Prospective, Phase 3, Randomized, Multi-center, Double-blind, Double-dummy Study of Efficacy, Tolerability & Safety of Sulopenem Followed by Sulopenem-etzadroxil/Probenecid vs Ertapenem Followed by Cipro for Treatment of cUTI in Adults
Phase: PHASE3
Conditions: Complicated Urinary Tract Infections
Sponsor: Iterum Therapeutics, International Limited

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Clinical Trial Protocol: IT001-302 
Study Title: 
A prospective, Phase 3, randomized, multi-center, double-blind, double 
dummy study of the efficacy, tolerability and safety of intravenous 
sulopenem followed by oral sulopenem-etzadroxil with probenecid 
versus intravenous ertapenem followed by oral ciprofloxacin or 
amoxicillin-clavulanate for treatment of complicated urinary tract 
infections in adults. 
Study Number: 
IT001-302 
Study Phase: 
Phase 3 
Product Name: 
Sulopenem (CP-70,429), Sulopenem-etzadroxil (PF-
03709270)/Probenecid 
IND Number: 
129,849; 129,834 
EudraCT Number 
2017-003772-31 
Indication: 
Complicated urinary tract infection 
Investigators: 
Multicenter 
Sponsor: 
Iterum Therapeutics International Limited 
Block 2 Floor 3, Harcourt Centre,  
Harcourt Street, Dublin 2, Ireland 
Sponsor Contact: 
Sailaja Puttagunta 
Sponsor’s US Agent: 
Iterum Therapeutics US Limited 
20 Research Parkway, Suite A 
Old Saybrook, CT 06475 
Medical Monitor: 
Bernard Brownstein 
Office phone number: +1 (267) 464 2572 ext:2172 
Cell phone number: +1 (267) 858 0655 
Email address: Bernard.Brownstein@psi-cro.com 
Pharmacovigilance 
PSI Pharmacovigilance 
Pharmacovigilance 
Contact 
PVG Mailbox: SafetyDesk@psi-cro.com 
 
 
 
 
 
 
Date 
Original Draft Protocol  
June 19, 2017 
Second Draft Protocol 
December 14, 2017 
Final Protocol 
June 4, 2018 
 
 

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Confidentiality Statement 
This document is strictly confidential.  It was developed by Iterum Therapeutics US Limited and 
should not be disclosed to a third party, with the exception of regulatory agencies and study 
audit personnel.  Reproduction, modification or adaptation, in part or in total, is strictly 
forbidden without prior written approval by Iterum Therapeutics US Limited. 
 
Throughout this document, symbols indicating proprietary names (®, ™) are not displayed.  The appearance of 
product names without these symbols does not imply that these names are not protected. 

Sulopenem/Sulopenem etzadroxil 
 
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Clinical Trial Protocol: IT001-302 
 
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SYNOPSIS 
Sponsor: 
Iterum Therapeutics International Limited 
Name of Finished Product: 
Sulopenem; Sulopenem etzadroxil/probenecid 
Name of Active Ingredient: 
Sulopenem (CP-70,429); Sulopenem-etzadroxil (PF-03709270)/probenecid 
Study Title: 
A prospective, Phase 3, randomized, multi-center, double-blind, double dummy study of the 
efficacy, tolerability and safety of intravenous sulopenem followed by oral sulopenem- 
etzadroxil with probenecid versus intravenous ertapenem followed by oral ciprofloxacin or 
amoxicillin-clavulanate for treatment of complicated urinary tract infections in adults. 
Study Number: 
IT001-302 
Study Phase: Phase 3 
Primary Objective(s):  
To compare the efficacy of sulopenem IV followed by oral sulopenem-etzadroxil plus 
probenecid with ertapenem IV followed by oral ciprofloxacin or amoxicillin-clavulanate for 
the treatment of complicated urinary tract infection at Day 21 (± 1 day; test of cure [TOC 
visit]).  
Secondary Objective(s):  
• To compare the per-patient microbiologic response across treatment groups. 
• To compare the efficacy outcomes at relevant time points.  
• To assess the safety profile of treatment with each regimen.  
• To assess the population PK profile of sulopenem and/or sulopenem-etzadroxil co-
administered with probenecid. 
Study Design:  
Sulopenem is an investigational thiopenem antibiotic being developed for treatment of 
uncomplicated urinary tract infections (uUTI), complicated urinary tract infections (cUTI), 
and complicated intra-abdominal infections (cIAI). Sulopenem-etzadroxil is an oral pro-drug 
of sulopenem. Upon oral absorption, sulopenem-etzadroxil is rapidly hydrolyzed to yield 
sulopenem, the active moiety, as well as the non-active moieties, formaldehyde and 2-
ethylbutyric acid (2-EBA).   
Sulopenem possesses potent activity against species of the Enterobacteriaceae that encode 
extended spectrum beta-lactamase (ESBLs) or AmpC-type β-lactamases that confer 
resistance to third generation cephalosporins. Sulopenem-etzadroxil is expected to be the first 
oral penem on the market in the United States and Europe and will offer the option of 
treatment in the outpatient setting, as well as IV to oral switch therapy for early discharge of 
patients hospitalized with serious complicated infections.  Probenecid, co-administered with 

