Clinical trial NCT03840148
Conditions: Urinary Tract Infections Acute Pyelonephritis
Keywords: Bacterial Infections Cefepime Meropenem Complicated Urinary Tract Infections Anti-Infective Agents β-Lactamase Inhibitors VNRX-5133 (taniborbactam)
Sponsor: Venatorx Pharmaceuticals, Inc.
Start date: 2019-08-07; Completion date: 2021-12-14
Enrollment: 661 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will assess the safety and efficacy of cefepime/VNRX-5133 compared with meropenem in both eradication of bacteria and in symptomatic response in patients with cUTIs.

Detailed description:

Arms: arm 1: Cefepime/VNRX-5133 administered q8h intravenously (IV) over a 2-hour period. arm 2: Meropenem will be administered q8h IV over 30 minutes.
Interventions: intervention 1: Cefepime/VNRX-5133 (taniborbactam) intervention 2: Meropenem
Intervention descriptions: intervention 1: Cefepime/VNRX-5133 administered q8h intravenously (IV) over a 2-hour period for 7 days (up to 14 days for patients with bacteremia). Patients will also receive meropenem placebo administered via IV over 30 minutes. intervention 2: Meropenem will be administered q8h IV over 30 minutes for 7 days (up to 14 days for patients with bacteremia). Patients will also receive cefepime/VNRX-5133 placebo administered via IV over a 2-hour period.

Protocol documents:
Prot_000.pdf: 
STUDY NUMBER: VNRX-5133-201 
PROTOCOL TITLE:  A Phase 3, Randomized, Double-blind, 
Active-controlled Noninferiority Study Evaluating 
the Efficacy, Safety, and Tolerability of 
Cefepime/VNRX-5133 in Adults with Complicated 
Urinary Tract Infections, Including Acute Pyelonephritis 
NCT Number:  NCT03840148 
Document Date: 10 December 2019 


Protocol VNRX-5133-201 Amendment 2 
VNRX-5133
Cefepime/VNRX-5133 for the Treatment of cUTI 
VenatoRx Pharmaceuticals, Inc.
 
 
 
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DRUG: 
VNRX-5133 
STUDY NUMBER: 
VNRX-5133-201 
PROTOCOL TITLE: 
A Phase 3, Randomized, Double-blind, 
Active-controlled Noninferiority Study Evaluating 
the Efficacy, Safety, and Tolerability of 
Cefepime/VNRX-5133 in Adults with Complicated 
Urinary Tract Infections, Including Acute 
Pyelonephritis 
IND NUMBER: 
126702 
EUDRACT NUMBER: 
2018-001451-13 
SPONSOR: 
VenatoRx Pharmaceuticals, Inc. (VenatoRx) 
 
 
ORIGINAL GLOBAL 
PROTOCOL DATE: 
30 October 2018 
PROTOCOL AMENDMENT 
NUMBER: 
2 
VERSION NUMBER: 
3.0 
VERSION DATE: 
10 December 2019 
 


Protocol VNRX-5133-201 Amendment 2 
Cefepime/VNRX-5 I 33 for the Treatment of cUTI 
VNRX-5133 
VenatoRx Pharmaceuticals, Inc. 
CLINICAL PROTOCOL APPROVAL FORM 
The signature below constitutes the approval of this protocol and the attachments and provides 
the necessary assurances that this study will be conducted according to all stipulations of the 
protocol including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable United States state and federal regulations, all other 
applicable local regulatory requirements, and ICH guidelines. Any modification of the clinical 
study protocol must be documented in writing by the sponsor. 
Sponsor: VenatoRx Pharmaceuticals, Inc. (VenatoRx) 
Signed: 
Date: 
---
Confidential 
 
 
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Protocol VNRX-5133-201 Amendment 2 
VNRX-5133
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SUMMARY OF CHANGES 
Current Amendment 2 
Version No., Date: 
3.0, 10-Dec-2019 
Replaces Previous Version No, Date. 
2.0, 30-Jan-2019 
 
Change 1: Inclusion/Exclusion Criteria 
Description:  Change of unit in Inclusion #4 
Section 
Revision 
Synopsis 
WBC >10 cells per high power field in urine sediment 
4.0 
WBC > 10 cells per high power field in urine sediment 
 
Change 2: Study Endpoints 
Description:  Clarification to the Primary Endpoint and updates to the Secondary Endpoints 
Section 
Revisions 
Synopsis/3.2/10.3.5 
Primary Endpoint:  Microbiological success is defined as 
any gram negative bacterial pathogen found at study entry are 
eradicated to <103 colony forming units per microliter 
Secondary Endpoints: 
 
Old version: 
 
The proportion of patients with both 
microbiological success and symptomatic clinical 
success at TOC in the extended microITT 
population 
The proportion of patients with per-patient 
microbiological success at TOC in the 
microbiologically evaluable (ME)-TOC population 
The proportion of patients with symptomatic 
clinical success at TOC in the clinically evaluable 
(CE)-TOC and ME-TOC populations 
The proportion of patients with clinical success 
based on investigator opinion at EOT, TOC, and 


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LFU in the microITT and relevant CE and ME 
populations 
The proportion of patients with per-patient 
microbiological success at EOT and LFU in the 
microITT, ME-EOT, and ME-LFU populations 
The proportion of patients with symptomatic 
clinical success at EOT and LFU in the microITT, 
CE-EOT, ME-EOT, CE-LFU, and ME-LFU 
populations 
The proportion of patients with per-pathogen 
microbiological success in the microITT, ME-
EOT, ME-TOC, and ME-LFU populations 
The proportion of patients with per-patient 
microbiological success among those with 
cefepime-resistant pathogens in the microITT, 
ME-EOT, ME-TOC, and ME-LFU populations 
The proportion of patients with per-pathogen 
microbiological success among those with 
cefepime-resistant pathogens in the microITT, 
ME-EOT, ME-TOC, and ME-LFU populations 
The proportion of patients with symptomatic 
clinical success among those with cefepime-
resistant pathogens in the microITT, CE-EOT, CE-
TOC, CE-LFU, ME-EOT, ME-TOC, and ME-LFU 
populations 
 
New version: 


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The proportion of patients with both 
microbiological success and symptomatic clinical 
success at TOC in the extended microITT 
population, clinically evaluable (CE)-TOC and 
microbiologically evaluable (ME)- TOC 
populations 
The proportion of patients with both 
microbiological success and symptomatic clinical 
success at EOT in the micro-ITT, ME-EOT and 
CE-EOT populations, and at LFU in the micro-
ITT, ME-LFU and CE-LFU populations 
The proportion of patients with per-patient 
microbiological success at EOT, TOC and LFU in 
the micro-ITT population andME- EOT, ME-TOC 
and ME-LFU populations 
The proportion of patients with symptomatic 
clinical success at EOT, TOC and LFU in the 
micro-ITT population andCE-EOT, CE-TOC and 
CE-LFU populations 
The proportion of patients with clinical success 
based on investigator opinion at TOC in the micro-
ITT population  
The proportion of patients with per-pathogen 
microbiological success at EOT in the micro-ITT 
and ME-EOT populations, TOC in the micro-ITT 
and ME-TOC populations, and at LFU in the 
micro-ITT and ME-LFU populations 
The proportion of patients with both 
microbiological success and symptomatic clinical 
success among those with cefepime-resistant 
pathogens at EOT in the micro-ITT, ME-EOT and 
CE-EOT populations, TOC in the micro-ITT, ME-
TOC, and CE-TOC populations, and at LFU in the 
micro-ITT, ME-LFU and CE-LFU populations 
The proportion of patients with per-patient 
microbiological success among those with 
cefepime-resistant pathogens at EOT in the micro-
ITT and ME-EOT populations, TOC in the micro-
ITT and ME-TOC populations, and at LFU in the 
micro-ITT and ME-LFU populations 
The proportion of patients with per-pathogen 
microbiological success among those with 


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cefepime-resistant pathogens at EOT in the micro-
ITT and ME-EOT populations, TOC in the micro-
ITT and ME-TOC populations, and at LFU in the 
micro-ITT and ME-LFU populations 
The proportion of patients with symptomatic 
clinical success among those with cefepime-
resistant pathogens at EOT in the micro-ITT and 
CE-EOT populations, TOC in the micro-ITT and 
CE-TOC populations, and at LFU in the micro-ITT 
and CE-LFU populations 
 
Change 3: Statistical Analysis 
Description: Clarification to ME-EOT, ME-TOC and ME-LFU populations 
Section 
Revision 
Synopsis/10.3.1 
Both study drugs are known to have antibacterial activity 
against all baseline gram negative pathogens 
 
Were evaluated at the respective EOT, TOC and LFU visits 
with a microbiological response of eradication or persistence 
(ie, per-patient microbiologic response of success or failure) 
 
Change 4: Study Drug Management 
Description:  Clarification to the treatment duration for patients without bacteremia 
Section 
Revision 
5.4 
All patients will receive 7 days of IV treatment.  Based on the 
scheduled study drug administration for patients without 
bacteremia, the patients could complete treatment of study day 
7 or study day 8. 
 
All non-bacteremic patients (who do not require dosing 
adjustments for renal dysfunction) will receive at least 19 
doses and no more than 21 doses of study drug. 
 
Added patients are not permitted to continue oral antibiotics at 
home prophylactically. 
Added the Investigator should continually assess whether the 
study drug has failed (ie, the patient has signs and symptoms 
of cUTI that have not improved or have recurred such that 
additional antibiotic therapy is warranted) and rescue therapy 
is required. 
 


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Change 5: Study Conduct 
Description:  Added criteria as a result of feedback from SUKL (Czech Republic) 
Section 
Revision 
6.3.1 
Added AST or ALT ≥10X ULN 
 
Change 6: Description of Study Procedures 
Description: Added language to the Definition of Success with treatment for asymptomatic 
bacteremia 
Section 
Revision 
Table 8 
Added treatment of asymptomatic bacteremia is prescribed 
based on the opinion of the investigator2 
 
2 According to guidelines in both Europe and the United 
States, treatment of asymptomatic bacteriuria (the presence of 
1 or more species of bacteria growing in the urine irrespective 
of the presence of pyuria, in the absence of signs or symptoms 
attributable to UTI) is in most cases not beneficial and may be 
harmful. Based on standard of care and protocol restrictions 
surrounding use of additional antibiotics, patients in this trial 
should not receive additional antibiotic for asymptomatic 
bacteriuria.  Additional therapy should only be given if signs 
and symptoms warrant ongoing treatment for symptomatic 
cUTI (i.e., based on their clinical course in the absence of 
microbiological data). 
 
Change 7: Description of Study Procedures 
Description:  Added note to ethnicity 
Section 
Revision 
7.8.2 
Added Ethnicity variable should only be used for African 
Americans 
 
Change 8: Adverse Event Assessment and Reporting 
Description: Clarified criteria as a result of feedback from SUKL (Czech Republic) 
Section 
Revision 
8.6.1 
Added laboratory abnormalities should be reported as adverse 
events if the result is considered to be clinically significant by 
the investigator. 


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Change 9: Other Reportable Events 
Description:  Clarified pregnancy reporting 
Section 
Revision 
9.3 
Added all pregnancies of female clinical study patients or 
partners of male study patients should be reported to sponsor. 
 
Added if written consent is obtained, monitoring should occur. 
 
Change 10: Administrative 
Description:  Removed CRO from Signature Page and Replaced Sponsor Medical 
Representative 
 


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Previous Amendment 1 
Version No., Date: 
2.0, 30-Jan-2019 
Replaces Previous Version No, Date. 
1.0, 30-Oct-2018 
 
Change 1: Schedule of Events 
Description:  Clarification regarding the assessments and procedures required at EOT when 
EOT occurs on Study Day 1. 
Section 
Revision 
Synopsis 
Added patient is alive, and patient has not received additional 
antibacterial therapy for cUTI. 
7.3 
Added or in the event that EOT occurs on Study Day 1. 
Table 1  
Added EOT occurs on Study Day 1 or to Footnote 4. 
 
Change 2: Study Endpoints 
Rationale:  Updates to the definitions used for the study endpoints in response to regulatory 
feedback from the European Medicines Agency, including a definition of symptomatic 
clinical failure that includes use of additional antibiotics for the treatment of cUTI occurring 
after end of treatment. 
Section 
Revision 
Synopsis 
Added patient is alive, and patient has not received additional 
antibacterial therapy for cUTI 
3.2 
Added patient is alive, and patient has not received additional 
antibacterial therapy for cUTI. 
7.7.1 
Modified Table 4 to specify at EOT and removed LFU and 
TOC:  Added patient is alive to definition of symptomatic 
clinical response. 
Added Table 5: Symptomatic Response Criteria at TOC and 
LFU 
 


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Change 3: Time Windows for Pharmacokinetic Assessments 
Rationale: Correction of an error in the collection window at Study Day 3. 
Section 
Revision 
7.1 
Table 10:  Study Day 3 collection window deleted 7 hours and 
added 5 hours. 
Deleted all times shown are relative to the start of the infusion 
from the footnote. 
 
 
 


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VNRX-5133-201 
A Phase 3, Randomized, Double-blind, Active-controlled Noninferiority Study 
Evaluating the Efficacy, Safety, and Tolerability of Cefepime/VNRX-5133 in 
Adults with Complicated Urinary Tract Infections, Including Acute 
Pyelonephritis 
 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT 
The information contained in this protocol and all other information relevant to VNRX-5133 are 
the confidential and proprietary information of VenatoRx Pharmaceuticals, Inc. (VenatoRx), and 
except as may be required by federal, state or local laws or regulation, may not be disclosed to 
others without prior written permission of VenatoRx. 
I have read the protocol, including all appendices, and I agree that it contains all of the necessary 
information for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein, in accordance with the regulations stated in the Federal Code of Regulations for 
Good Clinical Practices and International Council on Harmonisation guidelines, and will make a 
reasonable effort to complete the study within the time designated. 
I will provide all study site personnel under my supervision copies of the protocol and any 
amendments, and access to all information provided by VenatoRx or specified designees. I will 
discuss the material with them to ensure that they are fully informed about VNRX-5133 and the 
study. 
 
 
 
 
Investigator Name (printed) 
 
Signature 
 
 
 
 
Date 
 
Site Number 
 
*The protocol should be signed by the local investigator who is responsible for the study implementation 
at his/her specific site; i.e., if Investigational New Drug study, the individual who signs the Form 
FDA 1572. 


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STUDY SUMMARY 
Title:  
A Phase 3, Randomized, Double-blind, Active-controlled 
Noninferiority Study Evaluating the Efficacy, Safety, and 
Tolerability of Cefepime/VNRX-5133 in Adults with Complicated 
Urinary Tract Infections, Including Acute Pyelonephritis 
Phase of Study: 
Phase 3 
Target Population: 
Adult male and female patients with complicated urinary tract 
infection (cUTI), including acute pyelonephritis (AP) 
Number of Patients: 
582 patients will be randomized into 2 groups in a 2:1 ratio 
(388 patients to cefepime/VNRX-5133; 194 patients to 
meropenem) 
Number of Sites: 
Approximately 122 sites in the United States and other countries 
Study Duration: 
Approximately 14 months 
Duration of Treatment: 7 days (up to 14 days for patients with bacteremia) 
Drug Administered: 
Test: Cefepime/VNRX-5133 (2 g/0.5 g intravenously [IV] every 
8 hours [q8h]) 
Active comparator: Meropenem (1 g IV q8h) 
Study Drug 
Administration: 
All study drugs will be provided by the sponsor.  
For cefepime/VNRX-5133, cefepime hydrochloride (2 g/vial, 
sterile, white to pale yellow powder) and VNRX-5133 (0.5 g/vial 
sterile, white to yellow powder) will each be reconstituted 
independently, then combined into a single IV bag, and diluted 
with 0.9% sodium chloride solution for IV injection. 
Cefepime/VNRX-5133 will be administered q8h via IV pump over 
a 2-hour period. In order to maintain the blind, patients 
randomized to cefepime/VNRX-5133 will also receive meropenem 
placebo (0.9% sodium chloride solution) administered via IV 
pump over 30 minutes. 
Meropenem (1 g/vial) will be reconstituted in a single IV bag and 
will serve as active comparator for IV injection. Meropenem will 
be administered q8h via IV pump over 30 minutes. In order to 
maintain the blind, patients randomized to meropenem will also 
receive cefepime/VNRX-5133 placebo (0.9% sodium chloride 
solution) administered via IV pump over a 2-hour period. 
Study drug and placebo IV bags as well as IV tubing will be 
blinded with sleeves. 
All patients will be treated for 7 days of IV therapy. Patients with 
bacteremia may receive up to 14 days of treatment at the 
investigator’s discretion. 


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All study drugs will be prepared at the study site by an unblinded 
pharmacist or designee. A separate unblinded study monitor will 
periodically review pharmacy logs and drug accountability. The 
sponsor clinical team, investigator, patients, and all other study 
staff will remain blinded to study drug. 
Objectives:  
Primary objective:  
• To assess the efficacy of cefepime/VNRX-5133 compared 
with meropenem with respect to both per-patient 
microbiologic eradication and symptomatic resolution of 
all urinary tract infection (UTI)-core symptoms (or return 
to pre-morbid baseline) at the Test of Cure (TOC) visit 
Secondary objectives:  
• To determine the efficacy of cefepime/VNRX-5133 
compared with meropenem with respect to the per-patient 
microbiological response, per-pathogen microbiologic 
response, and symptomatic resolution of all UTI-core 
symptoms at various timepoints in various populations 
• To determine the efficacy of cefepime/VNRX-5133 
compared with meropenem with respect to the per-patient 
microbiological response, per-pathogen microbiologic 
response, and symptomatic resolution of all UTI-core 
symptoms in patients with cUTI due to cefepime-resistant 
pathogens at various timepoints in various populations  
• To evaluate the safety and tolerability profile of 
cefepime/VNRX-5133 compared with meropenem in the 
treatment of patients with a cUTI in the safety population 
• To evaluate the steady-state pharmacokinetics (PK) of 
cefepime and VNRX-5133 in patients using a population 
PK model 
Study Design: 
Study VNRX-5133-201 is a Phase 3, randomized, multicenter, 
double-blind, double-dummy, active-controlled noninferiority 
study to evaluate the efficacy, safety, and tolerability of 
cefepime/VNRX-5133 compared with an active control, 
meropenem, in adult patients with cUTI, including AP. Each 
patient is expected to complete the study within approximately 4 to 
5 weeks. 
After obtaining signed informed consent and confirming eligibility 
within 24 hours prior to randomization, patients will be 
randomized in a 2:1 ratio to receive either cefepime/VNRX-5133 


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(2 g/0.5 g IV q8h) or the active comparator, meropenem (1 g IV 
q8h) on Study Day 1.  
Patients will be stratified by the type of infection (AP only versus 
complicated lower UTI with or without AP) and by region (North 
America and Western Europe versus Eastern Europe versus rest of 
the world). At least 30% of the population will have AP.  
Patients may receive up to 24 hours of antibacterials for treatment 
of cUTI prior to randomization; however, the number of patients 
with prior antibacterial use will be limited to approximately 25% 
of the population. Before receipt of study drug, a urine specimen 
and blood cultures will be obtained from all patients for culture 
and for in vitro antibacterial susceptibility testing. Patients with an 
indwelling catheter should have urine samples collected following 
the placement of a new catheter, or if the indwelling catheter 
cannot be removed, aseptic techniques should be used through a 
properly disinfected collection port. Patients with an indwelling 
catheter should be randomized only if they are expected to 
permanently discontinue use of the catheter prior to Study Day 5. 
Screening assessments will also include a Daily Patient Symptom 
Questionnaire (DPSQ) and a Pre-morbid Patient Symptom 
Questionnaire (PPSQ). The DPSQ will be administered at 
screening, daily while on study drug, and at End of Treatment 
(EOT), TOC, and Late Follow-up (LFU) visits to determine the 
presence and intensity of cUTI symptoms. The PPSQ will be 
administered once at screening to determine whether a patient 
normally experiences urinary tract symptoms (i.e., in the absence 
of a UTI) that may be attributable to other disease processes 
(e.g., benign prostatic hyperplasia [BPH]).  
Study drug will be administered IV for 7 days and will be 
considered completed after the third dose on Study Day 7 for 
patients without bacteremia. All patients (who do not require 
dosing adjustments for renal dysfunction) will receive at least 
19 doses. Patients without bacteremia will receive a maximum of 
21 doses of active study drug. Patients with bacteremia at study 
entry may have their treatment extended up to 14 days at the 
investigator’s discretion.  
Patients will be admitted at screening and remain at the study site 
or hospital for the duration of the IV treatment period and through 
the EOT visit. The EOT visit will be performed within 24 hours 
after the last dose of IV study drug. Patients may be discharged 
from the study site after the EOT visit if clinically stable and at the 
investigator’s discretion.  


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Patients must return to the study site for the TOC visit (Study 
Days 19 to 23) and the LFU visit (Study Days 28 to 35). 
Inclusion/Exclusion 
Criteria: 
Patients must meet the following general inclusion criteria to be 
eligible for inclusion in the study: 
1. Provide signed informed consent 
2. Adult male or female, ≥18 years of age 
3. If female, meets at least 1 of the following criteria: 
• Surgically sterile 
• Age ≥50 years and postmenopausal for ≥12 months 
• Age <50 years and postmenopausal for ≥2 years 
• Patient has a negative serum pregnancy test and agrees not 
to attempt pregnancy and, if participating in sexual 
activity, agrees to use an effective dual method of 
contraception 
4. Patient has pyuria as demonstrated by at least 1 of the 
following: 
• Urine dipstick positive for leukocyte esterase 
• White blood cells (WBC) >10 cells/μL in unspun urine 
• WBC >10 cells per high power field (HPF) in urine 
sediment 
5. Demonstrates either AP or complicated lower UTI as 
defined by the following criteria: 
a. AP is indicated by the presence of both of the following 
criteria: 
• At least 1 of the following is present: 
o Nausea or vomiting 
o Chills or rigors or warmth associated with fever, 
defined as body temperature >38°C 
• Has flank pain or costovertebral angle tenderness 
b. Complicated lower UTI is indicated by the presence of 
all 3 of the following criteria: 


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• At least 1 of the following is present: 
o Nausea or vomiting 
o Chills or rigors or warmth associated with fever, 
defined as body temperature >38°C 
• At least 1 of the following signs/symptoms is present:  
o Dysuria 
o Urinary urgency 
o Urinary frequency 
o Pelvic pain or suprapubic tenderness/pelvic 
tenderness 
• At least 1 of the following complicating factors is present: 
o Chronic urinary retention 
o Obstructive uropathy (if complete obstruction, 
should intend to relieve obstruction within 
48 hours after randomization) 
o Neurogenic bladder with presence or history of 
urine residual volume of >100 mL 
o Indwelling catheter (with expectation for 
permanent discontinuation of the catheter by 
Study Day 5) 
6. Requires IV antibacterial therapy as initial treatment for 
cUTI 
Patients who meet any of the following general exclusion criteria 
will not be eligible for inclusion in the study:  
1. Receipt of effective antibacterial drug therapy for cUTI for 
a continuous duration of more than 24 hours during the 
previous 72 hours prior to randomization 
2. Where a urine culture result is available: 
• At least 1 uropathogen at ≥105 colony forming units per 
milliliter (CFU/mL) is resistant to meropenem, or 
• A gram-negative bacterial pathogen is not identified 
• More than 2 microorganisms are isolated regardless of the 
colony count, or 


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• The patient has a confirmed fungal UTI with colony count 
≥103 CFU/mL 
3. Requirement for use of nonstudy systemic antibacterial 
drug therapy that would have a potential effect on outcome 
evaluations in patients with cUTI 
4. Patients with suspected or confirmed prostatitis or urinary 
tract symptoms attributable to a sexually transmitted 
disease 
5. Patients with perinephric or renal abscess 
6. Patients with renal transplantation or receiving 
hemodialysis or peritoneal dialysis 
7. Patients with urinary diversions (e.g., ileal loops, cutaneous 
urostomy) 
8. Patients who may need ongoing antibacterial drug 
prophylaxis after treatment of cUTI (such as vesico-ureteral 
reflux) 
9. Any recent history of trauma to the pelvis or urinary tract 
10. Patient has any urinary catheter or device or foreign body 
that will not be discontinued by Study Day 5, including but 
not limited to indwelling bladder catheter, urinary catheter, 
nephrostomy tubes, or stent 
11. Patient is unlikely to respond to 7 days of antibacterial 
therapy for the treatment of cUTI without bacteremia or up 
to 14 days of therapy for treatment of cUTI with 
bacteremia 
12. Patient has acute hepatitis, cirrhosis (Child-Pugh Class B or 
C), acute hepatic failure, or acute decompensation of 
chronic hepatic failure  
13. Patient has had a heart, lung, heart-lung, or pancreatic 
transplant at any time; or bone marrow transplant in the 
preceding year 
14. Patient has any of the following laboratory values: 


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• Estimated glomerular filtration rate (eGFR) 
<30 mL/min/1.73 m2 calculated by the Modification of 
Diet in Renal Disease (MDRD) formula2 
• Hematocrit <25% or hemoglobin <8 g/dL 
• Platelet count <50,000/mm3 
• Total bilirubin >3.0× the upper limit of normal (ULN), 
unless isolated hyperbilirubinemia is directly related to the 
acute infection or due to known Gilbert’s disease 
• Alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) >3.0× ULN at screening. Patients 
with values >3.0× ULN and <5.0× ULN are eligible if 
these values are acute and documented as being directly 
related to the infectious process being treated.  
• Alkaline phosphatase >3.0× ULN. Patients with values 
>3.0× ULN and <5.0× ULN are eligible if this value is 
acute and documented as being directly related to the 
infectious process being treated. 
15. Patient has a history of serious hypersensitivity 
(e.g., anaphylaxis), serious allergy, or any serious reaction 
to cephalosporin, penicillin, carbapenem, or other β-lactam 
antibacterials 
16. Patient is considered unlikely to survive the 4- to 5-week 
study period or have a rapidly progressive or terminal 
illness, including septic shock, that is associated with a 
high risk of mortality 
17. Patient requires concomitant medication with valproic acid 
or divalproex 
18. Patient is in a situation or has a condition that, in the 
investigator’s opinion, may interfere with optimal 
participation in the study, or is unlikely to comply with 
protocol (e.g., inability to fully comprehend and clearly 
respond to questions on the PPSQ and DPSQ in a reliable 
manner, uncooperative attitude, inability to return for 
follow-up visit, or unlikely to complete the study) 
19. Patient is participating in any other clinical study that 
involves the administration of an investigational product at 


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the time of presentation or during the course of the study or 
has received treatment with an investigational product in 
the 30 days prior to study enrollment 
20. Female patients who are pregnant, lactating, or planning to 
become pregnant during this study 
Primary Endpoint:  
The primary endpoint is the demonstration of microbiological 
success (any gram negative bacterial pathogens found at study 
entry are eradicated to <103 CFU/mL on urine culture) and the 
demonstration of symptomatic clinical success (symptomatic 
resolution or return to pre-morbid baseline of all UTI-core 
symptoms including frequency, urgency, dysuria, 
suprapubic/pelvic pain, and flank pain, patient is alive, and patient 
has not received additional antibacterial therapy for cUTI) at TOC 
in the microbiological intent-to-treat (microITT) population. 
Secondary Endpoints: 
Clinical and Microbiological Efficacy: 
• The proportion of patients with both microbiological 
success and symptomatic clinical success at TOC in the 
extended microITT population, clinically evaluable (CE)-
TOC and microbiologically evaluable (ME)- TOC 
populations 
• The proportion of patients with both microbiological 
success and symptomatic clinical success at EOT in the 
micro-ITT, ME-EOT and CE-EOT populations, and at 
LFU in the micro-ITT, ME-LFU and CE-LFU populations 
• The proportion of patients with per-patient 
microbiological success at EOT, TOC and LFU in the 
micro-ITT,  ME- EOT, ME-TOC and ME-LFU 
populations 
• The proportion of patients with symptomatic clinical 
success at EOT, TOC and LFU in the micro-ITT 
population and CE-EOT, CE-TOC and CE-LFU 
populations 
• The proportion of patients with clinical success based on 
investigator opinion at TOC in the micro-ITT population  
• The proportion of patients with per-pathogen 
microbiological success at EOT in the micro-ITT and ME-
EOT populations, TOC in the micro-ITT and ME-TOC 
populations, and at LFU in the micro-ITT and ME-LFU 
populations 


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• The proportion of patients with both microbiological 
success and symptomatic clinical success among those 
with cefepime-resistant pathogens at EOT in the micro-
ITT, ME-EOT and CE-EOT populations, TOC in the 
micro-ITT, ME-TOC, and CE-TOC populations, and at 
LFU in the micro-ITT, ME-LFU and CE-LFU populations 
• The proportion of patients with per-patient 
microbiological success among those with cefepime-
resistant pathogens at EOT in the micro-ITT and ME-EOT 
populations, TOC in the micro-ITT and ME-TOC 
populations, and at LFU in the micro-ITT and ME-LFU 
populations 
• The proportion of patients with per-pathogen 
microbiological success among those with cefepime-
resistant pathogens at EOT in the micro-ITT and ME-EOT 
populations, TOC in the micro-ITT and ME-TOC 
populations, and at LFU in the micro-ITT and ME-LFU 
populations 
• The proportion of patients with symptomatic clinical 
success among those with cefepime-resistant pathogens at 
EOT in the micro-ITT and CE-EOT populations, TOC in 
the micro-ITT and CE-TOC populations, and at LFU in 
the micro-ITT and CE-LFU populations 
Safety and Tolerability: 
• Safety and tolerability will be assessed based on the 
incidence and severity of adverse events (AEs) and serious 
adverse events (SAEs), exposure, mortality, reasons for 
discontinuation of study drug and study withdrawal, vital 
sign measurements, and clinically significant changes in 
clinical chemistry, hematology, urinalysis, and 
coagulation laboratory values. 
Pharmacokinetics: 
• The population PK analysis using data from the study will 
be described in a population PK analysis plan and 
summarized in a separate report. 
Resolution of Fever:  


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• The time to first defervescence (≤37.8°C) in the microITT 
population for patients who have fever (>38°C) at baseline 
will be assessed as an exploratory endpoint. 
Statistical Analysis: 
The study will randomize 582 patients with cUTI into 2 groups in 
a 2:1 ratio (388 patients to cefepime/VNRX-5133; 194 patients to 
meropenem). The sample size was selected based on an anticipated 
evaluability rate of 68%, a response rate of 75%, 90% power, a 
2-sided alpha of 0.05, and a noninferiority margin of 15%.  
Study endpoints will be analyzed in the following populations: 
• Intent-to-treat (ITT) population: all randomized patients 
• microITT population: all patients randomized to treatment 
AND 
o Had a positive study entry urine culture defined 
as ≥105 CFU/mL of a gram-negative pathogen 
against which both cefepime/VNRX-5133 and 
meropenem have antibacterial activity AND 
o Had no more than 2 microorganisms identified 
in the study entry culture regardless of colony 
count 
• Extended microITT population: all patients randomized to 
treatment AND 
o Had a positive study entry urine culture defined 
as ≥105 CFU/mL of a gram-negative pathogen 
against which at least 1 study drug (i.e., 
cefepime/VNRX-5133 and/or meropenem) have 
antibacterial activity AND 
o Had no more than 2 microorganisms identified 
in the study entry culture regardless of colony 
count 
• CE-EOT, CE-TOC, and CE-LFU populations: all patients 
who meet the definition for the ITT population AND 
o Had an appropriate diagnosis of cUTI 
o Received treatment for ≥48 hours (or <48 hours 
if discontinued due to an AE or death) 


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o Were evaluated for the appropriate endpoint at 
the relevant timepoint (i.e., EOT, TOC, and 
LFU) with an outcome that is not indeterminate 
o Did not violate entry criterion surrounding use 
of prior antibacterials 
o Did not receive a concomitant systemic 
antibiotic with potential activity against any of 
the baseline pathogens between the time of 
randomization and EOT, TOC, and LFU, 
respectively, except therapies used to treat cUTI 
in patients who have failed study drug 
o Did not have other confounding factors that 
interfered with the assessment of outcome as 
assessed by a blinded evaluability team prior to 
database lock 
• ME-EOT, ME-TOC, and ME-LFU populations: all 
patients who meet the criteria for the microITT population 
AND 
o Both study drugs are known to have 
antibacterial activity against the baseline gram-
negative pathogens and had an appropriate 
diagnosis of cUTI 
o Received treatment for ≥48 hours (or <48 hours 
if discontinued due to an AE or death) 
o Were evaluated at the respective EOT, TOC, 
and LFU visits with a microbiological response 
of eradication or persistence (i.e., per-patient 
microbiologic response of success or failure) 
o Did not violate entry criterion surrounding use 
of prior antibacterials 
o Did not receive a concomitant systemic 
antibiotic with the potential activity against any 
of the baseline pathogens between the time of 
randomization and EOT, TOC, and LFU, 
respectively, except therapies used to treat cUTI 
in patients who have failed study drug 


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o Did not have other confounding factors that 
interfered with the assessment of outcome as 
assessed by a blinded evaluability team prior to 
database lock 
• Safety population: all patients who receive any dose of 
study drug 
Continuous clinical variables will be summarized descriptively 
(i.e., patient count, mean, standard deviation, median, minimum, 
and maximum). Categorical data will be summarized descriptively 
with frequencies and percentages based on the number of patients 
exposed within a treatment. 
Full details of the statistical analysis will be described in the 
statistical analysis plan. 
The population PK analysis methods using data from the study will 
be described in a population PK analysis plan, and the population 
PK modeling will be summarized in a separate report. 
 


