderate 
many 

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Note 1:  With the exception of AST, ALT, AP, total and direct  bilirubin, BUN, creatinine, CLCR (by the Cockcroft-Gault method), 
and urine protein, which should be within reference range, lab values of other analytes in the grade 1 range are 
acceptable for enrollment if (a) they are not considered to be clinically significant by the investigator and (b) there is no 
cluster of abnormal labs that combined are suggestive of an underlying disorder. 
Note 2: Other Exceptions to screening laboratory tests’ normal reference ranges are: 
a. Racially based low total WBC or neutrophil counts up to toxicity Grade 1 are allowed, but toxicity Grades 2 or 3 are 
exclusionary. 
b. Labs performed as part of a panel but not listed above are to be recorded in the database. If abnormal, they are not 
exclusionary and are not to be graded per Toxicity table, however, the investigator would make a clinical decision about 
their clinical significance and, if clinically significant, they will be graded according to the criteria in Section 9.2.1. 
(Examples include mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular 
hemoglobin concentration (MCHC), red cell distribution width (RDW), mean platelet volume (MPV), and nucleated red 
blood cell count (NRBC CT), which are included in a CBC with differential.)  
Note 3:  If a subject was accepted into the trial with a laboratory value of an analyte that overlaps with values used for grading 
Grade 1 laboratory abnormalities, a TEAE will be reported if the on-study value of the same analyte increases in 
severity to Grade 2 or higher compared to the baseline. 
Note 4: If the dipstick UA is abnormal for blood, protein, glucose and leukocyte esterase, a microscopic UA will be performed, 
and the results will supersede the results of the dipstick UA. 
Note 5: Menstruating females with a positive dipstick UA or microscopic UA may be retested following cessation of menses. 
Gross blood in urine that is confirmed due to menses is not a TEAE (but is for all other reasons. 
Note 6: Isolated laboratory values that are outside the range of eligibility but are thought to be due to an acute condition or due 
to collection or laboratory error may be repeated once. 
Note 7: For the microscopic UA, Lab-reported ranges 3 -10 for RBC and 6-10 for WBC would be Grade 1; 10-20 and 20-40 for 
both RBC and WBC would be Grade 2; and > 40 for both RBC and WBC would be Grade 3. 
 
 
 

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Table 4 Toxicity Grading Tables – ECG 
ECG interval 
abnormality  
Reference 
range 
Grade 1 
Grade 2 
Grade 3 
QTcF interval 
prolonged (msec): 
• 
Male 
• 
Female 
 
 
• 
≤450 msec 
• 
≤470 msec 
Asymptomatic,  
QTcF  
• 
451 - 479 msec 
• 
471 - 479 msec 
Asymptomatic,  
QTcF 480-500 msec  
OR  
increase in interval 30-59 
msec above baseline 
Asymptomatic,  
QTcF >500 msec  
OR 
increase in interval 
≥60 msec above baseline 
PR interval 
prolonged (msec) 
≤ 210 msec 
211-250 msec 
>250 msec 
Type II 2nd degree AV 
block  
OR  
ventricular pause >3.0 sec 
 
Note 1: Events will be coded as treatment-emergent SAEs if there are life-threatening associated symptoms or signs (arrhythmia, 
CHF, hypotension, syncope, TdP, etc.). 
Note 2: If a male subject was accepted into the trial with a QTcF value that overlaps with values used for grading Grade 1 QTcF 
prolongation, a TEAE will be reported if the QTcF value is higher than the baseline value. 

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APPENDIX C: BLOOD VOLUME WITHDRAWN DURING THE TRIAL 
Table 5: Laboratory Samples and Estimated Total Blood Volume (mL) 
Study Periods 
Out-
patient 
In-
patient  
In-patient Dosing Period (Days 1 – 7) 
 
Out-
patient 
 
Study Visit 
Screen 
Check-
in 
Dosing 
Dis-
charge 
Follow-
up 
ET 
Study Day a 
-28 to -2 
-1 
1 
2  
3  
4  
5  
6 
7 
8 
11 (+3 
days) 
HEMATOLOGY 1 
4 
4 
 
4 
 
4 
 
4 
 
4 
4 
4 
COAGULATION 1 
2.7 
2.7 
 
2.7 
 
2.7 
 
2.7 
 
2.7 
2.7 
2.7 
CHEMISTRY 1  
8.5 
8.5 
 
8.5 
 
8.5 
 
8.5 
 
8.5 
8.5 
8.5 
Serum β-HCG and FSH 1 
0 
 
 
 
 
 
 
 
 
 
 
 
Viral Serology (HIV, HBsAg, HCV) 3 
8.5 
 
 
 
 
 
 
 
 
 
 
 
PK 4 
 
 
100 
20 
20 
20 
20 
20 
100 
10 
 
10 
Total volume/visit 
23.7 
15.2 
100 
35.2 
20 
35.2 
20 
35.2 
100 
25.2 
15.2 
31.2 
Cumulative total volume 
23.7 
38.9 
138.9 
174.1 
194.1 
229.3 
249.3 
284.5 
384.5 
409.7 
424.9 
 
a Study Days shown correspond to days in each study period. For a view of the cumulative numbering of study days, please refer to Section 7. 
 
1 Clinical Safety blood tests (HEM, CHEM, COAG) are drawn at Screening Visit, on Day -1, pre-dose on Days 2, 4, and 6, on Days 8 and 11 (+ 3 days), or ET. The test includes 
serum β-HCG and FSH. 
2 Serum pregnancy test (β-HCG) in all women at Screening. FSH at Screening only in post-menopausal women. 
3 Viral serology tests are drawn at Screening. 
4 PK plasma samples are drawn on: 
Day 1 and Day 7: Before and at 7- 9 other timepoints after the start of infusion, depending on duration of infusion (See Appendix A and Section 8.3.1); Day 2 to Day 8: (daily, 
24 h after starting the infusion on the previous day, Day 1 to Day 7); Day 2 to Day 6 (daily, 12 h after the dose), or ET if occurs within 24 h of dosing.