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the oral prodrug, will reduce renal clearance and increase systemic exposure of the active 
moiety, sulopenem.   
This prospective, Phase 3, multicenter, double-blind, double-dummy, randomized, controlled 
study compares IV sulopenem followed by oral sulopenem-etzadroxil with probenecid and IV 
ertapenem followed by oral ciprofloxacin or amoxicillin-clavulanate for treatment of 
complicated urinary tract infection in adults. The site pharmacist will be unblinded in order to 
prepare the intravenous study medications and select the appropriate oral follow on therapy 
for patients randomized to the ertapenem arm. Approximately 1156 adults with cUTI will be 
randomized in a 1:1 fashion to receive either IV sulopenem 1000 mg once daily for at least 5 
days (5 doses) followed by sulopenem-etzadroxil 500 mg co-administered with oral 
probenecid 500 mg twice daily to complete 7-10 total days of treatment or ertapenem IV 1000 
mg once daily for at least 5 days (5 doses) followed by oral ciprofloxacin 500 mg or 
amoxicillin-clavulanate 875 mg twice daily to complete 7-10 total days of therapy. Duration 
of treatment may be extended up to a total duration of 14 days for patients with bacteremia at 
baseline, although recent literature suggests that dosing beyond 10 days has been shown to 
have no additional value, especially in urinary tract infection [Chotiprasitsakul 2018; 
Canzoneri 2017].  
The dose of study drugs may be adjusted for patients with severe renal impairment (CrCl <30 
mL/min) who are not on regular hemodialysis (see Appendix 3). 
The primary outcome measure for efficacy evaluation will be overall response defined as the 
resolution of the symptoms of cUTI present at trial entry (and no new symptoms such that no 
new antibiotics are required) and the demonstration that the bacterial pathogen(s) found at 
trial entry is reduced to <103 CFU/mL on urine culture on Day 21 (± 1 day; TOC).  
The primary outcome will be analyzed in the microbiologic-modified intent to treat 
population (m-MITT). The m-MITT population will be comprised of all randomized patients 
who received at least one dose of study drug and had a positive study entry urine culture 
defined as ≥105 CFU/mL of a uropathogen (Enterobacteriaceae only), and no more than 2 
species of microorganisms, regardless of colony count, except in the situation where one of 
the organisms cultured from the urine is also isolated from blood cultures drawn at baseline, 
prior to initiation of study drug therapy. 
Study Population:  
A total of 1156 patients are planned; the sample size may be adjusted at the blinded interim 
analysis if the baseline assumptions for overall response rate and evaluability are not met.  
Patients will be randomized using an Interactive Web Response System (IWRS) into the 
study, provided they have satisfied all patient selection criteria. The randomization schedule 
will be stratified by the type of infection (pyelonephritis vs cUTI without pyelonephritis). No 
more than 25% of patients may have received prior antibiotic therapy, and at least 30%, but 
no more than 70% of patients may have acute pyelonephritis. 
Inclusion Criteria: 
1. Adults ≥18 years of age with more than 24 hours of urinary symptoms attributable to a 
UTI  