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SCHEDULE OF ASSESSMENTS 
Table 1 
Schedule of Assessments 
Procedure and 
Assessment 
Screening1 
Treatment Period 
EOT4  
(Within 
24 hours of 
last IV dose) 
TOC5 
(Study 
Days 19-
23) 
LFU6 
(Study 
Days 
28-35) 
Section 
of 
Protocol 
Day 12 
Study Days 2-7 (up to Study Day 14 for patients 
with bacteremia)3  
Informed consent 
X 
 
 
 
 
 
4.4 
Confirm eligibility 
X 
 
 
 
 
 
4.2, 4.3 
Medical history 
X 
 
 
 
 
 
7.9.1 
Demographics 
X 
 
 
 
 
 
7.9.1 
Randomization7 
 
X 
 
 
 
 
6.1 
Prior and concomitant 
medications 
(including antibiotics) 
X 
X 
Daily 
X 
X 
X 
7.9.2 
Complete physical 
examination 
X 
 
 
 
 
 
7.9.3 
UTI-focused physical 
examination8 
X 
X9 
Daily 
X 
X 
X 
7.9.3 
DPSQ 
X 
X9 
Daily 
X 
X 
X 
7.7.1 
PPSQ 
X 
 
 
 
 
 
7.7.1 
Height and weight 
X 
 
 
 
 
 
7.9.4 
Vital signs10 
X 
X9 
Daily 
X 
X 
X 
7.8.1 
eGFR11 
X 
 
Repeat using local serum creatinine measurements as clinically indicated 
7.8.2 
12-lead ECG12 
X 
 
On Study Day 4 and as clinically indicated 
 
 
 
7.8.3 
Urine for dipstick or 
microscopy13 
X 
 
 
 
 
 
7.8.4 
Quantitative urine 
culture 
X 
 
 
X 
X 
X 
7.7.4.1 


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Procedure and 
Assessment 
Screening1 
Treatment Period 
EOT4  
(Within 
24 hours of 
last IV dose) 
TOC5 
(Study 
Days 19-
23) 
LFU6 
(Study 
Days 
28-35) 
Section 
of 
Protocol 
Day 12 
Study Days 2-7 (up to Study Day 14 for patients 
with bacteremia)3  
Blood cultures 
X 
 
For patients with positive baseline blood cultures, repeat every 2 to 3 days until negative. 
Also perform as clinically indicated. 
7.7.4.2 
Serum and urine 
β-HCG14 
X 
 
 
 
 
 
7.8.4 
Blood and urine for 
clinical laboratory 
safety assessments15 
X 
 
Study Day 4; Study Days 8 and 12 if still on study 
drug 
X 
X 
X 
7.8.4 
Plasma sampling for 
PK16 
 
X 
Study Days 2 and 3 only  
 
 
 
7.10 
AE monitoring 
X 
X 
Daily 
X 
X 
X 
7.8.5 
Study drug 
administration 
 
X 
Daily 
 
 
 
5.3 
Investigator Opinion 
of Clinical Response 
 
 
 
X 
X 
X 
7.7.5 
β-hCG=beta-human chorionic gonadotropin; AE=adverse event; DPSQ=Daily Patient Symptom Questionnaire; ECG=electrocardiogram; eGFR=estimated 
glomerular filtration rate; EOT=End of Treatment; IV=intravenous; LFU=Late Follow-up; MDRD=Modification of Diet in Renal Disease; 
PK=pharmacokinetics; PPSQ=Pre-morbid Patient Symptom Questionnaire; q8h=every 8 hours; TOC=Test of Cure; UTI=urinary tract infection; WBC=white 
blood cell. 
1 Perform screening assessment prior to first dose of IV study drug. Assessments performed as part of routine standard of care prior to consent (e.g., blood 
culture, laboratory tests) may be used to satisfy screening requirements; however, no study-specific procedures may be performed prior to informed consent. 
2 Administration of the first dose of IV study drug marks the beginning of Study Day 1. Subsequent study days are based on calendar days.  
3 The duration of treatment with study drug will be 7 days. Patients with bacteremia at study entry may have their treatment extended up to 14 days at the 
investigator’s discretion. 
4 EOT visit will be performed within 24 hours after the last dose of IV therapy. When EOT occurs on the same calendar day as the last day of IV therapy, any 
assessments already performed on that calendar day do not need to be repeated, unless EOT occurs on Study Day 1 or clinically indicated based on the 
investigator’s judgement. 
5 TOC visit will occur between Study Days 19 and 23. 
6 LFU visit will occur between Study Days 28 and 35.  
7 Randomization will occur after screening and prior to first dose of study drug. It may be on the same calendar day as Study Day 1 or on the previous calendar 
day. 
8 A UTI-focused physical examination includes assessment of costovertebral angle tenderness and suprapubic/pelvic tenderness.  


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9 UTI-focused physical examination, DPSQ, and vital signs do not need to be repeated on Study Day 1 if screening and Study Day 1 occur on the same calendar 
day.  
10 Record vital signs (heart rate, respiratory rate, temperature [oral or tympanic], and blood pressure). If more than 1 set of vital signs is acquired on a given 
calendar day, the highest temperature and the heart rate, respiratory rate, and blood pressure associated with that temperature (or those acquired nearest to that 
temperature) will be recorded. 
11 Calculate eGFR using the MDRD formula at screening. If the investigator (or designee) determines that calculation of eGFR during the treatment period is 
warranted postbaseline (e.g., due to change in clinical status or for evaluation of need for dose change), local laboratory serum creatinine should be used and 
the results should be reported as an unscheduled laboratory test. See Section 7.8.2 for details for the calculation of eGFR. 
12 ECGs will be performed at screening and on Study Day 4 immediately after completion of cefepime/VNRX-5133 or cefepime/VNRX-5133 placebo infusion. 
13 To demonstrate pyuria during screening, microscopy evaluation of urine for the identification of at least 10 WBCs per cubic millimeter OR microscopic 
evaluation of at least 10 WBCs per high-power field in urine sediment may be performed OR a urinary dipstick for the presence of leukocyte esterase may be 
performed during screening. 
14 Serum β-hCG must be performed as part of screening/eligibility in women of childbearing potential. A patient may begin study drug on the basis of a negative 
urine β-hCG performed at a local laboratory, but a serum β-hCG test must still be sent to the central laboratory for confirmation. 
15 Blood and urine specimens at screening will be sent to a local laboratory to confirm eligibility for randomization. Specimens will be also sent to the central 
laboratory at the timepoints noted in the table. 
16 Sparse PK sampling timepoints are detailed in Section 7.10. 


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TABLE OF CONTENTS 
CLINICAL PROTOCOL APPROVAL FORM .........................................................................2 
SUMMARY OF CHANGES .........................................................................................................3 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT .............................................11 
STUDY SUMMARY ....................................................................................................................12 
SCHEDULE OF ASSESSMENTS .............................................................................................24 
TABLE OF CONTENTS ............................................................................................................27 
LIST OF TABLES .......................................................................................................................30 
LIST OF FIGURES .....................................................................................................................30 
LIST OF ABBREVIATIONS .....................................................................................................31 
1 
INTRODUCTION AND RATIONALE .............................................................................34 
1.1 
Background ......................................................................................................................34 
1.2 
Study Rationale ................................................................................................................35 
1.2.1 
Dose Selection Rationale .............................................................................................35 
1.2.2 
Patient Selection Rationale .........................................................................................36 
1.3 
Benefit-Risk Assessment ..................................................................................................36 
2 
STUDY OBJECTIVES ........................................................................................................38 
2.1 
Primary .............................................................................................................................38 
2.2 
Secondary..........................................................................................................................38 
3 
STUDY PLAN .......................................................................................................................39 
3.1 
Study Design .....................................................................................................................39 
3.2 
Study Endpoints ...............................................................................................................42 
3.2.1 
Primary .........................................................................................................................42 
3.2.2 
Secondary .....................................................................................................................42 
3.3 
Schedule of Assessments ..................................................................................................43 
4 
POPULATION ......................................................................................................................44 
4.1 
Number of Patients ..........................................................................................................44 
4.2 
Inclusion Criteria .............................................................................................................44 
4.3 
Exclusion Criteria ............................................................................................................45 
4.4 
Timing of Enrollment and Randomization....................................................................47 
4.5 
Patient Screening and Replacement ...............................................................................47 
5 
STUDY DRUG MANAGEMENT .......................................................................................48 
5.1 
Identity of Investigational Products ...............................................................................48 
5.1.1 
Storage ..........................................................................................................................48 
5.1.2 
Packaging and Shipment ............................................................................................48 
5.2 
Preparation of Study Drug ..............................................................................................48 
5.3 
Dose and Administration .................................................................................................49 
5.3.1 
Dosing in Patients with Normal Renal Function or eGFR >60 mL/min/1.73 m2 ..50 
5.3.2 
Dose Adjustment for Patients with eGFR ≤60 mL/min/1.73 m2 .............................50 
5.4 
Treatment Duration .........................................................................................................51 
5.5 
Accountability ..................................................................................................................52 
5.6 
Treatment Compliance ....................................................................................................52 
6 
STUDY CONDUCT ..............................................................................................................53 
6.1 
Enrollment and Randomization .....................................................................................53 
6.1.1 
Incorrectly Randomized Patients ...............................................................................53 


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6.1.2 
Blinding ........................................................................................................................53 
6.1.3 
Unblinding ....................................................................................................................54 
6.2 
Study Restrictions and Prohibitions ..............................................................................54 
6.2.1 
Restricted and Prohibited Medications .....................................................................54 
6.2.2 
Contraception Requirements .....................................................................................55 
6.2.3 
Management of Indwelling Bladder Catheters .........................................................55 
6.3 
Premature Discontinuation .............................................................................................55 
6.3.1 
Study Drug Discontinuation .......................................................................................56 
6.3.2 
Study Withdrawal .......................................................................................................56 
6.4 
Protocol Deviations ..........................................................................................................56 
6.5 
Data Collection .................................................................................................................57 
7 
DESCRIPTION OF STUDY PROCEDURES ...................................................................58 
7.1 
Screening ...........................................................................................................................58 
7.2 
Treatment Period .............................................................................................................59 
7.2.1 
Study Day 1 ..................................................................................................................59 
7.2.2 
Study Days 2 to 7 (or up to Study Day 14 for Patients with Bacteremia) ..............60 
7.3 
End of Treatment Visit ....................................................................................................61 
7.4 
Test of Cure Visit .............................................................................................................61 
7.5 
Late Follow-up Visit ........................................................................................................62 
7.6 
Unscheduled Assessments ...............................................................................................63 
7.7 
Efficacy Evaluations ........................................................................................................63 
7.7.1 
Assessment of Symptomatic Clinical Response ........................................................63 
7.7.2 
Assessment of Microbiological Response ..................................................................65 
7.7.3 
Other Microbiological Outcomes ...............................................................................66 
7.7.4 
Specimen Collection and Analysis .............................................................................67 
7.7.5 
Investigator Opinion of Clinical Response ................................................................68 
7.8 
Safety Evaluations ............................................................................................................69 
7.8.1 
Vital Signs ....................................................................................................................69 
7.8.2 
Estimated Glomerular Filtration Rate ......................................................................70 
7.8.3 
Electrocardiogram .......................................................................................................70 
7.8.4 
Clinical Laboratory Tests ...........................................................................................70 
7.8.5 
Adverse Event Monitoring .........................................................................................72 
7.9 
Other Assessments ...........................................................................................................72 
7.9.1 
Medical History and Demographics ..........................................................................72 
7.9.2 
Prior and Concomitant Medication Collection .........................................................72 
7.9.3 
Physical Examination ..................................................................................................72 
7.9.4 
Height and Weight Measurement ..............................................................................73 
7.9.5 
Radiographic Examination .........................................................................................73 
7.9.6 
Surgical Procedures and Other Non-pharmacological Interventions ....................73 
7.10 
Pharmacokinetics .............................................................................................................73 
7.11 
Pharmacogenomics ..........................................................................................................74 
7.12 
Biomarkers .......................................................................................................................74 
7.13 
Total Volume of Blood .....................................................................................................74 
7.14 
Handling, Storage, Transport, and Destruction of Specimens ....................................75 
7.14.1 
Future Use of Stored Specimens ................................................................................75 
8 
ADVERSE EVENT ASSESSMENT AND REPORTING ................................................76 


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8.1 
Definition of an Adverse Event .......................................................................................76 
8.1.1 
Definition of a Serious Adverse Event .......................................................................76 
8.2 
Documenting Adverse Events .........................................................................................77 
8.2.1 
Reporting Serious Adverse Events ............................................................................77 
8.3 
Assessment of Adverse Events ........................................................................................78 
8.3.1 
Assessment of Intensity ...............................................................................................78 
8.3.2 
Assessment of Causality ..............................................................................................78 
8.4 
Adverse Event Follow-up ................................................................................................78 
8.5 
Adverse Events of Special Interest .................................................................................78 
8.6 
Exemptions from Adverse Event Reporting ..................................................................79 
8.6.1 
Laboratory Abnormalities ..........................................................................................79 
8.6.2 
Disease Progression and Lack of Effect ....................................................................79 
9 
OTHER REPORTABLE EVENTS ....................................................................................80 
9.1 
Abnormal Liver Enzymes ...............................................................................................80 
9.2 
Overdose ...........................................................................................................................80 
9.3 
Pregnancy Reporting .......................................................................................................80 
10 STATISTICS .........................................................................................................................81 
10.1 
General Procedures .........................................................................................................81 
10.2 
Sample Size .......................................................................................................................81 
10.3 
Statistical Methods ...........................................................................................................81 
10.3.1 
Study Population .........................................................................................................81 
10.3.2 
Demographic and Baseline Characteristics ..............................................................83 
10.3.3 
Signs and Symptoms ...................................................................................................83 
10.3.4 
Primary Endpoint ........................................................................................................83 
10.3.5 
Secondary Endpoints ..................................................................................................83 
10.3.6 
Analysis of Safety .........................................................................................................84 
10.3.7 
Analysis of Pharmacokinetics .....................................................................................85 
10.3.8 
Resolution of Fever ......................................................................................................85 
10.4 
Interim Analysis ...............................................................................................................85 
11 ETHICS AND RESPONSIBILITIES .................................................................................85 
11.1 
Good Clinical Practice .....................................................................................................86 
11.2 
Data and Safety Monitoring Board ................................................................................86 
11.3 
Institutional Review Board/Independent Ethics Committee .......................................86 
11.4 
Informed Consent ............................................................................................................87 
11.5 
Records Management ......................................................................................................87 
11.6 
Source Documentation.....................................................................................................87 
11.7 
Study Files and Record Retention ..................................................................................87 
12 AUDITING AND MONITORING ......................................................................................88 
12.1 
Clinical Monitoring Plan .................................................................................................88 
12.2 
Quality Control and Assurance ......................................................................................88 
13 AMENDMENTS ...................................................................................................................90 
14 STUDY REPORT AND PUBLICATIONS ........................................................................91 
15 STUDY DISCONTINUATION ...........................................................................................92 
16 CONFIDENTIALITY ..........................................................................................................93 
17 REFERENCES .....................................................................................................................94 
18 APPENDICES .......................................................................................................................95 


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Appendix 1. CONTACT INFORMATION ...............................................................................96 
Appendix 2. PATIENT SYMPTOM ASSESSMENT QUESTIONNAIRES .........................97 
Appendix 3. RECOMMENDED LABORATORY TESTING IN PATIENTS WITH 
ELEVATED LIVER ENZYMES ......................................................................................101 
 
LIST OF TABLES 
Table 1 
Schedule of Assessments ..........................................................................................24 
Table 2 
Investigational Products ..........................................................................................48 
Table 3 
Dose Guidelines for Patients Based on Renal Function ........................................51 
Table 4 
Symptomatic Clinical Response Criteria at EOT .................................................64 
Table 5 
Symptomatic Response Criteria at TOC and LFU ...............................................65 
Table 6 
Microbiological Response Criteria .........................................................................66 
Table 7 
Emergent Infection Criteria ....................................................................................67 
Table 8 
Investigator Opinion of Clinical Response Criteria ..............................................69 
Table 9 
Central Laboratory Assessments ............................................................................71 
Table 10 
Time Windows for Pharmacokinetic Assessments ................................................74 
Table 11 
Total Blood Volume Collected .................................................................................75 
LIST OF FIGURES 
Figure 1 
Study Schematic .......................................................................................................41 
Figure 2 
Study Drug Dosing in Patients with Normal Renal Function or eGFR 
>60 mL/min/1.73 m2 .................................................................................................50 
Figure 3 
Study Drug Dosing in Patients with eGFR >50 to 60 mL/min/1.73 m2 ...............51 
Figure 4 
Study Drug Dosing in Patients with eGFR 30 to 50 mL/min/1.73 m2 ..................51 
Figure 5 
Diagram of the Flank ...............................................................................................98 
 


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LIST OF ABBREVIATIONS 
β-hCG 
beta-human chorionic gonadotropin 
AE 
adverse event 
ALT 
alanine aminotransferase  
AP 
acute pyelonephritis 
AST 
aspartate aminotransferase 
BPH 
benign prostatic hyperplasia 
BUN 
blood urea nitrogen 
CE 
clinically evaluable 
CFU 
colony forming unit 
CI 
confidence interval 
cIAI 
complicated intra-abdominal infection 
CK 
creatine kinase 
CRE 
carbapenem-resistant Enterobacteriaceae 
CRO 
contract research organization 
CSR 
clinical study report 
cUTI 
complicated urinary tract infection 
DPSQ 
Daily Patient Symptom Questionnaire 
DSMB 
data and safety monitoring board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
EOT 
End of Treatment 
ESBL 
extended-spectrum β-lactamase 
GCP 
Good Clinical Practice 
HPF 
High Power Field 
IB 
Investigator’s Brochure 


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ICF 
informed consent form 
ICH 
International Council on Harmonisation 
IEC 
independent ethics committee 
INR 
international normalized ratio 
IRB 
institutional review board 
ITT 
intent-to-treat 
IV 
intravenous(ly) 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
LDH 
lactate dehydrogenase 
LFU 
Late Follow-up 
MDR 
multidrug resistance 
MDRD 
Modification of Diet in Renal Disease 
ME 
microbiologically evaluable 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
minimal inhibitory concentration 
microITT 
microbiological intent-to-treat 
PD 
pharmacodynamic 
PK 
pharmacokinetic(s) 
PPSQ 
Pre-morbid Patient Symptom Questionnaire 
PT 
preferred term 
PTT 
partial thromboplastin time 
q8h 
every 8 hours 
q12h 
every 12 hours 
RBC 
red blood cell 
SAE 
serious adverse event 
SOC 
system organ class 
SOP 
standard operating procedure 


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TEAE 
treatment-emergent adverse event 
TOC 
Test of Cure 
ULN 
upper limit of normal 
US 
United States 
USP 
United States Pharmacopeia 
UTI 
urinary tract infection 
VNRX 
VenatoRx Pharmaceuticals, Inc. (VenatoRx) 
WBC 
white blood cell 
WMA 
World Medical Association 
 


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1 INTRODUCTION AND RATIONALE 
1.1 
Background 
The β-lactam class of antibiotics, because of their efficacy and safety profile, are the most widely 
used class of antibacterial drugs in both the community and hospital settings. However, the 
utility of all members of this class of drugs is being threatened by the spread of new β-lactamases 
in gram-negative pathogens with a very broad spectrum of hydrolyzing activity. While different 
β-lactam class drugs (i.e., penicillins, cephalosporins, monobactams, and carbapenems) are 
differentially affected by various enzymes, no members of the class are unscathed.1 
VNRX-5133 is a non-β-lactam β-lactamase inhibitor with potent and selective direct inhibitory 
activity against both serine- and metallo-β-lactamases (i.e., Ambler Classes A, B, C, and D). 
VNRX-5133, in combination with cefepime, has the potential to address the serious unmet 
medical need for a safe and effective therapy for treatment of infections caused by multidrug 
resistant (MDR) gram-negative bacteria, particularly extended-spectrum β-lactamase-producing 
organisms and carbapenem-resistant Enterobacteriaceae (CRE) and Pseudomonas aeruginosa. 
Cefepime is a broad-spectrum, fourth-generation cephalosporin antibiotic administered 
intravenously (IV) that has been in clinical use for over 2 decades for the treatment of serious 
infections, including moderate to severe pneumonia, complicated urinary tract infections 
(cUTIs), and complicated intra-abdominal infections (cIAIs).  
VenatoRx Pharmaceuticals, Inc. (VenatoRx) is developing VNRX-5133 for use in combination 
with cefepime for the treatment of cUTI, a disease that has been associated with an alarming 
increase in the incidence of MDR β-lactamase-producing organisms. 
cUTI is defined as a clinical syndrome characterized by pyuria and a documented microbial 
pathogen on a culture of urine or blood accompanied by local and systemic signs and symptoms, 
including fever, chills, malaise, flank pain, back pain, and/or costovertebral angle pain or 
tenderness, that occur in the presence of a functional or anatomical abnormality of the urinary 
tract or in the presence of catheterization. Patients with acute pyelonephritis (AP), regardless of 
underlying abnormalities of the urinary tract, are considered a subset of patients with cUTIs.  
VNRX-5133 in combination with cefepime has demonstrated potent in vitro activity against 
CRE and P aeruginosa based on 90% minimal inhibitory concentration (MIC) determinations. 
Several in vitro studies have also shown that the antibacterial activity of cefepime/VNRX-5133 
is largely unaffected by the presence of urine, with most MICs determined in the presence of 
urine within one doubling dilution of MICs determined in its absence (LSI study VNRX-001-16; 
IHMA study 2931). A comprehensive nonclinical safety assessment program was conducted to 
support further clinical studies with VNRX-5133. The initial safety, tolerability, and 
pharmacokinetics (PK) study of cefepime/VNRX-5133 when administered IV to human subjects 
has been previously evaluated in Phase 1 studies. Cefepime/VNRX-5133 was well tolerated in 
these studies.  


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A detailed summary of the available nonclinical and clinical data for cefepime/VNRX-5133 is 
provided in the Investigator’s Brochure (IB).1 
1.2 
Study Rationale 
Cefepime/VNRX-5133 is being developed as an IV antibiotic formulation in combination for the 
treatment of patients with serious gram-negative bacterial infections. The strategy of using 
β-lactam/β-lactamase inhibitor combinations for treatment of infections caused by 
β-lactamases-producing pathogens has been successful in a variety of bacterial infections. 
Gram-negative pathogens, including those producing extended-spectrum β-lactamases (ESBLs), 
AmpC β-lactamases, and carbapenemases, are important causes of cUTIs. The spectrum of 
activity of cefepime/VNRX-5133 is well suited for the treatment of pathogens commonly 
responsible for cUTIs. 
Meropenem has been selected as the comparator because it has demonstrated efficacy against 
gram-negative pathogens isolated in cUTIs, including pyelonephritis. Although meropenem is 
approved for other indications, including cIAI, skin and soft tissue structure infections, and 
bacterial meningitis in pediatric patients, it is not approved for use in cUTI in the United States 
(US). However, meropenem is approved for cUTI in other geographic regions. Furthermore, 
carbapenems are the drugs of choice against ESBL-producing gram-negative pathogens, 
especially in serious infections. As such, it is an appropriate comparator to use when evaluating a 
new drug designed to treat infections due to bacteria harboring serine β-lactamases. 
1.2.1 
Dose Selection Rationale 
For the cefepime/VNRX-5133 treatment group, the selected dose and infusion duration of 
cefepime/VNRX-5133 selected are expected to provide drug exposure that will result in a high 
probability of the PK/pharmacodynamic (PD) target attainment. A number of in vitro and in vivo 
PK/PD studies have been conducted to characterize the pharmacological basis of VNRX-5133 
efficacy when combined with cefepime. The goals of these studies have been to 1) identify the 
PK/PD index that best describes the exposure-response relationship of VNRX-5133 administered 
in combination with cefepime and 2) characterize the magnitude of the PK/PD index required for 
various degrees of bacterial killing. In addition, the results from the nonclinical PK/PD studies 
conducted to date, the human PK data collected in Phase 1 studies, and human plasma protein 
binding data were used to select human therapeutic doses. Lastly, the probability of PK/PD target 
attainment in clinical efficacy studies was further explored by the construction of a population 
PK model based on Phase 1 data and use of Monte Carlo simulations. Taken together, these data 
demonstrate that a 0.5 g dose of VNRX-5133, when administered with cefepime 2 g every 
8 hours (q8h), is expected to be highly effective, even after taking into account increased PK 
variability expected in a patient population compared to that observed in healthy volunteers in 
Phase 1 studies. 
Cefepime/VNRX-5133 will be administered as an IV infusion over 2 hours. 
Meropenem 1 g q8h will be given as an active comparator. In the US and elsewhere, meropenem 
is approved at doses of 0.5 or 1 g q8h, depending on the type of infection. The Summary of 
Product Characteristics indicates that doses of 0.5 or 1 g meropenem q8h is appropriate for cUTI. 


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In order to ensure the best therapy against pathogens that are more difficult to treat, the dose of 
1 g has been chosen. Although meropenem is not approved in the US for cUTI, the 
US prescribing information indicates that 1 g meropenem q8h is appropriate for the treatment of 
patients with cIAIs and skin and soft tissue structure infections due to P aeruginosa, which is 
consistent with the goal to use a higher dose (i.e., 1 g) in more difficult-to-treat infections. 
Patients with bacteremia at study entry may have their treatment extended up to 14 days at the 
investigator’s discretion. 
Additional details on human PK and clinical dosing regimen are provided in the IB.1 
1.2.2 
Patient Selection Rationale 
The population enrolled into the study will include adult male and female patients with cUTI 
(AP or complicated lower urinary tract infection [UTI]). At least 30% of patients will be 
diagnosed with AP. Before receipt of study drug, urine specimen and blood cultures will be 
obtained from all patients for culture and for in vitro antimicrobial susceptibility testing. Patients 
known to have a pathogen with documented resistance to meropenem should be excluded from 
the study. 
1.3 
Benefit-Risk Assessment 
The population for this study will comprise patients with cUTI that are of sufficient severity to 
require hospitalization and treatment with IV antibiotics. The potential benefit to participating 
patients is in receiving effective antibiotic treatment for their infections. The potential benefit of 
the study, in general, is the identification of a novel antibiotic combination product that is an 
effective treatment for cUTI in the face of the changing pattern of antibiotic resistance and the 
need for antibiotics to treat increasingly resistant bacteria. It is possible that 
cefepime/VNRX-5133 will not prove to be a sufficiently effective treatment for cUTIs (i.e., not 
as effective as the comparator treatment). This risk is mitigated in that the patients will be closely 
monitored and managed with appropriate therapies as determined by the investigator who is 
providing treatment. 
The risk considerations for this study should encompass the known and potential risks for the 
development product cefepime/VNRX-5133 and its component products cefepime and 
VNRX-5133, as well as the marketed product meropenem. The risks for cefepime and 
meropenem are widely available in their respective prescribing information; such risks will not 
be discussed in this section.  
The risks for cefepime/VNRX-5133 have not been fully elucidated; however, it is assumed that 
known or potential risks for cefepime/VNRX-5133 should include those identified in the clinical 
study experience with cefepime/VNRX-5133, VNRX-5133 alone, and cefepime alone. Potential 
risks for cefepime/VNRX-5133 include the occurrence of events seen with cefepime alone but 
may occur at a greater frequency and/or severity than those seen with cefepime. In Phase 1 
studies, constipation and abdominal pain were reported. Additional risk information for 
VNRX-5133 and cefepime/VNRX-5133 are located in the VNRX-5133 IB.1 The full risk profile 
for cefepime is described in the prescribing information for the product.  


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In nonclinical studies of VNRX-5133 alone, the kidney was determined to be a target organ of 
VNRX-5133 toxicity in both rats and dogs. In nonclinical studies of VNRX-5133 in combination 
with cefepime, there was no evidence of new or increased severity of toxicity in the 
combination-treated animals relative to animals treated with either drug alone based on clinical 
pathology, gross pathology, or histological parameters. No evidence of renal toxicity has been 
observed in Phase 1 studies of VNRX-5133 when administered alone or in combination of 
cefepime/VNRX-5133. Further information on nonclinical safety assessment and clinical safety 
is summarized in the IB.1 
Meropenem is an approved medication with an established safety profile and will be 
administered at approved doses. Detailed information on the safety and risk profile of 
meropenem is provided in the package insert and SmPC. 


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2 STUDY OBJECTIVES 
2.1 
Primary 
The primary objective of the study is to assess the efficacy of cefepime/VNRX-5133 compared 
with meropenem with respect to both per-patient microbiologic eradication and symptomatic 
resolution of all UTI-core symptoms (or return to pre-morbid baseline) at the Test of Cure (TOC) 
visit. 
2.2 
Secondary 
The secondary objectives of the study are as follows: 
• To determine the efficacy of cefepime/VNRX-5133 compared with meropenem with 
respect to the per-patient microbiological response, per-pathogen microbiologic 
response, and symptomatic resolution of all UTI-core symptoms at various timepoints in 
various populations 
• To determine the efficacy of cefepime/VNRX-5133 compared with meropenem with 
respect to the per-patient microbiological response, per-pathogen microbiologic 
response, and symptomatic resolution of all UTI-core symptoms in patients with cUTI 
due to cefepime-resistant pathogens at various timepoints in various populations 
• To evaluate the safety and tolerability profile of cefepime/VNRX-5133 compared with 
meropenem in the treatment of patients with a cUTI in the safety population 
• To evaluate the steady-state PK of cefepime and VNRX-5133 in patients using a 
population PK model 


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3 STUDY PLAN 
3.1 
Study Design 
Study VNRX-5133-201 is a Phase 3, randomized, multicenter, double-blind, double-dummy, 
active-controlled noninferiority study to evaluate the efficacy, safety, and tolerability of 
cefepime/VNRX-5133 compared with an active control, meropenem, in adult patients with cUTI, 
including AP. Each patient is expected to complete the study within approximately 4 to 5 weeks.  
Patients with cUTI, including AP, will be enrolled. After obtaining signed informed consent and 
confirming eligibility within 24 hours prior to randomization, patients will be randomized in a 
2:1 ratio to receive either cefepime/VNRX-5133 (2 g/0.5 g IV q8h) infused over 2 hours plus 
meropenem placebo infused over 30 minutes or the active comparator, meropenem (1 g IV q8h) 
infused over 30 minutes plus cefepime/VNRX-5133 placebo infused over 2 hours starting on 
Study Day 1.  
Patients will be stratified by the type of infection (AP only versus complicated lower UTI with or 
without AP) and by region (North America and Western Europe versus Eastern Europe versus 
rest of the world). At least 30% of the population will have AP.  
Patients may receive up to 24 hours of antibacterials for treatment of cUTI prior to 
randomization; however, the number of patients with prior antibacterial use will be limited to 
approximately 25% of the population. Before receipt of study drug, urine specimen and blood 
cultures will be obtained from all patients for culture and for in vitro antibacterial susceptibility 
testing. Patients with an indwelling catheter should have urine samples collected following the 
placement of a new catheter, or if the indwelling catheter cannot be removed, aseptic techniques 
should be used through a properly disinfected collection port. Patients with an indwelling 
catheter should be randomized only if they are expected to permanently discontinue use of the 
catheter prior to Study Day 5. 
Screening assessments will also include a Daily Patient Symptom Questionnaire (DPSQ) and a 
Pre-morbid Patient Symptom Questionnaire (PPSQ). The DPSQ will be administered at 
screening, daily while on study drug, and at End of Treatment (EOT), TOC, and Late Follow-up 
(LFU) visits to determine the presence and intensity of cUTI symptoms. The PPSQ will be 
administered once at screening to determine whether a patient normally experiences urinary tract 
symptoms (i.e., in the absence of a UTI) that may be attributable to other disease processes 
(e.g., benign prostatic hyperplasia [BPH]).  
Study drug will be administered IV for 7 days and will be considered completed after the third 
dose on Study Day 7 for patients without bacteremia. All patients (who do not require dosing 
adjustments for renal dysfunction) will receive at least 19 doses. Patients without bacteremia will 
receive a maximum of 21 doses of active study drug. Patients with bacteremia at study entry may 
have their treatment extended up to 14 days at the investigator’s discretion.  
Patients will be admitted at screening and remain at the study site or hospital for the duration of 
the IV treatment period and through the EOT visit. The EOT visit will be performed within 
24 hours after the last dose of IV study drug. Patients may be discharged from the study site after 
the EOT visit if clinically stable and at the investigator’s discretion. 


