A Phase I, Open-label Study of the Metabolism and Excretion of [14C]-Zidebactam (WCK 5107) Following a Single Intravenous Infusion in Healthy Male Subjects.
Phase: PHASE1
Conditions: Healthy Subjects (HS)
Sponsor: Wockhardt

Clinical Study Report 
CONFIDENTIAL 
Covance Study: 8375685 
Sponsor Reference: W-5107-103 
  
16.1.1. 
Protocol and Amendments 
Final
Page 1 of 46

TITLE PAGE 
Protocol 
A Phase I, Open-label Study of the Metabolism and Excretion of 
[14C]-Zidebactam (WCK 5107) Following a Single Intravenous Infusion in 
Healthy Male Subjects 
Protocol Status: Final 
Protocol Date: 13 November 2017 
Investigator Product: Zidebactam 
 
Protocol Reference Number: W-5107-103 
Covance Study Number: 8375685 
IND Number:116002 
 
 
Sponsor: 
Wockhardt Bio AG. 
Grafenauweg 6 
6300 Zug 
Switzerland 
Study Site: 
Covance Clinical Research Unit 
3402 Kinsman Boulevard 
Madison, Wisconsin 53704 
 
 
Sponsor Signatory: 
Ashima Bhatia, MD  
Rakesh Chugh, MD 
Principal Investigator: 
Nicholas Siebers, MD 
 
 
Information described herein is confidential and may be disclosed only with the express 
written permission of the Sponsor. 
Page 2 of 46

Protocol 
Covance Study: 8375685 
CONFIDENTIAL 
Protocol Reference: W -5107-103 
SPONSOR APPROVAL 
I have read the protocol and approve it. 
Ashima Bhatia, MD 
Senior Vice President 
Global Research and Development 
Wockhardt Ltd 
Final, 13 November 2017 
\ "\ \QD\) 20il 
Date 
Page 2 of 45 
Page 3 of 46

Protocol 
CONFIDENTIAL 
Co\·al_1~-~Study: 8375685 
Protocol Reference: W-5!07-103 
SPONSOR APPROVAL 
I have read the protocol and dpprove it. 
Rakesh Chugh, MD 
Senior General Manager 
Global Research and Development 
Wockhardt Ltd 
Final, 13 November 2017 
--·-··--··-------------
Date 
Page 3 of 45 
Page 4 of 46

Protocol 
Covance Study: 8375685 
CONFIDENTIAL 
Protocol Reference: W-5107-103 
INVESTIGATOR AGREEMENT 
I have read the protocol and agree to conduct the study as described herein. 
Nicholas SiebelS,' 
Principal Investigator 
Final, 13 November 2017 
Date 
Page 4 of45 
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Protocol 
CONFIDENTIAL 
Covance Study: 8375685 
Protocol Reference: W-5107-103 
Final, 13 November 2017 
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STUDY IDENTIFICATION 
Sponsor 
Wockhardt Bio AG. 
Grafenauweg 6 
6300 Zug 
Switzerland 
Sponsor’s Study Contact 
Preeti Narayan, M. Pharm 
AGM, Global Clinical Development 
Wockhardt Ltd 
Wockhardt Towers 
Bandra Kurla Complex, Bandra (East) 
Mumbai 400051 
Sponsor’s Project Lead and  
Medical Monitor 
Rakesh Chugh, MD 
Senior General Manager – Global Clinical Development 
Wockhardt Ltd, Wockhardt Towers 
Bandra Kurla Complex, Bandra (East) 
Mumbai 400051 
+91-22-7159-6444 (Office Telephone No.) 
+91-997-139-2256 (Mobile Telephone No.) 
Study Site  
Covance Clinical Research Unit 
3402 Kinsman Boulevard 
Madison, Wisconsin 53704 
USA 
Principal Investigator 
Nicholas Siebers, MD 
Physician 
Covance Clinical Research Unit 
Tel: 608-442-8200 
nicholas.siebers@covance.com 
Sub-investigator(s)  
Obtain information from Form FDA 1572 
Clinical Laboratory 
Meriter Laboratories 
36 South Brooks Street 
Madison, Wisconsin 53715 
USA 
Bioanalytical Laboratory  
Covance Inc. 
3301 Kinsman Boulevard 
Madison, Wisconsin 53704 
USA 
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Protocol 
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Protocol Reference: W-5107-103 
Final, 13 November 2017 
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Radioanalytical Laboratory  
Covance Inc. 
3301 Kinsman Boulevard 
Madison, Wisconsin 53704 
USA 
Metabolite Profiling and 
Identification 
Covance Laboratories 
3301 Kinsman Boulevard 
Madison, Wisconsin 53704 
USA 
Radiation Safety Officer 
Robert G. Kochan, PhD 
Covance Inc. 
Clinical Nuclear Pharmacist  
Brett Pick, PharmD, RPh, BCNP 
Covance Inc. 
Statistician 
Izabela Antys, MSc 
Covance Biometrics 
Pharmacokineticist 
Sarah Korb, BS 
Covance Inc. 
Medical Writer 
Carwyn Edwards PhD 
Covance Inc. 
Page 7 of 46

Protocol 
CONFIDENTIAL 
Covance Study: 8375685 
Protocol Reference: W-5107-103 
Final, 13 November 2017 
Page 7 of 45 
SYNOPSIS 
Title of study: A Phase I, Open-label Study of the Metabolism and Excretion of [14C]-Zidebactam 
(WCK 5107) Following a Single Intravenous Infusion in Healthy Male Subjects. 
Objectives: 
The primary objectives of the study are: 
• 
To determine mass balance and routes of elimination of [14C]- zidebactam following 
administration of a single 1g (approximately 200 µCi) radiolabeled intravenous (IV) 
infusion of zidebactam in healthy male subjects 
• 
To assess the pharmacokinetics (PK) of a single IV infusion of zidebactam using 
[14C]-labeled zidebactam 
• 
To determine the whole blood and plasma concentrations of total radioactivity following a 
single IV infusion of [14C]-zidebactam 
• 
To determine the urinary and fecal recovery of the total administered radioactive dose 
The secondary objectives of the study are: 
• 
To characterize and identify metabolites of [14C]-zidebactam in plasma, urine, and 
feces, as applicable 
• 
To determine plasma and urine concentrations of non-radiolabeled zidebactam 
• 
To assess the safety and tolerability of zidebactam 
 
Study design: 
This will be an open-label, nonrandomized, metabolism and excretion study of [14C]-zidebactam 
administered as a 1g (approximately 200 µCi) IV infusion over 1 hour, administered in a fasted 
state. Subjects will be admitted into the Clinical Research Unit (CRU) on Day -1 and be confined to 
the CRU until discharged. 
Potential subjects will be screened to assess their eligibility to enter the study within 28 days prior 
to Check-in (Day -1). Subjects will be considered enrolled in the study after they have signed the 
informed consent form. 
Subjects will be discharged from the CRU starting on Day 5 if ≥90% of the radioactive dose is 
recovered AND ≤1% of the radioactive dose is recovered in urine and feces (combined) for 2 
consecutive 24 hour collection intervals. Subjects that do not meet discharge criteria will continue 
to stay in the CRU until either they have met discharge criteria or until the maximum stay is 
reached on Day 7. 
Number of subjects: 
Up to 8 subjects will be enrolled and studied as a single group in order that 6 complete the study. 
Diagnosis and main criteria for inclusion: 
Healthy male subjects aged 18 to 55 years, inclusive, with a body mass index 
between 18.5 and 29.9 kg/m2, inclusive, at Screening. 
Investigational products, dose, and mode of administration: 
Subjects will receive an IV infusion of 1g [14C]- zidebactam (200 µCi) over a period of 1 hour. 
Duration of subject participation in the study: 
Planned Screening Duration: 28 days 
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Protocol Reference: W-5107-103 
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Length of Confinement: Check-in on Day -1, discharge as early as Day 5 and/or as late as Day 7. 
Follow-up phone call: 4 ± 2 days post discharge. 
Planned Study Duration: approximately 10 to 14 days. 
Total duration (including Screening): Approximately 42 days maximum. 
 