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2. Patient or the patient’s legally acceptable representative able to provide a signed 
written informed consent prior to any study-specific procedures. 
3. Clinically documented pyelonephritis or complicated urinary tract infection: 
a) Pyelonephritis with normal anatomy, OR 
b) Complicated UTI as defined by one or more of the following factors: 
i. 
The presence of an indwelling urethral catheter 
ii. 
>100 mL of residual urine after voiding 
iii. 
Neurogenic bladder 
iv. 
Obstructive uropathy due to nephrolithiasis, tumor or fibrosis 
v. 
Azotemia (blood urea nitrogen [BUN] > 20 mg/dL and BUN/creatinine 
ratio <15) due to intrinsic renal disease 
vi. 
Urinary retention in men possibly due to benign prostatic hypertrophy 
vii. 
Surgically modified or abnormal urinary tract anatomy 
4. At least two of the following signs or symptoms: 
a) 
Rigors, chills or fever/hypothermia with temperature (oral, rectal, tympanic, 
temporal) >100.4ºF or 38ºC, or <95ºF or 35ºC 
b) Flank pain or pelvic pain 
c) 
Nausea or vomiting 
d) Dysuria, urinary frequency or urinary urgency 
e) 
Costovertebral angle tenderness on physical examination 
5. A mid-stream urine specimen with: 
a) a machine-read dipstick positive for nitrite AND 
b) evidence of pyuria as defined by either: 
i. a machine-read dipstick positive for leukocyte esterase AND/OR 
ii. at least 10 white blood cells per cubic millimeter on microscopic analysis 
of unspun urine AND/OR 
iii.  White blood cell count ≥10 cells/HPF in urine sediment 
Exclusion Criteria 
1. Receipt of effective antibacterial drug therapy for cUTI for a continuous duration of 
more than 24 hours in the 72 hours prior to randomization. Patients who have 
objective documentation of clinical progression of cUTI while on antibacterial drug 
therapy, or patients who received antibacterial drugs for surgical prophylaxis and then 
develop cUTI, may be appropriate for enrollment. 
2. Subjects with an organism isolated from the urine within the last year known to be 
resistant to ertapenem.  
3. Severe structural or functional urinary tract abnormality responsible for an intractable 
infection which in the opinion of the investigator would require > 10 days of therapy 
or post-treatment prophylaxis (eg. patients with chronic vesiculo-ureteral reflux). 

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4. Uncomplicated UTI 
5. Patients with paraplegia/quadriplegia 
6. Hypotension with systolic blood pressure < 90 mm Hg 
7. Complicated UTI associated with complete obstruction, emphysematous 
pyelonephritis, known or suspected renal or perinephric abscess or expected to require 
surgical intervention (not placement of catheters, stents or nephrostomy tubes) to 
achieve cure 
8. Patients with a known history of myasthenia gravis 
9. Patients who require concomitant administration of tizanidine or valproic acid 
10. Patients with a history of allergy to carbapenems or quinolones or amoxicillin-
clavulanate or other beta-lactams, or hypersensitivity to probenecid 
11. Renal transplantation 
12. Patients requiring hemodialysis, hemofiltration or peritoneal dialysis 
13. Acute or chronic prostatitis 
14. High risk for cUTI caused by Pseudomonas spp. (eg,. history of prior UTI due to 
Pseudomonas spp, recent steroid use (>40 mg/day equivalent prednisolone for 5 days 
or more in the 30 days prior to randomization), multiple sclerosis, chronic supra-pubic 
catheter) 
15. Chronic indwelling catheters or stents (>2 weeks) 
16. Ileal loops or vesico-ureteral reflux 
17. Recent trauma to the pelvis or urinary tract within the prior 30 days 
18. History of seizures 
19. Patients with a history of blood dyscrasias 
20. Patients with a history of uric acid kidney stones 
21. Patients with acute gouty attack 
22. Patients on chronic methotrexate therapy 
23. Females of child-bearing potential who are unable to take adequate contraceptive 
precautions (refer to Section 4.4.1), have a positive pregnancy test result within 24 
hours of study entry, are otherwise known to be pregnant, or are currently 
breastfeeding an infant. 
24. Male subjects who do not agree to use an effective barrier method of contraception 
(refer to Section 4.4.2) during the study and for 28 days after dosing 
25. Patients known to have a history of liver disease or neutropenia as defined by the 
following baseline laboratory criteria: 
a. 
Alanine aminotransferase (ALT)or aspartate aminotransferase (AST) >3 X 
Upper Limit of Normal (ULN) 
b. 
Total bilirubin >2 X ULN  