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Patients must return to the study site for the TOC visit (Study Days 19 to 23) and the LFU visit 
(Study Days 28 to 35). 
The study design is summarized in Figure 1. 


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Figure 1 
Study Schematic 
 


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3.2 
Study Endpoints 
3.2.1 
Primary 
The primary endpoint is the demonstration of microbiological success (any gram negative 
bacterial pathogens found at study entry are eradicated to <103 colony forming units per milliliter 
[CFU/mL] on urine culture) and the demonstration of symptomatic clinical success 
(symptomatic resolution or return to pre-morbid baseline of all UTI-core symptoms including 
frequency, urgency, dysuria, suprapubic/pelvic pain, and flank pain, patient is alive, and patient 
has not received additional antibacterial therapy for cUTI) at TOC in the microbiological intent-
to-treat (microITT) population. 
3.2.2 
Secondary 
Clinical and Microbiological Efficacy: 
• The proportion of patients with both microbiological success and symptomatic clinical 
success at TOC in the extended microITT population, clinically evaluable (CE)- TOC 
and microbiologically evaluable (ME)- TOC populations 
• The proportion of patients with both microbiological success and symptomatic clinical 
success at EOT in the micro-ITT, ME-EOT and CE-EOT analysis populations and at 
LFU in the micro-ITT, ME-LFU and CE-LFU populations 
• The proportion of patients with per-patient microbiological success at EOT, TOC and 
LFU in the micro-ITT, ME-EOT, ME-TOC and ME-LFU populations 
• The proportion of patients with symptomatic clinical success at EOT, TOC and LFU in 
micro –ITT, CE- EOT, CE-TOC and CE-LFU populations 
• The proportion of patients with clinical success based on investigator opinion at TOC in 
the microITT population 
• The proportion of patients with per-pathogen microbiological success at EOT in the 
micro-ITT and ME-EOT populations, TOC in the micro-ITT and ME-TOC populations, 
and at LFU in the micro-ITT and ME-LFU populations 
• The proportion of patients with both microbiological success and symptomatic clinical 
success among those with cefepime-resistant pathogens at EOT in the micro-ITT, ME-
EOT and CE-EOT populations, TOC in the micro-ITT, ME-TOC, and CE-TOC 
populations, and at LFU in the micro-ITT, ME-LFU and CE-LFU populations 
• The proportion of patients with per-patient microbiological success among those with 
cefepime-resistant pathogens at EOT in the micro-ITT and ME-EOT populations, TOC 
in the micro-ITT and ME-TOC populations, and at LFU in the micro-ITT and ME-LFU 
populations 


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• The proportion of patients with per-pathogen microbiological success among those with 
cefepime-resistant pathogens at EOT in the micro-ITT and ME-EOT populations, TOC 
in the micro-ITT and ME-TOC populations, and at LFU in the micro-ITT and ME-LFU 
populations 
• The proportion of patients with symptomatic clinical success among those with 
cefepime-resistant pathogens at EOT in the micro-ITT and CE-EOT populations, TOC 
in the micro-ITT and CE-TOC populations, and at LFU in the micro-ITT and CE-LFU 
populations 
Safety and Tolerability: 
• Safety and tolerability will be assessed based on the incidence and severity of adverse 
events (AEs) and serious adverse events (SAEs), exposure, mortality, reasons for 
discontinuation of study drug and study withdrawal, vital sign measurements, and 
clinically significant changes in clinical chemistry, hematology, urinalysis, and 
coagulation laboratory values. 
Pharmacokinetics: 
• The population PK analysis using data from the study will be described in a population 
PK analysis plan and summarized in a separate report. 
Resolution of Fever:  
• The time to first defervescence (≤37.8°C) in the microITT population for patients who 
have fever (>38°C) at baseline will be assessed as an exploratory endpoint.  
3.3 
Schedule of Assessments 
See Table 1 for general schedule of assessments and Table 10 for the schedule of PK 
assessments. 


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4 POPULATION 
4.1 
Number of Patients 
A total of 582 adult male and female patients will be randomized into 2 groups in a 2:1 ratio 
(388 patients to cefepime/VNRX-5133; 194 patients to meropenem) at approximately 122 sites. 
The study duration will be approximately 14 months. 
4.2 
Inclusion Criteria 
Patients must meet the following general inclusion criteria to be eligible for inclusion in the 
study: 
1. Provide signed informed consent 
2. Adult male and female, ≥18 years of age 
3. If female, meets at least 1 of the following criteria: 
• Surgically sterile 
• Age ≥50 years and postmenopausal for ≥12 months 
• Age <50 years and postmenopausal for ≥2 years 
• Patient has a negative serum pregnancy test and agrees not to attempt pregnancy and, 
if participating in sexual activity, agrees to use an effective dual method of 
contraception 
4. Patient has pyuria as demonstrated by at least 1 of the following: 
• Urine dipstick positive for leukocyte esterase 
• White blood cells (WBC) >10 cells/μL in unspun urine 
• WBC >10 cells per high power field (HPF) in urine sediment 
5. Demonstrates either AP or complicated lower UTI as defined by the following criteria: 
a. AP is indicated by the presence of both of the following criteria: 
• At least 1 of the following is present: 
o Nausea or vomiting 
o Chills or rigors or warmth associated with fever, defined as body 
temperature >38°C 
• Has flank pain or costovertebral angle tenderness 


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b. Complicated lower UTI is indicated by the presence of all 3 of the following 
criteria: 
• At least 1 of the following is present: 
o Nausea or vomiting 
o Chills or rigors or warmth associated with fever, defined as body 
temperature >38°C 
• At least 1 of the following signs/symptoms is present:  
o Dysuria 
o Urinary urgency 
o Urinary frequency 
o Pelvic pain or suprapubic tenderness/pelvic tenderness 
• At least 1 of the following complicating factors is present: 
o Chronic urinary retention 
o Obstructive uropathy (if complete obstruction, should intend to relieve 
obstruction within 48 hours after randomization) 
o Neurogenic bladder with presence or history of urine residual volume of 
>100 mL 
o Indwelling catheter (with expectation for permanent discontinuation of the 
catheter by Study Day 5) 
6. Requires IV antibacterial therapy as initial treatment for cUTI 
4.3 
Exclusion Criteria 
Patients who meet any of the following general exclusion criteria will not be eligible for 
inclusion in the study: 
1. Receipt of effective antibacterial drug therapy for cUTI for a continuous duration of more 
than 24 hours during the previous 72 hours prior to randomization 
2. Where a urine culture result is available: 
• At least 1 uropathogen at ≥105 CFU/mL is resistant to a meropenem, or 
• A gram-negative bacterial pathogen is not identified 
• More than 2 microorganisms are isolated regardless of the colony count, or 
• The patient has a confirmed fungal UTI with colony count ≥103 CFU/mL 


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3. Requirement for use of nonstudy systemic antibacterial drug therapy that would have a 
potential effect on outcome evaluations in patients with cUTI 
4. Patients with suspected or confirmed prostatitis or urinary tract symptoms attributable to 
sexually transmitted disease 
5. Patients with perinephric or renal abscess 
6. Patients with renal transplantation or receiving hemodialysis or peritoneal dialysis 
7. Patients with urinary diversions (e.g., ileal loops, cutaneous urostomy) 
8. Patients who may need ongoing antibacterial drug prophylaxis after treatment of cUTI 
(such as vesico-ureteral reflux) 
9. Any recent history of trauma to the pelvis or urinary tract 
10. Patient has any urinary catheter or device or foreign body that will not be discontinued by 
Study Day 5, including, but not limited to, indwelling bladder catheter, urinary catheter, 
nephrostomy tubes, or stent 
11. Patient is unlikely to respond to 7 days of antibacterial therapy for the treatment of cUTI 
without bacteremia or up to 14 days of therapy for treatment of cUTI with bacteremia 
12. Patient has acute hepatitis, cirrhosis (Child-Pugh Class B or C), acute hepatic failure, or 
acute decompensation of chronic hepatic failure  
13. Patient has had a heart, lung, heart-lung, or pancreatic transplant at any time; or bone 
marrow transplant in the preceding year 
14. Patient has any of the following laboratory values: 
• Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 calculated by 
Modification of Diet in Renal Disease (MDRD) formula2 
• Hematocrit <25% or hemoglobin <8 g/dL 
• Platelet count <50,000/mm3 
• Total bilirubin >3.0× the upper limit of normal (ULN), unless isolated 
hyperbilirubinemia is directly related to the acute infection or due to known Gilbert’s 
disease 
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3.0× ULN at 
screening. Patients with values >3.0× ULN and <5.0× ULN are eligible if these 
values are acute and documented as being directly related to the infectious process 
being treated. 


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• Alkaline phosphatase >3.0× ULN. Patients with values >3.0× ULN and <5.0× ULN 
are eligible if this value is acute and documented as being directly related to the 
infectious process being treated. 
15. Patient has a history of serious hypersensitivity (e.g., anaphylaxis), serious allergy, or any 
serious reaction to cephalosporin, penicillin, carbapenem, or other β-lactam antibacterials 
16. Patient is considered unlikely to survive the 4- to 5-week study period or have a rapidly 
progressive or terminal illness, including septic shock, that is associated with a high risk of 
mortality 
17. Patient requires concomitant medication with valproic acid or divalproex 
18. Patient is in a situation or has a condition that, in the investigator’s opinion, may interfere 
with optimal participation in the study, or is unlikely to comply with protocol (e.g., inability 
to fully comprehend and clearly respond to questions on the PPSQ and DPSQ in a reliable 
manner, uncooperative attitude, inability to return for follow-up visit, or unlikely to complete 
the study) 
19. Patient is participating in any other clinical study that involves the administration of an 
investigational product at the time of presentation or during the course of the study or has 
received treatment with an investigational product in the 30 days prior to study enrollment 
20. Female patients who are pregnant, lactating, or planning to become pregnant during this 
study 
4.4 
Timing of Enrollment and Randomization 
Assessments performed as part of routine standard of care prior to consent (e.g., blood culture, 
laboratory tests) may be used to satisfy screening requirements; however, no study-specific 
procedures may be performed prior to informed consent. The timing of enrollment (i.e., informed 
consent) and randomization of patients to receive study drug is presented in Table 1. 
4.5 
Patient Screening and Replacement 
Patients who drop out or withdraw for any reason without completing all screening evaluations 
successfully or who fail to meet the inclusion and exclusion criteria will be considered 
“screening failures”. Randomized patients who are withdrawn from the study will not be 
replaced. 
Detailed discontinuation and withdrawal requirements and procedures are detailed in Section 6.3. 


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5 STUDY DRUG MANAGEMENT 
5.1 
Identity of Investigational Products 
The investigational products for the study are detailed in Table 2. 
Further details on investigational products, preparation, storage, and administration are provided 
in the pharmacy manual. 
Table 2 
Investigational Products 
Drug Product 
Dose Administered 
Dosage Form 
Meropenem  
1 g IV q8h 
1 g/vial 
Cefepime 
2 g IV q8h 
2 g/vial 
VNRX-5133 
0.5 g IV q8h 
0.5 g/vial 
Meropenem placebo 
Matching meropenem 
Sodium chloride injection USP 0.9% 
Cefepime/VNRX-5133 placebo 
Matching cefepime/VNRX-5133 
Sodium chloride injection USP 0.9% 
IV=intravenous; q8h=every 8 hours; USP=United States Pharmacopeia. 
5.1.1 
Storage 
VNRX-5133 drug product will be stored according to instructions in the pharmacy manual. 
Cefepime and meropenem will be stored according to the manufacturer’s recommendations in 
their respective package inserts.  
5.1.2 
Packaging and Shipment 
VNRX-5133 drug product will be supplied as a sterile, white to yellow powder in single-dose 
vials. 
Cefepime will be supplied as a sterile, white to pale yellow powder in single-dose vials.  
Meropenem will be supplied as a sterile white to pale yellow powder in single-dose vials. 
Sodium chloride (0.9% solution) used for study drug reconstitution and for placebo will be 
obtained. 
5.2 
Preparation of Study Drug 
Study drug will be prepared by an unblinded pharmacist or designee as outlined in the pharmacy 
manual. Blinded study staff, including the investigator and blinded study site personnel, cannot 
participate in the preparation of study drug.  
Meropenem (1 g/vial) will be reconstituted solution as described in the package insert.  


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For cefepime/VNRX-5133, cefepime hydrochloride (2 g/vial, sterile, white to pale yellow 
powder) and VNRX-5133 (0.5 g/vial sterile, white to yellow powder) will each be reconstituted 
independently, then combined into a single IV bag, and diluted with 0.9% sodium chloride 
solution. 
For cefepime/VNRX-5133 placebo and meropenem placebo, 0.9% sodium chloride for injection 
will be used matching cefepime/VNRX-5133 and meropenem, respectively. 
Details on the preparation of study drug and blinding of the prepared bags are provided in the 
pharmacy manual. Study drug and placebo IV bags as well as IV tubing will be blinded with 
sleeves. 
5.3 
Dose and Administration 
Each patient will receive a 30-minute infusion and a 2-hour infusion q8h. If only 1 line is 
available for IV medication administration, the 30-minute infusion should be administered prior 
to the 2-hour infusion. The 30-minute and 2-hour infusions may be administered concurrently if 
2 separate lines are used. 
Patients randomized to cefepime/VNRX-5133 will receive meropenem placebo IV immediately 
followed by cefepime/VNRX-5133 (2 g/0.5 g IV q8h). Meropenem placebo will be administered 
via IV pump over 30 minutes. Cefepime/VNRX-5133 will be administered via IV pump over a 
2-hour period.  
Patients randomized to receive meropenem will also receive cefepime/VNRX-5133 placebo IV 
immediately following meropenem (1 g IV q8h). Meropenem will be infused over 30 minutes. 
Cefepime/VNRX-5133 placebo will be administered via IV pump over a 2-hour period. 
Study drug administration for patients with normal renal function or mild renal impairment is 
presented in Figure 2. For patients with normal renal function or mild renal impairment with 
eGFR ≥60 mL/min/1.73 m2, a 1-time adjustment of dose regimen for cefepime/VNRX-5133 or 
meropenem may be made after administration of the first dose to allow the patient to shift onto a 
hospital medication administration schedule. Their second dose may be administered as soon as 
4 hours and as long as 10 hours after administration of the first dose. No other adjustments to 
cefepime/VNRX-5133 or meropenem may be made, except for patients with changes in eGFR as 
described in Section 5.3.2.  
The date and time of each infusion (start and stop time of infusion) will be recorded. In the event 
that there is an issue with a patient’s IV infusion site, the planned infusion may be paused to 
restart another IV. The stop and restart times must be recorded. 
Dosing adjustments for cefepime/VNRX-5133 (or cefepime/VNRX-5133 placebo) and 
meropenem (or meropenem placebo) in patients with renal insufficiency are described in 
Section 5.3.2. The initial dose chosen should be based on the most recent eGFR value obtained 
prior to dosing. However, because dosing recommendations for the study drugs vary depending 
on the patient’s renal function, the investigator should consider whether the change in eGFR 
warrants a change in IV study drug dosage or frequency. Since a decline in renal function may be 


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transient, eGFR should be closely followed in patients demonstrating renal dysfunction at any 
point before or during the study to ensure that therapeutic doses are being administered. In 
particular, when the eGFR falls between 50 and 60 mL/min/1.73 m2 (at which point there are 
different dosing recommendations for cefepime/VNRX-5133 [or cefepime/VNRX-5133 placebo] 
and meropenem [or meropenem placebo]) or when eGFR falls below 30 mL/min/1.73 m2 (at 
which point study drug should be discontinued), a repeat serum creatinine test result should be 
obtained, and eGFR calculation should be repeated before dose adjustments are made. 
5.3.1 
Dosing in Patients with Normal Renal Function or eGFR >60 mL/min/1.73 m2 
Study drug dosing in patients with normal renal function or mild renal impairment 
(eGFR >60 mL/min/1.73 m2) is presented in Figure 2. 
Figure 2 
Study Drug Dosing in Patients with Normal Renal Function or eGFR 
>60 mL/min/1.73 m2 
 
eGFR=estimated glomerular filtration rate; MDRD=Modification of Diet in Renal Disease. 
Note: eGFR is calculated using the MDRD formula. 
5.3.2 
Dose Adjustment for Patients with eGFR ≤60 mL/min/1.73 m2 
When clinically indicated, eGFR calculation should be repeated to determine whether dose 
adjustment is needed. If the dose is adjusted, local clinical laboratory and eGFR results should be 
recorded on the unscheduled/local laboratory electronic case report form (eCRF). 
The dose regimen of all study drugs should be adjusted according to the guidelines detailed in 
Table 3 based on eGFR. Given the different eGFR requirements for dose change across the 
treatment regiments, eGFR should be re-tested before adjusting therapy if the eGFR is between 
50 and 60 mL/min/1.73 m2. Similarly, eGFR should be re-tested before discontinuing therapy 
when the eGFR is <30 mL/min/1.73 m2.  
The adjusted dose regimens for patients based eGFR are also presented in Figure 3 and Figure 4. 


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Table 3 
Dose Guidelines for Patients Based on Renal Function 
eGFR1  
(mL/min/1.73 m2) 
Cefepime/VNRX-5133 or  
Cefepime/VNRX-5133 placebo 
Meropenem or  
Meropenem placebo  
>60 
2 g/0.5 g IV q8h over 2 hours 
1 g IV q8h over 30 minutes 
>50-60  
2 g/0.5 g IV q12h over 2 hours2 
1 g IV q8h over 30 minutes2 
30-50 
2 g/0.5 g IV q12h over 2 hours 
1 g IV q12h over 30 minutes 
<30 
Discontinue study drug3 
Discontinue study drug3 
eGFR=estimated glomerular filtration rate; IV=intravenous; MDRD=Modification of Diet in Renal Disease; 
q8h=every 8 hours; q12h=every 12 hours. 
1 eGFR is calculated using the MDRD formula.  
2 Repeat serum creatinine test and recalculate eGFR. If eGFR remains >50 to 60 mL/min/1.73 m2, adjust dose 
accordingly. 
3 Repeat serum creatinine test and recalculate eGFR. If eGFR remains <30 mL/min/1.73 m2, discontinue all study 
drug. 
Figure 3 
Study Drug Dosing in Patients with eGFR >50 to 60 mL/min/1.73 m2 
 
eGFR=estimated glomerular filtration rate; MDRD=Modification of Diet in Renal Disease. 
Note: eGFR is calculated using the MDRD formula. 
Figure 4 
Study Drug Dosing in Patients with eGFR 30 to 50 mL/min/1.73 m2 
 
eGFR=estimated glomerular filtration rate; MDRD=Modification of Diet in Renal Disease. 
Note: eGFR is calculated using the MDRD formula. 
5.4 
Treatment Duration 
All patients will receive 7 days of IV treatment.  Based on the scheduled study drug 
administration for patients without bacteremia, the patient could complete treatment on study day 
7 or study day 8.  
All non-bacteremic patients (who do not require dosing adjustments for renal dysfunction) will 
receive at least 19 doses and no more than 21 doses of study drug.  


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Patients with bacteremia at study entry may have their treatment extended up to 14 days at the 
investigator’s discretion, but may complete therapy as early as Study Day 7 after their third dose.  
There is no oral stepdown therapy, and patients are not permitted to continue oral antibacterials 
at home after completion of IV study drug (e.g. prophylaxis). If prophylactic therapy is 
warranted due to recurrent cUTIs, it should not be started until after the LFU visit if possible. 
Patients who are known to require prophylactic therapy and for whom withholding therapy until 
the LFU visit is not in their best interest should not be enrolled (see Exclusion Criterion 8).  The 
Investigator should continually assess whether the study drug has failed (i.e., the patient has 
signs and symptoms of cUTI that have not improved or have recurred such that additional 
antibiotic therapy is warranted) and rescue therapy is required. 
5.5 
Accountability 
Study drug will only be prepared by the unblinded pharmacist or designee. Study drug will be 
dispensed in a blinded manner to the investigator or medically qualified designated personnel by 
the unblinded pharmacist or designee. Study drug will only be administered to patients by 
medically qualified designated personnel who have been appropriately trained to administer 
study drug. 
The unblinded pharmacist is responsible for the control of study drugs under investigation. 
Adequate records of the receipt and disposition of the study drug must be maintained. Drug 
disposition records must be kept current. 
A separate unblinded study monitor will periodically review pharmacy logs and drug 
accountability. All records and drug supplies must be available for inspection by the study 
monitor at every monitoring visit. Any reconstituted unused study drug has to be inactivated, and 
unused, used, or partially used vials should be destroyed after use at the study site per local 
institute policy and procedures. If the study site does not have a destruction policy, the unused, 
used, or partially used vials can be shipped back to the depot for destruction. Completed drug 
dispensation records will be returned to the sponsor. The investigator’s copy of the drug 
dispensation record(s) must accurately document the return of all study drug supplies to the 
depot, if applicable. 
5.6 
Treatment Compliance 
All study drug will be administered by medically qualified designated personnel. To ensure 
treatment compliance, date, and exact start and stop times of study drug administration, including 
times for any interruptions that occur, will be recorded for all study drug administered in the 
eCRF by the investigator or authorized designee. 


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6 STUDY CONDUCT 
All procedures will be performed in accordance with the schedule of assessments as detailed in 
Table 1. Detailed instructions for specific study procedures are provided in Section 7. Detailed 
requirements for reporting AEs and SAEs are provided in Section 8. 
6.1 
Enrollment and Randomization 
After providing informed consent, patients will be enrolled into the study, entered into the 
Interactive Web Response System/Interactive Voice Response System (IWRS/IVRS), and 
assigned a unique screening number from the IWRS/IVRS for the screening process. After 
completing the screening process, patients who meet all eligibility criteria will be re-entered into 
the IWRS/IVRS and assigned a unique randomization number and study drug randomly 
computer-generated by the IWRS/IVRS. Randomization and screening numbers will not be 
reused. Patients will be randomly assigned to receive either cefepime/VNRX-5133 (2 g/0.5 g IV 
q8h) plus meropenem placebo, or the active comparator, meropenem (1 g IV q8h) plus 
cefepime/VNRX-5133 placebo, in a 2:1 ratio according to the randomization number. 
Randomization occurs after screening and prior to administration of the first dose of study drug. 
Administration of the first dose of study drug marks the start of Study Day 1. Therefore, 
randomization may occur on the same calendar day as Study Day 1 or on the previous calendar 
day.  
Patients will be stratified by the type of infection (AP only versus complicated lower UTI with or 
without AP) and by region (North America and Western Europe versus Eastern Europe versus 
rest of the world). At least 30% of the population will have AP. Patients may receive up to 
24 hours of antibacterial for treatment of cUTI prior to randomization; however, the number of 
patients with prior antibacterial use will be limited to approximately 25% of the population.  
Patients who fail to meet the inclusion and exclusion criteria should not be randomized or 
receive study drug. There will be no exceptions to this rule. Patients who fail to meet the 
inclusion and exclusion criteria will not be rescreened. Procedures for ineligible patients who are 
erroneously randomized are described in Section 6.1.1. 
6.1.1 
Incorrectly Randomized Patients 
The investigator should inform the sponsor or designee of patients who are randomized 
erroneously, do not meet the selection criteria, are incorrectly started on study drug, or who 
subsequently fail to meet the study criteria after treatment initiation. The patient should continue 
to receive study drug unless the investigator or sponsor considers that it is not in the best interest 
of the patient. The investigator should use their clinical discretion to determine whether 
discontinuation of study drug is warranted. 
6.1.2 
Blinding 
All study drugs will be prepared at the study site by an unblinded pharmacist or designee. 
Prepared study drug and placebo IV bags and IV tubing will be blinded with sleeves to maintain 
the blind. To maintain blinding, the randomization code and study drug assignment will be 
provided by the IWRS/IVRS to the unblinded pharmacist or unblinded designee for dispensing 


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purposes and kept in the pharmacy, accessible to the unblinded pharmacist and designee only. 
The unblinded pharmacist or designee is not permitted to perform any other study procedures. 
The sponsor, investigator, patient, and study site staff, with the exception of the unblinded 
pharmacist or designee, will remain blinded to study drug. The unblinded study monitor 
(separate from the other blinded monitors) will also remain unblinded.  
The bioanalytical laboratory where the PK samples will be analyzed will be provided treatment 
assignment information to facilitate analyzing samples using methods for only treatments 
administered. A third party pharmacokineticist responsible for the PK analysis may be unblinded 
in order to begin analysis of data prior to study completion. This pharmacokineticist will have no 
involvement in the conduct of the study. No one else will have access to the treatment 
assignment information. 
Procedures to maintain study blinding will be detailed in a separate blinding plan. 
6.1.3 
Unblinding 
Unblinding of therapy assignment may be requested in an emergency if unblinding is considered 
necessary for medical management of the patient. In such case, the investigator is strongly 
encouraged to contact the medical monitor to discuss the case prior to unblinding; however, the 
decision and ability to unblind is independent of medical monitor’s input. 
If the data and safety monitoring board (DSMB) determines individual treatment assignment 
unblinding for patients is required to support an ad hoc meeting, an independent statistician will 
provide treatment information to the DSMB, and the DSMB will review unblinded data in the 
closed session. 
6.2 
Study Restrictions and Prohibitions  
6.2.1 
Restricted and Prohibited Medications 
Use of systemic antibacterials other than study drug therapy, including prophylactic 
antibacterials, is not permitted during the study except in the following circumstances: 
• If Enterococcus spp. or methicillin-resistant Staphylococcus aureus is isolated or 
suspected, then open-label vancomycin, linezolid, or daptomycin may be added to either 
of the study regimens according to the usual practice of the investigator.  
• When the investigator considers addition of nonstudy antibacterials essential to the 
safety and well-being of the patient due to an AE (i.e., a new infection develops at 
another site). In this circumstance, if possible, the investigator should attempt to choose 
an antibacterial that will not have activity against the patient’s baseline cUTI 
pathogen(s) to avoid confounding the assessment of the effect of study drug.  
Patients who are known to require prophylactic therapy and for whom withholding therapy until 
LFU visit is not in their best interest should not be enrolled (see Exclusion Criterion 8). 


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Probenecid should not be administered. Probenecid may decrease excretion of β-lactam 
antibiotics. 
Valproic acid and divalproex sodium should not be administered. Valproic acid concentrations in 
the blood may drop below the therapeutic range when co-administered with meropenem. 
The following medications should be used with caution in all patients:  
• Aminoglycosides: Concomitant administration of cefepime results in an increased 
potential of nephrotoxicity and ototoxicity of aminoglycoside antibacterial drugs. 
Monitor renal function closely if aminoglycosides are administered  
• Diuretic nephrotoxicity has been reported following concomitant administration of other 
cephalosporins with potent diuretics such as furosemide. Monitor renal function when 
cefepime is concomitantly administered with potent diuretics.  
6.2.2 
Contraception Requirements 
Male patients who are not surgically sterilized and female patients of childbearing potential must 
agree to use an effective dual method of contraception during the study. A woman is considered 
of childbearing potential unless postmenopausal (age ≥50 years and ≥12 months without menses 
or age <50 years and ≥2 years without menses) or surgically sterilized. Male patients may not 
donate sperm from the first dose of study drug until 90 days after the last dose of study drug is 
administered. 
6.2.3 
Management of Indwelling Bladder Catheters 
Indwelling bladder catheters that have been in place for >24 hours prior to screening must be 
removed or replaced prior to collection of urine at screening for urinalysis and culture (unless 
removal or replacement is considered unsafe or is contraindicated due to a recent procedure or 
urological condition), so that the urine culture results are an accurate representation of the 
pathogen(s) present.  
Patients should only be enrolled if the indwelling bladder catheter is expected to be permanently 
discontinued prior to Study Day 5.  
Indwelling bladder catheters should be maintained as a sterile, closed drainage system, and the 
junction of the catheter and drainage tube should not be disconnected. Besides permanent 
catheter discontinuation, other indications for indwelling bladder catheter change may include 
malfunction or leakage, obstruction, and contamination of the system (breakage between the 
catheter and drainage tube). 
6.3 
Premature Discontinuation 
Patients are free to withdraw from the study or study drug at any time. Patients may also be 
prematurely discontinued from study drug or withdrawn from the study at the discretion of the 
investigator or sponsor at any time. Once a patient has been withdrawn from the study, they may 


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not be re-entered. Reasons for discontinuation from study drug or from the study will be 
collected in the eCRF. 
6.3.1 
Study Drug Discontinuation 
Patients may be prematurely discontinued from study drug (i.e., before 7 full days of therapy 
and/or before cure of the infection [i.e., rescue therapy is necessary]) for the following reasons:  
• Insufficient therapeutic effect of the study drug (i.e., requirement for additional nonstudy 
antibacterial therapy to treat cUTI based on the investigator’s clinical judgement) 
• AE 
• Withdrawal by patient (the patient is free to discontinue therapy at any time) 
• Physician decision (i.e., in the opinion of the investigator, it is not in the best interest of 
the patient to continue study drug) 
• Sponsor decision 
• A decrease in eGFR to <30 mL/min/1.73 m2 (An eGFR <30 mL/min/1.73 m2 should be 
rechecked and confirmed before discontinuation.) 
• AST or ALT ≥10× ULN 
If a patient is prematurely discontinued from study drug, the EOT visit should be performed, and 
every effort should be made to retain the patient in the study and perform all assessments at the 
TOC and LFU visits. Patients withdrawn from study drug should receive rescue therapy (if 
appropriate) as determined by the investigator. 
6.3.2 
Study Withdrawal 
Participation in the study is strictly voluntary. A patient has the right to withdraw from the study 
at any time for any reason without prejudice to further treatment (withdrawal of consent). Such 
patients will always be asked about the reason(s) and the presence of any AEs. If possible, the 
patient will be seen and assessed by the investigator at the time of withdrawal. If the patient has 
withdrawn from the study prior to completion of study therapy, every effort should be made to 
perform the EOT visit. AEs and SAEs will be followed up.  
6.4 
Protocol Deviations 
A protocol deviation is any change, divergence, or departure from the study design or procedures 
defined in the protocol. 
All deviations will be compiled in a centralized location.  
Deviations will be classified by whether or not they meet the definition of important protocol 
deviations in a blinded manner. Important protocol deviations are a subset of deviations that 


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might significantly affect the completeness, accuracy, and/or reliability of the study data or that 
might significantly affect a patient’s rights, safety, or well-being. 
Deviations will be categorized by type and will be reviewed on an ongoing basis. Protocol 
deviation notification and reports are submitted to regulatory authorities and/or relevant 
institutional review boards (IRBs) according to applicable requirements/guidelines/law. 
6.5 
Data Collection 
All clinical data, including AEs and prior/concomitant medications, will be collected for each 
patient by an electronic data capture (EDC) system in an eCRF. Source data supporting EDC 
entries will be recorded in the patient’s medical records according to the standard practice of the 
study site.  
Investigators and study site personnel will be responsible for entering data within the eCRF and 
will respond to queries within the EDC system. Correction of any data errors and other such 
changes will be made within the EDC system and captured in the electronic audit trail. 