Endpoints: 
Pharmacokinetics: 
Blood, urine and feces will be collected at specified timepoints or intervals starting on Day -1 
through discharge from the CRU. The following PK parameters will be calculated using 
noncompartmental methods, based upon the plasma concentration of zidebactam and 14C total 
radioactivity in plasma and whole blood: area under the concentration-time curve (AUC) from time 
zero extrapolated to infinity (AUC0-∞), AUC from time zero to the last quantifiable concentration 
maximum observed concentration (Cmax), time of Cmax, apparent terminal elimination half-life (t1/2), 
total systemic clearance (zidebactam only), volume of distribution during the terminal elimination 
phase (zidebactam only), volume of distribution at steady state (zidebactam only), AUC of plasma 
zidebactam relative to AUC of plasma total radioactivity, AUC of whole blood total radioactivity to 
AUC of plasma total radioactivity . 
The following PK parameters will be calculated based on zidebactam concentration and total 
radioactivity in urine: amount excreted in urine (Aeu), cumulative Aeu, percentage excreted in urine 
(feu), cumulative feu, renal clearance (zidebactam only). 
The following PK parameters will be calculated based on total radioactivity in feces: amount 
excreted in feces (Aef), cumulative Aef, percentage excreted in feces (fef), and cumulative fef. 
Other PK parameters may be included. 
Safety: 
Safety variables include clinical laboratory evaluations, electrocardiograms, physical examinations, 
vital signs, and adverse event (AE) assessments. 
Statistical methods: 
Pharmacokinetic parameters will be summarized using descriptive methodology, and AEs will be 
listed and summarized using descriptive methodology. No formal statistical analysis will be 
performed. 
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Protocol 
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Covance Study: 8375685 
Protocol Reference: W-5107-103 
Final, 13 November 2017 
Page 9 of 45 
TABLE OF CONTENTS 
TITLE PAGE .............................................................................................................................1 
SPONSOR APPROVAL ...........................................................................................................2 
SPONSOR APPROVAL ...........................................................................................................3 
INVESTIGATOR AGREEMENT.............................................................................................4 
STUDY IDENTIFICATION .....................................................................................................5 
SYNOPSIS .................................................................................................................................7 
TABLE OF CONTENTS ...........................................................................................................9 
LIST OF TABLES AND FIGURES........................................................................................12 
LIST OF ABBREVIATIONS ..................................................................................................13 
1. 
INTRODUCTION ...........................................................................................................15 
1.1. 
Overview ................................................................................................................15 
1.2. 
Summary of Nonclinical Pharmacokinetics ...........................................................15 
1.3. 
Summary of Clinical Experience ...........................................................................15 
1.3.1. 
Safety ...........................................................................................................16 
1.3.2. 
Pharmacokinetics .........................................................................................16 
1.4. 
Study Rationale ......................................................................................................17 
1.5. 
Benefit-risk Assessment .........................................................................................17 
2. 
OBJECTIVES AND ENDPOINTS .................................................................................18 
2.1. 
Objectives ..............................................................................................................18 
2.1.1. 
Primary Objectives .......................................................................................18 
2.1.2. 
Secondary Objectives ...................................................................................18 
2.2. 
Endpoints ...............................................................................................................18 
2.2.1. 
Primary Endpoints .......................................................................................18 
2.2.2. 
Secondary Endpoints ...................................................................................19 
3. 
INVESTIGATIONAL PLAN ..........................................................................................20 
3.1. 
Overall Study Design and Plan ..............................................................................20 
3.2. 
Discussion of Study Design ...................................................................................21 
3.3. 
Selection of Doses in the Study .............................................................................21 
4. 
SELECTION OF STUDY POPULATION .....................................................................21 
4.1. 
Inclusion Criteria ...................................................................................................21 
4.2. 
Exclusion Criteria ..................................................................................................22 
4.3. 
Subject Number and Identification ........................................................................23 
4.4. 
Subject Withdrawal and Replacement ...................................................................24 
4.5. 
Study Termination .................................................................................................24 
5. 
STUDY TREATMENTS .................................................................................................25 
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5.1. 
Description, Storage, Packaging, and Labeling .....................................................25 
5.2. 
Study Treatment Administration ............................................................................25 
5.3. 
Randomization .......................................................................................................25 
5.4. 
Blinding..................................................................................................................25 
5.5. 
Treatment Compliance ...........................................................................................26 
5.6. 
Drug Accountability...............................................................................................26 
6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ................................26 
6.1. 
Concomitant Therapies ..........................................................................................26 
6.2. 
Diet .........................................................................................................................26 
6.3. 
Smoking .................................................................................................................27 
6.4. 
Exercise ..................................................................................................................27 
6.5. 
Blood Donation ......................................................................................................27 
6.6. 
Contraception .........................................................................................................27 
7. 
STUDY ASSESSMENTS AND PROCEDURES ...........................................................28 
7.1. 
Pharmacokinetic Assessments ...............................................................................28 
7.1.1. 
Pharmacokinetic, Total Radioactivity, and Metabolite Blood Sample 
Collection and Processing ............................................................................28 
7.1.2. 
Pharmacokinetic, Total Radioactivity, and Metabolite Urine, and Feces 
Collection and Processing ............................................................................28 
7.1.3. 
Analytical Methodology ..............................................................................29 
7.2. 
Safety and Tolerability Assessments .....................................................................29 
7.2.1. 
Adverse Events ............................................................................................29 
7.2.2. 
Clinical Laboratory Evaluations ..................................................................29 
7.2.3. 
Vital Signs ....................................................................................................30 
7.2.4. 
12-Lead Electrocardiogram .........................................................................30 
7.2.5. 
Physical Examination...................................................................................30 
8. 
SAMPLE SIZE AND DATA ANALYSIS ......................................................................31 
8.1. 
Determination of Sample Size ...............................................................................31 
8.2. 
Analysis Populations ..............................................................................................31 
8.2.1. 
Pharmacokinetic Population ........................................................................31 
8.2.2. 
Safety Population .........................................................................................31 
8.3. 
Pharmacokinetic Analyses .....................................................................................31 
8.4. 
Safety Analysis ......................................................................................................31 
8.5. 
Interim Analysis .....................................................................................................31 
9. 
REFERENCES ................................................................................................................31 
10. APPENDICES .................................................................................................................33 
Appendix 1: Adverse Event Reporting ..............................................................................34 
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Appendix 2: Clinical Laboratory Evaluations ...................................................................37 
Appendix 3: Total Blood Volume ......................................................................................38 
Appendix 4: Regulatory, Ethical, and Study Oversight Considerations ............................39 
Appendix 5: Schedule of Assessments ..............................................................................43 
 
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Protocol 
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LIST OF TABLES AND FIGURES 
Table 1: 
Schedule of Assessments ...........................................................................44 
Figure 1: 
Study Schematic.........................................................................................20 
 