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c. 
Neutropenia (absolute neutrophil count <1000 cells/mm3) 
26. Patients participating in any other clinical study that involved the administration of an 
investigational medication at the time of presentation, during the course of the study, 
or who had received treatment with an investigational medication in the 30 days prior 
to study enrollment, or had previously been randomized to this study or had been 
treated with sulopenem.  
27. Patients immunocompromised as evidenced by any of the following: 
a. Human immunodeficiency virus (HIV) infection, with either a recent (in the past 
6 months) acquired immune deficiency syndrome-defining condition or a CD4 + 
T lymphocyte count <200/mm3  
b. Systemic or hematological malignancy requiring chemotherapeutic or 
radiation/immunologic interventions within 6 weeks prior to randomization or 
anticipated to begin prior to completion of study 
c. Immunosuppressive therapy, including maintenance corticosteroid therapy (>40 
mg/day equivalent prednisolone for 5 days or more in the 30 days prior to 
randomization). 
28. Patient unlikely to comply with protocol e.g., uncooperative attitude, inability to 
return for follow-up visits, and unlikely to complete the study. 
29. Patient considered unlikely to survive the 4-week study period or has a rapidly 
progressive or terminal illness, including septic shock that was associated with a high 
risk of mortality. 
Test Product, Dose, and Mode of Administration:  
Investigational study medications include sulopenem 1000 mg IV over 3 hours, sulopenem-
etzadroxil (PF-03709270) 500 mg PO twice daily co-administered with probenecid 500 mg 
PO twice daily, ertapenem 1000 mg IV once daily over 30 minutes, ciprofloxacin 500 mg PO 
twice daily or amoxicillin-clavulanate 875 mg PO twice daily.  
Other Systemic Antibiotics: 
For Clostridium difficile infections, metronidazole (IV or oral) or oral vancomycin may be 
used in both treatment groups.  
Patients with a coinfection with a gram-positive uropathogen resistant to study drugs are 
allowed to receive agents with narrow spectrum gram-positive coverage (i.e., such as 
linezolid, daptomycin or vancomycin). 
Formulation and Packaging: 
Sulopenem treatment group: Sulopenem 1000 mg IV will be supplied as a single-use vial 
with lyophilized powder for injection.  The IV solution will be prepared for dosing by an 
unblinded pharmacist according to the dosing instruction provided by the sponsor.  The oral 
medications will be packaged in a suitable packaging container and provided to the sites. 
Comparator treatment group:  Ertapenem 1000 mg IV will be supplied as a single-use vial. 
The IV solution will be prepared for dosing by an unblinded pharmacist.  The oral 
medications will be packaged in a suitable packaging container and provided to the sites. 

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Dosing and administration instructions will be provided in the pharmacy manual for 
preparation of doses using the sulopenem vials, comparator vials and saline solution for 
blinding. 
All oral study drugs and placebos are matched for blinding. 
Preparation and Dispensing: 
Sulopenem or ertapenem IV: Each dose of IV study medication will be prepared by an 
unblinded pharmacist or other qualified personnel at the site according to the dosing 
instructions provided by the sponsor.  Dosing and administration instructions will be provided 
in the pharmacy manual for preparation of doses of sulopenem and ertapenem.  
Sulopenem etzadroxil/probenecid or comparator oral solid dose (OSD): All investigational 
product including supplies of the oral solid dose study drug will be provided to the study site 
by Iterum Therapeutics.  Written study medication preparation and administration instructions 
will be provided to each study site in a study pharmacy manual.   
The pharmacy manual will contain detailed instructions for the preparation and administration 
of study medication. 
Administration 
Sulopenem arm:  
Patients with normal renal function: Patients randomized to the sulopenem treatment group 
will receive 1000 mg sulopenem IV infused over 3 hours, once daily for 5 days. For blinding 
purposes sulopenem will be co-administered with a 30-minute infusion of saline solution to 
simulate the comparator. 
After at least 5 days of intravenous therapy those patients with a baseline pathogen 
susceptible to ciprofloxacin and who meet criteria for oral step-down will take one sulopenem 
etzadroxil/probenecid tablet twice daily and one over-encapsulated placebo ciprofloxacin 
capsule twice daily to complete 7-10 total days of treatment. Patients with a baseline 
pathogen non-susceptible to ciprofloxacin but susceptible to amoxicillin-clavulanate, and who 
meet criteria for oral step-down will take one sulopenem etzadroxil/probenecid tablet twice 
daily and one over-encapsulated placebo amoxicillin-clavulanate capsule twice daily to 
complete 7-10 total days of treatment. Patients with a baseline pathogen non-susceptible to 
ciprofloxacin and amoxicillin-clavulanate will receive a 30 minute IV infusion of saline daily 
to match the comparator infusion and take one sulopenem etzadroxil/probenecid tablet twice 
daily to keep the blinding intact. The duration of treatment may be extended up to a total 
duration of 14 days for patients with bacteremia at baseline, although recent literature 
suggests that dosing beyond 10 days has been shown to have no additional value, especially 
in urinary tract infection [Chotiprasitsakul 2018; Canzoneri 2017]. 
Patients with severe renal impairment (CrCl <30mL/min): Patients with severe renal 
impairment randomized to the sulopenem treatment group will receive 250 mg sulopenem IV 
infused over 3 hours once daily for 5 days. For blinding purposes sulopenem will be co-
administered with a 30-minute infusion of saline solution to simulate the comparator. 