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7 DESCRIPTION OF STUDY PROCEDURES 
Study procedures are specified in the general schedule of assessments in Table 1 and the 
schedule of PK assessments are presented in Table 10. 
7.1 
Screening 
Screening assessments and procedures must be performed within 24 hours prior to 
randomization. The following assessments and procedures will be performed at screening: 
• Obtain informed consent (see Section 4.4) 
• Confirm eligibility (see Sections 4.2 and 4.3) 
• Collect medical and surgical history (see Section 7.9.1) 
• Collect demographics (see Section 7.9.1) 
• Collect prior and concomitant medications (including prior antibiotic therapy) (see 
Section 7.9.2) 
• Perform complete physical examination (see Section 7.9.3) 
• Perform UTI-focused physical examination (see Section 7.9.3) 
• Perform DPSQ (see Section 7.7.1) 
• Perform PPSQ (see Section 7.7.1) 
• Measure height and weight (see Section 7.9.4) 
• Measure vital signs: blood pressure, heart rate, respiratory rate, and temperature (oral or 
tympanic) (see Section 7.8.1) 
• Calculate eGFR (see Section 7.8.2) 
• Perform 12-lead electrocardiogram (ECG; see Section 7.8.3) 
• Obtain blood cultures (see Section 7.7.4.2) 
• Obtain quantitative urine culture (see Section 7.7.4.1) 
• Obtain urine microscopy or urine dipstick to document WBCs or leukocyte esterase, 
respectively (see Section 7.8.4) 


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• Perform serum or urine beta-human chorionic gonadotropin (β-hCG) test at a local 
laboratory site for women of childbearing potential to confirm eligibility (see Section 
7.8.4) 
• Obtain serum sample for β-hCG for women of childbearing potential and send to the 
central laboratory (see Section 7.8.4) 
• Obtain blood and urine samples for central laboratory safety assessments (use local 
laboratory results to confirm eligibility; see Section 7.8.4) 
• Monitor AEs (see Section 7.8.5) 
Randomization marks the end of the screening/baseline period and the start of the treatment 
period. 
7.2 
Treatment Period 
Randomized patients will receive study drug as described in Section 5. The duration of therapy 
for each patient in both treatment groups will be 7 days of IV therapy (see Section 5.4). Patients 
with bacteremia at study entry may have their treatment extended up to 14 days at the 
investigator’s discretion. 
Administration of the first dose of study drug marks the beginning of Study Day 1. Subsequent 
study days are based on calendar days. 
Patients must remain hospitalized at the study site while receiving treatment. After the EOT visit, 
patients may be discharged at the investigator’s discretion.  
7.2.1 
Study Day 1 
Administration of the first dose of study drug marks the beginning of Study Day 1. The 
following assessments and procedures will be performed during Study Day 1 of the treatment 
period: 
• Randomization (Note: Randomization occurs after screening and prior to administration 
of the first dose of study drug. It may occur on the same calendar day as Study Day 1 or 
on the previous calendar day; see Section 6.1) 
• Review concomitant medications (see Section 7.9.2) 
• Perform UTI-focused physical examination (Note: Does not need to be repeated on 
Study Day 1 if screening and Study Day 1 occur on the same calendar day; see Section 
7.9.3) 
• Perform DPSQ (Note: Does not need to be repeated on Study Day 1 if screening and 
Study Day 1 occur on the same calendar day; see Section 7.7.1) 


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• Measure vital signs: blood pressure, heart rate, respiratory rate, and temperature (oral or 
tympanic) (Note: Does not need to be repeated on Study Day 1 if screening and Study 
Day 1 occur on the same calendar day; see Section 7.8.1) 
• Collect blood samples prior to the first dose of study drug for PK analysis (see 
Section 7.10) 
• Monitor AEs (see Section 7.8.5) 
• Administer study drug (see Section 5.3) 
7.2.2 
Study Days 2 to 7 (or up to Study Day 14 for Patients with Bacteremia) 
The following assessments and procedures will be performed during Study Days 2 to 7 (or up to 
Study Day 14 for patients with bacteremia) of the treatment period: 
• Review concomitant medications daily (see Section 7.9.2) 
• Perform UTI-focused physical examination daily (see Section 7.9.3) 
• Perform DPSQ daily (see Section 7.7.1) 
• Measure vital signs: blood pressure, heart rate, respiratory rate, and temperature (oral or 
tympanic) daily (see Section 7.8.1) 
• As clinically indicated: eGFR using serum creatinine results from local laboratory. 
Report eGFR if results are clinically significant or if results warrant a change in dose of 
study drug (see Section 7.8.2) 
• On Study Days 2 and 3 only: collect blood samples for PK analysis (see Section 7.10) 
• On Study Day 4 only: perform 12-lead ECG immediately after completion of study drug 
infusion and as clinically indicated (see Section 7.8.3) 
• Obtain blood cultures if clinically indicated, or if a previous blood culture was positive, 
repeat blood cultures should be performed every 2 to 3 days until clearance of 
bacteremia is documented (see Section 7.7.4.2) 
• On Study Day 4 and on Study Days 8 and 12 if still on IV study drug: obtain blood and 
urine samples for central laboratory safety assessments (see Section 7.8.4) 
• Monitor AEs daily (see Section 7.8.5) 
• Administer study drug daily (see Section 5.3) 


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7.3 
End of Treatment Visit 
The EOT visit will be performed within 24 hours after the last IV dose of study drug (i.e., on 
Study Day 7 or 8 for patients without bacteremia who complete a full course of therapy, or Study 
Days 7, 8, 9, 10, 11, 12, 13, 14, or 15 for patients with bacteremia [depending on the when the 
investigator determines treatment is complete]). Patients who discontinue treatment early should 
have the EOT visit performed within 24 hours of the last dose of IV study drug. Patients may be 
discharged from the study site after the EOT visit if clinically stable and at the investigator’s 
discretion.  
When EOT occurs on the same calendar day as the last day of IV therapy, any assessments 
already performed on that calendar day (see Section 7.2.2) do not need to be repeated, unless 
clinically indicated based on the investigator’s judgement or in the event that EOT occurs on 
Study Day 1. 
The following assessments and procedures will be performed at EOT: 
• Review concomitant medications (see Section 7.9.2) 
• Perform UTI-focused physical examination (see Section 7.9.3) 
• Perform DPSQ (see Section 7.7.1)  
• Measure vital signs: blood pressure, heart rate, respiratory rate, and temperature (oral or 
tympanic) (see Section 7.8.1)  
• As clinically indicated: eGFR using serum creatinine results from local laboratory (see 
Section 7.8.2) 
• Obtain blood cultures if clinically indicated, or if a previous blood culture was positive, 
repeat blood cultures should be performed every 2 to 3 days until clearance of 
bacteremia is documented (see Section 7.7.4.2) 
• Obtain blood and urine samples for central laboratory safety assessments (see 
Section 7.8.4) 
• Obtain quantitative urine culture (see Section 7.7.4.1) 
• Determine Investigator Opinion of Clinical Response (see Section 7.7.5) 
• Monitor AEs (see Section 7.8.5) 
7.4 
Test of Cure Visit 
The TOC visit will be performed between Study Days 19 and 23. Patients who were discharged 
must return to the study site for the TOC visit. 


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The following assessments and procedures will be performed at TOC: 
• Review concomitant medications (see Section 7.9.2) 
• Perform UTI-focused physical examination (see Section 7.9.3) 
• Perform DPSQ (see Section 7.7.1) 
• Measure vital signs: blood pressure, heart rate, respiratory rate, and temperature (oral or 
tympanic) (see Section 7.8.1) 
• As clinically indicated: calculate eGFR using serum creatinine results from local 
laboratory (see Section 7.8.2) 
• Obtain blood cultures if clinically indicated, or if a previous blood culture was positive, 
repeat blood cultures should be performed every 2 to 3 days until clearance of 
bacteremia is documented (see Section 7.7.4.2) 
• Obtain blood and urine samples for central laboratory safety assessments (see 
Section 7.8.4) 
• Obtain quantitative urine culture (see Section 7.7.4.1) 
• Determine Investigator Opinion of Clinical Response (see Section 7.7.5) 
• Monitor AEs (see Section 7.8.5) 
7.5 
Late Follow-up Visit 
The LFU visit will be performed between Study Days 28 and 35. Patients who were discharged 
must return to the study site for the LFU visit. 
The following assessments and procedures will be performed at LFU: 
• Review concomitant medications (see Section 7.9.2) 
• Perform UTI-focused physical examination (see Section 7.9.3) 
• Perform DPSQ (see Section 7.7.1) 
• Measure vital signs: blood pressure, heart rate, respiratory rate, and temperature (oral or 
tympanic) (see Section 7.8.1) 
• As clinically indicated: calculate eGFR using serum creatinine results from local 
laboratory (see Section 7.8.2) 


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• Obtain blood cultures if clinically indicated, or if a previous blood culture was positive, 
repeat blood cultures should be performed every 2 to 3 days until clearance of 
bacteremia is documented (see Section 7.7.4.2) 
• Obtain blood and urine samples for central laboratory safety assessments (see 
Section 7.8.4) 
• Obtain quantitative urine culture (see Section 7.7.4.1) 
• Determine Investigator Opinion of Clinical Response (see Section 7.7.5) 
• Monitor AEs (see Section 7.8.5) 
7.6 
Unscheduled Assessments  
Unscheduled assessments may be conducted at any time according to the investigator’s 
discretion, as clinically appropriate. 
7.7 
Efficacy Evaluations  
7.7.1 
Assessment of Symptomatic Clinical Response 
The symptomatic clinical success at TOC is one of the components of the primary outcome of 
this study; responses at EOT and LFU are secondary endpoints.  
During study conduct, patients will be required to report their cUTI symptoms on a series of 
formal questionnaires that will be administered by trained study center staff. The PPSQ will be 
administered once at screening to determine whether a patient normally experiences urinary tract 
symptoms (i.e., in the absence of a UTI) that may be attributable to other disease processes 
(e.g., BPH). The patients will be administered the DPSQ at screening, daily while on study drug, 
and at EOT, TOC, and LFU visits. The data collected from the questionnaires will be used to 
programmatically assess the symptomatic clinical response as defined in Table 4 and Table 5. 
Instructions for performing the PPSQ and DPSQ are detailed in Appendix 2. 
The DPSQ should also be performed at any unscheduled visit occurring for any reason between 
the EOT and TOC visits and/or between the TOC and LFU visits. 


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Table 4 
Symptomatic Clinical Response Criteria at EOT 
Response Category 
Definition 
Symptomatic clinical success 
All  of the following have occurred: 
• Resolution (or return to pre-morbid state) of the core 
symptoms of cUTI (dysuria, frequency, urgency, 
suprapubic/pelvic pain, and flank pain) present at study 
entry  
• No new core cUTI symptoms have developed and no 
symptoms have worsened 
• Patient is alive 
Symptomatic clinical failure 
Occurrence of 1 or more of the following:  
• Confirmed persistence of at least 1 symptom 
(i.e., non-resolution or not having returned to pre-morbid 
state) of the core symptoms of cUTI (dysuria, frequency, 
urgency, suprapubic/pelvic pain, and flank pain) 
• Development of 1 or more core symptoms of cUTI not 
present at baseline 
• Death 
Indeterminate symptomatic 
clinical response 
Cases where the symptomatic clinical response could not be assessed  
cUTI=complicated urinary tract infection; EOT=End of Treatment;  


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Table 5 
Symptomatic Response Criteria at TOC and LFU 
Response Category 
Definition 
Symptomatic clinical success 
All  of the following have occurred: 
• Resolution (or return to pre-morbid state) of the core 
symptoms of cUTI (dysuria, frequency, urgency, 
suprapubic/pelvic pain, and flank pain) present at study 
entry 
• No new core cUTI symptoms have developed and no 
symptoms have worsened 
• Patient is alive 
• Patient has not received additional antibiotics for the 
treatment of cUTI (other than those permitted per 
protocol) after EOT  
Symptomatic clinical failure 
Occurrence of 1 or more of the following:  
• Confirmed persistence of at least 1 symptom 
(i.e., non-resolution or not having returned to pre-morbid 
state) of the core symptoms of cUTI (dysuria, frequency, 
urgency, suprapubic/pelvic pain, and flank pain) 
• Development of 1 or more core symptoms of cUTI not 
present at baseline 
• Death 
• Patient has received additional antibiotics for the treatment 
of cUTI (other than those permitted per protocol) after EOT 
 
Indeterminate symptomatic 
clinical response 
Cases where the symptomatic clinical response could not be assessed  
cUTI = complicated urinary tract infection; TOC= Test of Cure; LFU = Late Follow-up 
A patient will be said to have symptomatic clinical relapse at the LFU visit if their symptomatic 
clinical response was success at the TOC visit and is failure at the LFU visit. Similarly, a patient 
will be said to have sustained symptomatic clinical success at the LFU visit if their symptomatic 
clinical response was success at the TOC visit and is success at the LFU visit. 
7.7.2 
Assessment of Microbiological Response 
The microbiological response of per-patient eradication at the TOC visit in the microITT 
population is one of the components of the primary outcome. The per-pathogen microbiologic 
response in the microITT, ME population at the EOT, TOC, and LFU visits as well as the 


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per-patient microbiological response in the microITT population at EOT and LFU and in ME 
population at EOT, TOC, and LFU are secondary outcomes. Microbiological response will be 
assessed per-pathogen and per-patient according to the definitions below. Microbiological 
outcome per-patient is assessed in a blinded manner. It is based on outcome per-pathogen 
isolated at the initial visit (considered as causative) and on the isolation of pathogens during the 
course of treatment or the posttreatment period. 
Each baseline pathogen will be categorized at EOT, TOC, and LFU visits according to the 
microbiological response criteria shown in Table 6. 
Table 6 
Microbiological Response Criteria 
Microbiological Response 
Definition 
Eradication 
Demonstration that the bacterial pathogen found at study entry 
(≥105 CFU/mL) is eradicated to <103 CFU/mL  
Persistence 
Demonstration that the bacterial pathogen found at study entry 
(≥105 CFU/mL) grows ≥103 CFU/mL  
Indeterminate microbiological response 
Repeat cultures are not performed  
CFU=colony forming unit. 
For patients from whom more than 1 baseline pathogen is isolated, the overall per-patient 
microbiological response assessment will be favorable only if the microbiologic response 
assessment for each of the baseline pathogens is eradication. 
A patient will be said to have microbiologic recurrence at the LFU visit if their response was 
eradication at the TOC visit and persistence at the LFU visit. Similarly, a patient will be said to 
have sustained eradication at the LFU visit if their response was eradication at the TOC visit and 
is eradication at the LFU visit. 
Pathogens identified in blood will be assigned a per-pathogen microbiologic response. In 
instances of cUTI with bacteremia, a favorable outcome for a baseline pathogen will require a 
favorable microbiologic response from the urine sample as well as the blood. 
7.7.3 
Other Microbiological Outcomes 
7.7.3.1 
Emergent Infections 
Pathogens first appearing after baseline in patients with a different baseline pathogen are 
categorized as described in Table 7 and will be considered separately from microbiological 
response. 


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Table 7 
Emergent Infection Criteria 
Emergent Infection 
Definition 
Superinfection 
Isolation of a new pathogen(s) (other than the original baseline pathogen[s]) from 
urine during treatment with study drug that is accompanied by new or worsening 
signs and symptoms of infection requiring alternative antimicrobial therapy 
New infection 
Isolation of a new pathogen(s) (other than the original baseline pathogen[s]) from 
urine after completion of study drug that is accompanied by new or worsening 
signs and symptoms of infection requiring alternative antimicrobial therapy 
7.7.3.2 
Persistence with Increasing Minimal Inhibitory Concentration 
In patients with persistence, MICs of study drugs against pathogens isolated at baseline will be 
compared to MICs of study drugs against postbaseline pathogens. An outcome of persistence 
with increasing MIC is indicated by the organism displaying a ≥4-fold higher MIC to study drug 
received in a urine or blood culture obtained at EOT or later compared to baseline. 
7.7.4 
Specimen Collection and Analysis 
Detailed instructions for the collection, storage, and transport of specimens are provided in the 
laboratory manual. 
7.7.4.1 
Urine Specimen 
An adequate urine specimen for microbiologic evaluation must be obtained and sent to the local 
laboratory for culture, identification, and in vitro antibacterial susceptibility testing per 
institutional operating procedures at screening prior to randomization and at EOT, TOC, and 
LFU visits. 
Urine samples should not be obtained from urinary catheter bags. Acceptable methods of 
collection of urine for culture include the following:  
• Midstream clean catch (straight catheterization using sterile technique is preferred for 
female patients)  
• Straight catheterization using sterile technique 
• Suprapubic specimen collection using sterile technique  
• Whenever possible, urine specimens should not be obtained from indwelling bladder 
catheters. When necessary, urine specimens in patients with indwelling bladder catheters 
should be obtained by sterile aspiration through the catheter port or by puncturing the 
catheter tubing with a needle and syringe if a port is not present.  
The urine specimen should be plated for culture within 2 hours from the collection time, if the 
specimen is kept at room temperature. Alternatively, these tests may be performed within 
24 hours of collection if the specimen is stored at 2°C to 8°C before processing. Refer to the 
laboratory manual for specimen storage and handling instructions. 


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The specimens should be processed according to recognized methods3, 4 and following the 
standard operating procedures (SOPs) of the clinical microbiology laboratory at each study site.  
All isolates of uropathogens at ≥105 CFU/mL from the screening cultures and isolates of 
gram-negative uropathogens at ≥103 CFU/mL from subsequent (i.e., follow-up) urine cultures 
must be sent by local laboratory to the central laboratory, where pathogen identification will be 
confirmed, and further susceptibility testing and characterization will be performed. Urine 
samples from which more than 2 pathogens were isolated may be considered to represent 
contamination. 
All cultured isolates should be kept by the local laboratory until the end of the study as described 
in the laboratory manual.  
7.7.4.2 
Blood Cultures 
Blood samples for microscopic evaluation, culture, identification, and in vitro susceptibility 
testing will be collected at screening for all patients and processed at the local microbiology 
laboratory per institutional SOPs. Postbaseline, blood cultures will be performed as clinically 
indicated. For patients with positive baseline blood cultures, cultures will be repeated every 2 to 
3 days until negative.  
Two sets of blood cultures should be collected from 2 different sites for aerobic incubation and, 
if possible, anaerobic incubation (i.e., 4 tubes). Each bottle should be inoculated with 10 to 
15 mL of blood for a total of 40 to 60 mL per collection. Ideally, at least 1 set of blood cultures 
should be obtained through a venipuncture. Details concerning the collection and processing of 
blood cultures are provided in the laboratory manual. 
Isolated pathogens will be sent to the central microbiology laboratory where pathogen 
identification will be confirmed and further susceptibility testing and characterization will be 
performed. Bacteria not considered pathogens (i.e., contaminants) should not be sent to the 
central laboratory.  
Blood specimens should be processed according to recognized methods for aerobic and 
anaerobic organisms (e.g., as found in Jorgensen JH and Pfaller MA, Manual of Clinical 
Microbiology5; Leber AL, Clinical Microbiology Procedures Handbook6) following the SOPs of 
the qualified clinical microbiology laboratory at each study site. Microscopic evaluation and 
culture of specimens will be performed by the qualified local laboratory, along with 
susceptibility testing of pathogens cultured from the specimens if such testing is consistent with 
standard procedures at the institution.  
All cultured isolates should be kept by the local laboratory until the end of the study as described 
in the laboratory manual. 
7.7.5 
Investigator Opinion of Clinical Response 
Based on the entirety of the patient’s clinical course and current status, including an evaluation 
of signs and symptoms (including systemic and cUTI-specific symptoms), physical examination, 


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laboratory values, and general well-being, the investigator should provide an Investigator 
Opinion of Clinical Response at the EOT, TOC, and LFU visits according to the definitions 
listed in Table 8. 
Table 8 
Investigator Opinion of Clinical Response Criteria 
Investigator Opinion of 
Clinical Response 
Definition 
Success 
All or most pretherapy signs and symptoms of the index infection have improved 
or resolved such that no additional antibiotics1 are required for treatment of the 
cUTI 
Success with treatment for 
asymptomatic bacteriuria 
All or most pretherapy signs and symptoms of the index infection have improved 
or resolved such that no additional antibiotics1 are required; however, treatment of 
asymptomatic bacteriuria is prescribed based on the opinion of the investigator2 
Failure 
Patients who meet at least one of the following criteria: 
• 
Death related to cUTI 
• 
Persistence or progression of cUTI symptoms such that additional 
antibiotics for cUTI are required  
• 
Patient previously met criteria for failure (not applicable for the EOT 
visit) 
Indeterminate 
An assessment was not performed due to any of the following: 
• 
Death where cUTI was clearly non-contributory  
• 
Assessment was not performed (e.g., due to missed visit, withdrawal of 
consent, or loss to follow-up) 
cUTI=complicated urinary tract infection; EOT=End of Treatment. 
1 This does not include antibacterials that are permitted per protocol for patients with Enterococcus or 
methicillin-resistant S aureus infections. 
2 According to guidelines in both Europe and the United States, treatment of asymptomatic bacteriuria (the presence 
of 1 or more species of bacteria growing in the urine irrespective of the presence of pyuria, in the absence of signs or 
symptoms attributable to UTI) is in most cases not beneficial and may be harmful. Based on standard of care and 
protocol restrictions surrounding use of additional antibiotics, patients in this trial should not receive additional 
antibiotic for asymptomatic bacteriuria.  Additional therapy should only be given if signs and symptoms warrant 
ongoing treatment for symptomatic cUTI (i.e., based on their clinical course in the absence of microbiological data).  
7.8 
Safety Evaluations 
Safety and tolerability assessments will consist of AEs, clinical laboratory, vital signs, and 
12-lead ECG examinations. Assessments will be performed in accordance with the schedule of 
assessments (see Table 1). 
7.8.1 
Vital Signs 
Vital signs will be collected at screening, daily while on study drug therapy, at EOT, TOC, and 
LFU visits.  
Vital signs do not need to be repeated on Study Day 1 if screening and Study Day 1 occur on the 
same calendar day.  


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At EOT, assessments already performed on the same calendar day do not need to be repeated 
unless clinically indicated based on the investigator’s judgement. 
Vital signs include heart rate, respiratory rate, temperature (oral or tympanic), and blood 
pressure. If more than 1 set of vital signs is acquired on a given calendar day, record the highest 
temperature and the heart rate, respiratory rate, and blood pressure associated with that 
temperature (or those acquired nearest to that temperature). Systolic and diastolic blood pressure 
and heart rate will be recorded after the patient has been resting for at least 5 minutes in the 
supine position. These assessments should made using an automated device.  
Vital signs should also be performed at any unscheduled visit occurring for any reason between 
the EOT and TOC visits and/or between the TOC and LFU visits.  
7.8.2 
Estimated Glomerular Filtration Rate 
The eGFR will be calculated at screening to determine eligibility and appropriate dosing of study 
drug using local laboratory serum creatinine results using the MDRD formula.2 If the 
investigator determines that calculation of eGFR is warranted postbaseline (e.g., due to change in 
clinical status and/or for evaluation of need for dose change), local laboratory serum creatinine 
should be used and the results reported as an unscheduled laboratory test. An eGFR will also be 
calculated by the central laboratory using central blood results. 
Calculation of eGFR is detailed below: 
eGFR=175 × (Scr)-1.154 × (age)-0.203 × 0.742 [if female] × 1.212 [if black] 
Note:  The ethinicity factor should only be used for African Americans and should not be used 
with black patients of all other nationalities. 
where Scr is serum creatinine in mg/dL and eGFR is measured in mL/min/1.73m2. 
7.8.3 
Electrocardiogram 
A standard 12-lead ECG will be recorded after the patient has been resting for at least 5 minutes 
in the supine position. Safety ECGs should be reviewed by a medically qualified designated 
personnel at the site.  
Baseline ECGs will be performed at screening. Study Day 4 ECGs will be collected immediately 
after completion of the cefepime/VNRX-5133 or cefepime/VNRX-5133 placebo infusion. 
Additional ECGs can be performed for safety reasons at any time as clinically indicated at the 
discretion of the investigator. Abnormalities should be followed up by the investigator. Copies of 
the ECGs should be kept as source documents. 
7.8.4 
Clinical Laboratory Tests 
All blood and urine specimens will be sent to a central reference laboratory for analysis and 
testing. Blood and urine samples will be obtained during screening, on Study Days 4 and Study 
Days 8 and 12 if on IV treatment, and at EOT, TOC, and LFU visits. At screening, blood and 


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urine specimens will also be sent to a local laboratory to confirm eligibility for randomization. In 
the event that baseline central laboratory results are not consistent with eligibility criteria, the site 
will be asked to document the screening local laboratory result on a local laboratory result eCRF. 
The procedures for the collection, handling, and shipping of testing samples are based on the 
central laboratory SOPs and are specified in the laboratory manual(s) provided to the study site.  
All laboratory assessments listed in Table 9 will be performed on all samples at screening or 
baseline, during and post treatment, except for procedures used for screening purposes only. 
Baseline values will be obtained at screening. 
Additional unscheduled samples may be collected at any time. 
Table 9 
Central Laboratory Assessments 
Panel 
Parameter(s) 
Coagulation 
Prothrombin time 
PTT 
INR 
Chemistry 
ALT 
Albumin 
Alkaline phosphatase 
AST 
Bicarbonate  
Bilirubin, total, direct, and indirect 
BUN 
Calcium 
Chloride 
CK 
Creatinine 
Glucose (nonfasting) 
LDH 
Potassium 
Phosphorus 
Protein, total 
Sodium 
Hematology 
Hematocrit 
Hemoglobin 
Platelet count 
RBC count 
WBC count with differential 
Urinalysis 
Urinalysis (appearance, bilirubin, glucose, ketones, leukocyte 
esterase, nitrite, pH, protein specific gravity, urobilirubin) 


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Panel 
Parameter(s) 
Microscopy1 
Pregnancy testing2  
Serum β-hCG 
β-hCG=beta-human chorionic gonadotropin; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
BUN=blood urea nitrogen; CK=creatine kinase; INR=international normalized ratio; LDH=lactate dehydrogenase; 
PTT=partial thromboplastin time; RBC=red blood cell; WBC=white blood cell. 
Note: Local laboratory results should be used at screening to confirm eligibility for randomization. 
1 Microscopy should include assessment of WBCs, RBCs, casts, crystals, bacteria, and yeast. 
2 Serum β-hCG must be performed as part of screening/eligibility in women of childbearing potential. However, a 
patient may begin study drug on the basis of a negative urine β-hCG, but a serum β-hCG test must still be 
obtained for confirmation. 
7.8.5 
Adverse Event Monitoring 
AEs, including SAEs, will be collected from the time of informed consent through the last study 
visit. AEs that are ongoing at the LFU visit or at study withdrawal should be monitored until 
resolution, stabilization with sequelae, or death. 
Definitions and procedures for AE and SAE reporting are detailed in Section 8. Other reportable 
events, though not considered AEs, should be reported as discussed in Section 9.  
7.9 
Other Assessments 
7.9.1 
Medical History and Demographics 
A complete history to include medical and surgical history during the prior 5 years, as well as 
any other medical/surgical history relevant to the diagnosis of cUTI and/or participation in this 
study, and demographics (i.e., age, sex, ethnicity, and race) will be obtained at screening. Events 
occurring prior to the time of informed consent will be recorded as medical history.  
7.9.2 
Prior and Concomitant Medication Collection 
Prior medications are defined as any prescription medication, over-the-counter medication, 
herbal supplement, and traditional medicines taken by the patient before randomization. All prior 
medications, including antimicrobials, taken during the 2 weeks prior to randomization will be 
collected at screening.  
Concomitant medications are defined as any prescription medication, over-the-counter 
medication, herbal supplement, or traditional medicines taken by the patient after randomization. 
All concomitant medication, including antibacterials, will be collected from the time of 
randomization through the last study visit. Saline and similar volume replacers are not required 
to be recorded as a concomitant medication.  
7.9.3 
Physical Examination 
A complete physical examination will be performed at screening consisting of general 
appearance, skin/subcutaneous tissue, head, ears, nose, throat, neck and thyroid, thorax, lungs, 


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cardiovascular, lymph nodes, abdomen, musculoskeletal, and neurological examinations. 
Genitalia, anus/rectal, and breast examinations will only be performed if medically indicated.  
UTI-focused physical examinations, including assessment of costovertebral angle tenderness and 
suprapubic/pelvic tenderness, will be performed during screening, daily while on IV therapy at 
EOT, TOC, and LFU visits.  
A UTI-focused examination should also be performed at any unscheduled visit occurring for any 
reason between the EOT and TOC visits and/or between the TOC and LFU visits.  
7.9.4 
Height and Weight Measurement  
Height and weight measurement will be performed at screening.  
7.9.5 
Radiographic Examination 
Radiographic imaging including X-ray imaging, ultrasonography, computed tomography, 
positron emission tomography, and magnetic resonance imaging scan is not required for this 
study, but may be performed at the investigator’s discretion at any time as clinically appropriate. 
Results of any radiologic tests performed that are clinically relevant to the cUTI or an SAE 
should be recorded for all patients.  
7.9.6 
Surgical Procedures and Other Non-pharmacological Interventions 
Any patient planning to undergo surgical treatment not compatible with the aims of the study 
must not be enrolled. For patients who need to undergo an unplanned surgical procedure during 
the study, the reason for the surgery must be documented as an AE in the eCRF. 
Other non-pharmacological procedures that occur during the study will be entered into the eCRF 
including the date and reason for treatment/procedure. 
7.10 
Pharmacokinetics 
Sparse plasma sampling for population PK analysis will be performed in all patients on 
Study Days 1, 2, and 3.  
PK blood samples will be taken via an indwelling IV catheter or by direct venipuncture into 
dipotassium ethylenediaminetetraacetic acid (K2-EDTA)-containing tubes. To ensure that 
accurate PK samples are obtained, the IV infusion site used for study drug administration must 
not be used for collection of blood for PK assessments, and it should not be drawn from the same 
arm as the line used for infusion.  
PK blood samples should be taken relative to the start/end of the 2-hour infusion of 
cefepime/VNRX-5133 or placebo. Samples will be collected around the scheduled sampling time 
within the specified collection windows. The sites are encouraged to vary the sampling within 
the collection windows, at times convenient for the collection. The exact dates and times of 
blood sampling will be recorded in the eCRF.  


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Details on PK sample collection, handling, storage, and shipping are described in the laboratory 
manual. Time windows for PK assessments are presented in Table 10. 
Table 10 
Time Windows for Pharmacokinetic Assessments 
Study Day 
Scheduled Sampling Time 
Collection Window 
Study Day 1 
Predose 
Prior to initiation of study drug, within 3 hours prior to the 
first dose of study drug 
Study Day 2 
Predose 
Within 30 minutes prior to the morning dose of study drug  
Study Day 3 
Predose 
Within 30 minutes prior to the morning dose of study drug  
Study Day 3 
During infusion 
Between 30 and 90 minutes after the start of infusion, and 
prior to the end of infusion 
Study Day 3 
End of infusion 
Immediately after the infusion to within 30 minutes after 
the completion of the infusion 
Study Day 3 
2 hours after the end of infusion 
Between 1 and 3 hours after the end of infusion 
Study Day 3 
4 hours after the end of infusion 
Between 3 and 5 hours after the end of infusion 
Study Day 3 
6 hours after the end of infusion 
Between 5 hours after the end of infusion and prior to the 
start of the next infusion  
Note: After collection of the Study Day 3 predose sample, other Study Day 3 samples can be collected after any of 
the infusions on Study Day 3.  
PK samples will only be assayed for patients randomized to receive cefepime/VNRX-5133. 
All PK blood samples will be processed and assayed for VNRX-5133 and cefepime using 
validated assays. The steady-state PK of VNRX-5133 and cefepime will be determined in this 
patient population. Intrinsic and extrinsic factors will be explored in the population PK analysis. 
Population PK analysis methods will be described in a separate population PK analysis plan that 
will be finalized before the clinical database lock. 
7.11 
Pharmacogenomics 
Pharmacogenomics analysis will not be performed. 
7.12 
Biomarkers 
Assessment of biomarkers will not be performed. 
7.13 
Total Volume of Blood 
Table 11 presents the number and approximate volume of blood samples and the total volume of 
blood that will be collected during the study.  
If deemed necessary by the investigator or the sponsor, the number and/or volume of blood 
samples per assessment may be modified as long as the total volume of blood drawn for a patient 
does not surpass 500 mL (except when extra blood samples need to be taken for safety reasons). 