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Protocol 
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Protocol Reference: W-5107-103 
Final, 13 November 2017 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
Aef 
amount excreted in feces 
Aeu 
amount excreted in urine 
ALARA 
as low as (is) reasonably achievable 
API 
active pharmaceutical ingredient 
AUC 
area under the concentration-time curve 
AUC0-∞ 
area under the concentration-time curve from time zero to infinity 
AUC0-t 
area under the concentration-time curve from time zero to the last 
quantifiable concentration 
CFR 
Code of Federal Regulations 
CL 
total clearance 
CLR 
renal clearance 
Cmax 
maximum observed concentration 
CRO 
Contract Research Organization 
CRU 
Clinical Research Unit 
CSA 
clinical study agreement 
EDC 
electronic data capture 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
FDA 
Food and Drug Administration 
fef 
percentage excreted in feces 
feu 
percentage excreted in urine 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HDYF? 
How Do You Feel? 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for/Conference on Harmonisation 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
IV 
intravenous 
MAD 
multiple-ascending dose 
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Protocol 
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NCE 
new chemical entity 
PK 
pharmacokinetic(s) 
RBC 
red blood cell 
SAD 
single-ascending dose 
SAE 
serious adverse event 
t1/2 
apparent terminal elimination half-life 
TEAE 
Treatment-Emergent Adverse Event 
tmax 
time of maximum observed concentration 
WBC 
white blood cell 
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Protocol 
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1. INTRODUCTION 
1.1. 
Overview 
Zidebactam (WCK 5107) is a New Chemical Entity (NCE) exhibiting a dual mechanism of 
action as a β-lactamase inhibitor and an enhancer specifically binding to Gram-negative 
penicillin binding protein 2. A combination of cefepime, a 4th generation cephalosporin β-
lactam, and zidebactam (WCK 5222) is being developed as an intravenous (IV) injectable 
formulation for the treatment of Gram-negative bacterial infections. WCK 5222 has been shown 
to be active against a variety of bacteria representing a diversity of resistance mechanisms. In 
view of the complementary properties of cefepime and zidebactam, a cefepime-zidebactam 
combination is expected to provide highly synergistic composition for treating infections caused 
by a wide variety of bacteria, including those producing one or more β-lactamases. 
This study is an evaluation of the metabolism and excretion of zidebactam in healthy human 
subjects following a single dose of 1 g (approximately 200 µCi) of [14C]-zidebactam 
administered as an IV infusion. As coadministration with cefepime has been demonstrated to 
have no effect on the pharmacokinetics (PK) of zidebactam (Section 1.3.2), cefepime will not be 
administered in this study. 
Refer to the Investigator’s Brochure (IB)1 for more detailed information on the background of 
zidebactam and cefepime-zidebactam. 
1.2. 
Summary of Nonclinical Pharmacokinetics 
Preclinical pharmacokinetic and safety studies have been conducted in mice, rats, and dogs using 
single and multiple doses. Zidebactam exposure was dose-proportional, either alone, or in 
combination with cefepime, following subcutaneous administration in rodents and IV 
administration in dogs. Zidebactam was rapidly eliminated in all 3 species, with a maximum 
apparent terminal elimination half-life (t1/2 ) of 2.1 h (standard deviation ±0.5 h) observed 
following a single IV dose of 10 mg/kg in dog. 
Zidebactam was primarily excreted as unchanged drug in urine, in all 3 species, with 2 trace 
urinary metabolites detected in dogs and one trace urinary metabolite in rodents. No zidebactam 
or metabolites were detected in fecal samples from any of the 3 species, suggesting that 
zidebactam is cleared by urinary excretion alone. The pharmacokinetic and safety profile of 
cefepime is well established as the drug has been licensed since 1996; however no 
pharmacokinetic interactions between zidebactam and cefepime were observed in the 3 animal 
species studied following single or multiple dose administration of the cefepime-zidebactam 
combination. 
1.3. 
Summary of Clinical Experience 
Cefepime-zidebactam or zidebactam alone have been administered to a total of 107 healthy adult 
human subjects in 3 completed Phase I studies, including a single-ascending dose (SAD) study 
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(74 subjects) and 2 multiple-ascending dose (MAD) studies (33 subjects). In the SAD study, 
zidebactam alone was administered as single doses ranging from 250 mg to 3000 mg to healthy 
adult subjects in the US. Subjects in 2 crossover cohorts (2 dose levels of zidebactam) received 
cefepime and zidebactam both alone and in combination. Two Phase I studies in healthy 
subjects, and 1 in subjects with normal or impaired renal function, have been conducted and not 
yet reported. The studies in healthy subjects aimed to assess the effect of a single 
supratherapeutic IV dose of 2 g cefepime and 4 g zidebactam on QT/corrected QT interval and to 
assess and compare the plasma, epithelial lining fluid and alveolar macrophage concentrations 
following a seven combined IV doses of 2 g cefepime and 1 g zidebactam. The open-label 
Phase I study in subjects with normal or impaired renal function administered a single IV dose of 
cefepime-zidebactam. 
1.3.1. 
Safety 
No deaths, serious adverse events (SAEs), or discontinuations due to adverse events (AEs) were 
reported in the conducted SAD study. Across the study and all cohorts, 22 (29.7%) subjects 
reported 42 treatment-emergent adverse events (TEAEs), the majority of which were mild in 
severity; only 2 subjects had TEAEs of moderate severity (both headache). Three subjects 
(37.5%) administered 1 g zidebactam as a 1 hour infusion reported 6 TEAEs, of which 1 was 
considered drug related (headache). No subject had a severe TEAE. Headache was the most 
commonly reported TEAE (10.8% subjects across all cohorts). 
No deaths or SAEs were reported in either MAD study and all TEAEs were mild in severity. In 
the zidebactam MAD study, the most frequently reported TEAEs were infusion site swelling 
(4 subjects), infusion site erythema (4 subjects), and headache (4 subjects). In the cefepime-
zidebactam MAD study, the most frequently reported TEAEs were headache (6 subjects), 
infusion site pain (5 subjects), and infusion site swelling (3 subjects). Discontinuations due to 
AEs were reported for 4 subjects in the cefepime-zidebactam MAD study due to drug eruption, 
diarrhea, abdominal pain, and Clostridium difficile colitis. 
No deaths or SAEs were noted in the completed, unreported studies, and no AEs leading to 
discontinuation were noted in the QT or renal impairment studies. No effect on QT was noted 
following administration of cefepime-zidebactam. Refer to the IB1 for more detailed information 
regarding safety and tolerability of zidebactam. 
1.3.2. 
Pharmacokinetics 
Following single-ascending IV infusion doses of zidebactam from 250 mg to 3000 mg, the area 
under the concentration-time curve from time zero to infinity (AUC0-∞) ranged from 44.3 to 458 
µg•h/mL and maximum concentration (Cmax) from 16.5 to 174 µg/mL; the AUC and Cmax 
increased in a dose-proportional manner. The t½ ranged from 1.84 to 2.39 h and appeared to be 
independent of dose. Median time to Cmax (tmax) was 1.00 and 3.00 h in the 60-minute and 180-
minute infusion cohorts, respectively. For the crossover cohorts, AUC0-∞ , Cmax, t½, and related 
PK parameters were consistent for both cefepime and zidebactam. The ratio of Cmax and ratio of 
AUC for each drug given in combination divided by each drug administered alone were close to 
unity (range 0.88 to 0.99), indicating no relevant PK interaction between the 2 drugs at the 
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evaluated dose combinations. Renal clearance accounted for the majority of plasma clearance, 
which appeared to be independent of dosage regimen (for zidebactam the 2 crossover cohorts) 
and treatment sequence (when each drug was given alone versus in combination). The majority 
(>80%) of the administered dose of zidebactam and cefepime was excreted as unchanged drug 
within the first (0 to 6 hour) collection interval, with complete dose recovery within 24 hours 
postdose. 
In the MAD studies, sequential cohorts received multiple IV infusions of either zidebactam alone 
(1 g or 2 g every 8 hours) for 7 days or the cefepime-zidebactam combination (2 g cefepime and 
1 g zidebactam, or 2 g cefepime, and 2 g zidebactam, every 8 hours) for 10 days. Exposure 
parameters for zidebactam (AUC0-∞ , Cmax) were comparable for each dosing interval within each 
dosing day and between dosing days. In the zidebactam alone MAD study, AUC0-∞ ranged from 
150 to 343 µg•h/ml and Cmax from 59.5 to 129 µg/ml. In the cefepime-zidebactam MAD study, 
AUC0-∞ for zidebactam ranged from 152 to 402 µg•h/ml and Cmax from 57.2 to 130 µg/ml, 
whereas cefepime AUC0-∞ ranged from 341 to 508 µg•h/ml and Cmax from 130 to 160 µg/ml. The 
majority of the administered doses of zidebactam and cefepime were excreted unchanged in 
urine. 
1.4. 
Study Rationale 
Knowledge of the metabolism and excretion of parent drug and its metabolites is useful for 
evaluating the Metabolites in Safety Testing requirements elucidated in the FDA Guidance2 and 
International Conference on Harmonisation M33 and the likelihood of effects of renal or hepatic 
impairment on the disposition of zidebactam and the likelihood for drug-drug interactions with 
zidebactam. The results from this study may guide future study designs using special populations 
or evaluating the potential for drug-drug interactions. 
The purpose of this study is to determine the excretion kinetics of zidebactam and to identify and 
characterize metabolites present in plasma, urine, and feces in healthy male subjects following a 
single dose of 1 g (approximately 200 µCi) of [14C]-zidebactam administered as an IV infusion. 
Data from this study may be used to guide the design of future studies conducted in special 
populations or to address potential drug-drug interactions. 
1.5. 
Benefit-risk Assessment 
Healthy subjects in the current study will not receive any health benefit (beyond that of an 
assessment of their medical status) from participating in the study. The risks of participation are 
primarily those associated with adverse reactions to the study treatments, although there may 
also be some discomfort from collection of blood samples and other study procedures. The 
radioactive dose is an acceptable dose to give to healthy male subjects (Section 3.3). More 
information about the known and expected benefits, risks, and reasonably anticipated AEs 
associated with zidebactam may be found in the IB.1 
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2. OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
2.1.1. 
Primary Objectives 
The primary objectives of the study are: 
• To determine mass balance and routes of elimination of [14C]- zidebactam following 
administration of a single 1g (approximately 200 µCi) radiolabeled IV infusion of 
zidebactam in healthy male subjects 
• To assess the PK of a single IV infusion of zidebactam using [14C]-labeled zidebactam 
• To determine the whole blood and plasma concentrations of total radioactivity following 
a single IV infusion of [14C]- zidebactam 
• To determine the urinary and fecal recovery of the total administered radioactive dose. 
2.1.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• To characterize and identify metabolites of [14C]-zidebactam in plasma, urine, and 
feces, as applicable 
• To determine plasma and urine concentrations of non-radiolabeled zidebactam 
• To assess the safety and tolerability of zidebactam. 
2.2. 
Endpoints 
2.2.1. 
Primary Endpoints 
The primary PK endpoints of zidebactam and total radioactivity derived from the whole blood 
and plasma concentration-time profiles following IV administration of [14C]- zidebactam are as 
follows: 
• area under the concentration-time curve (AUC) from time zero extrapolated to infinity 
(AUC0-∞) 
• AUC from time zero to the last quantifiable concentration (AUC0-t) 
• maximum observed concentration (Cmax) 
• time of Cmax (tmax) 
• apparent terminal elimination half-life (t1/2) 
• total systemic clearance (zidebactam only; CL) 
• volume of distribution during the terminal elimination phase (zidebactam only; Vz) 
• volume of distribution at steady state (zidebactam only; Vss) 
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• AUC of plasma zidebactam relative to AUC of plasma total radioactivity (AUC Plasma 
zidebactam/ Total Radioactivity Ratio) 
• AUC of whole blood total radioactivity to AUC of plasma total radioactivity (AUC 
Blood/Plasma Ratio). 
The primary PK outcome endpoints of zidebactam and total radioactivity derived from urine 
collections are as follows: 
• amount excreted in urine (Aeu) 
• cumulative Aeu 
• percentage excreted in urine (feu) 
• cumulative feu 
• renal clearance (zidebactam only; CLR). 
The primary PK outcome endpoints of total radioactivity derived from feces collections are as 
follows: 
• amount excreted in feces (Aef) 
• cumulative Aef 
• percentage excreted in feces (fef) 
• cumulative fef. 
Other PK parameters may also be added. 
2.2.2. 
Secondary Endpoints 
The secondary metabolite endpoints are as follows: 
• metabolic profile of [14C]-zidebactam 
• identification of [14C]-zidebactam metabolites. 
The secondary safety outcome measures for this study are as follows: 
• incidence and severity of AEs 
• incidence of laboratory abnormalities, based on hematology, clinical chemistry, 
coagulation, and urinalysis test results 
• 12-lead electrocardiogram (ECG) parameters 
• vital signs measurements 
• physical examinations. 
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3. INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
This will be an open-label, nonrandomized, metabolism and excretion study of [14C]-zidebactam 
administered as a 1g (approximately 200 µCi) IV infusion over 1 hour in up to 8 healthy male 
subjects following at least an 8-hour fast from food (not including water). 
An overview of the study design is shown in Figure 1. 
Figure 1: 
Study Schematic 
 