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After at least 5 days of intravenous therapy those patients with a baseline pathogen 
susceptible to ciprofloxacin and who meet criteria for oral step-down will take one sulopenem 
etzadroxil/probenecid tablet twice daily and one over-encapsulated placebo ciprofloxacin 
capsule approximately every 18 hours to complete 7-10 total days of treatment. Patients with 
a baseline pathogen non-susceptible to ciprofloxacin and who meet criteria for oral step-down 
will receive a 30 minute IV infusion of saline daily to match the comparator infusion and will 
take one sulopenem etzadroxil/probenecid tablet twice daily to complete 7-10 total days of 
treatment. The duration of treatment may be extended up to a total duration of 14 days for 
patients with bacteremia at baseline. 
Comparator arm:  
Patients with normal renal function: Patients with normal renal function randomized to the 
comparator treatment group will receive 1000 mg of IV ertapenem infused over 30 minutes, 
once daily for 5 days. For blinding purposes comparator will be co-administered with a 3 
hour infusion of saline solution to simulate sulopenem IV. 
After at least 5 days of intravenous therapy those patients with a baseline pathogen that is 
susceptible to ciprofloxacin who meet criteria for oral step-down will take one placebo 
sulopenem etzadroxil/probenecid tablet twice daily and take one over-encapsulated 
ciprofloxacin capsule twice daily to complete 7-10 total days of treatment. Patients with a 
baseline pathogen non-susceptible to ciprofloxacin, but susceptible to amoxicillin-
clavulanate, and who meet criteria for oral step-down will take one placebo sulopenem 
etzadroxil/probenecid tablet twice daily and take one over-encapsulated amoxicillin-
clavulanate capsule twice daily to complete 7-10 total days of treatment.  
Patients with a baseline pathogen non-susceptible to ciprofloxacin and amoxicillin-
clavulanate will receive a 30 minute IV infusion of ertapenem daily and take one placebo 
sulopenem etzadroxil/probenecid tablet twice daily to keep the blinding intact; patients will 
not receive the placebo/active ciprofloxacin/amoxicillin-clavulanate.  
The duration of treatment may be extended up to a total duration of 14 days for patients with 
bacteremia at baseline, although recent literature suggests that dosing beyond 10 days has 
been shown to have no additional value, especially in urinary tract infection [Chotiprasitsakul 
2018; Canzoneri 2017]. 
Patients with severe renal impairment (CrCl <30mL/min): Patients with severe renal 
impairment randomized to the comparator treatment group will receive 500 mg of IV 
ertapenem infused over 30 minutes, once daily for 5 days. For blinding purposes comparator 
will be co-administered with a 3 hour infusion of saline solution to simulate sulopenem IV. 
After at least 5 days of intravenous therapy those patients with a baseline pathogen that is 
susceptible to ciprofloxacin who meet criteria for oral step-down will take one placebo 
sulopenem etzadroxil/probenecid tablet twice daily and take one over-encapsulated 
ciprofloxacin capsule approximately every 18 hours to complete 7-10 total days of treatment. 
Patients with a baseline pathogen non-susceptible to ciprofloxacin will need to remain on IV 
ertapenem 500 mg infused over 30 minutes once daily and take one placebo sulopenem 
etzadroxil/probenecid tablet twice daily to keep the blinding intact and complete 7-10 total 
days of treatment.  
The duration of treatment may be extended up to a total duration of 14 days for patients with 
bacteremia at baseline, although recent literature suggests that dosing beyond 10 days has 