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Table 11 
Total Blood Volume Collected 
Assessment 
Sample Volume (mL) 
Total Number of Samples 
Total Volume (mL) 
Clinical chemistry 
5 
5 to 7 
25 to 35 
Hematology 
3 
5 to 7 
15 to 21 
Coagulation 
4.5 
5 to 7 
22.5 to 31.5 
Serum β-hCG 
8.5 
1 
8.5 
Blood culture1 
10 to 15/vial, 
40 to 60/culture (4 vials) 
1 
40 to 60 
PK sampling 
4 
8 
32 
Total (approximate) 
 
25 to 31 
143 to 188 
β-hCG=beta-human chorionic gonadotropin; PK=pharmacokinetic(s). 
1 Four vials (10 to 15 mL/vial) will be collected for each blood culture collection. All patients will have 4 vials of 
blood collected at screening; additional blood culture samples will be collected only as clinically indicated or 
every 2 to 3 days until blood has cleared for patients with bacteremia at baseline. 
7.14 
Handling, Storage, Transport, and Destruction of Specimens 
Detailed instructions for the handling, storage, transport, and destruction of biological specimens 
are provided in the laboratory manual. 
7.14.1 
Future Use of Stored Specimens 
Blood, urine, and microbiological specimens remaining after safety and/or efficacy assessments 
are performed will not be stored for future use. A backup sample of each isolated pathogen (not 
specimen) from urine or blood that is shipped to the central microbiology laboratory must be 
retained at the local laboratory in case the central laboratory or the sponsor requests that it is to 
be shipped to the central laboratory for reanalysis. 
Blood specimens remaining after PK assessments are performed will be stored for possible 
future drug metabolism and PK analyses. 
No genetic or biomarker analysis will be performed. 


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8 ADVERSE EVENT ASSESSMENT AND REPORTING 
8.1 
Definition of an Adverse Event 
An AE is any untoward medical occurrence associated with the use of a drug in humans whether 
or not considered drug related.  
An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medical treatment or procedure that 
may or may not be considered related to the medical treatment or procedure. AE definitions will 
be followed as stated in the “Note for Guidance on Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting” (International Council on Harmonisation 
[ICH] topic E2A).7 
8.1.1 
Definition of a Serious Adverse Event 
An SAE is any untoward medical occurrence that, on the basis of medical and scientific 
judgment, has any of the following characteristics: 
• Results in death 
• Is life-threatening (This refers to an event in which the patient is at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused 
death if it was more severe) 
• Requires inpatient hospitalization for a medical reason or prolongation of existing 
hospitalization (This refers to hospital admission required for treatment of the AE. Note: 
this does not include confinement in, for example, a respite unit, a skilled nursing unit, 
rehabilitation facility, the clinical research unit, or confinement due to planned or 
unplanned reason unrelated to study) 
• Is a congenital anomaly/birth defect 
• Is a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• Is an important medical event (Note: important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require intervention to prevent one of the other outcomes listed in the 
definition above should also usually be considered serious) 
The intensity and causality of SAEs will be determined as described in Section 8.3.1 and 
Section 8.3.2, respectively. 


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8.2 
Documenting Adverse Events 
All AEs and SAEs encountered during the clinical study will be reported in detail in the source 
documents and documented in the eCRF from the time of consent until completion of the LFU 
visit.  
Events occurring over the previous 5 years prior to the time of informed consent will be recorded 
as medical and surgical history. Any medical occurrences that are new or worsened from the 
time of informed consent and up to and including the last study visit must be reported as AEs and 
SAEs.  
Whenever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be reported. Each AE or SAE reported will be assessed for intensity. The date 
and time of onset, time relationship to dosing, and duration and outcome of each event will be 
noted. 
Information to be collected for AEs includes event description, date of onset, assessment of 
severity and relationship to study product, and date of resolution of the event, seriousness, and 
outcome. AEs occurring during the collection and reporting period will be documented 
appropriately regardless of relationship. AEs will be followed until resolution, stabilization with 
sequelae, or death.  
8.2.1 
Reporting Serious Adverse Events 
SAEs will be collected from the time of informed consent through the last study visit. SAEs that 
are ongoing at the time of the LFU visit will be followed until resolution, stabilization with 
sequelae, or death. SAEs that begin after the patient’s participation in the study is complete, but 
that the investigator considers to be related to study drug, should be reported. 
The investigator or study site personnel should notify the appropriate sponsor/contract research 
organization (CRO) pharmacovigilance representatives of all SAEs, regardless of relationship to 
study drug, within 24 hours of becoming aware of the event. The investigator or study site 
personnel will provide the initial notification by completing the SAE page in the eCRF, which 
must include the investigator’s assessment of the relationship of the event to study drug and must 
be signed by the investigator. There may be situations in which minimal information is available. 
However, it is very important that the investigator always makes an assessment of causality. The 
investigator may change his/her assessment of the causality based on follow-up information and 
should amend the SAE report form accordingly. The causality assessment is one of the criteria 
used when determining regulatory reporting requirements. 
Covance Pharmacovigilance will forward SAE queries directly to the investigator requesting 
additional information. It is the investigator’s responsibility to be diligent in providing this 
information as soon as it is available. 
If an event meets serious criteria and it is not possible to access the EDC, the SAE should be 
submitted electronically using this email address: SAEintake@covance.com. If email access is 


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not available, the SAE may be reported telephonically using the following regional telephone 
numbers: 
• Europe: +44 1628 540028  
• North America: +1 888 887 8097 
• Latin America: +1 609 419 2609 
• Asia Pacific: +61 2 9888 8322 
8.3 
Assessment of Adverse Events 
8.3.1 
Assessment of Intensity 
The severity of AEs will be assessed as mild, moderate, or severe according to the criteria below: 
• Mild: patient has awareness of signs or symptoms, but they are easily tolerated and of 
minor irritant type causing no loss of time from normal activities. Symptoms do not 
require treatment or medical evaluation; signs and symptoms are transient. 
• Moderate: event introduces a low level of inconvenience or concern to the patient and 
may interfere with daily activities but is usually improved by simple therapeutic 
measures; the event may cause some interference with functioning. 
• Severe: event interrupts the patient’s normal daily activities and generally requires 
systemic drug therapy or other treatment; the event may be incapacitating. 
It is emphasized that the term severe is a measure of severity: thus, a severe AE is not necessarily 
serious. For example, itching for several days may be rated as severe but may not be clinically 
serious. 
8.3.2 
Assessment of Causality 
The investigator will assess the causal relationship between study drug and each AE and answer 
“yes” or “no” to the question “Do you consider that there is a reasonable possibility that the 
event may have been caused by the study drug?” 
8.4 
Adverse Event Follow-up 
Follow-up of AEs will continue until resolution, stabilization with sequelae, or death. In case of 
ongoing AEs at the moment of database lock, the data obtained at the moment of database lock 
will be used in the statistical analysis. 
8.5 
Adverse Events of Special Interest 
There are currently no AEs of special interest. 


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8.6 
Exemptions from Adverse Event Reporting 
8.6.1 
Laboratory Abnormalities 
Laboratory abnormalities should be reported as adverse events if the result is considered to be 
clinically significant by the investigator. Clinically significant abnormal clinical laboratory 
findings or other abnormal assessments that are associated with the disease being studied (unless 
judged by the investigator as more severe than expected for the patient’s condition) or that are 
present or detected at the start of the study and do not worsen, will not be reported as AEs. 
8.6.2 
Disease Progression and Lack of Effect 
Disease progression or deterioration of the patient’s condition due to lack of improvement or 
worsening of the cUTI may or may not reflect failure of the study drug. Insufficient therapeutic 
effect will be captured as an efficacy outcome. Therefore, clinical and microbiological failures 
should not be reported as an AE. Furthermore, any event or extended hospitalization that is 
unequivocally due to disease progression should not be reported as an SAE unless it is believed 
that study drug actively contributed to the progression of the disease (i.e., not by way of 
insufficient therapeutic effect). Events that are a direct result of progression of the cUTI that 
progress to death will not be reported as SAEs but will instead be reported on a separate death 
form. 


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9 OTHER REPORTABLE EVENTS 
9.1 
Abnormal Liver Enzymes 
The investigator is responsible for notifying the sponsor or sponsor representative within 
24 hours of becoming aware of either of the following findings based on local or central 
laboratory testing results: 
• AST or ALT ≥3× ULN and total bilirubin ≥2× ULN, OR 
• ALT or AST ≥10× ULN 
In cases meeting either of the above criteria (based on central or local laboratory results), the 
investigator must complete the liver enzyme eCRF. Appendix 3 describes the recommended 
diagnostic test that should be considered. If any diagnostic testing is performed, the results 
should be reported in the eCRF. Liver laboratory results should be followed locally over several 
days until resolution or stabilization of the laboratory abnormalities and should be documented in 
the local laboratory eCRF.  
If a nonserious or serious AE is associated with the laboratory abnormalities, it should be 
reported separately as described in Section 8. 
9.2 
Overdose 
Overdose is defined as administration of more than the intended dose in any given infusion of 
study drug or more than 4 infusions of study drug in a given 24-hour period. Any instance of 
overdose (suspected or confirmed) must be communicated to the sponsor or a specified designee 
within 24 hours and be fully documented. Overdose is not necessarily an AE, but if the 
consequences of the overdose result in a serious or nonserious AE, they should be reported as 
such, separate from the overdose. Details of any signs or symptoms and their management 
should be recorded including details of any antidote(s) administered. 
9.3 
Pregnancy Reporting  
A female clinical study patient may no longer receive the study drug and must immediately 
inform the investigator if she becomes pregnant during the study. Monitoring of the patient 
should continue until the outcome of the pregnancy is known. 
The investigator should report all pregnancies of female clinical study patients or partners of 
male patients to the sponsor within 24 hours of becoming aware of them. The investigator should 
report all pregnancies to the IRB/independent ethics committee (IEC). 
If written consent is obtained from the pregnant partner, monitoring of the partner should 
continue until the outcome of the pregnancy is known. 


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10 STATISTICS 
10.1 
General Procedures 
Continuous clinical variables will be summarized descriptively (i.e., patient count, mean, 
standard deviation, minimum, median, and maximum). Categorical data will be summarized 
descriptively with frequencies and percentages based on the number of patients exposed within a 
treatment. Full details of the analysis will be described in the statistical analysis plan. 
For the evaluation of clinical and microbiological response, missing data will be classified as 
indeterminate. Further details will be provided for the handling of all missing data in the 
statistical analysis plan. 
10.2 
Sample Size 
The study will randomize 582 patients with cUTI into 2 groups in a 2:1 ratio (388 patients to 
cefepime/VNRX-5133; 194 patients to meropenem) at multiple study sites worldwide. 
Approximately 30% or more of patients should be diagnosed with AP. Randomization at study 
entry will be stratified by the type of infection (AP only versus complicated lower UTI with or 
without AP) and by region (North America and Western Europe versus Eastern Europe versus 
rest of the world). Patients with prior antibacterial use for cUTI will be limited to approximately 
25% of the study population. 
This sample size will provide at least 264 cefepime/VNRX-5133 patients and 132 meropenem 
patients for the primary comparisons of interest, based on an anticipated evaluability rate of 68%, 
a response rate of 75%, 90% power, a 2-sided alpha of 0.05, and a noninferiority margin of 15%.  
10.3 
Statistical Methods 
10.3.1 
Study Population 
Study endpoints will be presented in the following populations: 
• Intent-to-treat (ITT) population: all randomized patients  
• microITT population: all patients randomized to treatment AND  
o Had a positive study entry urine culture defined as ≥105 CFU/mL of a gram-negative 
pathogens against which both cefepime/VNRX-5133 and meropenem have 
antibacterial activity AND 
o Had no more than 2 microorganisms identified in the study entry culture regardless of 
colony count 
• Extended microITT population: all patients randomized to treatment AND 


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o Had a positive study entry urine culture defined as ≥105 CFU/mL of a gram-negative 
pathogen against which at least 1 study drug (i.e., cefepime/VNRX-5133 and/or 
meropenem) have antibacterial activity AND 
o Had no more than 2 microorganisms identified in the study entry culture regardless of 
colony count 
• CE-EOT, CE-TOC, and CE-LFU populations: all patients who meet the definition for the 
ITT population AND 
o Had an appropriate diagnosis of cUTI 
o Received treatment for ≥48 hours (or <48 hours if discontinued due to an AE or 
death) 
o Were evaluated for the appropriate endpoint at the relevant timepoint (i.e., EOT, 
TOC, and LFU) with an outcome that is not indeterminate 
o Did not violate entry criterion surrounding use of prior antibacterials 
o Did not receive a concomitant systemic antibiotic with potential activity against any 
of the baseline pathogens between the time of randomization and EOT, TOC, and 
LFU, respectively, except therapies used to treat cUTI in patients who have failed 
study drug 
o Did not have other confounding factors that interfered with the assessment of 
outcome as assessed by a blinded evaluability team prior to database lock 
• ME-EOT, ME-TOC, and ME-LFU populations: all patients who meet the criteria for the 
microITT population AND 
o Both study drugs are known to have antibacterial activity against the baseline gram-
negative pathogens AND 
o Had an appropriate diagnosis of cUTI 
o Received treatment for ≥48 hours (or <48 hours if discontinued due to an AE or 
death) 
o Were evaluated at the respective EOT, TOC, and LFU visits with a microbiological 
response of eradication or persistence (i.e., per-patient microbiologic response of 
success or failure) 
o Did not violate entry criterion surrounding use of prior antibacterials 
o Did not receive a concomitant systemic antibiotic with the potential activity against 
any of the baseline pathogens between the time of randomization and EOT, TOC, 


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and LFU, respectively, except therapies used to treat cUTI in patients who have 
failed study drug 
o Did not have other confounding factors that interfered with the assessment of 
outcome as assessed by a blinded evaluability team prior to database lock 
• Safety population: all patients who receive any dose of study drug 
10.3.2 
Demographic and Baseline Characteristics 
Demographic and baseline data will be summarized for each dose group with descriptive 
statistics as detailed in Section 10.1. Enrollment, protocol deviations, and discontinuations from 
the study drug and the study will be summarized by treatment group. Demographics (age, race, 
ethnicity, and sex) and baseline characteristics such as medical history, baseline pathogen, renal 
function category, and presence of bacteremia will also be summarized by treatment group. 
10.3.3 
Signs and Symptoms 
Signs and symptoms including frequency, urgency, dysuria, suprapubic/pelvic pain, and flank 
pain will be summarized for each dose group at each timepoint with descriptive statistics as 
detailed in Section 10.1. 
10.3.4 
Primary Endpoint 
The primary clinical efficacy endpoint in this study is the proportion of cUTI patients with 
microbiological and symptomatic clinical success at TOC in the microITT population.  
The aim of the analysis is to demonstrate that cefepime/VNRX-5133 is noninferior to 
meropenem with respect to this primary endpoint. 
The response rate will be calculated for each treatment group as the number of successes divided 
by the total number of patients (success + failure + indeterminate). The difference in response 
rates between treatments (VNRX-5133 minus meropenem) will be presented along with a 
95% confidence interval (CI), calculated using the method of Miettinen and Nurminen.8 If the 
lower limit of the 95% CI for the difference in response is greater than or equal to the 
noninferiority margin of -15%, noninferiority will be declared. Further, if noninferority is 
concluded a test for superiority will be conducted. In this case, if the lower limit of the 95% CI 
for the difference in response is greater than or equal to zero superiority will be concluded. 
A sensitivity analyses stratified by the the pre-specified stratification factors will also be 
performed for the primary endpoint. In addition, a sensitivity analysis will be performed which 
will define any additional antibacterial therapy given for cUTI as a symptomatic clinical failure. 
10.3.5 
Secondary Endpoints 
The secondary clinical and microbiological efficacy endpoints are detailed in Section 3.2.2.  


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Cefepime-resistant pathogen endpoints will be analyzed in the same way as described for the 
primary endpoint (see Section 10.3.4) and secondary (clinical, per-patient and per-pathogen 
microbiological response) endpoints. Other by-pathogen data presentations will be summarized 
by frequency counts but not analyzed. 
Additional analyses including sensitivity analyses using other visits or other poulations will be 
specified in the SAP. 
10.3.6 
Analysis of Safety 
All safety analyses will be conducted in the safety population and will be summarized by 
treatment received. 
Safety and tolerability will be assessed based on the incidence and severity of AEs and SAEs, 
exposure, mortality, reasons for discontinuation of study drug and study withdrawal, vital sign 
measurements, and clinically significant changes in clinical chemistry, hematology, urinalysis, 
and coagulation laboratory values. 
Mortality rates will be presented by treatment group. 
10.3.6.1 
Adverse Events 
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA). A 
treatment-emergent adverse event (TEAE) is defined as an AE that occurs during or after 
treatment through the last study visit. 
The incidence of TEAEs and SAEs will be summarized by treatment, by treatment and 
relationship, and by treatment and severity. The incidence will be presented by system organ 
class (SOC) and preferred term (PT); SOC, PT, and relationship to study drug administration; 
and SOC, PT, and severity. Tables of any TEAE resulting discontinuation of study drug and 
SAEs will also be provided.  
10.3.6.2 
Clinical Laboratory Evaluations 
Clinical laboratory data (i.e., clinical chemistry, hematology, urinalysis, and coagulation 
parameters) will be listed and summarized by assessment and by timepoint including the actual 
value and change from baseline, and parameters outside the reference range will be noted. The 
number and percent of patients with treatment-emergent potentially clinically significant (PCS) 
laboratory values will be tabulated for each treatment group. PCS will be defined based on 
pre-specified criteria outlined in the statistical analysis plan. Plots of laboratory values versus 
time for key laboratory parameters will also be provided.  
Liver enzymes will be classified as >3×, >5×, and >10× ULN, and the number and percentage of 
patients with any postbaseline value in one of the categories will be presented by treatment 
group. 


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10.3.6.3 
Vital Signs 
Descriptive statistics of vital sign measurements will be presented by treatment group and study 
assessment, as well as the change from baseline at each study visit.  
10.3.6.4 
Exposure 
Exposure to study drug is defined as administration of any amount of study drug. The number of 
days of treatment and the total dose of treatment received per patient will be summarized. 
Enrollment and withdrawals from the study and from study drug will be summarized by 
treatment group. 
10.3.7 
Analysis of Pharmacokinetics 
The population PK analysis methods using data from the study will be described in a population 
PK analysis plan that will be finalized before clinical database lock. The population PK analysis 
plan will describe the analysis population, methods, and reporting for the population PK analysis. 
The population PK modeling will be summarized in a separate report. 
10.3.8 
Resolution of Fever 
The time to first defervescence (≤37.8°C) in the microITT population for patients who have 
fever (>38°C) at baseline will be assessed as an exploratory endpoint. 
The time to first defervescence will be assessed for patients in the specified study populations 
who have fever (>38ºC) at baseline, where defervescence (≤37.8ºC) is defined as the absence of 
fever based on the highest temperature recorded on each study day.  
Time to first defervescence data will be summarized as the mean, median, minimum, and 
maximum number of days and number of patients. Data will also be presented as the frequency 
of patients achieving defervescence by day for each study day. 
10.4 
Interim Analysis 
There are no plans for a formal interim analysis for efficacy. 
Interim safety data will be reviewed by the independent DSMB as described in Section 11.2.  
11 ETHICS AND RESPONSIBILITIES 
This study will be conducted in accordance with the ethical principles that have their origin in 
the World Medical Association (WMA) Declaration of Helsinki, adopted by the 18th WMA 
General Assembly, Helsinki, Finland, June 1964, and subsequent amendments through 2013.9 
This study is also designed to comply with the ICH E6 Guideline for Good Clinical Practice 
(GCP) (Committee for Proprietary Medicinal Products [CPMP]/ICH/135/95)10 and any 


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applicable national and local laws and regulations (e.g., Code of Federal Regulations Title 21, 
Parts 11, 50, 54, 56, 312, and 314, and Title 45 Part 46).  
Guidelines adopted by the ICH and other relevant international guidelines, recommendations, 
and requirements will be taken into account as comprehensively as possible, as long as they do 
not violate local law. 
The investigator will be responsible for the care of the patients throughout the study. If the 
investigator is not present at the study site, he will leave instructions for the study site personnel 
and a telephone number where the investigator can be reached. 
The investigator will be responsible for the medical follow up of patients. 
11.1 
Good Clinical Practice 
This study will be carried out in accordance with GCP as required by the applicable national and 
local laws and regulations. 
11.2 
Data and Safety Monitoring Board 
An independent DSMB will be formed to monitor interim safety data during the study. 
Procedures for DSMB reviews/meetings will be defined in the DSMB charter. The DSMB will 
review applicable data at scheduled timepoints during the study as defined in the charter.  
Additional data may be requested by the DSMB. The DSMB will review grouped and unblinded 
data in the closed session only. As an outcome of each review/meeting, the DSMB will make a 
recommendation as to the advisability of proceeding with study drug administration, and to 
continue, modify, or terminate this study. 
11.3 
Institutional Review Board/Independent Ethics Committee 
The protocol and the Informed Consent Form (ICF) will be submitted for review and approval by 
an IRB/IEC prior to the eligibility screening. The composition of the IRB/IEC will be in 
accordance with applicable national and local laws and regulations and the recommendations of 
the ICH E6 Guideline for GCP.10  
The CRO and/or clinical site personnel will keep the IRB/IEC informed regarding the progress 
of the study. All pregnancies will be reported to the IRB/IEC. All changes in research activities 
and all unanticipated problems involving risks to human patients will be immediately reported to 
the IRB/IEC. The study may be suspended pending further review by the IRB/IEC, except 
insofar as suspension would jeopardize the patient’s health. 
No changes will be made in the study without IRB/IEC approval, except when required to 
eliminate apparent immediate hazards to human patients (see Section 13). 
Notification of the end of the study will be sent to the IRB/IEC within 90 days after completion 
of follow-up for the last patient. In case a study is ended prematurely, the IRB/IEC will be 
notified within 15 days, including the reasons for the premature termination. A summary of the 


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results of the study will be sent to the competent authority and the IRB/IEC within 1 year after 
the end of the study. The end of the study is defined as the date of receipt of the last data point 
for statistical analysis of the last patient participating in the study. 
11.4 
Informed Consent 
All patients will be informed verbally and in writing regarding the objectives, procedures, and 
risks of study participation. Patients will have the opportunity to ask questions regarding the 
study and any information in the consent document before signing. For patients who are unable 
to provide informed consent, the investigator must obtain informed consent from the patient’s 
legally authorized representative in accordance with applicable law. 
The written consent document will embody the elements of informed consent as described in 
applicable national and local laws and regulations and will adhere to the ICH Harmonized 
Tripartite Guideline for GCP.10 Informed consent will be obtained in accordance with applicable 
national and local laws and regulations, prior to performing any protocol-specified procedures or 
interventions. 
Patients will be provided copies of the signed and dated consent form and any amendments. 
Original consent forms will be kept on file by the investigator and made available if requested, 
by regulatory authorities, the sponsor, and/or other Quality Compliance representatives. 
11.5 
Records Management 
The data management team is responsible for the accuracy, quality, completeness, and internal 
consistency of the data from this study. Data handling, including data quality control, will 
comply with international regulatory guidelines, including ICH-GCP guidelines. Data 
management and control processes specific to this study, along with all steps and actions taken 
regarding data management and data quality control, will be described in a data management 
plan. The data management plan will be written by the CRO and finalized prior to performing 
any data validation. 
11.6 
Source Documentation 
All data will be collected on source documents and then entered in the eCRFs. 
11.7 
Study Files and Record Retention 
All documents concerning the study will be kept on file in the central archives for at least 
15 years after conduct of the study.  


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12 AUDITING AND MONITORING 
Site monitoring is conducted to ensure that the human patient protection, study and laboratory 
procedures, study intervention administration, and data collection processes are of high quality 
and meet ICH-GCP guidelines, when appropriate, and sponsor’s regulatory guidelines. Site visits 
may be conducted by an authorized representative of the sponsor or regulatory agencies to 
inspect study data, patients’ medical records, and eCRFs in accordance with ICH guidelines, 
GCP, and the respective local and national government regulations and guidelines.  
The clinical research site will be monitored by a sponsor-approved study monitor to ensure 
correct performance of the study procedures and assure that the study will be conducted 
according to the relevant regulatory requirements. The eCRF entries will be verified with the 
source documentation.  
A separate unblinded study monitor will periodically review pharmacy logs and drug 
accountability. Procedures to maintain study blinding will be detailed in the blinding plan. 
12.1 
Clinical Monitoring Plan 
During study conduct, the sponsor or its designee will conduct periodic monitoring visits in 
accordance with a separate clinical monitoring plan to ensure that the protocol and GCPs are 
being followed. The monitors will review source documents to confirm that the data recorded on 
eCRFs are accurate. The investigator and institution will allow sponsor representatives, monitors, 
or its designee direct access to source documents to perform this verification. 
It is important that the investigator and relevant personnel are available during the monitoring 
visits and that sufficient time is devoted to the process. 
12.2 
Quality Control and Assurance 
The study may be audited to assess adherence to the clinical study protocol and quality system. 
During the conduct of the study, process related audits may be performed. An audit certificate 
will be provided in the appendices of the final clinical study report (CSR) outlining any audits 
and other related activities performed. 
The sponsor (or a designee) may conduct site audits. 
Quality control principles will be applied throughout the performance of this study. Review 
procedures will be followed at the study site for all documents that are generated in relation with 
the study. 
The study site will generate and implement a study-specific plan describing routine quality 
control and quality assurance activities for assessing the quality of the study data, protections of 
human patients, compliance with applicable federal regulations, and ICH E6 GCP guidelines.10 
The investigator will ensure all study site personnel are appropriately trained and applicable 
documentations are maintained on site. Study site monitors will verify that the clinical study is 
conducted and data are generated, documented (recorded), and reported in compliance with the 


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protocol, GCP, and the applicable regulatory requirements. Data management and control 
processes specific to this study, along with all steps and actions taken regarding data 
management and data quality control, will be described in a data management plan. 


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13 AMENDMENTS 
Protocol modifications, except those intended to reduce immediate risk to study patients, may be 
made only by the sponsor. A protocol change intended to eliminate an apparent immediate 
hazard to patients may be implemented immediately, provided the IRB/IEC is notified within 
5 days. 
Any permanent change to the protocol must be handled as a protocol amendment. The written 
amendment must be submitted to the IRB/IEC and the investigator must await approval before 
implementing the changes. The sponsor will submit protocol amendments to the appropriate 
regulatory authorities for approval. 
If in the judgment of the IRB/IEC, the investigator, CRO, and/or the sponsor, the amendment to 
the protocol substantially changes the study design and/or increases the potential risk to the 
patient and/or has an impact on the patient’s involvement as a study participant, the currently 
approved written ICF will require similar modification. In such cases, informed consent will be 
renewed for patients enrolled in the study before continued participation. 


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14 STUDY REPORT AND PUBLICATIONS 
The data generated by this study are confidential information of the sponsor. By signing the 
study protocol, the investigator agrees that the results of the study may be used for the purposes 
of national and international registration, publication, and information for medical and 
pharmaceutical professionals by the sponsor. If necessary, the authorities will be notified of the 
investigator’s name, address, qualifications, and extent of involvement.  
If an investigator or study site is to be included as an author of a publication manuscript prepared 
by the sponsor, the sponsor will allow the investigator or study site an adequate time for full 
review of the manuscript before publication. 
The sponsor is responsible for preparing and providing the appropriate regulatory authorities 
with CSRs according to the applicable regulatory requirements. The sponsor’s publication policy 
is discussed in the investigator’s clinical research agreement. 


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15 STUDY DISCONTINUATION 
Both the sponsor and the investigator reserve the right to terminate the study at the investigator’s 
site at any time. Should this be necessary, the sponsor or a specified designee will inform the 
appropriate regulatory authorities of the termination of the study and the reasons for its 
termination, and the investigator will inform the IRB/IEC of the same. In terminating the study, 
the sponsor and the investigator will assure that adequate consideration is given to the protection 
of the patients’ interests. 


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16 CONFIDENTIALITY 
Patient confidentiality is held strictly in trust by the participating investigator, study site 
personnel, and the sponsor and their agents. This confidentiality is extended to cover testing of 
biological samples in addition to the clinical information relating to participating patients. Study 
documents will be secured to maintain patient confidentiality. 
All personal details of patients will be treated as confidential by the investigator and study site 
personnel, and handling of personal data will comply with applicable national and local laws and 
regulations. 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval from the sponsor. 
The study monitor or other authorized representatives of the sponsor may inspect any documents 
maintained by the investigator, such as available medical records (office, clinic, or hospital) and 
pharmacy records for the patients in this study. The clinical study site will permit access to such 
records. 


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17 REFERENCES 
1. 
VNRX-5133 Investigator’s Brochure, Edition 2.0, 13 September 2017. 
2. 
Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, Kusek JW, Van 
Lente F; Chronic Kidney Disease Epidemiology Collaboration. Using standardized serum 
creatinine values in the modification of diet in renal disease study equation for estimating 
glomerular filtration rate. Ann Intern Med. 2006;145(4):247-54. 
3. 
Jorgensen JH, Pfaller MA, eds. Manual of Clinical Microbiology. 11th ed. Washington, 
DC: ASM Press; 2015. 
4. 
Leber AL, ed. Clinical Microbiology Procedures Handbook. 4th ed. Washington, DC: 
ASM Press; 2016. 
5. 
Jorgensen JH and Pfaller MA, eds. Manual of Clinical Microbiology. 11th ed. 
Washington, DC: ASM Press; 2015. 
6. 
Leber AL, ed. Clinical Microbiology Procedures Handbook. 4th ed. Washington, DC: 
ASM Press; 2016. 
7. 
ICH of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH 
Harmonised Tripartite Guideline, E2A: Clinical Safety Data Management: Definitions 
and Standards for Expedited Reporting, Note for Guidance on Clinical Safety Data 
Management, June 1995. 
8. 
Miettinen O, Nurminen M. Comparative analysis of two rates. Statistics in Medicine 
1985;4:213–26. 
9. 
WMA Declaration of Helsinki (18th WMA General Assembly 1964), revised at 64th 
World Medical Association General Assembly, Fortaleza, Brazil, October 2013. 
10. 
ICH of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH 
Harmonised Tripartite Guideline, E6: Guideline for Good Clinical Practice 
(CPMP/ICH/135/95), January 1997. 


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18 APPENDICES 


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APPENDIX 1. CONTACT INFORMATION 
Sponsor: 
VenatoRx Pharmaceuticals, Inc. (VenatoRx) 
 
Sponsor Medical 
Representative: 
 
 
VenatoRx Pharmaceuticals, Inc. (VenatoRx) 
 
 
 
Medical Monitor: 
 
Covance Inc. 
  
 
 


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APPENDIX 2. PATIENT SYMPTOM ASSESSMENT QUESTIONNAIRES 
Interviewer Instructions for Administering Questionnaires 
A standardized procedure for the administration of the patient symptom assessment 
questionnaires will be applied at every site to minimize bias. Please read these instructions 
carefully before administering the questionnaires and follow them exactly while administering it 
to your patient.  
The Pre-morbid Patient Symptom Questionnaire (PPSQ) and the Daily Patient Symptom 
Questionnaire (DPSQ) should be administered according to the timepoints detailed in the 
schedule of assessments. 
• Use a quiet place where the patient can be interviewed alone without interference from 
family or other staff members. 
• Read the questionnaire instructions out-loud to the patient exactly as written. 
• Read each item in the questionnaire and the response options to each item out-loud to 
the patient exactly as written. 
• Read each item out-loud to the patient in the order provided in the questionnaire. 
• Instruct patients to choose only 1 response for each item, and record the response 
selected by the patient. 
• Show the diagram of the flank to the patient when reading the item on flank pain (see 
Figure 5). 
• Repeat the instructions, questions, and response options to the patient, but do not 
interpret the questions for the patient, attempt to further explain the questions to the 
patient, or comment on the patient response. 
 