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to Check-in (Day 1). Subjects will be admitted into the Clinical Research Unit (CRU) on 
Day -1 and be confined to the CRU until Clinic Discharge. Up to 8 subjects will be dosed on 
Day 1 to ensure that 6 subjects complete the study. Subjects will be discharged from the CRU 
starting on Day 5 if ≥90% of the radioactive dose is recovered AND ≤1% of the radioactive dose 
is recovered in urine and feces (combined) for 2 consecutive 24 hour collection intervals. 
Subjects that do not meet discharge criteria will continue to stay in the CRU until either they 
have met discharge criteria or until the maximum stay is reached on Day 7. 
Blood, urine, and fecal samples will be collected at specified times during the study for PK, 
metabolite profiling, and radioanalysis. Safety will be evaluated using the following assessments: 
physical examinations, 12-lead ECGs, vital signs, How Do You Feel? (HDYF?) inquiries, and 
clinical laboratory evaluations (Appendix 2). All AEs will be recorded throughout the study (ie, 
from the time of signing the informed consent until completion of the Follow-up phone call). 
The total duration of study participation for each subject (from Screening through Follow-up 
phone call) is anticipated to be a maximum of approximately 42 days. 
The start of the study is defined as the date the first enrolled subject signs an informed consent 
form (ICF). The point of enrollment occurs at the time of subject number allocation. The end of 
the study is defined as the date of the last subject’s last assessment (scheduled or unscheduled). 
A Schedule of Assessments is presented in Appendix 5. 
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3.2. 
Discussion of Study Design 
This study will be open-label because the primary endpoints of the study are considered 
objective. Conducting the study in healthy subjects mitigates the potential confounding effects of 
the disease state and concomitant medications. 
Female subjects will be excluded to align with regulatory guidance. The “as low as (is) 
reasonably achievable” (ALARA) principle prescribed by both the FDA and Nuclear Regulatory 
Commission (2007)2 recommends that radiation exposure to subjects should be kept ALARA; 
therefore, if no specific reason exists to include females (ie, no available data suggest 
metabolism of the study drug is different in females versus males), then the radiation exposure to 
female subjects should be kept at zero potential by not including females in radioactivity studies 
and only enrolling and dosing male subjects. 
IV administration was chosen since this is the intended clinical route of administration. Based on 
the nonclinical data and the known plasma PK and excretion pattern of zidebactam, the sample 
collection timing, and duration of this study are considered adequate to achieve the study 
objectives. 
3.3. 
Selection of Doses in the Study 
The chosen single 1 g IV dose of zidebactam provides pharmacokinetically- and 
pharmacodynamically relevant concentrations in healthy subjects. Safety data from previous 
Phase 1 studies has demonstrated that single IV doses of 1 g have been well tolerated in healthy 
subjects. 
The planned radioactive dose of approximately 200 μCi of [14C]-zidebactam is expected to 
provide a sufficient radioactive signal to achieve the study objectives with minimal radiation risk 
to subjects. Based upon whole-body dosimetry studies conducted in rat, the maximum whole-
body radiation dose expected in a human male subject following administration of a single 
200 μCi (7.4 MBq) IV dose of [14C]-zidebactam was estimated (by conversion of dosimetry 
report, which was based on a 100 μCi dose) to be 3.8 mrem (0.038 mSv).4 This value is well 
below the FDA exposure limit of 3000 mrem after a single dose for human isotope studies. 
4. SELECTION OF STUDY POPULATION 
4.1. 
Inclusion Criteria 
Subjects must satisfy all of the following criteria unless otherwise stated: 
1. Males, of any race, between 18 and 55 years of age, inclusive. 
2. Body mass index between 18.5 and 29.9 kg/m2, inclusive at Screening and Check-in 
(Day -1). 
3. In good health, determined by no clinically significant findings from medical history, 
physical examination (at Check-in [Day -1]), 12-lead ECG, vital signs measurements, and 
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clinical laboratory evaluations (congenital nonhemolytic hyperbilirubinemia [eg, 
Gilbert’s syndrome] is not acceptable) at Screening or Check-in as assessed by the 
Investigator (or designee). 
4. Blood pressure between 90 and 140 mmHg systolic, inclusive, and not higher than 90 
mmHg diastolic, unless deemed not clinically significant by the Investigator (or 
designee). 
5. Subjects will agree to use contraception as detailed in Section 6.6. 
6. Able to comprehend and willing to sign an ICF and to abide by the study restrictions. 
7. History of a minimum of 1 bowel movement per day. 
4.2. 
Exclusion Criteria 
Subjects will be excluded from the study if they satisfy any of the following criteria at the 
Screening visit unless otherwise stated: 
1. Significant history or clinical manifestation of any metabolic, allergic, dermatological, 
hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, neurological, 
respiratory, endocrine, or psychiatric disorder, as determined by the Investigator (or 
designee). 
2. History of significant hypersensitivity, intolerance, or allergy to any drug compound, 
food, or other substance, unless approved by the Investigator (or designee). 
3. History of alcoholism or drug/chemical abuse within 1 year prior to Check-in (Day -1). 
4. Alcohol consumption of >28 units per week for males. One unit of alcohol equals 12 oz. 
(360 mL) of beer, 1½ oz. (45 mL) of liquor, or 5 oz. (150 mL) of wine. 
5. Positive urine drug screen at Screening, or positive alcohol breath test or positive urine 
drug screen at Check-in. 
6. Positive hepatitis panel and/or positive human immunodeficiency virus test (Appendix 2). 
Subjects whose results are compatible with prior immunization may be included at the 
discretion of the Investigator. 
7. Participation in a clinical study involving administration of an investigational drug (NCE) 
in the past 30 days or within 5 half-lives (if known), whichever is longer, prior to Check-
in. 
8. Use or intend to use any medications/products known to alter drug absorption, 
metabolism, or elimination processes, including St. John’s Wort, within 14 days prior to 
Check-in, unless deemed acceptable by the Investigator (or designee). 
9. Use or intend to use any prescription medications/products within 14 days prior to 
Check-in, unless deemed acceptable by the Investigator (or designee). 
10. Use or intend to use slow-release medications/products considered to still be active 
within 14 days prior to Check-in, unless deemed acceptable by the Investigator (or 
designee). 
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11. Use or intend to use any nonprescription medications/products including vitamins, 
minerals, and phytotherapeutic/herbal/plant-derived preparations within 7 days prior to 
Check-in, unless deemed acceptable by the Investigator (or designee). 
12. Consumption of foods and beverages containing poppy seeds, grapefruit, or Seville 
oranges from 7 days prior to Check-in and for the duration of the study. 
13. Use of tobacco- or nicotine-containing products within 3 months prior to Check-in, as 
determined by medical history and cotinine test. 
14. Unwilling to refrain from strenuous exercise from 48 hours prior to Check-in (Day -1) 
and for the duration of the study. 
15. Unwilling to refrain from consumption of caffeine- or xanthine-containing products for 
48 hours prior to Check-in (Day -1) and for the duration of the study. 
16. Consumption of alcohol 48 hours prior to Check-in (Day -1) and for the duration of the 
study. 
17. Receipt of blood products within 2 months prior to Check-in. 
18. Donation of blood from 56 days prior to Screening, plasma from 2 weeks prior to 
Screening, or platelets from 6 weeks prior to Screening until after the Follow-up phone 
call. 
19. Poor peripheral venous access. 
20. Have previously completed or withdrawn from this study or any other study investigating 
zidebactam, and have previously received the investigational product. 
21. Subjects with exposure to significant diagnostic or therapeutic radiation (eg, serial X-ray, 
computed tomography scan, barium meal) or current employment in a job requiring 
radiation exposure monitoring within 12 months prior to Check-in. 
22. Subjects who have participated in a radiolabeled drug study where exposures are known 
to the Investigator within the previous 4 months prior to admission to the clinic for this 
study or participated in a radiolabeled drug study where exposures are not known to the 
Investigator within the previous 6 months prior to admission to the clinic for this study. 
The total 12-month exposure from this study and a maximum of 2 other previous 
radiolabeled studies within 4 to 12 months prior to this study will be within the Code of 
Federal Regulations (CFR) recommended levels considered safe, per US Title 21 CFR 
361.1: less than 5,000 mrem whole-body annual exposure with consideration given to the 
half-lives of the previous radiolabeled study drugs received. 
23. Subjects who, in the opinion of the Investigator (or designee), should not participate in 
this study. 
4.3. 
Subject Number and Identification 
Subjects will have a unique identification number used at Screening. Subjects will be assigned a 
subject number prior to dosing. Assignment of subject numbers will be in ascending order and no 
numbers will be omitted (eg, Subjects 101, 102, 103). 
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Subjects will be identified by either their Screening number or subject number only on all study 
documentation. A list identifying the subjects by subject number will be kept in the Site Master 
File. 
4.4. 
Subject Withdrawal and Replacement 
A subject is free to withdraw from the study at any time. In addition, a subject will be withdrawn 
if any of the following criteria are met: 
• change in compliance with any inclusion/exclusion criterion that is clinically relevant and 
affects subject safety as determined by the Investigator (or designee) 
• noncompliance with the study restrictions that might affect subject safety or study 
assessments/objectives, as considered applicable by the Investigator (or designee) 
• any clinically relevant sign or symptom that, in the opinion of the Investigator (or 
designee), warrants subject withdrawal. 
If a subject is withdrawn from the study, the Sponsor will be notified and the date and reason(s) 
for the withdrawal will be documented in the subject’s electronic Case Report Form (eCRF). If a 
subject is withdrawn, efforts will be made to perform all discharge assessments, if possible 
(Appendix 5). Other safety procedures may be performed at the Investigator’s (or designee’s) 
and/or Sponsor’s discretion .If the subject is in-house, these procedures should be performed 
before the subject is discharged from the clinic. The Investigator (or designee) may also request 
that the subject return for an additional Follow-up visit. All withdrawn subjects will be followed 
until resolution of all their AEs or until the unresolved AEs are judged by the Investigator (or 
designee) to have stabilized. 
The replacement of subjects withdrawn from the study will be discussed between the 
Investigator and Sponsor. 
4.5. 
Study Termination 
The study may be discontinued at the discretion of the Investigator (or designee), Sponsor, or 
Sponsor’s Medical Monitor if any of the following criteria are met: 
• AEs unknown to date (ie, not previously reported in any similar investigational study 
drug trial with respect to their nature, severity, and/or duration) 
• increased frequency, severity, and/or duration of known, anticipated, or previously 
reported AEs (this may also apply to AEs defined at Check-in as baseline signs and 
symptoms) 
• medical or ethical reasons affecting the continued performance of the study 
• difficulties in the recruitment of subjects 
• cancellation of drug development. 
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5. STUDY TREATMENTS 
5.1. 
Description, Storage, Packaging, and Labeling 
Active pharmaceutical ingredient (API; nonradiolabeled powder) will be supplied by the Sponsor 
and radiolabeled API (powder) will be supplied by Arcinova, along with the batch/lot numbers 
and Certificates of Analysis. A Covance CRU licensed pharmacist will manufacture and label the 
investigational medical product (IMP) from bulk supplies, such that each unit dose contains a 
total of 1 g zidebactam containing approximately 200 μCi of [14C]-zidebactam. The completed 
drug product will be released by GMP Quality Assurance under GMP conditions or by a second 
licensed pharmacist if under non-GMP conditions prior to administration to subjects. 
The Sponsor will supply a sufficient quantity of the applicable API for the manufacture of the 
unit doses at Covance CRU. All excipients will be sourced by Covance. Specific instructions 
regarding dose preparation will be mutually agreed upon between the Sponsor and the 
appropriate clinical staff and will be presented in a separate document. 
The API and IMP will be stored according to the instructions on the label at the CRU in a 
location that is locked with restricted access. 
5.2. 
Study Treatment Administration 
Appropriate unit doses will be administered to consecutively numbered subjects. Although the 
timing of events requires that each subject will be consistently administered the appropriate dose 
at specific times, the exact dose time of consecutive subjects may be staggered to obviate the 
need to have all subjects on precisely the same study schedule. For each dose, the subject’s 
actual dosing time will be recorded in the source documents and transcribed into the eCRFs. 
On Day 1, following at least an 8-hour fast from food (not including water), subjects will receive 
an IV infusion of [14C]-zidebactam over a period of 1 hour. Subjects will be asked to be semi-
supine/supine for the IV dosing. For each subject, the start, and end of infusion time, as well as 
any dosing interruptions, will be documented in the source data. 
Except when they are using the toilet, study subjects will be observed for approximately 4 hours 
postdose to ensure that they are not experiencing AEs, becoming nauseated, or experiencing 