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been shown to have no additional value, especially in urinary tract infection [Chotiprasitsakul 
2018; Canzoneri 2017]. 
Study drug administration will be documented in accordance with the Pharmacy Manual.  
The site pharmacist will be unblinded in order to prepare the IV study medications and select 
the appropriate oral follow on therapy for patients randomized to the ertapenem regimen.   
Both Treatment Groups:  
In both treatment groups, patients found to have pathogens isolated from blood cultures that 
are resistant to carbapenems including ertapenem should be discontinued from study drug 
therapy, but should remain in the study and treated appropriately. Patients found to have 
pathogens isolated from urine cultures that are resistant to carbapenems including ertapenem, 
may be allowed to continue on study drug therapy based on clinical response and investigator 
judgement, and are not required to receive alternative antibiotic therapy. 
Dosing with food:  
Food significantly increases bioavailability of sulopenem and consequently results in 
decreased rates of diarrhea. Therefore, dosing of oral sulopenem-etzadroxil with food 
whenever possible is recommended.  Since adequate target attainment appears to be achieved 
in the fasted state, an inability to administer the dose with food should not preclude dosing. 
Dosing with food does not affect the overall absorption of ciprofloxacin and has a minimal 
effect on the pharmacokinetics of amoxicillin-clavulanate. 
Efficacy Assessments: 
Patients will complete a questionnaire based on their assessment of the following symptoms:  
dysuria, urinary frequency, urinary urgency, burning on micturition, suprapubic pain and 
flank or pelvic pain.  
Investigator assessment of clinical response will be documented. 
Microbiologic response assessments will be made based on quantitative cultures performed 
on collected urine specimens. 
Other Assessments 
Plasma sampling for population PK evaluations will be collected in a subset of patients at 
selected study sites. 

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Safety Assessments 
Safety will be assessed by means of vital signs, collection of adverse events and clinical 
laboratory tests. A targeted physical examination will be performed at Baseline. At Day 5, 
Day 10 (± 1 day; or Day 11-14 (± 1 day) for patients with bacteremia at Baseline), and Day 
21 (± 1 day; TOC) visits or at premature discontinuation from study drug therapy or study, 
the targeted physical examination will be performed as needed according to symptoms. Vital 
signs will be collected at Baseline, and at Day 5, Day 10 (± 1 day; or Day 11-14 (± 1 day) for 
patients with bacteremia at Baseline), and Day 21 (± 1 day; TOC) or premature 
discontinuation from study drug therapy or study. Adverse events will be collected at every 
visit, beginning from the signing of Informed Consent. Clinical laboratory tests will be 
obtained at Baseline, and at Day 5 and Day 10 (± 1 day; or Day 11-14 (± 1 day) for patients 
with bacteremia at Baseline) visit, in follow-up of any clinically significant laboratory finding 
or at premature discontinuation from study. 
Statistical Methods:  
Sample Size Considerations:  
The study is designed to determine whether sulopenem IV followed by oral sulopenem-
etzadroxil co-administered with probenecid is non-inferior (NI) to ertapenem followed by oral 
ciprofloxacin or amoxicillin-clavulanate for the outcome measure of overall response, defined 
as resolution of the symptoms of cUTI present at trial entry with no new symptoms such that 
no new antibiotics are required, and the demonstration that the bacterial pathogen found at 
trial entry is reduced to <103 CFU/mL on urine culture. 
The proposed sample size for the ITT population is 1156 patients.  This ITT sample size 
estimate is based on the assumption that 80%, or 924 patients, of this ITT population will be 
microbiologic-modified Intent-To-Treat (m-MITT) evaluable.  The sample size of the m-
MITT population is 462 patients per arm based on a continuity-corrected Z-test with 
unpooled variance. This 924 m-MITT sample size assumes a non-inferiority margin of 10%, a 
power of 90%, a one-sided alpha level of 0.025 and a 70% overall response rate in both 
treatment groups. The final ITT sample size may be increased based on the observed response 
rate at the blinded interim analysis, as well as the evaluability rate, to maintain a power of 
90%. 
Statistical Analysis:   
The number and percentage of patients in each treatment group with an overall outcome of 
response, non-response and indeterminate will be determined in the m-MITT population. A 
two-sided 95% confidence interval (CI) for the observed difference in the responder rates 
(sulopenem/sulopenem-etzadroxil minus ertapenem/oral ciprofloxacin or amoxicillin-
clavulanate) will be calculated using a continuity corrected Z-statistic.  If the lower bound of 
the 95% CI is greater than -10%, non-inferiority of sulopenem/sulopenem-etzadroxil to 
ertapenem/oral ciprofloxacin or amoxicillin-clavulanate will be concluded. 
The number and percentage of patients in each response category for each of the secondary 
efficacy outcomes will be provided.  Two-sided 95% CIs for the difference in outcome rates 
between the two treatment groups will be provided. 
Safety analyses will be conducted in the Safety population (all patients who received any 
amount of study drug).  Adverse events will be coded using the Medical Dictionary for 