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Figure 5 
Diagram of the Flank 
 
Note: Location of flank on patient is indicated in yellow. 


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Pre-morbid Patient Symptom Questionnaire (PPSQ) 
Patient number 
 
Date 
 
Time 
 
Instructions to Read to the Patient: 
This questionnaire asks about symptoms you might be suffering from due to your current urinary 
tract infection. Some symptoms that we will ask about can be caused by health problems other 
than a urinary tract infection. That’s why we want to know what you experience when you do not 
have a urinary tract infection. 
You may have some of these symptoms when you don’t have a urinary tract infection. In some 
cases, you may have some of these symptoms, but they could have gotten worse with your 
urinary tract infection.  
Please respond whether you have had any of the following symptoms before the start of your 
current urinary tract infection started and how severe those symptoms were. In other words, tell 
us whether you have any of these symptoms when you are not suffering from a urinary tract 
infection. 
Answer each question by choosing only one response from the following possible options: no 
symptoms, mild symptoms, moderate symptoms, or severe symptoms. When answering these 
questions, don’t think about how you feel now. Think about how you felt before the start of your 
current urinary tract infection. 
Symptom 
No Symptoms 
Mild 
Moderate 
Severe 
Back pain—specifically flank pain (show the 
figure indicating flank area to the patient) 
 
 
 
 
Pain or discomfort in the lower abdomen or 
pelvic area 
 
 
 
 
Pain or burning when passing urine 
 
 
 
 
Urinating very often or frequency of urination  
 
 
 
 
A strong and uncontrollable urge to pass urine 
or urgency of urination  
 
 
 
 
 


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Daily Patient Symptom Questionnaire 
Patient number 
 
Date 
 
Time 
 
 
Instructions to Read to the Patient: 
This questionnaire asks you about your symptoms in the past 24 hours. Please respond whether 
you have had the following symptoms or problems in the past 24 hours and how severe they 
were. 
Answer each question by selecting only one response from the following possible options: no 
symptoms, mild symptoms, moderate symptoms, or severe symptoms. 
Symptom 
No Symptoms 
Mild 
Moderate 
Severe 
Back pain—specifically flank pain 
(show the figure indicating flank area to 
the patient) 
 
 
 
 
Pain or discomfort in the lower abdomen 
or pelvic area 
 
 
 
 
Pain or burning when passing urine 
 
 
 
 
Urinating very often or frequency of 
urination  
 
 
 
 
A strong and uncontrollable urge to pass 
urine or urgency of urination  
 
 
 
 
 


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APPENDIX 3. RECOMMENDED LABORATORY TESTING IN PATIENTS WITH 
ELEVATED LIVER ENZYMES 
The investigator is responsible for notifying the sponsor or sponsor representative within 
24 hours of becoming aware of either of the following based on local or central laboratory testing 
results: 
• AST or ALT ≥3× ULN and total bilirubin ≥2× ULN, OR 
• AST or ALT ≥10× ULN 
When the investigator indicates that either of these criteria have been met in the EDC system 
(Medidata/RAVE™), an automatic notification will be sent to the Covance PV & DSS team.  
In all cases, the investigator should: 
• Assess the patient for risk factors for liver enzyme abnormalities (e.g., heavy alcohol 
use, history of intravenous drug use, hypertriglyceridemia, history of hepatitis B or C 
infection, other) 
• Evaluate for signs and symptoms of liver disease, including fatigue, nausea, vomiting, 
right upper quadrant abdominal pain or tenderness, fever, or rash 
• Re-evaluate liver enzymes (AST, ALT, alkaline phosphatase, and bilirubin [total, direct, 
and indirect]) at a local laboratory until resolution or stabilization. The suggested 
frequency is approximately every 24 to 48 hours until enzyme abnormalities have 
improved and less often thereafter until resolution or stabilization. The local laboratory 
results should be documented in the local laboratory eCRF.  
In addition, the following recommended diagnostic tests may be considered: 
Hepatitis A (IgG, IgM) 
Antinuclear antibodies 
Hepatitis B (HBsAb, HBcAb, HBeAg, HBsAg, HBV DNA) 
Antimitochondrial antibodies 
Hepatitis C (HCV Ab, HCV RNA) 
Iron studies (serum iron, serum ferritin, total 
iron binding capacity, transferrin saturation) 
Cytomegalovirus serology 
Liver ultrasound 
Epstein-Barr virus serology 
 
DNA=deoxyribonucleic acid; HBcAb=hepatitis B core antibody; HBeAg=hepatitis B e antigen; HBsAb=hepatitis B; 
HBsAg=hepatitis B surface antibody; HBV=hepatitis B virus; HCV Ab=hepatitis C virus antibody; 
HCV RNA=hepatitis C virus ribonucleic acid; Ig=immunoglobulin. 

SAP_001.pdf: 
STUDY NUMBER: VNRX-5133-201 
PROTOCOL TITLE:  A Phase 3, Randomized, Double-blind, 
Active-controlled Noninferiority Study Evaluating 
the Efficacy, Safety, and Tolerability of 
Cefepime/VNRX-5133 in Adults with Complicated 
Urinary Tract Infections, Including Acute Pyelonephritis 
NCT Number:  NCT03840148 
Document Date: 02 February 2022 






Statistical Analysis Plan: VNRX-5133-201 
02 February 2022 
Page | 3 
 
 
CONTENTS 
CONTENTS .................................................................................................................................... 3 
LIST OF ABBREVIATIONS ........................................................................................................5 
1.0 
INTRODUCTION ..............................................................................................................8 
2.0 
STUDY DESIGN ................................................................................................................8 
3.0 
STUDY OBJECTIVES ......................................................................................................9 
3.1 
Primary .....................................................................................................................9 
3.2 
Secondary .................................................................................................................9 
4.0 
ANALYSIS POPULATIONS ..........................................................................................10 
4.1 
Intent-to-Treat Analysis Population (ITT) .............................................................10 
4.2 
Microbiological ITT (microITT) Analysis Population ..........................................10 
4.3 
Extended microITT Analysis Population ...............................................................11 
4.4 
Clinically Evaluable (CE) Analysis Populations ....................................................11 
4.5 
Microbiologically Evaluable (ME) Analysis Populations ......................................12 
4.6 
Safety Analysis Population ....................................................................................12 
5.0 
ENDPOINTS ....................................................................................................................12 
5.1 
Primary Endpoint ...................................................................................................12 
5.2 
Secondary Endpoints ..............................................................................................14 
5.2.1 
Assessment of Symptomatic Clinical Response ....................................15 
5.2.2 
General Microbiological Considerations ...............................................18 
5.2.3 
Assessment of Microbiological Response .............................................18 
5.2.4 
Other Microbiological Outcomes ..........................................................22 
5.2.5 
Investigator Opinion of Clinical Response............................................23 
5.3 
Exploratory Endpoints ............................................................................................23 
5.4 
Safety Outcomes ....................................................................................................23 
6.0 
STATISTICAL METHODS ...........................................................................................24 
6.1 
Sample Size ............................................................................................................24 
6.2 
Study Visits ............................................................................................................24 
6.3 
Randomization........................................................................................................25 
6.4 
Interim Analysis .....................................................................................................25 
6.5 
Reporting Conventions ...........................................................................................25 
6.6 
Handling of Missing Data ......................................................................................26 
7.0 
STATISTICAL ANALYSES ...........................................................................................27 


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7.1 
Patient Disposition and Protocol Deviations ..........................................................27 
7.2 
Demographics, Baseline Characteristics and Medical History ..............................28 
7.3 
Baseline Pathogens .................................................................................................28 
7.4 
Extent of Exposure and Study Drug Treatment Compliance .................................29 
7.4.1 
Duration of Study Drug Therapy ...........................................................29 
7.4.2 
Prior and Concomitant Medications ......................................................30 
7.5 
Efficacy Analyses ...................................................................................................31 
7.5.1 
Primary Efficacy Analysis .....................................................................31 
7.5.2 
Additional Analyses of the Primary Efficacy Endpoint ........................31 
7.5.3 
Secondary Efficacy Analyses ................................................................32 
7.5.4 
Additional Efficacy Analyses ................................................................35 
7.6 
Safety Analyses ......................................................................................................36 
7.6.1 
Adverse Events ......................................................................................36 
7.6.2 
Clinical Laboratory Evaluations ............................................................37 
7.6.3 
Vital Signs and ECG .............................................................................39 
8.0 
CHANGES FROM THE PROTOCOL SPECIFIED ANALYSES .............................39 
9.0 
LIST OF MAJOR CHANGES FROM THE ORIGINAL STATISTICAL 
ANALYSIS PLAN ............................................................................................................39 
10.0 
REFERENCES .................................................................................................................42 


Statistical Analysis Plan: VNRX-5133-201 
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LIST OF ABBREVIATIONS 
 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AP 
Acute pyelonephritis 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BPH 
Benign prostatic hyperplasia 
CE 
Clinically evaluable 
CE-EOT 
Clinically Evaluable at End-of-Treatment 
CE-LFU 
Clinically Evaluable at Late Follow Up 
CE-TOC 
Clinically Evaluable at Test-of-Cure 
CFU 
Colony forming unit 
CI 
Confidence interval 
CSR 
Clinical study report 
cUTI 
Complicated urinary tract infection 
DPSQ 
Daily Patient Symptom Questionnaire 
DSMB 
Data and safety monitoring board 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eCrCl 
Estimated creatinine clearance 
eGFR 
Estimated Glomerular Filtration Rate 
ECMAP 
Evaluation of clinical and microbiology assessment plan 
ECMRT 
Evaluation and clinical/microbiology review team 
EmicroITT 
Extended Microbiological Intent-to-Treat 
EMA 
European Medicines Agency 
EOT 
End of Treatment 


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ESBL 
Extended spectrum beta-lactamase 
FDA 
US Food and Drug Administration 
ITT 
Intent-to-treat 
IV 
Intravenous(ly) 
IVRS / IWRS 
Interactive Voice Response System / Interactive Web Response System 
LFU 
Late Follow-up 
MDR 
Multidrug resistant 
MDRD 
Modification of diet in renal disease 
ME 
Microbiologically evaluable 
ME-EOT 
Microbiologically Evaluable at End-of-Treatment 
ME-LFU 
Microbiologically Evaluable at Late Follow Up 
ME-TOC 
Microbiologically Evaluable at Test-of-Cure 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
Minimal inhibitory concentration 
MicroITT 
Microbiological intent-to-treat 
MRSA 
Methicillin resistant Staphylococcus aureus 
MSSA 
Methicillin susceptible Staphylococcus aureus 
PCS 
Potentially Clinically Significant 
PK 
Pharmacokinetic(s) 
PPSQ 
Pre-morbid Patient Symptom Questionnaire 
PT 
Preferred term 
q8h 
every 8 hours 
QTc 
QT interval corrected for heart rate 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SOC 
System organ class 


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TEAE 
Treatment-emergent adverse event 
TOC 
Test of Cure 
ULN 
Upper limit of normal 
UTI 
Urinary tract infection 
VNRX 
Venatorx Pharmaceuticals, Inc. (Venatorx) 


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1.0 
INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the planned summary and analysis of clinical 
data from the study, “A Phase 3, Randomized, Double-blind, Active-controlled 
Noninferiority Study Evaluating the Efficacy, Safety, and Tolerability of Cefepime/VNRX 
5133 in Adults with Complicated Urinary Tract Infections, Including Acute Pyelonephritis”. 
The study has been designed to address global regulatory requirements, and this SAP 
addresses the analyses to be performed for both EMA and FDA. 
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be identified herein. If additional analyses 
are required to supplement the planned analyses described in this SAP, they may be 
performed and will be identified in the clinical study report (CSR). Any substantial deviations 
from this SAP will be clearly documented. 
Changes made to the SAP after it has been signed but prior to database lock will be 
documented in an amendment. Any important changes made to the analysis after database 
lock will be described in the CSR. 
The population PK analysis using data from the study will be described in a population PK 
analysis plan and summarized in a separate report. 
2.0 
STUDY DESIGN 
Study VNRX-5133-201 is a Phase 3, randomized, multicenter, double-blind, double-dummy, 
active-controlled noninferiority study to evaluate the efficacy, safety, and tolerability of 
cefepime/VNRX-5133 compared with an active control, meropenem, in adult patients with a 
complicated urinary tract infection (cUTI), including acute pyelonephritis (AP). Each patient 
is expected to complete the study within approximately 4 to 5 weeks. 
Patients with cUTI, including AP, will be enrolled. After obtaining signed informed consent 
and confirming eligibility within 24 hours prior to randomization, patients will be 
randomized in a 2:1 ratio to receive either cefepime/VNRX-5133 (2 g/0.5 g IV q8h) infused 
over 2 hours plus meropenem placebo infused over 30 minutes or the active comparator, 
meropenem (1 g IV q8h) infused over 30 minutes plus cefepime/VNRX-5133 placebo 
infused over 2 hours starting on Study Day 1. 
Patients will be stratified by the type of infection (AP only versus complicated lower UTI 
with or without AP) and by region (North America and Western Europe versus Eastern 
Europe versus Rest of the World). Complicated urinary tract infection (cUTI) is the same as 
complicated lower UTI with or without AP for the purposes of the SAP. At least 30% of the 
population will have AP. 
Patients may receive up to 24 hours of antibacterials for treatment of cUTI prior to 
randomization; however, the number of patients with prior antibacterial use will be limited to 
approximately 25% of the population. Before receipt of study drug, urine specimen and blood 
cultures will be obtained from all patients for culture and for in vitro antibacterial 
susceptibility testing. Patients with an indwelling catheter should have urine samples 
collected following the placement of a new catheter, or if the indwelling catheter cannot be 
removed, aseptic techniques should be used through a properly disinfected collection port. 


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Patients with an indwelling catheter should be randomized only if they are expected to 
permanently discontinue use of the catheter prior to Study Day 5. 
Screening assessments will also include a Daily Patient Symptom Questionnaire (DPSQ) and 
a Pre-morbid Patient Symptom Questionnaire (PPSQ). The DPSQ will be administered at 
screening, daily while on study drug, and at End of Treatment (EOT), Test of Cure (TOC), 
and Late Follow-up (LFU) visits to determine the presence and intensity of cUTI symptoms. 
The PPSQ will be administered once at screening to determine whether a patient normally 
experiences urinary tract symptoms (i.e., in the absence of a UTI) that may be attributable to 
other disease processes (e.g., benign prostatic hyperplasia [BPH]). 
Study drug will be administered IV for 7 days and will be considered completed after the 
third dose on Study Day 7 for patients without bacteremia. All patients (who do not require 
dosing adjustments for renal dysfunction) will receive at least 19 doses. Patients without 
bacteremia will receive a maximum of 21 doses of active study drug. Patients with 
bacteremia at study entry may have their treatment extended up to 14 days at the 
investigator’s discretion. 
Patients will be admitted at screening and remain at the study site or hospital for the duration 
of the IV treatment period and through the EOT visit. The EOT visit will be performed within 
24 hours after the last dose of IV study drug. Patients may be discharged from the study site 
after the EOT visit if clinically stable and at the investigator’s discretion. 
Patients must return to the study site for the TOC visit (Study Days 19 to 23) and the LFU 
visit (Study Days 28 to 35). 
3.0 
STUDY OBJECTIVES 
3.1 
Primary 
The primary objective of the study is to assess the efficacy of cefepime/VNRX-5133 
compared with meropenem with respect to both per-patient microbiological eradication and 
symptomatic resolution of all UTI-core symptoms (or return to pre-morbid baseline) at the 
Test of Cure (TOC) visit. 
The primary objective refers to per-patient microbiological eradication. Although eradication 
is used to define per-pathogen outcomes, “per-patient microbiological eradication” is 
considered the same as per-patient microbiological success for the purposes of this SAP. 
3.2 
Secondary 
The secondary objectives of the study are as follows: 
• To determine the efficacy of cefepime/VNRX-5133 compared with 
meropenem with respect to the per-patient microbiological response, per-pathogen 
microbiological response, and symptomatic resolution of all UTI-core symptoms 
at various timepoints in various analysis populations. 
• To determine the efficacy of cefepime/VNRX-5133 compared with 
meropenem with respect to the per-patient microbiological response, per-pathogen 
microbiological response, and symptomatic resolution of all UTI-core symptoms 


Statistical Analysis Plan: VNRX-5133-201 
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in patients with cUTI due to cefepime-resistant pathogens at the Test of Cure 
(TOC) visit in various analysis populations 
• To evaluate the safety and tolerability profile of cefepime/VNRX-5133 
compared with meropenem in the treatment of patients with a cUTI in the safety 
analysis population 
• To evaluate the steady-state PK of cefepime and VNRX-5133 in patients using 
a population PK model 
4.0 
ANALYSIS POPULATIONS 
4.1 
Intent-to-Treat Analysis Population (ITT) 
The ITT analysis population will consist of all randomized patients regardless of whether the 
patient received study drug. A patient is considered randomized when a randomization 
number has been assigned. 
4.2 
Microbiological ITT (microITT) Analysis Population 
The microITT analysis population will consist of all patients in the ITT analysis population 
and 
o Had a positive study entry urine culture defined as ≥105 CFU/mL of a gram-negative 
pathogen(s) against which both cefepime/VNRX-5133 and meropenem have antibacterial 
activity AND 
o Had no more than 2 microorganisms identified in the study entry culture regardless of 
colony count 
Antibacterial activity for meropenem is defined as Susceptible [S], or Intermediate [I], for 
Enterobacteriaceae and Susceptible [S] or Intermediate [I] for P. aeruginosa according to 
2019 CLSI criteria[1]. For cefepime/VNRX-5133, ‘antibacterial activity’ is defined for 
Enterobacteriaceae as provisionally susceptible (MIC≤16 µg/mL); for P. aeruginosa, 
‘antibacterial activity’ is also defined as provisionally susceptible (MIC≤16 µg/mL). 
Table 1 Antibacterial activity of study drugs as defined by Minimum Inhibitory 
Concentration (MIC) against Enterobacteriaceae and P. aeruginosa 
 
MIC (µg/mL) corresponding to antibacterial activity 
Study drug 
Enterobacteriaceaea 
P. aeruginosa 
Meropenem 
≤2 
≤4 
Cefepime/VNRX-5133 
≤16 
≤16 
aDue to changes in nomenclature, Enterobacteriaceae is the same as Enterobacterales for the purposes of this 
analysis. 
 
For patients with two gram-negative baseline pathogens, both study drugs must have 
antibacterial activity against both pathogens. 


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4.3 
Extended microITT Analysis Population 
The extended microITT analysis population will consist of all patients in the ITT analysis 
population and 
o Had a positive study entry urine culture defined as ≥105 CFU/mL of a gram-negative 
pathogen against which at least 1 study drug (i.e., cefepime/VNRX-5133 and/or 
meropenem) have antibacterial activity AND 
o Had no more than 2 species of microorganisms identified in the study entry culture 
regardless of colony count. 
Antibacterial activity for meropenem and cefepime/VNRX-5133 is defined as outlined in 
Section 4.2. 
4.4 
Clinically Evaluable (CE) Analysis Populations 
Three CE analysis populations will be defined, the CE-EOT, CE-TOC and CE-LFU analysis 
populations. The CE analysis populations will consist of all patients included in the ITT 
analysis population who also meet the criteria listed below. These criteria will be 
programmed from the database and/or be reviewed manually by the Sponsor in a blinded 
manner prior to database lock to confirm each patient’s inclusion in the CE analysis 
populations. 
Details regarding the programming and review of electronic case report form (eCRF) data 
and the database to establish inclusion in the CE analysis populations will be included in the 
micro and clinical/microbiological assessment plan (ECMAP). 
o Had an appropriate diagnosis of cUTI 
o Received treatment for ≥48 hours (or <48 hours if discontinued due to an AE or 
death) 
o Were evaluated for the appropriate endpoint at the relevant timepoint (i.e., EOT, 
TOC, and LFU) with a response that is not indeterminate and within the protocol 
defined windows 
o Did not violate entry criterion surrounding use of prior antibacterials 
o Did not receive a concomitant systemic antibiotic with potential activity against any 
of the baseline pathogens between the time of randomization and EOT, TOC, and 
LFU, respectively, except therapies used to treat cUTI in patients who have failed 
study drug 
o Did not have other confounding factors that interfered with the assessment of 
outcome as assessed by a blinded evaluability and clinical/microbiological review 
team (ECMRT) prior to database lock. This includes but is not limited to unblinding 
events. 


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4.5 
Microbiologically Evaluable (ME) Analysis Populations 
Three ME analysis populations will be defined, the ME-EOT, ME-TOC and ME-LFU 
analysis populations. The ME analysis populations will consist of all patients included the 
microITT analysis population who also meet the criteria listed below. These criteria will be 
programmed from the database and/or be reviewed manually by the Sponsor in a blinded 
manner prior to database lock to confirm each patient’s inclusion in the ME analysis 
populations. 
Details regarding the programming and review of CRF data and the database to establish 
inclusion in the ME analysis populations will be included in the ECMAP. 
o Both study drugs are known to have antibacterial activity against all baseline gram- 
negative pathogens (antibacterial activity as defined above) AND 
o Had an appropriate diagnosis of cUTI 
o Received treatment for ≥48 hours (or <48 hours if discontinued due to an AE or 
death) 
o Were evaluated at the respective EOT, TOC, and LFU visits with a microbiological 
response of eradication or persistence (ie, per-patient microbiological response of 
success or failure) and within the protocol defined windows 
o Did not violate entry criterion surrounding use of prior antibacterials 
o Did not receive a concomitant systemic antibiotic with the potential activity against 
any of the baseline pathogens between the time of randomization and EOT, TOC, 
and LFU, respectively, except therapies used to treat cUTI in patients who have 
failed study drug. 
o Did not have other confounding factors that interfered with the assessment of 
outcome as assessed by a blinded ECMRT prior to database lock. This includes but 
is not limited to unblinding events. 
4.6 
Safety Analysis Population 
The Safety analysis population will consist of all patients who receive any dose of study drug. 
Data will be presented based upon the study drug actually received. All safety analyses will 
be conducted in this analysis population. 
5.0 
ENDPOINTS 
5.1 
Primary Endpoint 
The primary endpoint is the demonstration of microbiological success (all gram-negative 
bacterial pathogens found at baseline are eradicated to <103 colony forming units per 
milliliter [CFU/mL] on urine culture post-baseline) and the demonstration of symptomatic 
clinical success (symptomatic resolution or return to pre-morbid baseline of all UTI-core 
symptoms including frequency, urgency, dysuria, suprapubic/pelvic pain, and flank pain, 
patient is alive and has not received additional antibacterial for cUTI) at TOC in the 
microbiological intent-to-treat (microITT) analysis population. 


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Patients with missing data such that a symptomatic clinical and/or microbiological response 
cannot be determined will be considered an indeterminate response. Since the analysis of the 
primary endpoint is based on the microITT Analysis Population, patients with an 
indeterminate response are considered non-responders. For the microITT analysis 
population, the proportion of microITT patients considered responders is defined using the 
following formula (where the denominator is comprised of the total number of patients in the 
microITT analysis population): 
Number of patients who are responders 
(Number of patients who are responders + Number of patients who are non-responders + 
Number of patients who have an indeterminate response) 
The various scenarios of microbiological response and symptomatic clinical response will 
result in an overall response as outlined in Table 2. Additional details regarding definition of 
symptomatic clinical and microbiological response are provided in Section 5.2.1 and 5.2.3. 
Table 2 Definition of overall response for the primary endpoint of Per-Patient 
Microbiological Response and Symptomatic Clinical Response 
 
Symptomatic 
Clinical Response 
Per-Patient Microbiological Response 
Success 
Failure 
Indeterminate 
Success 
Responder 
Non-responder 
Indeterminate 
Failure 
Non-responder 
Non-responder 
Non-responder 
Indeterminate 
Indeterminate 
Non-responder 
Indeterminate 
 
Microbiological response definition due to COVID-19 
Due to the COVID-19 pandemic there is a reasonable likelihood that it will not be possible to 
obtain microbiological samples at the TOC and LFU visits from all patients. The missing 
samples would not be related to study treatment or procedures, but due to the inability to 
collect samples during the pandemic. The common practice in cUTI studies of considering 
indeterminate microbiological response as a non-responder (see above) would not be 
appropriate in this case and would also have the effect of reducing statistical power down to 
85% (with 10% missing data) or 80% (with 20% missing data). 
As a result, a set of sensitivity analyses will be performed where microbiological response at 
TOC and LFU will be defined using a presumed microbiological response if the 
microbiological data are missing (i.e. Indeterminate) at TOC or LFU as outlined in Table 3. 
This means that if microbiological data are missing (i.e. Indeterminate) at TOC or LFU 
respectively, but the symptomatic clinical response is a success, then a patient would be 
assigned “presumed eradication”; in situations when the symptomatic clinical response is 
failure a patient would be assigned “presumed persistence”. 


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Table 3 Definition of Overall response for Per-Patient Microbiological Response and 
Symptomatic Clinical Response When Using Presumed 
Microbiological Response 
 
Symptomatic 
Clinical Response 
Per-Patient Microbiological Response 
Success 
Failure 
Indeterminate 
Success 
Responder 
Non-responder 
Respondera 
Failure 
Non-responder 
Non-responder 
Non-responderb 
Indeterminate 
Indeterminate 
Non-responder 
Indeterminate 
a based upon presumed eradication; b based upon presumed persistence. 
 
5.2 
Secondary Endpoints 
Clinical and Microbiological Efficacy: 
• The proportion of patients with both microbiological success and symptomatic clinical 
success at TOC in the extended microITT and microbiologically evaluable (ME)-TOC 
analysis populations. 
• The proportion of patients with both microbiological success and symptomatic clinical 
success at EOT in the microITT, and ME-EOT analysis populations, and at LFU in the 
microITT, and ME-LFU analysis populations. 
• The proportion of patients with per-patient microbiological success at EOT, TOC and 
LFU in the microITT and relevant ME-EOT, ME-TOC and ME-LFU analysis 
populations. 
• The proportion of patients with symptomatic clinical success at EOT, TOC, and LFU in 
the microITT, and relevant CE-EOT, CE-TOC and CE-LFU analysis populations. 
• The proportion of patients with clinical success based on investigator opinion at TOC in 
the microITT analysis population. 
• The proportion of patients with per-pathogen microbiological success (eradication) at 
EOT in the microITT and ME-EOT populations, TOC in the microITTand ME-TOC 
populations, and at LFU in the microITTand ME-LFU populations 
• The proportion of patients with both microbiological success and symptomatic clinical 
success among those with cefepime-resistant pathogens at EOT in the microITT and ME- 
EOT analysis populations, TOC in the microITT and ME-TOC analysis populations, and 
at LFU in the microITT, and ME-LFU analysis populations. 
• The proportion of patients with per-patient microbiological success among those with 
cefepime-resistant pathogens at EOT in the microITTand ME-EOT populations, TOC in 
the microITTand ME-TOC populations, and at LFU in the microITTand ME-LFU 
populations. 


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• The proportion of patients with per-pathogen microbiological eradication among those 
with cefepime-resistant pathogens at EOT in the microITTand ME-EOT populations, 
TOC in microITT and ME-TOC populations, and at LFU in the microITTand ME-LFU 
populations. 
• The proportion of patients with symptomatic clinical success among those with cefepime- 
resistant pathogens at EOT in the microITT and CE-EOT populations, TOC in the 
microITTand CE-TOC populations, and at LFU in the microITT and CE-LFU 
populations. 
Safety and Tolerability: 
• Safety and tolerability will be assessed based on the incidence and severity of adverse 
events (AEs) and serious adverse events (SAEs), exposure, mortality, reasons for 
discontinuation of study drug and study withdrawal, vital sign measurements, and 
clinically significant changes in clinical chemistry, hematology, urinalysis, and 
coagulation laboratory values. 
Pharmacokinetics: 
• The population PK analysis using data from the study will be described in a population 
PK analysis plan and summarized in a separate report. 
Resolution of Fever: 
• The time to first defervescence (≤37.8°C) in the microITT analysis population for patients 
who have fever (>38°C) at baseline will be assessed as an exploratory endpoint. 
In addition to the endpoints listed above, proportion of patients with both microbiological and 
symptomatic clinical success at TOC, the proportion of patients with symptomatic success at 
TOC, and per-patient and per-pathogen microbiological success at TOC in the microITT 
analysis population will be presented by treatment group amongst the subset of patients with 
MDR pathogens, amongst the subset of patients with ESBL pathogens, by baseline pathogen 
and also by MIC of baseline pathogen and by disk size. Details of the presentations to be 
produced are described in Section 7.5.3. 
5.2.1 
Assessment of Symptomatic Clinical Response 
The symptomatic clinical success at TOC in the microITT analysis population is one of the 
components of the primary endpoint of this study; responses at EOT and LFU are secondary 
endpoints. 
During study conduct, patients will be required to report their cUTI symptoms on a series of 
formal questionnaires that will be administered by trained study center staff. The PPSQ will 
be administered once at screening to determine whether a patient normally experiences 
urinary tract symptoms (i.e., in the absence of a UTI) that may be attributable to other disease 
processes (e.g., BPH), and these data will be used to define pre-morbid symptoms. The 
patients will be administered the DPSQ at screening, daily while on study drug, and at EOT, 
TOC, and LFU visits. The data collected from the questionnaires will be used to 
programmatically assess the symptomatic clinical response as defined in Table 4 and Table 5. 
Instructions for performing the PPSQ and DPSQ are detailed in the protocol. 