emesis. 
5.3. 
Randomization 
This is a nonrandomized study. 
5.4. 
Blinding 
This is an open-label study. 
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5.5. 
Treatment Compliance 
All doses will be administered under the supervision of suitably qualified study site staff. 
5.6. 
Drug Accountability 
The Investigator (or designee) will maintain an accurate record of the receipt of the study 
supplies received. In addition, an accurate drug disposition record will be kept, specifying the 
amount dispensed to each subject and the date of dispensing. This drug accountability record will 
be available for inspection at any time. At the completion of the study, the original drug 
accountability record will be available for review by the Sponsor upon request. 
Any unused assembled unit doses will be retained until completion of the study. 
At the completion of the study, all unused supplies will be returned to the Sponsor or disposed of 
by the study site, per the Sponsor’s written instructions and/or in accordance with 
local/state/federal guidelines governing waste disposal of investigational drugs. 
6. CONCOMITANT THERAPIES AND OTHER RESTRICTIONS 
6.1. 
Concomitant Therapies 
Subjects will refrain from participation in a clinical study involving administration of an 
investigational drug (NCE) in the past 30 days, or 5 half-lives (if known), whichever is longer, 
prior to Check-in. 
Subjects will refrain from use of any prescription medications/products, or any 
medications/products known to alter drug absorption, metabolism or elimination processes from 
14 days prior to Check-in (Day -1) or any nonprescription medications/products including 
vitamins, minerals, and phytotherapeutic/herbal/plant-derived preparations within 7 days prior to 
Check-in, unless deemed acceptable by the Investigator (or designee). 
A mild laxative (ie, Milk of Magnesia®, Colace®) may be used to help with bowel movements if 
necessary and will not be considered a concomitant medication. Paracetamol/acetaminophen 
(2 g/day for up to 3 consecutive days) is an acceptable concomitant medication. The 
administration of any other concomitant medications during the study is prohibited, until the 
follow-up phone call, without prior approval of the Investigator (or designee), unless its use is 
deemed necessary in a medical emergency. Any medication taken by a subject during the course 
of the study and the reason for its use will be documented in the source data. 
6.2. 
Diet 
While confined at the study site, subjects will receive a standardized, high-fiber diet at scheduled 
times that do not conflict with other study-related activities. Prune juice may be administered on 
an as-needed basis to aid in normal bowel function and will not be considered a concomitant 
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medication. Subjects will be fasted overnight (at least 8 hours) before collection of blood 
samples for clinical laboratory evaluations. 
Foods and beverages containing poppy seeds, grapefruit, or Seville oranges will not be allowed 
from 7 days prior to Check-in (Day -1) and for the duration of the study. 
Caffeine- or xanthine-containing foods and beverages will not be allowed from 48 hours prior to 
Check-in (Day -1) and for the duration of the study. 
Consumption of alcohol will not be permitted from 48 hours prior to Check-in and for the 
duration of the study. 
6.3. 
Smoking 
Subjects will not be permitted to use tobacco- or nicotine-containing products within 3 months 
prior to Check-in (Day -1) and for the duration of the study. 
6.4. 
Exercise 
Subjects are required to refrain from strenuous exercise from 48 hours prior to Check-in (Day -1) 
and for the duration of the study. Subjects will otherwise maintain their normal level of physical 
activity during this time (ie, will not begin a new exercise program nor participate in any 
unusually strenuous physical exertion). 
6.5. 
Blood Donation 
Subjects are required to refrain from donation of blood from 56 days prior to Screening, plasma 
from 2 weeks prior to Screening, and platelets from 6 weeks prior to Screening until after the 
Follow-up phone call. 
6.6. 
Contraception 
Male subjects will be surgically sterile for at least 90 days or when sexually active with female 
partners of childbearing potential will be required to use a male condom with spermicide from 
Check-in until 90 days after the last dose of study drug. 
Sexual intercourse with female partners who are pregnant or breastfeeding should be avoided 
unless condoms are used from the time of the first dose until 90 days after the last dose of study 
drug. Male subjects are required to refrain from donation of sperm from Check-in until 90 days 
after the last dose of study drug. 
Subjects who practice true abstinence, because of the subject’s lifestyle choice (ie, the subject 
should not become abstinent just for the purpose of study participation), are exempt from 
contraceptive requirements. Periodic abstinence (eg, calendar ovulation, symptothermal, 
postovulation methods) and withdrawal are not acceptable methods of contraception. If a subject 
who is abstinent at the time of signing the ICF becomes sexually active they must agree to use 
contraception as described previously. 
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For subjects who are exclusively in same sex relationships, contraceptive requirements do not 
apply. If a subject who is in a same sex relationship at the time of signing the ICF becomes 
engaged in a heterosexual relationship, they must agree to use contraception as described 
previously. 
7. STUDY ASSESSMENTS AND PROCEDURES 
Every effort will be made to schedule and perform the procedures as closely as possible to the 
nominal time, giving considerations to appropriate posture conditions, practical restrictions, and 
the other procedures to be performed at the same timepoint. 
The order of priority for scheduling procedures around a timepoint is (in descending order of 
priority): 
• dosing 
• ECGs 
• blood samples for PK, total radioactivity, and metabolites 
• start and end of urine, collections for PK assessments 
• vital signs measurements 
• blood and urine samples for clinical laboratory evaluations 
• physical examinations 
7.1. 
Pharmacokinetic Assessments 
7.1.1. 
Pharmacokinetic, Total Radioactivity, and Metabolite Blood Sample Collection 
and Processing 
Blood samples will be collected by venipuncture or cannulation at the times indicated in the 
Schedule of Assessments in Appendix 5 for determination of zidebactam plasma concentrations, 
total radioactivity whole blood and plasma concentrations, and metabolite profiling, and 
identification. Blood samples will be collected from the contralateral arm to the arm/hand used 
for dose administration on Day 1. Procedures for collection, processing, and shipping of blood 
samples will be detailed in a separate document. 
7.1.2. 
Pharmacokinetic, Total Radioactivity, and Metabolite Urine, and Feces 
Collection and Processing 
Urine will be collected over the time intervals indicated in the Schedule of Assessments in  
Table 1 for determination of zidebactam concentration, total radioactivity, and metabolite 
profiling, and identification. Procedures for collection, processing, and shipping of urine 
collections will be detailed in a separate document. 
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Feces will be collected over the time intervals indicated in the Schedule of Assessments in 
Table 1 for determination of total radioactivity, and where possible, metabolite profiling, and 
identification. If possible, a single baseline fecal sample will be collected from after Check-in on 
Day -1 until just predose administration on Day 1. Procedures for collection, processing, and 
shipping of feces collections will be detailed in a separate document. 
7.1.3. 
Analytical Methodology 
Plasma and urine concentrations of zidebactam will be determined using a validated analytical 
procedure. 
Total radioactivity concentrations will be determined in whole blood, plasma, urine, and feces 
using liquid scintillation counting. Profiling and identification of metabolites in plasma, urine, 
and, where possible, feces will be conducted using standard laboratory procedures. 
Specifics of the analytical methods will be provided in separate documents. 
7.2. 
Safety and Tolerability Assessments 
7.2.1. 
Adverse Events 
Adverse event definitions, assignment of severity and causality, and procedures for reporting 
serious AEs are detailed in Appendix 1. 
The condition of each subject will be monitored from the time of signing the ICF to the follow 
up phone call. Subjects will be observed for any signs or symptoms and asked about their 
condition by open questioning, such as “How have you been feeling since you were last asked?”, 
at least once each day while resident at the study site and at each study visit and follow-up phone 
call. Subjects will also be encouraged to spontaneously report AEs occurring at any other time 
during the study. 
All nonserious AEs, whether reported by the subject voluntarily or upon questioning, or noted on 
physical examination, will be recorded from initiation of study drug until study completion. 
Nonserious AE information should also be collected from the start of a washout period or other 
observational period intended to establish a baseline status for the subjects. Serious AEs will be 
recorded from the time the subject signs the ICF until study completion. The nature, time of 
onset, duration, and severity will be documented, together with an Investigator’s (or designee’s) 
opinion of the relationship to study drug. 
Adverse events recorded during the course of the study will be followed up, where possible, until 
resolution. This will be completed at the Investigator’s (or designee’s) discretion. 
7.2.2. 
Clinical Laboratory Evaluations 
Blood and urine samples will be collected for clinical laboratory evaluations (including clinical 
chemistry, hematology, urinalysis, coagulation and serology) at the times indicated in the 
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Schedule of Assessments in Appendix 5. Clinical laboratory evaluations are listed in 
Appendix 2. 
Subjects will be fasted overnight (at least 8 hours) before collection of blood samples for clinical 
laboratory evaluations. 
Subjects will be asked to provide urine samples for drugs of abuse screen and cotinine test, and 
will undergo an alcohol breath test at the times indicated in the Schedule of Assessments in 
Appendix 5. 
An Investigator (or designee) will perform a clinical assessment of all clinical laboratory data. 
7.2.3. 
Vital Signs 
Supine blood pressure, supine pulse rate, respiratory rate, and oral body temperature will be 
assessed at the times indicated in the Schedule of Assessments in Appendix 5. Vital signs may 
also be performed at other times if judged to be clinically appropriate or if the ongoing review of 
the data suggests a more detailed assessment of vital signs is required. 
All measurements will be performed singly, and repeated once if outside the relevant clinical 
reference range. 
Subjects must be supine for at least 5 minutes before blood pressure and pulse rate 
measurements. 
7.2.4. 
12-Lead Electrocardiogram 
Resting 12-lead ECGs will be recorded after the subject has been supine and at rest for at least 
5 minutes at the times indicated in the Schedule of Assessments in Appendix 5. 
Single 12-lead ECGs may be repeated once if outside the clinical reference range at the request 
of the Investigator or designee. 
Additional 12-lead ECGs may be performed at other times if judged to be clinically appropriate 
or if the ongoing review of the data suggests a more detailed assessment of ECGs is required. 
The Investigator (or designee) will perform a clinical assessment of each 12-lead ECG. 
7.2.5. 
Physical Examination 
A full physical examination or abbreviated physical examinations will be performed at the 
timepoints specified in the Schedule of Assessments in Appendix 5. 
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8. SAMPLE SIZE AND DATA ANALYSIS 
8.1. 
Determination of Sample Size 
No formal statistical assessment of sample size has been conducted. The sample size chosen for 
this study is common in human radiolabeled studies and is considered sufficient to achieve the 
objectives of the study. Up to 8 subjects will be enrolled and studied as a single group in order 
that 6 complete the study. 
8.2. 
Analysis Populations 
8.2.1. 
Pharmacokinetic Population 
The PK population will include all subjects who received [14C]-zidebactam and have evaluable 
PK data. 
8.2.2. 
Safety Population 
The safety population will include all subjects who received [14C] -zidebactam and have at least 
1 postdose safety assessment. 
8.3. 
Pharmacokinetic Analyses 
The plasma and urine PK parameters of zidebactam and whole blood, plasma, urine, and fecal 
PK parameters of total radioactivity will be calculated using standard noncompartmental 
methods. Additional noncompartmental PK parameters may be determined where appropriate. 
Pharmacokinetic parameters will be summarized using descriptive methodology. No formal 
statistical analysis will be performed. 
8.4. 
Safety Analysis 
All AEs will be listed and summarized using descriptive methodology. No formal statistical 
analysis will be performed. The incidence of AEs will be presented by severity and by 
association with the study drug as determined by the Investigator (or designee). Each AE will be 
coded using the Medical Dictionary for Regulatory Activities. 
8.5. 
Interim Analysis 
No interim analyses are planned for this study. 
9. REFERENCES 
1. Wockhardt. Cefepime-Zidebactam – Investigator’s Brochure (Version 02). 18 August 2016. 
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2. US Department of Health and Human Services, Food and Drug Administration. Center for 
Drug Evaluation and Research (CDER); Guidance for Industry, Safety Testing of Drug 
Metabolites; Availability. Federal Register. 2008; 73 (31): 8884-8885. 
3. ICH Harmonised Tripartite Guideline M3: Guidance on Nonclinical Safety Studies for the 
Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals; July 
1997. Available at: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Multidisciplinary/
M3_R2/Step4/M3_R2__Guideline.pdf. 2009. 
4. Crossman, L; Murphy, B; Holdsworth, C; Potchioiba, MJ. Covance 8337156. 
[14C]-WCK 5107: Absorption, Distribution, Metabolism, and Excretion in the Rat. Covance 
Laboratories, Inc.; Madison, Wisconsin; 2016. 
 