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The DPSQ should also be performed at any unscheduled visit occurring for any reason 
between the EOT and TOC visits and/or between the TOC and LFU visits. 
In the event that all pre-morbid symptoms as measured by the PPSQ take the same values as 
those measured at baseline on the DPSQ, it will be necessary for all symptoms to be resolved 
for this patient to be considered a symptomatic clinical success. Similarly, on the rare 
occasion where an individual symptom as measured by the PPSQ appears to be worse than 
that measure at baseline on the DPSQ, that symptom would need to subsequently show 
complete resolution to be considered a success. 
Table 4 Symptomatic Clinical Response Criteria at EOT 
 
Response Category 
Definition 
Symptomatic clinical success 
All of the following have occurred: 
• 
Resolution (or return to pre-morbid state) of the core 
symptoms of cUTI (dysuria, frequency, urgency, 
suprapubic/pelvic pain, and flank pain) present at study entry 
• 
No new core cUTI symptoms have developed and no 
symptoms have worsened 
• 
Patient is alive 
For patients with identical symptoms for the pre-morbid PPSQ assessment and 
baseline DPSQ assessment, all symptoms have to be resolved to be considered a 
success; If an individual symptom is better at baseline DPSQ when compared with 
PPSQ, that symptom must subsequently be completely resolved to be considered a 
success 
Symptomatic clinical failurea 
Occurrence of 1 or more of the following: 
• 
Confirmed persistence of at least 1 symptom 
(i.e., non-resolution or not having returned to pre-morbid 
state) of the core symptoms of cUTI (dysuria, frequency, 
urgency, suprapubic/pelvic pain, and flank pain) 
• 
Development of 1 or more core symptoms of cUTI not 
present at baseline 
• 
Death 
Indeterminate symptomatic 
clinical response 
Cases where the symptomatic clinical response could not be assessed for 
the following reasons: 
• 
Lost to follow-up 
• 
Patient withdrew consent 
• 
Missed Visit 
• 
One or more symptoms not obtained at relevant visit 
cUTI=complicated urinary tract infection; EOT=End of Treatment; 
a any patient receiving additional antibiotics for the treatment of cUTI after the last dose of randomized therapy 
but before the EOT visit will be classified a failure 


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Table 5 Symptomatic Response Criteria at TOC and LFU 
 
Response Category 
Definition 
Symptomatic clinical 
success 
All of the following have occurred: 
• 
Resolution (or return to pre-morbid state) of the core symptoms of 
cUTI (dysuria, frequency, urgency, suprapubic/pelvic pain, and flank 
pain) present at study entry 
• 
No new core cUTI symptoms have developed and no symptoms have 
worsened 
• 
Patient is alive 
• 
Patient has not received additional antibiotics for the treatment of 
cUTI (other than those permitted per protocol) after EOT 
For patients with identical symptoms for the pre-morbid PPSQ assessment and 
baseline DPSQ assessment, all symptoms have to be resolved to be considered a 
success. If an individual symptom is better at baseline DPSQ when compared with 
PPSQ, that symptom must subsequently be completely resolved to be considered a 
success 
Symptomatic clinical failure 
Occurrence of 1 or more of the following: 
• 
Confirmed persistence of at least 1 symptom (i.e., non-resolution or 
not having returned to pre-morbid state) of the core symptoms of 
cUTI (dysuria, frequency, urgency, suprapubic/pelvic pain, and flank 
pain) 
• 
Development of 1 or more core symptoms of cUTI not present at 
baseline 
• 
Death 
• 
Patient has received additional antibiotics for the treatment of cUTI 
(other than those permitted per protocol) after EOT 
Indeterminate symptomatic 
clinical response 
Cases where the symptomatic clinical response could not be assessed 
cUTI = complicated urinary tract infection; TOC= Test of Cure; LFU = Late Follow-up 
 
For the analysis of clinical endpoints in the microITT and extended microITT analysis 
populations, the success rate will be calculated as follows: 
Number of patients who are a success 
(Number of patients who are a success + Number of patients who are a failure + Number of 
patients who have an indeterminate response) 
Patients with an indeterminate response at the EOT, TOC and LFU visits will be excluded 
from the analysis of clinical response endpoints in the CE and ME analysis populations. For 
the analysis of clinical response rate in the CE and ME analysis populations, the success rate 
will be calculated as follows: 
Number of patients who are a success 
(Number of patients who are a success + Number of patients who are a failure) 
In addition to assessing response as success or failure at LFU, responses will be assessed as 
sustained symptomatic clinical success or symptomatic clinical relapse depending upon the 
response seen at TOC. Clinical relapse is a sub-category of failure at LFU and includes 


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patients with clinical success at TOC who are failures at LFU. Patients with clinical success 
at LFU that are not classified as sustained success at LFU would have been indeterminate at 
TOC. 
5.2.2 
General Microbiological Considerations 
A baseline urine pathogen is defined as the presence of causative bacteria present at ≥ 105 
CFU/mL in baseline urine culture with no more than 2 organisms isolated from the sample 
collected. A post baseline urine pathogen is defined as the presence of causative bacteria 
present at ≥ 103 CFU/mL in a post baseline urine culture with no more than 2 organisms 
isolated from the sample collected. 
A baseline blood pathogen is defined as a non-contaminant bacteria identified in blood 
culture obtained at baseline. A post baseline blood pathogen is defined as a non-contaminant 
bacteria identified in post baseline blood cultures. A patient with a blood pathogen will be 
considered bacteremic. 
Susceptibility to carbapenems including meropenem will be defined using current CLSI 
criteria[1]. Susceptibility to cefepime/VNRX-5133 will be defined using provisional 
Susceptible breakpoints of an MIC of ≤16 µg/mL for Enterobacteriaceae, and an MIC of ≤16 
µg/mL for Pseudomonas aeruginosa. In this case, a provisional Resistant breakpoint would 
be defined as ≥32 µg/mL. 
In addition, a presentation including a provisional Intermediate breakpoint of an MIC of 32 
µg/mL will be produced for one or both of the Enterobacteriaceae and Pseudomonas 
aeruginosa organism groups. In this case the categories used will be Susceptible (≤16 
µg/mL), Intermediate (32 µg/mL) and Resistant (≥64 µg/mL). 
Susceptibility to cefepime (without VRNX-5133) will be defined using current CLSI 
criteria[1]. 
The ECMRT will be convened to review all patients prior to database lock and unblinding for 
inclusion in the clinically and microbiologically evaluable analysis population and to confirm 
that all baseline pathogens, follow up pathogens, emergent infections and microbiologic 
outcomes have been appropriately categorized programmatically. For more details on the 
responsibilities of the ECMRT, refer to the evaluability and clinical/microbiological 
assessment plan (ECMAP). The source raw data used for evaluability review will be included 
in SDTM datasets used to generate evaluability review outputs, whilst decisions from the 
ECMRT review will be included in ADaM datasets. 
5.2.3 
Assessment of Microbiological Response 
The identification of baseline pathogens and the assessment of microbiological response will 
always use the central laboratory results unless the central laboratory did not receive an 
isolate. For example, this could be if a sample was not sent, if a sample was lost or if the 
sample was non-viable. If it is not possible to use central microbiological laboratory results, 
local microbiological laboratory results will be used. 
The definition of per-patient microbiological response will not consider gram-positive 
pathogens. Per-pathogen microbiological eradication will not be summarized for gram- 
positive pathogens but will be listed. 






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Table 9 Definition of Microbiological Response when blood and urine pathogens are 
identified 
 
Baseline 
Post baseline 
Overall per-patient 
microbiological response 
Urine gram- 
negative 
pathogen 
Blood pathogen 
Urine gram- 
negative 
pathogen 
Blood pathogen 
X 
X 
X = Eradicated 
X = Eradicated 
Success 
X 
X 
X = Eradicated 
X 
Failure 
X 
X 
X = Eradicated 
Not done 
Success if symptomatic 
clinical success or failure if 
symptomatic clinical 
failure 
X 
Y 
X = Eradicated 
Y 
Successa 
X 
X, Y 
X = Eradicated 
X=eradicated, Y 
Successa 
X 
None 
X= Eradicated 
X 
Failure 
X=pathogen X; Y=pathogen Y. Therefore, these would represent different pathogens 
a When a different pathogen is isolated in urine and in blood, the blood infection is not considered related to the 
cUTI. These cases will be described in the CSR. 
 
A pathogen will be said to have microbiologic recurrence at the LFU visit if the response was 
eradication at the TOC visit and persistence at the LFU visit. Similarly, a pathogen will be 
said to have sustained eradication at the LFU visit if the response was eradication at the TOC 
visit and is eradication at the LFU visit. Per-patient microbiologic recurrence is a sub- 
category of persistence at LFU and will be summarized as a sub-category of failure at LFU. 
The other subcategory of persistence at LFU include failures that were carried forward from 
TOC. Sustained eradication is a sub-category of eradication at LFU. Patients with 
eradication at LFU that are not classified as sustained eradication at LFU would have been 
indeterminate at TOC. 
Pathogens identified in blood will also be assigned a per-pathogen microbiological response. 
In instances of bacteremia, a successful outcome for a baseline pathogen will require a 
successful microbiological response from the urine sample as well as the blood. 
For the analysis of per-patient microbiological endpoints in the microITT and extended 
microITT analysis populations, the success rate will be calculated as follows: 
Number of patients who are a success 
(Number of patients who are a success + Number of patients who are a failure + Number of 
patients who have an indeterminate response) 
Patients with an indeterminate response at the EOT, TOC and LFU visits will be excluded 
from the analysis of microbiological response endpoints in the CE and ME analysis 
populations. For the analysis of microbiological response rate in the CE and ME analysis 
populations, the success rate will be calculated as follows: 
Number of patients who are a success 
(Number of patients who are a success + Number of patients who are a failure) 


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5.2.4 
Other Microbiological Outcomes 
5.2.4.1 
By pathogen microbiological response 
The by-pathogen microbiological success rate at EOT, TOC and LFU in the microITT 
analysis population will be calculated as follows: 
Number of patients who are a success for the specific pathogen 
(Number of patients who are a success for the specific pathogen + Number of patients who 
are a failure for the specific pathogen + Number of patients with an indeterminate outcome 
for the specific pathogen) 
For each pathogen, the denominator should therefore be equal to the number of patients with 
a given pathogen identified at baseline. 
Patients with an indeterminate Microbiological Response at the EOT, TOC and LFU visits 
will be excluded from the relevant ME analysis population (ME-EOT, ME-TOC or ME- 
LFU). Therefore, the by–pathogen Microbiological Response of success will be calculated as 
follows: 
Number of patients with a success for the specific pathogen 
(Number of patients with a success for the specific pathogen + Number of patients with a 
failure for the specific pathogen) 
5.2.4.2 
Emergent Infections 
Pathogens first appearing after baseline in patients with a different baseline pathogen are 
categorized as described in Table 10 and will be considered separately from microbiological 
response. 
Table 10 Emergent Infection Criteria 
 
Emergent Infection 
Definition 
Superinfection 
Isolation of a new pathogen(s) >10^5 (other than the original baseline 
pathogen[s]) from urine during treatment with study drug that is accompanied 
by new or worsening signs and symptoms of infection requiring alternative 
antimicrobial therapy 
New infection 
Isolation of a new pathogen(s) >10^5 (other than the original baseline 
pathogen[s]) from urine after completion of study drug that is accompanied by 
new or worsening signs and symptoms of infection requiring alternative 
antimicrobial therapy 
5.2.4.3 
Persistence with Increasing Minimal Inhibitory Concentration 
In patients with persistence, MICs of study drugs against pathogens isolated at baseline will 
be compared to MICs of study drugs against post-baseline pathogens. An outcome of 
persistence with increasing MIC is indicated by the organism displaying a ≥4-fold higher 
MIC to study drug received in a urine or blood culture obtained at EOT or later compared to 
baseline. 


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5.2.5 
Investigator Opinion of Clinical Response 
Based on the entirety of the patient’s clinical course and current status, including an 
evaluation of signs and symptoms (including systemic and cUTI-specific symptoms), 
physical examination, laboratory values, and general well-being, the investigator should 
provide an Investigator Opinion of Clinical Response at the TOC, visit according to the 
definitions listed in Table 11. 
Table 11 Investigator Opinion of Clinical Response Criteria at TOC 
 
Investigator Opinion of 
Clinical Response 
Definition 
Success 
All or most pretherapy signs and symptoms of the index infection have 
improved or resolved such that no additional antibiotics0 are required for 
treatment of the cUTI 
Success with treatment for 
asymptomatic bacteriuria 
All or most pretherapy signs and symptoms of the index infection have 
improved or resolved such that no additional antibioticsa are required; however, 
treatment of asymptomatic bacteriuria is warranted based on the opinion of the 
investigator 
Failure 
Patients who meet at least one of the following criteria: 
• 
Death related to cUTI 
• 
Persistence or progression of cUTI symptoms such that additional 
antibiotics for cUTI are required 
• 
Patient previously met criteria for failure 
Indeterminate 
An assessment was not performed due to any of the following: 
• 
Death where cUTI was clearly non-contributory 
• 
Assessment was not performed (e.g., due to missed visit, withdrawal of 
consent, or loss to follow-up) 
cUTI=complicated urinary tract infection; EOT=End of Treatment. 
a This does not include antibacterials that are permitted per protocol for patients with Enterococcus or 
methicillin-resistant S aureus infections. 
 
 
5.3 
Exploratory Endpoints 
Time to first defervescence (≤37.8°C) in the microITT analysis population for patients who 
have fever (>38°C) at baseline (based upon vital signs assessments and), where 
defervescence (≤37.8ºC) is defined as the absence of fever based on the highest temperature 
recorded on each study day. 
Additional presentations will be produced but were not stated in the protocol. These 
presentations relate to the number of hospital days and time to resolution of all symptoms (in 
days) based upon PPSQ and DPSQ as outlined in Section 5.2.1. All hospital re-admissions 
will also be listed. 
5.4 
Safety Outcomes 
Safety will be assessed by analysis of deaths, withdrawals, the occurrence of adverse events 
(AEs), as well as by adverse changes in laboratory evaluations (chemistry and hematology) 
and vital signs. AE definitions will be followed as stated in the “Note for Guidance on 


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Clinical Safety Data Management: Definitions and Standards for Expedited Reporting” 
(International Council on Harmonisation [ICH] topic E2A) [2]. 
6.0 
STATISTICAL METHODS 
6.1 
Sample Size 
The study will randomize at least 582 patients with cUTI into 2 groups in a 2:1 ratio 
(388 patients to cefepime/VNRX-5133; 194 patients to meropenem) at multiple study sites 
worldwide. Approximately 30% or more of patients should be diagnosed with AP. 
Randomization at study entry will be stratified by the type of infection (AP only versus cUTI) 
and by region (North America and Western Europe versus Eastern Europe versus Rest of the 
World). Patients with prior antibacterial use for cUTI will be limited to approximately 25% 
of the study population. 
This sample size will provide at least 264 cefepime/VNRX-5133 patients and 132 
meropenem patients for the primary comparisons of interest, based on an anticipated 
evaluability rate of 68%, a response rate of 75%, 90% power, a 2-sided alpha of 0.05, and a 
noninferiority margin of 15%. The anticipated response rate and evaluability rates are 
estimated based upon recently conducted trials of cUTI. The non-inferiority margin of 15% 
is justified based upon the FDA Guidance “cUTI Infections: Developing Drugs for 
Treatment, June 2018, Revision 1” [3]. This guidance demonstrates that the benefit of active 
antibacterial therapy over no treatment (M1) is estimated to be 30% after discounting. 
Therefore, an NI margin of 15% is considered appropriate. 
As the number of patients included in the microITT population is necessary to assure the 
stated level of power, at least 582 patients will be enrolled to ensure that at least 396 patients 
will be included in the microITT population. 
6.2 
Study Visits 
Baseline is defined as the last assessment prior to receipt of randomized therapy. Post- 
baseline is defined as during or after the first dose of study drug. 
Patients must return to the study site for the TOC visit (Study Days 19 to 23) and the LFU 
visit (Study Days 28 to 35). 
The following visit windows are permitted when presenting data at specific visits: 
• For efficacy: The nominal visit for EOT, TOC or LFU is to be taken. If the EOT visit 
occurs before the final dose, but on the same calendar day, this would be deemed a 
protocol deviation but would not be considered significant to require exclusion for the CE 
or ME analysis populations. 
• For safety: The time window is ±1 calendar day. For example, if the Day 4 laboratory 
assessments do not occur on Day 4 but laboratory assessments are performed on Day 3 or 
Day 5 these would be summarized under the Day 4 visit. 


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6.3 
Randomization 
After providing informed consent, patients will be enrolled into the study, entered into the 
Interactive Web Response System/Interactive Voice Response System (IWRS/IVRS), and 
assigned a unique screening number from the IWRS/IVRS for the screening process. After 
completing the screening process, patients who meet all eligibility criteria will be re-entered 
into the IWRS/IVRS and assigned a unique randomization number and study drug randomly 
computer generated by the IWRS/IVRS. Randomization and screening numbers will not be 
reused. Patients will be randomly assigned to receive either cefepime/VNRX-5133 (2 g/0.5 g 
IV q8h) plus meropenem placebo, or the active comparator, meropenem (1 g IV q8h) plus 
cefepime/VNRX-5133 placebo, in a 2:1 ratio according to the randomization number. 
Randomization occurs after screening and prior to administration of the first dose of study 
drug. The calendar day on which the first dose of study drug is administered marks the start 
of Study Day 1. Therefore, randomization may occur on the same calendar day as Study Day 
1 or on the previous calendar day. 
Patients will be stratified by the type of infection (AP only versus cUTI) and by region (North 
America and Western Europe versus Eastern Europe versus Rest of the World). At least 30% 
of the population will have AP. Patients may receive up to 24 hours of antibacterial for 
treatment of cUTI prior to randomization; however, the number of patients with prior 
antibacterial use will be limited to approximately 25% of the population. 
6.4 
Interim Analysis 
There are no plans for a formal interim analysis for efficacy. 
An independent DSMB will be formed to monitor interim safety data during the study. 
Procedures for DSMB reviews/meetings will be defined in the DSMB charter. The DSMB 
will review applicable data at scheduled timepoints during the study as defined in the charter. 
Additional data may be requested by the DSMB. The DSMB will review grouped and 
unblinded data in the closed session only. As an outcome of each review/meeting, the DSMB 
will make a recommendation as to the advisability of proceeding with study drug 
administration, and to continue, modify, or terminate this study. 
6.5 
Reporting Conventions 
• All clinical data will be listed. All listings will include trial, and patient ID. 
• Continuous variables will be summarized using number (N), mean, standard deviation 
(SD), median, minimum, and maximum, while categical data will be presented using 
frequency counts and percentages. 
• For AEs with onset on or after the date of the first dose of study drug, onset day will 
be calculated as the date of onset of the AE minus the date of the first dose of study 
drug plus one day. For AEs with onset prior to the date of the first dose of study drug, 
onset day will be calculated as the date of onset of the AE minus the date of the first 
dose of study drug. Events with an onset on study day 1 will be assumed to be 
treatment emergent. 
• Prior medications are those taken by the patient prior to randomization. . Concomitant 
medications are those taken by the patient after randomization. Concomitant 
medications are those with a start date on or after randomization, or those with a start 


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date before randomization and a stop date on or after randomization, or with a start 
date before randomization and are reported as ongoing. When time of medication is 
not collected (eg, non-antibiotic medications), medications that starts or ends on study 
day 1 will be considered both prior and concomitant medications. 
• For prior medications, start day will be calculated as the start date of the medication 
minus the date of randomization. For concomitant medications and prior medications 
taken on the same day as randomization, start day will be calculated as the start date 
of the medication minus the date of randomization plus one day. 
6.6 
Handling of Missing Data 
Missing data will be handled as follows: 
• All missing and partial dates for events occurring after randomization or for 
medications received after randomization will be queried for a value. If no value can 
be obtained, substitutions will be made as follows: 
o For start dates, missing year will be defined as the year of the first dose of IV 
study drug; missing months and days will be defined as "01", as long as this 
occurs on or after the first dose of study drug. If the algorithm produces a date 
prior to the first dose of study drug, the date of the first dose of study drug will be 
used for the partial date. 
o For missing stop dates, medications or advese events will be assumed ongoing. 
• The severity and causality assessment for adverse events should not be missing for 
treatment emergent adverse events and will be queried for a value. Should there be 
missing data, adverse events with missing severity will be considered severe and 
adverse events with missing causality will be considered related to study drug 
provided the event started on or after the first dose of study treatment. 
• For clinical and microbiological response, missing data will be handled as follows: 
o Programmatic determination of clinical response: If data for any component of 
clinical response are missing (PPSQ or DPSQ) such that it cannot be determined if 
the patient is a clinical success or failure, the patient will be defined as an 
indeterminate response. 
o Microbiological response: If no interpretable post-baseline specimen is available 
for a specific visit, the microbiological response for that visit is considered 
indeterminate. 
o Clinical response based upon Investigator opinion: Patients will be defined an 
indeterminate response if the Investigator cannot determine if the patient is a 
clinical cure or failure, if the Investigator did not complete the assessment or if the 
patient did not complete all relevant assessments provided that the patient was not 
previously a failure. 
• For baseline eGFR and serum creatinine, if the baseline central laboratory data are 
missing, local laboratory results will be used. 
• Local laboratory results will be used if the central laboratory data are missing and the 
site has received approval from the Sponsor to use baseline or follow up local 
laboratory data in place of central laboratory data (eg, due to temporary or permanent 
issues with import/export licenses). 


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• Missing values for other individual data points will remain as missing. Missing values 
will not be imputed and only observed values will be used in data analyses and 
presentation. 
• When individual data points are missing, categorical data will be summarized 
including a category for missing. 
7.0 
STATISTICAL ANALYSES 
7.1 
Patient Disposition and Protocol Deviations 
The number of patients randomized overall, by region, and country will be summarized by 
treatment group in the ITT analysis population. Region, country and center will be listed. 
The number of patients included in each of the study analysis populations (ITT, microITT, 
Extended microITT, Safety, CE-EOT, CE-TOC, CE-LFU, ME-EOT, ME-TOC and ME- 
LFU, Safety) will be summarized by treatment group and geographic region. Regions are 
defined as North America (USA) and Western Europe versus Eastern Europe (Bulgaria, 
Croatia, Czech Republic, Hungary, Latvia, Romania, Russia, Serbia, Turkey and Ukraine) 
versus Rest of the World (Argentina, Brazil, China, Mexico and Peru). 
The reasons for exclusion from the microITT, Extended microITT, CE-EOT, CE-TOC, CE- 
LFU, ME-EOT, ME-TOC and ME-LFU and Safety analysis populations will be tabulated. A 
by-patient listing will be provided that will include the reason(s) for exclusion from each of 
the study analysis populations. 
The number of patients completing the study (ie, completed the LFU visit), prematurely 
withdrawing from the study, completing study drug, prematurely discontinuing study drug, 
and the reasons for premature withdrawal and premature discontinuation will be summarized 
by treatment group and overall for all patients in the ITT analysis population. A listing of 
study completion/premature withdrawal and study drug completion/premature 
discontinuation for all patients will be provided. 
Premature discontinuation is defined as any patient who stopped study drug prior to their last 
scheduled dose of treatment on Day 7 or who did not complete study drug treatment 
according to the investigator. 
An important protocol deviation is defined as “a deviation that might significantly affect the 
completeness, accuracy, and/or reliability of the study data or that might significantly affect 
a patient’s rights, safety, or well-being”. For the purposes of exclusion from the CE and ME 
analysis populations an important protocol deviation also needs to be considered likely to 
have an impact on the assessment of clinical efficacy. The review and definition of 
deviations leading to exclusion from the CE/ME analysis populations will be documented as 
part of the review by the ECMRT prior to study unblinding. 
The number and percentage of patients in the ITT analysis population with at least one 
important protocol deviation (irrespective of whether this led to exclusion from the CE/ME 
populations) will be summarized by treatment group and overall. In addition, the number and 
percentage of patients with at least one important protocol deviation leading to exclusion 
from the CE/ME analysis populations will be listed. A by-patient listing of all important 
protocol deviations will also be provided and include a flag for whether the patient was 
included in the CE/ME analysis populations (Y/N). 


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7.2 
Demographics, Baseline Characteristics and Medical History 
Demographic information including sex, ethnicity, race, geographic region of randomization, 
country of enrollment, age and age category (<65, 65-75 and >75 years), BMI (<18.5, 18.5- 
24.9, 25-29.9 and ≥30 kg/m2) and renal status of Normal (GFR ≥ 90 mL/min), Mild 
impairment (GFR 60-89 mL/min), Moderate (GFR 30-59 mL/min) and Severe (GFR <30 
mL/min) will be summarized by treatment group and overall for the ITT and microITT 
analysis populations. 
The number and percentage of patients with each infection type used for randomization 
stratification (AP only versus cUTI with or without AP) will be summarized for the ITT and 
microITT analysis populations. Infection type based on actual diagnosis as determined by 
using symptomatic and other data reported in the eCRF will also be summarized. 
The number of patients with bacteremia (Y/N), diabetes (Y/N), prior cUTI within the past 
year (Y/N), use of antibiotics to treat the current cUTI in the 72 hours prior to the start of 
study treatment (Y/N), and the number of patients meeting SIRS criteria will be summarized 
for the ITT and microITT analysis populations. SIRS criteria will be defined as at least two 
of the following criteria: fever >38.0°C or hypothermia <36.0°C, tachycardia >90 
beats/minute, tachypnea >20 breaths/minute, leukocytosis >12*109/l or leucopoenia <4*109/l. 
Complicating factor and type of complicating factor will be summarized overall and by type 
of infection. A by patient listing will also be created. 
A summary of the baseline PPSQ, the baseline DPSQ and the symptoms of nausea, vomiting, 
rigors and chills as well as supra-pubic tenderness and costovertebral angle tenderness on 
exam will be produced for the ITT and microITT analysis populations and listed. Baseline 
vital signs will be summarized for the Safety analysis population. 
Medical history will be coded into standardized System Organ Classes (SOC), Preferred 
Terms (PT), and Lower Level Term (LLT) using the Medical Dictionary for Regulatory 
Activities (MedDRA, version 21.1 or later). 
Medical history (including diseases/conditions and surgical procedures) will be summarized 
by treatment group and overall for patients in the ITT and microITT analysis populations. 
For the summary of medical history, patients with more than one abnormality within the 
same preferred term will be counted only once for that preferred term. 
Demography, baseline characteristics and medical history data will be listed for all patients in 
the ITT analysis population. 
7.3 
Baseline Pathogens 
A baseline urine pathogen is defined as the presence of causative bacteria present at ≥ 105 
CFU/mL in baseline urine culture with no more than 2 organisms isolated from the sample 
collected. Carbapenem resistance is defined in Appendix 1. 
The number and percentage of patients with each baseline pathogen will be summarized for 
the microITT, Extended microITT and ME-TOC analysis populations. This summary will be 
produced for all patients within each analysis population, by infection type at stratification 
(AP only versus cUTI with or without AP) and by Enterobacteriaceae baseline gram-negative 
pathogens (Y/N), ESBL-producing baseline gram-negative pathogens (Y/N), MDR baseline 


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gram-negative pathogens (Y/N), cefepime-resistant gram-negative pathogens (Y/N) and 
carbapenem-resistant baseline pathogens (Y/N). 
The number and percentage of patients with bacteremia at baseline will be summarized and 
the number of patients with each different baseline blood pathogen will also be summarized 
in the microITT and ME-TOC analysis population. 
The number and percentage of patients with monomicrobial and polymicrobial (overall and 2 
Gram-negative pathogens vs. one Gram-negative and one Gram-positive) infections and with 
cefepime-resistant pathogens at baseline will be summarized in the microITT analysis 
population. 
For each baseline urine pathogen, a summary of the distribution of minimum inhibitory 
concentration (MIC) results to each study drug and to cefepime alone will be presented by 
treatment group and for all patients combined for the microITT, and ME-TOC analysis 
populations. A similar summary MIC results to each study drug will be produced for blood 
pathogens in the microITT analysis population (for cefepime/VNRX-5133 MIC and 
meropenem). Similarly, a summary of the disk zone size distribution to each study drug and 
to cefepime alone will be produced for urine pathogens in the microITT, and ME-TOC 
analysis populations and for blood pathogens in the microITT population (for 
cefepime/VNRX-5133 MIC and meropenem). 
A separate susceptibility summary will be produced for cefepime/VNRX-5133 MIC and 
meropenem in the microITT and ME-TOC populations. The MIC50, MIC90, and MIC range to 
the specific drug, as well as a tabulated MIC distribution (n at MIC, % at MIC, and 
cumulative % at MIC) and %S, %I and %R (using CLSI, EUCAST and provisional 
breakpoints), will be provided. In situations when a patient has both a blood and urine 
pathogen of a given species, the isolate with the highest MIC to study drug received will be 
selected for summarization. 
A susceptibility summary will also be produced presenting information regarding MIC50, 
MIC90, MIC range and %S, %I and %R (using CLSI, EUCAST and provisional breakpoints) 
for all tested antibacterial agents (such as CAZ-AVI) in the microITT and ME-TOC analysis 
populations. 
By-patient listings of pathogen MICs and susceptibilities as determined by the central lab 
(when available) and interpretations to all drugs tested based on CLSI and EUCAST criteria 
will also be provided for all patients in the ITT analysis population. 
MIC of both study drugs obtained via broth microdilution versus gradient test strip will be 
plotted for Enterobacteriaceae overall and all baseline gram-negative pathogens seen in ≥ 10 
patients in both the microITT and ITT analysis populations. In addition, disk zone size 
versus MIC result by broth microdilution of both study drugs will be plotted for 
Enterobacteriaceae overall and all baseline gram-negative pathogens seen in ≥ 10 patients in 
the microITT and emicroITT analysis populations. 
7.4 
Extent of Exposure and Study Drug Treatment Compliance 
7.4.1 
Duration of Study Drug Therapy 
Duration of study drug treatment will be summarized for the Safety and microITT Analysis 
Populations. These summaries will be produced for all patients, and separately for patients 


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with bacteremia and without bacteremia. Duration of study drug treatment will be calculated 
as follows: (date of last dose – date of first dose) +1. 
The number and percentage of patients who received study drug for 1-2 days, 3-5, 6-8 and >8 
for patients without bacteremia and 1-2, 3-5, 6-8, 9-11, 12-14 and >14 for patients with 
bacteremia will be summarized. Descriptive statistics of the number of days on study drug 
(n, mean, standard deviation, minimum, median, and maximum) will also be presented by 
treatment group. Summaries will be provided for all patients, and separately for those 
patients with and without bacteremia. 
Data on duration of study drug therapy will be listed for all patients, along with whether the 
patient had bacteremia. 
Compliance (%) is defined as 100 x (actual number of doses / expected number of doses). 
The expected number of doses would be calculating based upon the day/time of the patient’s 
last dose and calculating the number of doses expected for that time period. The expected 
number of doses is based on frequency of dosing as determined at baseline as well as when/if 
the “impact” field within the estimated Glomerular Filtration Rate (eGFR) CRF is completed 
as “change in dose”. In this case the expected dose will be adjusted accordingly. 
Compliance data will be summarized by treatment group for the microITT and Safety 
analysis populations. 
7.4.2 
Prior and Concomitant Medications 
Prior and/ or concomitant medications will be coded using WHODRUG (Enhanced version 
Sep 2018, B3 or later). 
Prior medications are defined as any prescription medication, over-the-counter medication, 
herbal supplement, and traditional medicines taken by the patient before randomization. All 
prior medications, including antimicrobials, taken during the 2 weeks prior to randomization 
will be collected at screening. 
Concomitant medications are defined as any prescription medication, over-the-counter 
medication, herbal supplement, or traditional medicines taken by the patient after 
randomization. All concomitant medication, including antibacterial therapy, will be collected 
from the time of randomization through the last study visit. Saline and similar volume 
replacers are not required to be recorded as a concomitant medication. 
A summary of receipt of any antibacterial within 72-hours prior to the start of study treatment 
will be provided by treatment group and overall for the ITT, microITT and CE-TOC Analysis 
populations. This will include a summary of the reasons for receipt of prior antibacterial 
therapy (given for cUTI versus given for other indications), a summary of longer versus 
shorter duration (>24 hours versus ≤24 hours) of prior antibacterial therapy and the type of 
antibiotic given, summarized by preferred term. 
Prior and concomitant non-antibacterial medications will be presented in a listing. 
The reasons for receipt of concomitant systemic antibacterial medications will be listed for all 
patients and summarized by treatment group and for all patients for the ITT, microITT and 
CE-TOC analysis populations. For concomitant systemic antibacterial medications, the 
number and percentage of patients will be summarized by antibacterial received, and by 


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whether the patient was excluded from the CE analysis populations due to receipt of an 
antibacterial (Yes/No) in the ITT, microITT and CE-TOC analysis populations. 
7.5 
Efficacy Analyses 
For all efficacy analyses, patients will be analyzed in the group to which they were 
randomized. Unless otherwise stated, patients who are randomized to the wrong 
randomization strata will be analyzed in the stratum to which they were randomized. 
7.5.1 
Primary Efficacy Analysis 
The primary clinical efficacy endpoint in this study is the proportion of cUTI patients with 
microbiological and symptomatic clinical success at TOC in the microITT analysis 
population. The aim of the analysis is to demonstrate that cefepime/VNRX-5133 is 
noninferior to meropenem with respect to this primary endpoint. 
Each patient will be programmatically categorized as a responder, non-responder, or 
indeterminate based on data on the eCRF. Patients with missing data or who are lost to 
follow up will be defined as indeterminate for the primary analysis and are included in the 
denominator for the calculation of the response rate. Thus, patients with an indeterminate 
response are considered non-responders for the primary analysis. The number and percentage 
of patients in each treatment group in each response category (success, failure and 
indeterminate) will be reported. 
The null and alternative hypotheses for the primary analysis are: 
H0: P1-P2 ≤- ∆ 
H1: P1-P2 >- ∆ 
Where P1 = the primary efficacy outcome rate in the VNRX-5133 group 
P2 = the primary efficacy outcome rate in the meropenem group 
∆ = the non-inferiority margin 
The response rate will be calculated for each treatment group as the number of successes 
divided by the total number of patients (success + failure + indeterminate). The difference in 
response rates between treatments (VNRX-5133 minus meropenem) will be presented along 
with a 95% confidence interval (CI) calculated using the method of Miettinen and Nurminen. 
If the lower limit of the 95% CI for the difference in response is greater than or equal to the 
noninferiority margin of -15%, noninferiority will be declared. Further, if non-inferiority is 
concluded, a test for superiority will be conducted. In this case, superiority will be concluded 
if the lower limit of the 95% CI for the difference in response is greater than or equal to zero. 
7.5.2 
Additional Analyses of the Primary Efficacy Endpoint 
A sensitivity analyses stratified by the pre-specified stratification factors of type of infection 
(AP only versus cUTI) and region (North America and Western Europe versus Eastern 
Europe versus Rest of the World) will also be performed for the primary endpoint (the 
proportion of cUTI patients with microbiological and symptomatic clinical success at TOC in 
the microITT analysis population). 


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A sensitivity analysis of the primary endpoint at TOC in the microITT population will be 
performed where the receipt of additional antibacterial therapy given for cUTI will not be 
considered as a reason for symptomatic clinical failure. 
Due to the difficulties in collecting urine samples at TOC due to COVID-19, a sensitivity 
analysis setting indeterminate microbiological responses to presumed eradication or 
presumed persistent based upon clinical response will be performed, as described in Section 
5.1. 
An additional sensitivity analysis will be performed for the primary outcome at TOC in the 
ME-TOC population, but excluding patients who had an indeterminate clinical outcome at 
the TOC visit (i.e. includes patients who are in both the ME and CE populations). 
For all sensitivity analyses, a 95% confidence interval using the method proposed with 
stratification by Miettinen and Nurminen will be computed for the difference in primary 
endpoint between VNRX-5133 minus meropenem. Cochran-Mantel-Haenzsel weights will 
be used for the stratum weights in the calculation of the CI. 
Subgroup analyses of the primary efficacy outcome and for microbiological response at TOC 
and symptomatic clinical response at TOC in the microITT analysis population will also be 
conducted for descriptive purposes. Forest plot of the treatment difference and 95% CI will 
be produced for the following subgroups: 
 
• Age category (<65, 65-75, >75 years) 
• Race 
• Sex 
• Region (North American & Western Europe versus Eastern Europe versus Rest of World) 
• Diagnosis for the purposes of stratification (AP only versus cUTI with or without AP) 
• Prior antibiotics (Y/N) (in the previous 72 hours) 
• Baseline renal status (normal (GFR > 90 mL/min) versus mild impairment (GFR 60-89 
mL/min) versus moderate impairment (GFR 30-59 mL/min) 
• Bacteremia (Y/N) 
• Complicating factor present (Y/N) and type of Complicating Factor 
• SIRS (as defined in Section 7.2). 
• Diabetes (Y/N) 
• Prior cUTI in last year (Y/N) 
• Monomicrobial v polymicrobial infections [monomicrobial, polymicrobial (2 gram- 
negative), polymicrobial (1 gram-negative, 1 gram-positive)] 
If any of the above subgroups indicate a difference in treatment effect, further evaluation will 
be undertaken to understand whether such differences apply for patients with AP and those 
with cUTI. 
A Forest plot of the treatment difference in primary endpoint and CI by the stratification 
factors and subgroups will be provided. 
7.5.3 
Secondary Efficacy Analyses 
The following secondary endpoints will use the same analysis method as the primary 
endpoint. For summaries of both microbiological and symptomatic clinical response, 


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microbiological response and symptomatic clinical response all outcomes (success, failure, 
relapse/recurrence [LFU only], and indeterminate) will be presented for analyses performed 
at EOT, TOC and LFU in the microITT analysis population. For all other secondary and 
additional analyses, outcomes of success will be presented unless otherwise specified. 
Forest plots will be produced to demonstrate both microbiological and symptomatic clinical 
success, microbiological success and symptomatic clinical success at EOT, TOC and LFU in 
the microITT, extended microITT (composite success), relevant ME analysis populations 
(composite and microbiological success only) and relevant CE analysis populations 
(symptomatic clinical success only). 
No formal non-inferiority margin is defined for the secondary endpoints, but rather the aim is 
to assess consistency of treatment effect with the primary efficacy analysis. A forest plot 
will be produced for each of the following endpoints along with a summary of the number 
and percentage of patients with a success, presented by treatment group and for all patients. 
• The proportion of patients with both microbiological and symptomatic clinical 
success at TOC in the Extended microITT, and ME-TOC analysis populations 
• The proportion of patients with both microbiological success and symptomatic 
clinical success at EOT in the microITT and ME-EOT analysis populations, and at 
LFU in the microITT and ME-LFU analysis populations 
• The proportion of patients with per-patient microbiological success at EOT, TOC and 
LFU in the microITT, ME-EOT, ME-TOC and ME-LFU analysis populations 
• The proportion of patients with symptomatic clinical success at EOT, TOC, and LFU 
in the microITT, CE-EOT, CE-TOC and CE-LFU analysis populations 
• The proportion of patients with clinical success based on investigator opinion at TOC 
in the microITT analysis population. 
The following secondary endpoints are expected to involve a smaller number of patients 
and/or involve the summary of a large number of individual pathogens. As such, these data 
will be summarized including all pathogens including ≥10 patients across both treatment 
groups: 
• The proportion of patients with both microbiological success and symptomatic clinical 
success among those with cefepime-resistant pathogens at EOT in the microITT and ME- 
EOT analysis populations, TOC in the microITT and ME-TOC analysis populations, and 
at LFU in the microITT and ME-LFU analysis populations. 
• The proportion of patients with per-patient microbiological success at EOT, TOC and 
LFU among those with cefepime-resistant pathogens in the microITT and ME-EOT, ME- 
TOC, and ME-LFU analysis populations 
• The proportion of patients with symptomatic clinical success at EOT, TOC and LFU 
among those with cefepime-resistant pathogens in the microITT and CE-EOT, CE-TOC, 
and CE-LFU analysis populations 
• The proportion of patients with per-pathogen microbiological eradication at EOT in the 
microITT and ME-EOT populations, TOC in the microITT and ME-TOC populations, 
and LFU in the microITT and ME-LFU populations 
• The proportion of patients with per-pathogen microbiological eradication at EOT, TOC 
and LFU among those with cefepime-resistant pathogens in the microITT and ME-EOT, 
ME-TOC and ME-LFU analysis populations 


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In addition, the following data will be summarized: 
• 
Both microbiological and symptomatic clinical success at EOT, TOC and LFU by 
baseline pathogen in the microITT and ME-EOT, ME-TOC, and ME-LFU analysis 
populations 
• Per-patient microbiological success at EOT, TOC, and LFU by baseline pathogen in the 
microITT analysis population 
• Symptomatic clinical success at EOT, TOC, and LFU by baseline pathogen in the 
microITT analysis population 
• The proportion of patients with both microbiological and symptomatic clinical success at 
TOC, the proportion of patients with symptomatic success and per-patient and per- 
pathogen microbiological success at TOC amongst patients with and without 
Enterobacteriaceae, multidrug resistant (MDR) pathogens and extended spectrum beta- 
lactamase (ESBL) pathogens in the microITT analysis population. The definition of 
MDR and ESBL pathogens are included in Appendix 1. 
A Forest plot which demonstrates both microbiological and symptomatic clinical success, 
microbiological success, and symptomatic clinical success at TOC by baseline pathogen and 
baseline gram-negative sub-groups (cefepime-resistant, Enterobacteriaceae, ESBL 
producing, MDR) in the microITT analysis population will be produced. This plot will only 
include baseline pathogens and gram-negative category groups where there are at least 10 
patients (total across both treatment groups) with the relevant baseline pathogen. 
The following summary tables will only be produced where there are at least 10 patients 
(total across both treatment groups) with the relevant baseline pathogen. 
• The Proportion of patients with both microbiological and symptomatic clinical success at 
TOC will be summarized by MIC of the baseline pathogen for both study drugs and 
cefepime alone as well as by disk size for all 3 drugs, in the microITT and ME-TOC 
analysis populations. 
• The proportion of patients with microbiological success at TOC will be summarized by 
MIC of the baseline pathogen for both study drugs and cefepime alone as well as by disk 
size for all 3 drugs, in the microITT and ME-TOC analysis populations. 
• The proportion of patients with symptomatic clinical response at TOC will be 
summarized by MIC of the baseline pathogen for both study drugs and cefepime alone as 
well as, and by disk size for all 3 drugs, in the microITT and ME-TOC analysis 
populations. 
For all by-pathogen analyses, patients with a pathogen of the same genus and species with 
more than one phenotype will be counted once for the overall tabulation of the pathogen, for 
example, E. coli. In this case, the pathogen with the highest MIC to study drug received will 
be taken for the purposes of presentation. 
A summary of the DPSQ categories (absent/mild/moderate/severe) will also be produced 
with a shift table of change in category from baseline to each visit in the microITT analysis 
population. 


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A listing of baseline pathogen genus and species, MIC to study drug received, symptomatic 
clinical success, microbiological success and clinical success based on investigator opinion at 
the EOT, TOC and LFU visits will be produced for all patients in the extended microITT 
population. 
All patients with a superinfection or new infection will also be identified in a listing. 
Patients showing at least one pathogen with decreasing susceptibility will be listed, and will 
include information on pathogen, study day, MIC value by day and susceptibility to study 
drug received. This is defined as persistence with a ≥4-fold increase in MIC to study drug 
received versus baseline. 
7.5.4 
Additional Efficacy Analyses 
A sensitivity analysis will be performed in which all patients with a gram-negative 
uropathogen isolated at study entry at ≥10^4 CFU/mL will be included. This sensitivity 
analysis will be performed for the endpoints of overall (clinical and microbiological) 
response at TOC, symptomatic clinical success at TOC, per-patient microbiological success 
at TOC and per-pathogen microbiological eradication in the microITT and extended 
microITT populations. 
Concordance between microbiological and symptomatic clinical responses at EOT, TOC and 
LFU will be summarized by treatment group in the microITT analysis population. In 
addition, the reasons for non-response or indeterminate response for symptomatic clinical 
success at EOT, TOC and LFU will be summarized in the microITT analysis population. 
All post-baseline uropathogens of the same genus and species as the corresponding baseline 
uropathogen(s) from the same patient will undergo epidemiology typing to assess relatedness 
(clonality). Data will be used to further characterize persistent infections. The number and 
percentage of failures at EOT, TOC and LFU with a post-baseline pathogen clonally related 
to the baseline pathogen will be summarized in the microITT analysis population, as will the 
number and percentage of failures with a post-baseline pathogen clonally unrelated to the 
baseline pathogen. Typing results will also be listed. Relatedness of post-baseline pathogens 
to baseline pathogens from the same patient will be assessed and determined by the 
Evaluability and Clinical/ Microbiologic Review Team. 
All baseline and post-baseline Enterobacteriaceae and Pseudomonas aeruginosa clinical 
isolates that meet the MIC screening criteria outlined in Appendix 1 will undergo genotypic 
characterization to identify the presence of β-lactam resistance and other resistance 
mechanisms. Composite clinical and microbiological, symptomatic clinical, and 
microbiological responses will be summarized based on presence or absence of β-lactamase 
as well as by specific β-lactamase present. β-lactam resistance mechanisms present in 
clinical isolates that display development of resistance to cefepime/VNRX-5133 during 
treatment or MIC result(s) of post-baseline strain(s) ≥4-fold higher when compared with the 
respective baseline isolate will be described. Results of all genotypic testing for β-lactam 
resistance and other resistance mechanisms will be listed. 
The time to first defervescence (≤37.8°C) will be assessed for patients in the microITT 
analysis population who have fever (>38ºC) at baseline, where defervescence (≤37.8ºC) is 
defined as the absence of fever based on the highest temperature recorded on each study day. 


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Time to first defervescence data will be summarized using a Kaplan-Meier plot. It will also 
be summarized as the mean, median, minimum, and maximum number of days and number 
of patients by treatment and by treatment and use of prior antibiotics Y/N. 
Time to resolution of all symptoms will be presented for the microITT analysis population 
using the same method as for time to first defervescence. 
Number of hospital days and the number of hospital days since randomization will be 
summarized for patients in the microITT analysis population by mean, SD, minimum, 
median, maximum and number of patients. The number and percent of patients with each 
number of days of hospitalization will also be presented. 
Time to defervescence, number of hospital days and the time to resolution of each individual 
symptom will be listed by patient. 
7.6 
Safety Analyses 
All safety analyses will be conducted in the Safety analysis population. Patients who receive 
the wrong study drug for their entire course of treatment will be analyzed in the group based 
on the drug received. Patients who receive the wrong study drug less than the entire course 
of treatment will be analyzed as predominantly treated and will be highlighted in the listings 
and included as a footnote to the summary tables. 
7.6.1 
Adverse Events 
Adverse events (AEs), including SAEs, will be collected from the time of informed consent 
to the last study visit. AEs will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) Version 21.1 or higher. 
A treatment emergent adverse event (TEAE) is defined as an AE that occurs during or after 
treatment through the last study visit. This is defined as any AE that starts or worsens during 
that time through the last study visit. If the AE start date is unknown or is a partial date such 
that it cannot be determined if the AE started on or after the first study drug administration, it 
will be categorized as a TEAE. 
An overall summary of AEs will include the number of patients who experienced at least one 
AE of the following categories: any AE, any TEAE, any serious TEAE, any drug-related 
TEAE, any drug-related serious TEAE, any TEAE leading to premature discontinuation of 
study drug, any TEAE leading to death, any drug-related TEAE leading to premature 
discontinuation of study drug and any drug-related TEAE leading to death. 
The number and percentage of patients reporting TEAEs, will be summarized by treatment, 
by treatment and relationship, and by treatment and severity. The incidence will be presented 
by system organ class (SOC) and decreasing frequency of preferred term (PT). 
The number and percentage of patients reporting related TEAEs, TEAEs resulting in 
discontinuation of study drug, related TEAEs resulting in discontinuation of study drug, 
SAEs, related SAEs and SAEs resulting in discontinuation of study drug will be summarized 
by treatment and presented by SOC and decreasing frequency of PT. 


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The number and percentage of deaths due to AEs and disease progression will be 
summarized. 
If the same AE (based on preferred term) is reported for the same patient more than once, the 
AE is counted only once for that preferred term at its highest severity and strongest 
relationship to study drug. 
A summary of TEAEs and a summary of SAEs sorted by decreasing frequency of preferred 
term in cefepime/VNRX-5133 patients will also be provided. 
A listing of all TEAES and all TEAEs leading to discontinuation of study drug will be 
provided and will include date and onset day of the AE, duration, system organ class, 
preferred term, verbatim term, seriousness, severity, relationship to study drug 
administration, action taken, and outcome. 
A listing of all serious TEAEs will also be provided and will include date and onset day of 
the serious AE, duration, system organ class, preferred term, verbatim term, severity, 
relationship to study drug administration, action taken, outcome, and date and onset day of 
death (where applicable). 
A listing of all deaths will include cause of death, date and onset day of death, as well as age, 
sex, diagnosis, bacteremia Y/N and baseline renal category. 
7.6.2 
Clinical Laboratory Evaluations 
All blood and urine specimens will be sent to a central reference laboratory for analysis and 
testing. 
 
Clinical laboratory data collected during scheduled visits and analyzed at the central 
laboratory (i.e., clinical chemistry, hematology, urinalysis, and coagulation parameters) will 
be summarized by assessment and by timepoint including the actual value and change from 
baseline; normal, high and low parameters based on each parameter’s reference range will be 
summarized by visit, and compared to baseline (ie, shift tables). All data (scheduled and 
unscheduled visits and from central and local laboratories) will be listed, and out of range 
values flagged. eGRF (based on Modification of Diet in Renal Disease [MDRD] formula) 
will be derived based on central laboratory serum creatinine results and summarized and 
listed. 
 
Calculation of eGFR by MDRD: 
 
eGFR=175 × (Scr)-1.154 × (age)-0.203 × 0.742 [if female] × 1.212 [if black] 
where Scr is serum creatinine in mg/dL and eGFR is measured in mL/min/1.73m2. 
Note: The ethinicity factor should only be used for African Americans and should not be used 
with black patients of all other nationalities. 
The number and percent of patients with treatment-emergent potentially clinically significant 
(PCS) laboratory values (as defined in Table 12) at any time post-baseline and by visit will be 
tabulated for each treatment group. This assessment will use all scheduled and unscheduled 
non-missing central laboratory data except in specific instances of missing scheduled central 


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laboratory data as described in Section 6.6 where local laboratory data will be used. Plots of 
central laboratory values (or local laboratory values in specific instances described in Section 
6.6) by visit for laboratory parameters will also be produced. 
Table 12 Criteria for Potentially Clinically Significant Laboratory Results 
 
Parameter 
Low value and change from 
baseline 
High value and change from 
baseline 
HEMATOLOGY 
Hemoglobin 
<0.8 x LLN and >20% decrease 
>1.3 x ULN and >30% increase 
Hematocrit 
<0.8 x LLN and >20% decrease 
>1.3 x ULN and >30% increase 
Leukocytes (white blood cells) 
<0.65 x LLN and >60% decrease 
>1.6 x ULN and >100% increase 
Neutrophils 
<0.65 x LLN and >75% decrease 
>1.6 x ULN and >100% increase 
Lymphocytes 
<0.65 x LLN and >75% decrease 
>1.6 x ULN and >100% increase 
Eosinophils 
NA 
>4 x ULN and >300% increase 
Monocytes 
NA 
>4 x ULN and >300% increase 
Basophils 
NA 
>4 x ULN and >300% increase 
Platelets 
<0.65 x LLN and >50% decrease 
>1.5 x ULN and >100% increase 
COAGULATION 
Prothrombin time 
NA 
>1.5 x ULN and >100% increase 
International normalized ratio 
NA 
>1.5 x ULN and >100% increase 
Partial thromboplastin time 
NA 
>2 x ULN and >100% increase 
CHEMISTRY 
Sodium 
<0.85 x LLN and >10% decrease 
>1.1 x ULN and >10% increase 
Potassium 
<0.8 x LLN and 20% decrease 
>1.2 x ULN and >20% increase 
Creatinine 
NA 
>2.0 x ULN and>100% increase 
Blood Urea Nitrogen 
NA 
> 3.0 x ULN and >200% increase 
Calcium 
<0.7 x LLN and >30% decrease 
>1.3 x ULN and >30% increase 
Magnesium 
<0.5 x LLN and >50% decrease 
NA 
Phosphorus 
<0.5 x LLN and >50% decrease 
>3.0 x ULN and >200% increase 
Alkaline phosphatase 
<0.5 x LLN and >80% decrease 
>2.0 x ULN and >100% increase 
Alanine aminotransferase 
NA 
>3.0 x ULN and >200% increase 
Aspartate aminotransferase 
NA 
>3.0 x ULN and >200% increase 
Gamma-glutamyl transferase 
NA 
>3.0 x ULN and >200% increase 
Total bilirubin 
NA 
>2.0 x ULN and >150% increase 
Direct bilirubin 
NA 
>2. 0 x ULN and >150% increase 
The number and percentage of patients in each treatment group with an elevated transaminase 
level (>3 x ULN, >5 x ULN, and >10 x ULN), an elevated bilirubin level (>1.5 x ULN and 
>2 x ULN) with and without an elevated alkaline phosphatase (ALP) level [>2.0 x ULN] will 
be presented by treatment group up to EOT, up to TOC and up to LFU. This assessment will 
use all scheduled and unscheduled data obtained at both local and central laboratories. 


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Actual laboratory values and change from baseline values will be listed for all patients within 
the Safety analysis population. 
A listing will be produced for patients who meet the reportable liver abnormalities criteria. 
These are: 
• ALT or AST >3xULN AND Total bilirubin >2xULN 
• ALT or AST >10x ULN 
• Potential Hy’s law, defined as (ALT or AST)>3x ULN, total bilirubin >2x ULN, and 
alkaline phosphatase <2x ULN. These assessments will be based upon scheduled and 
unscheduled visits and using data from the central and local laboratories). 
7.6.3 
Vital Signs and ECG 
Vital signs include heart rate, respiratory rate, temperature (oral or tympanic), and blood 
pressure. Descriptive statistics at each visit, and the change from baseline at each post- 
baseline visit will be summarized by treatment group. Change from baseline will be 
calculated for each patient at the specified Visit as the value at the specified Visit minus the 
baseline value. 
Actual vital signs values and change from baseline will be listed for all patients. 
No analysis of ECG data is planned. 
8.0 
CHANGES FROM THE PROTOCOL SPECIFIED ANALYSES 
Due to the COVID-19 pandemic there is a reasonable likelihood that microbiological samples 
at the TOC and LFU will not be available from all patients. Therefore, sensitivity analyses 
will be performed where microbiological response at TOC and LFU will be defined using 
presumed microbiological response if the microbiological data are Indeterminate. 
The proportion of patients with both microbiological success and symptomatic clinical 
success (overall response) at EOT, TOC, and LFU will not be assessed for the clinically 
evaluable population. Microbiological data is necessary to assess overall response and are not 
always available for patients included in the CE population. 
An additional sensitivity analysis has been added which will include patients with a gram- 
negative uropathogen at study entry ≥10^4 CFU/mL for the endpoints of overall (clinical and 
microbiological) response, clinical success, per-patient microbiological success and per- 
pathogen microbiological eradication at TOC in the microITT and extended microITT 
populations. 
9.0 
LIST OF MAJOR CHANGES FROM THE ORIGINAL STATISTICAL 
ANALYSIS PLAN 
This is version 6.0 of the statistical analysis plan. The original version, 1.0, was dated 09 
March 2020. Version 2.0 was dated 30 March 2021. Version 3.0 was dated 19 April 2021. 
Version 4.0 was dated 24 September 2021, Version 4.1 was dated 02 November 2021, and 
Version 5.0 was dated 30 November 2021. Table 13 lists the major changes from the original 
version of the statistical analysis plan and the rationale for each change. Only minor changes 
were made to Version 3.0. 


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Table 13 Major changes from the original version of the Statistical Analyais Plan 
 
SAP Version 
Change Description 
Sections Impacted 
Rationale for 
Change 
6.0 
Text referring to the use of presumed 
response for the primary analysis is 
removed. Specifically, “In the event >10% 
of microbiological data are missing at 
TOC, microbiological response at TOC 
will be defined using presumed response 
for the primary analysis. In this case a 
sensitivity analysis will be performed 
setting missing microbiological data at 
TOC to indeterminate” was removed. 
5.1 Primary Endpoint 
7.5.2 Additional 
Analyses of the 
Primary Efficacy 
Endpoint 
COVID impact on 
TOC visits did not 
meet 10% 
threshold. 
6.0 
Table 9 table clarified for bacteremic 
patients without post-baseline blood 
cultures. Microbiological response will be 
defined using a presumed microbiological 
response based on the symptomatic clinical 
response. 
5.2.3 Assessment of 
Microbiological 
Response 
U.S. Food and 
Drug 
Administration 
5.0 
The provisional susceptible breakpoint of 
cefepime/VNRX-5133 was updated from 
an MIC of ≤8 µg/mL to an MIC of ≤16 
µg/mL for both Enterobacteriaceae and 
Pseudomonas aeruginosa. 
4.2 Microbiological 
ITT (microITT) 
Analysis Population; 
5.2.2 General 
Microbiological 
Considerations 
The extended 
duration of infusion 
of cefepime / 
VNRX-5133 
support MICs of 
≤16 µg/mL using 
the optimized 
administered doses 
in the cUTI trial. 
4.0 
The proportion of patients with both 
microbiological success and symptomatic 
clinical success at EOT, TOC, and LFU 
will not be assessed for the clinically 
evaluable population 
5.2 Secondary 
Endpoints; 
7.5.3 Secondary 
Efficacy Analyses 
The 
microbiological 
data required to 
assess overall 
response are not 
always available 
for patients 
included in the CE 
population. 
4.0 
Updated the sample size from “582 
patients” to “at least 582 patients.” 
6.1 Sample Size 
Clarify that more 
than 582 patients 
may be required to 
ensure an adequate 
number of patients 
in the microITT 
population. 
4.0 
A sensitivity analysis will be performed in 
which all patients with a gram-negative 
uropathogen isolated at study entry at 
≥10^4 CFU/mL will be included. This 
sensitivity analysis will be performed for 
the endpoints of overall (clinical and 
microbiological) response at TOC, 
symptomatic clinical success at TOC, per- 
patient microbiological success at TOC 
and per-pathogen microbiological 
eradication in the microITT and extended 
microITT populations. 
7.5.4 Additional 
Efficacy Analyses 
Microbiological 
success is defined 
as a CFU count < 
103 CFU/mL. 
Therefore patients 
with a uropathogen 
isolated at study 
entry at ≥104 
CFU/mL can be 
evaluated for a 
microbiological 
response. 
2.0 
Added Microbiological Response 
Definition due to COVID-19. A set of 
sensitivity analyses will be performed 
5.1 Primary Endpoint 
A sensitivity 
analysis and a 
potential alternative 


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where microbiological response at TOC 
and LFU will be defined using a presumed 
microbiological response if the 
microbiological data are missing (i.e., 
Indeterminate) at TOC or LFU. In the 
event >10% of microbiological data are 
missing at TOC, microbiological response 
at TOC will be defined using presumed 
response for the primary analysis. In this 
case a sensitivity analysis will be 
performed setting missing microbiological 
data at TOC to indeterminate. 
primary endpoint 
was introduced due 
to a higher 
likelihood that the 
COVID-19 
pandemic would 
result in missing 
microbiological 
data and increases 
in indeterminate 
responses. 
2.0 
The assessment of symptomatic clinical 
response was clarified when there are 
discrepancies between the DPSQ and 
PPSQ. In the event that all pre-morbid 
symptoms as measured by the PPSQ take 
the same values as those measured at 
baseline on the DPSQ, it will be necessary 
for all symptoms to be resolved for this 
patient to be considered a symptomatic 
clinical success. Similarly, on the rare 
occasion where an individual symptom as 
measured by the PPSQ appears to be worse 
than that measure at baseline on the DPSQ, 
that symptom would need to subsequently 
show complete resolution to be considered 
a success. 
5.2.1 Assessment of 
Symptomatic Clinical 
Response 
Clarification to 
response definition. 
2.0 
The assessment of symptomatic clinical 
response was clarified that symptomatic 
clinical failure was not carried forward to 
subsequent endpoints. 
5.2.1 Assessment of 
Symptomatic Clinical 
Response 
Clarification to 
response definition. 
2.0 
The assessment of symptomatic clinical 
response at EOT was clarified. Any patient 
receiving additional antibiotics for the 
treatment of cUTI after the last dose of 
randomized therapy but before the EOT 
visit will be classified a failure. 
5.2.1 Assessment of 
Symptomatic Clinical 
Response, Table 4, 
footnote a 
Clarification to 
response definition. 
2.0 
CE and ME population definitions were 
updated to specify that the endpoint 
definition excludes patients with an 
indeterminate response or the endpoint was 
evaluated outside the protocol defined 
window. 
4.4 Clinically 
Evaluable Analysis 
Populations; 
4.5 Microbiologically 
Evaluable Populations 
Clarification to 
population 
definition. 


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10.0 REFERENCES 
1. 
CLSI. Performance Standards for Antimicrobial Susceptibility Testing; 31st ed. CLSI 
supplement M100. CLSI, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 
19087 USA, 2021. 
2. 
ICH of Technical Requirements for Registration of Pharmaceuticals for Human Use. 
ICH Harmonised Tripartite Guideline, E2A: Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting, Note for Guidance on Clinical 
Safety Data Management, June 1995. 
3. 
Guidance for Industry. Complicated Urinary Tract Infections: Developing Drugs for 
Treatment. U.S. Department of Health and Human Services. Food and Drug 
Administration. Center for Drug Evaluation and Research (CDER), Revision 1, June 
2018. 
4. 


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APPENDIX 1 
DEFINITIONS OF CARBAPENEM RESISTANCE, MDR AND ESBL PATHOGENS 
Carbapenem resistance is defined as the following: 
• 
Enterobacteriaceae: meropenem MIC ≥4 µg/mL 
• 
P. aeruginosa: meropenem MIC ≥8 µg/mL and/or imipenem MIC ≥8 µg/mL 
Extended-spectrum β-lactamases (ESBLs) are β-lactamases that hydrolyze extended-spectrum 
cephalosporins with an oxyimino side chain (e.g. cefuroxime, cefotaxime, ceftriaxone, ceftazidime 
and cefepime) and aztreonam, an oxyimino monobactam. For the purpose of the VNRX-5133-201 
SAP and based on the limited number of antibacterial agents that are being tested at the central 
laboratory, ESBL producers would be defined as isolates of Enterobacteriaceae with ceftazidime 
and/or aztreonam and/or cefepime MIC ≥2 µg/mL. These isolates, as well as isolates of P. 
aeruginosa with ceftazidime MIC ≥16 µg/mL and/or imipenem or meropenem MIC ≥2 µg/mL will be 
assessed for β-lactamase content and other resistance mechanisms. 
Multidrug-resistant (MDR) organisms are those that are non-susceptible to at least one agent in three 
or more categories of antibacterial agents (Magiorakos et al. 2012. CMI 18:268-281). For the purpose 
of the VNRX-5133-201 SAP, and based on the limited number of antibacterial agents that are being 
tested at the central laboratory, MDR organisms would be defined as isolates of Enterobacteriaceae or 
P. aeruginosa that are resistant to at least one agent from three or more categories in the 
corresponding tables below: 
Enterobacteriaceae 
Agents to be tested at CCLS 
Category 
Exceptions due to intrinsic 
resistance* 
Aztreonam 
Monobactam 
Cefepime, ceftazidime 
Extended-spectrum cephalosporin 
Cefepime/VNRX-5133 
Extended-spectrum cephalosporin + 
boronate β-lactamase inhibitor 
Tobramycin 
Aminoglycoside 
P. stuartii 
Ceftazidime/avibactam, 
ceftolozane/tazobactam 
Extended-spectrum cephalosporin + 
β-lactamase inhibitor 
Imipenem, meropenem 
Carbapenem 
Meropenem/vaborbactam 
Carbapenem + boronate β-lactamase 
inhibitor 
Ampicillin/sulbactam 
Penicillin + β-lactamase inhibitor 
C. freundii, K. aerogenes, E. 
cloacae, H. alvei, S. marcescens 
TMP/SMX 
Folate pathway inhibitor 
Levofloxacin 
Fluoroquinolone 
Piperacillin/tazobactam 
Antipseudomonal penicillin + β- 
lactamase inhibitor 
Tetracycline 
Tetracycline 
P. mirabilis, P. penneri, P. vulgaris, 
P. rettgeri, P. stuartii 
*These organisms are intrinsically resistant to the noted agents (CLSI M100 Appendix B Table B1). 


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P. aeruginosa* 
Agents to be tested at 
CCLS 
Category 
Aztreonam 
Monobactam 
Cefepime, ceftazidime 
Extended-spectrum cephalosporin 
Cefepime/VNRX-5133 
Extended-spectrum cephalosporin + boronate β-lactamase inhibitor 
Tobramycin 
Aminoglycoside 
Ceftazidime/avibactam, 
ceftolozane/tazobactam 
Extended-spectrum cephalosporin + β-lactamase inhibitor 
Imipenem, meropenem 
Carbapenem 
Meropenem/vaborbactam 
Carbapenem + boronate β-lactamase inhibitor 
Levofloxacin 
Fluoroquinolone 
Piperacillin/tazobactam 
Antipseudomonal penicillin + β-lactamase inhibitor 
*P. aeruginosa is intrinsically resistant to ampicillin/sulbactam, TMP/SMX and tetracycline (CLSI 
M100 Appendix B Table B2) hence those agents are not included in the table. 




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Per-Patient Microbiological Response with two gram-negative baseline pathogens 
 
Microbiological response of 
gram-negative 
Baseline Pathogen #1 
Microbiological response of 
gram-negative 
Baseline Pathogen #2 
Overall per-patient 
microbiological assessment 
Eradication or 
Presumed Eradication 
Eradication or 
Presumed Eradication 
Success 
Eradication or 
Presumed Eradication 
Persistence or 
Presumed Persistence 
Failure 
Persistence or 
Presumed Persistence 
Eradication, Presumed 
Eradication, Persistence or 
Presumed Persistence 
Failure