 
 
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10. APPENDICES 
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Appendix 1: Adverse Event Reporting 
Definitions 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product, which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and/or unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
study drug, whether, or not related to the study drug. 
Assessment of Severity 
The Investigator will be asked to provide an assessment of the severity of the AE using the 
following categories: 
• Mild: Usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of daily living. 
• Moderate: Usually alleviated with additional specific therapeutic intervention. The event 
interferes with usual activities of daily living, causing discomfort but poses no significant 
or permanent risk of harm to the subject. 
• Severe: Interrupts usual activities of daily living, significantly affects clinical status, or 
may require intensive therapeutic intervention. 
Relationship to Study Treatment 
The Investigator will make a determination of the relationship of the AE to the study drug using 
a 2-category system according to the following guidelines: 
• Not Related: The AE is definitely caused by the subject’s clinical state or the study 
procedure/conditions, and/or has no reasonable temporal relationship with administration 
of the study drug 
• Related: The AE follows a reasonable temporal sequence from administration of the 
study drug, and does not have another apparent clinical cause 
Action Taken for Adverse Events 
The Investigator or designee will record the action taken for the AE in the eCRF. Actions taken 
will include: 
• Dose not changed: The medication schedule was not changed 
• Drug withdrawn: The medication schedule was modified through termination of the 
prescribed regimen of medication 
• Subject withdrawn from study 
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• Not applicable 
• Unknown 
Follow-up of Adverse Events 
Every reasonable effort will be made to follow-up with subjects who have AEs. Any subject who 
has an ongoing AE that is possibly related or related to the IMP or study procedures at Discharge 
will be followed up, where possible, until resolution. This will be completed at the Investigator’s 
(or designee’s) discretion. Any subject who has an ongoing AE that is not related or unlikely 
related to the IMP or study procedures at Discharge visit can be closed out as ongoing at the 
Investigator’s discretion. 
Adverse Drug Reactions 
All noxious and unintended responses to an IMP (ie, where a causal relationship between an IMP 
and an AE is at least a reasonable possibility) related to any dose should be considered adverse 
drug reactions. 
For marketed medicinal products, a response to a drug which is noxious and unintended and that 
occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of diseases, or for 
modification of physiological function is to be considered an adverse drug reaction. 
An unexpected adverse drug reaction is defined as an adverse reaction, the nature or severity of 
which is not consistent with the applicable product information (eg, IB for an unapproved IMP). 
Serious Adverse Events 
An SAE is defined as any untoward medical occurrence that at any dose either: 
• results in death 
• is life-threatening 
• requires inpatient hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability/incapacity (disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions) 
• results in a congenital anomaly/birth defect 
• results in an important medical event (see below). 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs 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. 
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Instances of death or congenital abnormality, if brought to the attention of the Investigator at any 
time after cessation of the study treatment and considered by the Investigator to be possibly 
related to the study treatment, will be reported to the Sponsor. 
Definition of Life-threatening 
An AE is life-threatening if the subject was at immediate risk of death from the event as it 
occurred (ie, does not include a reaction that might have caused death if it had occurred in a 
more serious form). For instance, drug-induced hepatitis that resolved without evidence of 
hepatic failure would not be considered life-threatening even though drug-induced hepatitis can 
be fatal. 
Definition of Hospitalization 
Adverse events requiring hospitalization should be considered serious. In general, hospitalization 
signifies that the subject has been detained (usually involving an overnight stay) at the hospital 
or emergency ward for observation and/or treatment that would not have been appropriate at the 
CRU. When in doubt as to whether hospitalization occurred or was necessary, the AE should be 
considered as serious. 
Hospitalization for elective surgery or routine clinical procedures, which are not the result of an 
AE, need not be considered AEs and should be recorded on a Clinical Assessment Form and 
added to the eCRF. If anything untoward is reported during the procedure, this must be reported 
as an AE and either ‘serious’ or ‘nonserious’ attributed according to the usual criteria. 
Serious Adverse Event Reporting 
Food and Drug Administration-reportable AEs are AEs that are associated with the use of the 
drug and are serious and unexpected. Food and Drug Administration-reportable AEs will be 
reported by the study site to the Sponsor, Medical Monitor assigned by the Sponsor, and the 
responsible Institutional Review Board (IRB). 
The Sponsor and Medical Monitor will be notified in writing (eg, facsimile) within 24 hours of 
when an AE that is potentially FDA-reportable is first recognized or reported. 
Subsequently, a written confirmation or summary of the AE (using FDA Form 3500A or 
equivalent) will be sent to the Sponsor within 3 working days of the original notification. 
The IRB will be notified of any FDA-reportable AEs within the timeframe required by the IRB. 
The IRB Serious and Unexpected Adverse Experience Submission Form will be completed and 
submitted with the copy of the written confirmation or summary of the AE. 
The responsibility for reporting SAEs will be transferred to the Sponsor 30 days after the end of 
the study. 
 
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Appendix 2: Clinical Laboratory Evaluations 
Clinical chemistry: 
Hematology: 
Urinalysis: 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Blood urea nitrogen 
Calcium 
Chloride 
Cholesterol 
Creatinine 
Gamma-glutamyl transferase 
Glucose 
Phosphorus 
Potassium 
Sodium 
Total bilirubina 
Total CO2 (measured as 
bicarbonate) 
Total protein 
Uric acid 
Hematocrit 
Hemoglobin 
Mean cell hemoglobin 
Mean cell hemoglobin 
concentration 
Mean cell volume 
Platelet count 
Red blood cell (RBC) count 
RBC distribution width 
White blood cell (WBC) count 
WBC differential: 
 Basophils 
 Eosinophils 
 Lymphocytes 
 Monocytes 
 Neutrophils 
Bilirubin 
Blood 
Color and appearance 
Glucose 
Ketones 
Leukocyte esterase 
Nitrite 
pH 
Protein 
Specific gravity 
Urobilinogen 
Microscopic examination (if 
protein, leukocyte esterase, nitrite, 
or blood is positive) 
 
Serologyb: 
Drug Screenc: 
Coagulation 
Anti-hepatitis B surface antibody 
Hepatitis C antibody 
Human immunodeficiency virus 
(HIV-1 and HIV-2) antibodies 
p24 antigen 
Including but not limited to: 
Amphetamines/methamphetamines 
Barbiturates 
Benzodiazepines 
Cocaine (metabolite) 
Cotinine 
Methadone 
Phencyclidine 
Opiates 
Tetrahydrocannabinol/ 
cannabinoids 
Alcohol breath testd 
International normalized ratio 
Prothrombin time 
a Direct bilirubin will be analyzed if total bilirubin is elevated 
b Only analyzed at Screening 
c Only analyzed at Screening and Check-in 
d Alcohol testing is not included at Screening 
 
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Appendix 3: Total Blood Volume 
The following blood volumes are the maximum that will be withdrawn for each subject. 
 
 
Up to Day 7a 
 
Volume per blood 
sample (mL) 
Maximum number 
of blood samples 
Total amount of 
blood (mL) 
Clinical laboratory evaluations 
10.7 
4 
42.8 
Serology 
4 
1 
4 
Plasma for zidebactam 
concentration 
4 
22 
88 
Whole blood and plasma for 
total radioactivity 
4 
22 
88 
Plasma for metabolite profiling 
and identification 
10 
10 
100 
Total: 
322.8 
a Subjects could be discharged on Day 5 if the discharge criteria are met or may be resident within the Clinical Research Unit for 
additional 24-hour collections (blood, urine, and feces) for total radioactivity up to Day 7. 
If extra blood samples are required, the maximum blood volume to be withdrawn per subject will 
not exceed the volume of a normal blood donation 
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Protocol 
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Appendix 4: Regulatory, Ethical, and Study Oversight Considerations 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
International Ethical Guidelines 
• Applicable International Conference on Harmonisation (ICH) GCP Guidelines 
• Applicable laws and regulations 
The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, advertisements) 
must be submitted to an IRB by the Investigator and reviewed and approved by the IRB before 
the study is initiated. 
Any amendments to the protocol will require IRB and regulatory authority (as locally required) 
approval before implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study subjects. 
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB 
• Notifying the IRB of serious adverse events or other significant safety findings as 
required by IRB procedures 
• Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations 
The study will additionally be approved by the Radiation Safety Committee. 
Finances and Insurance 
Financing and insurance will be addressed in a separate agreement. 
Informed Consent 
Prior to starting participation in the study, each subject will be provided with a study-specific 
ICF giving details of the study drug, procedures, and potential risks of the study. Subjects will be 
instructed that they are free to obtain further information from the Investigator (or designee) and 
that their participation is voluntary and they are free to withdraw from the study at any time. 
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Subjects will be given an opportunity to ask questions about the study prior to providing consent 
for participation. 
Following discussion of the study with CRU personnel, subjects will sign 2 copies of the ICF in 
the presence of a suitably trained member of staff to indicate that they are freely giving their 
informed consent. One copy will be given to the subject, and the other will be maintained in the 
subject’s records. 
Subjects must be re-consented to the most current version of the ICF(s) during their participation 
in the study. 
Subject Data Protection 
Subjects will be assigned a unique identifier and will not be identified by name or full date of 
birth in eCRFs, study-related forms, study reports, or any related publications. Subject and 
Investigator personal data will be treated in compliance with all applicable laws and regulations. 
In the event the study protocol, study report, or study data are included in a public registry, all 
identifiable information from individual subjects or Investigator will be redacted according to 
applicable laws and regulations. 
The subject must be informed that his personal study-related data will be used by the Sponsor in 
accordance with local data protection law. The level of disclosure must also be explained to the 
subject. The subject must also be informed that his study-related data may be examined by 
Sponsor or Contract Research Organization (CRO) auditors or other authorized personnel 
appointed by the Sponsor, by appropriate IRB members, and by inspectors from regulatory 
authorities. 
Disclosure 
All information provided regarding the study, as well as all information collected and/or 
documented during the course of the study, will be regarded as confidential. The Investigator (or 
designee) agrees not to disclose such information in any way without prior written permission 
from the Sponsor. 
Data Quality Assurance 
The following data quality steps will be implemented: 
• All subject data relating to the study will be recorded on eCRFs unless directly 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
electronically signing the eCRF. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
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• The Investigator must permit study-related monitoring, audits, IRB review, and 
regulatory agency inspections, and provide direct access to source data documents. 
• Covance is responsible for the data management of this study including quality checking 
of the data. Predefined, agreed risks, monitoring thresholds, quality tolerance thresholds, 
controls, and mitigation plans will be documented in a risk management register. 
Additional details of quality checking to be performed on the data may be included in a 
Data Management Plan. 
• A Study Monitor will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of subjects are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator in accordance with 21 CFR 312.62(c) unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the Sponsor. No 
records may be transferred to another location or party without written notification to the 
Sponsor. 
Investigator Documentation Responsibilities 
All individual, subject-specific study data will also be entered into a 21 CFR Part 11-compliant 
electronic data capture (EDC) system on an eCRF in a timely fashion. 
All data generated from external sources (eg, laboratory and bioanalytical data), and transmitted 
to the Sponsor or designee electronically, will be integrated with the subject’s eCRF data in 
accordance with the Data Management Plan. 
An eCRF must be completed for each subject who signs an ICF and undergoes any Screening 
procedures, according to the eCRF completion instructions. The Sponsor, or CRO, will review 
the supporting source documentation against the data entered into the eCRFs to verify the 
accuracy of the electronic data. The Investigator will ensure that corrections are made to the 
eCRFs and that data queries are resolved in a timely fashion by the study staff. 
The Investigator will sign and date the eCRF via the EDC system’s electronic signature 
procedure. These signatures will indicate that the Investigator reviewed and approved the data on 
the eCRF, data queries, and site notifications. 
Publications 
If on completion of the study the data warrant publication, the Investigator may publish the 
results in recognized (refereed) scientific journals patient to the provisions of the clinical study 
agreement (CSA). Unless otherwise specified in the CSA, the following process shall occur: 
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If the Investigator expects to participate in the publication of data generated from this site, the 
institution, and Investigator shall submit reports, abstracts, manuscripts, and/or other presentation 
materials to the Sponsor for review before submission for publication or presentation. The 
Sponsor shall have 60 days to respond with any requested revisions, including without limitation, 
the deletion of confidential information. The Investigator shall act in good faith upon requested 
revisions, except the Investigator shall delete any confidential information from such proposed 
publications. The Investigator shall delay submission of such publication or presentation 
materials for up to an additional 90 days in order to have a patent application(s) filed. 
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Appendix 5: Schedule of Assessments 
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Table 1: 
Schedule of Assessments 
 
Study Procedures 
Screening 
Check-in 
Treatment Period 
Clinic 
Discharge / 
ET 
Follow-up 
Phone Call  
Days -29 
through -2 
Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 or up to 
Day 7 
4 ± 2 days 
after 
discharge 
Informed Consent 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical History 
X 
Xa 
 
 
 
 
 
 
Height, Weight, and BMI 
X 
Xb 
 
 
 
 
 
 
Hepatitis and HIV Screen 
X 
 
 
 
 
 
 
 
Alcohol and Drug Screenc 
X 
X 
 
 
 
 
 
 
Cotinine Screen 
X 
X 
 
 
 
 
 
 
Confined to the Clinical Site 
 
X 
X 
X 
X 
X 
X 
 
Physical Examination 
 
X 
 
 
 
 
Xd,m 
 
12-Lead ECGe 
X 
X 
 
 
 
 
Xm 
 
Vital Signsf 
X 
X 
X 
X 
X 
X 
X 
 
Clinical Laboratory Evaluations 
X 
X 
 
X 
 
 
Xm 
 
HDYF? Inquiryg 
 
X 
X 
X 
X 
X 
X 
X 
AE Evaluations 
X 
X 
X 
X 
X 
X 
X 
X 
Review of Concomitant Medications and Procedures 
X 
X 
X 
X 
X 
X 
X 
X 
[14C]-Zidebactam Administrationh 
 
 
X 
 
 
 
 
 
Blood Samples for PK and Total Radioactivity 
Analysisi 
 
 
X 
X 
X 
X 
X 
 
Blood Samples for Metabolite Profiling and 
Identificationj 
 
 
X 
X 
X 
X 
X (Day 5 only) 
 
Urine Samplesk 
 
X 
X 
X 
X 
X 
X 
 
Fecal Samplesl 
 
X 
X 
X 
X 
X 
X 
 
AE = adverse event; BMI = body mass index; CBC = complete blood count; ECG = electrocardiogram; HDYF? = How Do You Feel? Inquiry; 
HIV = human immunodeficiency virus; PK = pharmacokinetics; UA = urinalysis 
a Interim medical history only. 
b Height measured at Screening only. BMI to be recalculated on Day -1. 
c Drug screen does not include alcohol testing at Screening but does include an alcohol breath test at Check-in. 
d Abbreviated physical examination only. 
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e Single 12-lead ECGs will be obtained at Screening, Check-in (Day -1), and prior to Clinic Discharge. The ECGs will be collected after the subject has 
been resting in a supine position for at least 5 minutes. The 12-lead ECGs will be performed before blood draws on appropriate days and when blood draw 
and ECG timepoints coincide, ECGs will be performed prior to the blood draws and as close to the scheduled timepoint as possible. 
f Vital signs (oral temperature, respiratory rate, and supine blood pressure and pulse) will be obtained at Screening; Check-in (Day -1); on Day 1 at predose 
(0 Hour) and 1, 3, and 12 hours postdose; daily at 24-hour intervals; and prior to Clinic Discharge. Vital signs measurements will be performed with the 
subject supine and after the subject has rested for at least 5 minutes. When the timepoints for blood draws and vital signs measurements coincide, the vital 
signs measurements will be collected prior to the blood draws and as close to the scheduled timepoint as possible. 
g How Do You Feel? inquiry performed at Check-in, each postdose vital signs measurement, and during the Follow-up phone call. 
h Single IV dose of [14C]-zidebactam at 1g (approximately 200 µCi) will be administered as an IV infusion over 1 hour. 
i Blood samples for PK and radioanalysis will be collected prior to start of infusion and 0.25, 0.5, 1 (just prior to end of infusion), 1.5, 2, 2.5, 3, 4, 6, 8, 10, 
12, 16, 20, 24, 36, 48, 72, and 96 hours after the start of infusion. If subject is not discharged on Day 5, additional blood samples will be collected every 
24 hours until Clinic Discharge. 
j Blood samples for metabolite identification and profiling will be collected at prior to start of infusion and 1 (just prior to end of infusion), 2, 4, 8, 12, 24, 
48, 72, and 96 hours post start of infusion. 
k Urine samples will be collected at -12 hours through 0 hour (predose) and at the following collection intervals: 0 to 6, 6 to 12, 12 to 24, 24 to 48, 48 to 72, 
and 72 to 96 hours after start of infusion. If subjects are not eligible for discharge on Day 5, urine will continue to be collected for 24-hour intervals until 
the subject meets discharge criteria or until the maximum stay (Day 7). 
l If possible, a baseline fecal sample will be collected after Check-in (Day -1) until just prior to dosing on Day 1. All postdose fecal samples will then be 
collected daily (24-hour intervals) from Days 1 through 5 (96 hours postdose) to determine total [14C]-radioactivity in feces and/or for metabolite 
profiling/identification. If subjects are not eligible for discharge, fecal samples will continue to be collected for 24-hour intervals until either the subject 
meets discharge criteria or until the maximum stay (Day7). 
m Assessment to be completed at Clinic Discharge or Early Termination only. 
 
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