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Regulatory Activities (MedDRA). The number and percentage of patients in each treatment 
group reporting at least one occurrence of a treatment emergent AE (TEAE) for each unique 
System Organ Class and Preferred Term will be tabulated. Treatment-emergent adverse 
events will also be tabulated by treatment group, severity, and the relationship to study drug 
as assessed by the Investigator. The number and percentage of patients in each treatment 
group reporting at least one occurrence of a treatment emergent serious adverse event (SAE) 
and prematurely discontinuing study drug treatment due to a TEAE will be tabulated by 
System Organ Class and Preferred Term. 
Safety laboratory and vital signs data will be presented by descriptive statistics of the post-
baseline value and the change from baseline, as well as the number and percentage of patients 
with potentially clinically significant (PCS) values. 
Interim Analysis: 
The aggregate blinded response rate will be assessed when approximately 60% of the subjects 
have been randomized and have efficacy outcome data at TOC available. If the aggregate 
response rate at that point is <70%, or if the evaluability rate (proportion of ITT subjects 
included in the m-MITT population) is < 80%, the sample size may be increased.   
Date of Original Approved Protocol:  June 4, 2018 
Date of Most Recent Protocol Amendment (if applicable):  NA 
Prepared in:  Microsoft Word 2016 

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TABLE OF CONTENTS 
SYNOPSIS ................................................................................................................................ 3 
LIST OF APPENDICES ......................................................................................................... 16 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ......................................... 17 
1 
INTRODUCTION ........................................................................................................... 20 
1.1 
Indication ............................................................................................................... 20 
1.2 
Background and Rationale .................................................................................... 20 
1.2.1 
Safety data ................................................................................................... 22 
1.2.1.1 
Sulopenem-etzadroxil (PF-03709270; oral prodrug) ........................ 22 
1.2.1.2 
Sulopenem (CP-70,429; Intravenous) ............................................... 23 
1.2.2 
Rationale for Study...................................................................................... 25 
1.2.3 
Dose Rationale ............................................................................................ 26 
2 
STUDY OBJECTIVES ................................................................................................... 27 
2.1 
Objectives .............................................................................................................. 27 
3 
STUDY DESIGN ............................................................................................................ 27 
3.1 
Investigational Study Medications ........................................................................ 28 
3.2 
Adjunctive Systemic Antibiotics ........................................................................... 28 
3.3 
Additional, Non-Study Therapy Antibiotics ......................................................... 28 
4 
STUDY POPULATION SELECTION ........................................................................... 29 
4.1 
Inclusion Criteria ................................................................................................... 29 
4.2 
Exclusion Criteria .................................................................................................. 30 
4.3 
Randomization Criteria ......................................................................................... 31 
4.4 
Life Style Guidelines ............................................................................................. 32 
4.4.1 
Women of Child-Bearing Potential ............................................................. 32 
4.4.2 
Males ........................................................................................................... 32 
5 
STUDY TREATMENTS ................................................................................................ 32 
5.1 
Allocation to Treatment ........................................................................................ 32 
5.1.1 
Criteria for Switch from IV to Oral Therapy .............................................. 33 
5.2 
Drug Supplies ........................................................................................................ 33 
5.2.1 
Formulation and Packaging ......................................................................... 33 
5.2.2 
Preparation and Dispensing ......................................................................... 34 
5.2.3 
Administration ............................................................................................. 34 
5.2.4 
Compliance.................................................................................................. 36 
5.3 
Drug Storage and Drug Accountability ................................................................. 36 
5.4 
Concomitant Medication(s), Adjunctive Therapy and Non-drug Therapy ........... 37 
5.4.1 
Concomitant Medications ........................................................................... 37 
5.4.2 
Concomitant Antibacterial Medications...................................................... 37 
5.4.3 
Adjunctive Antibacterial Therapy ............................................................... 38 

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5.4.4 
Non-drug Adjunctive Therapy .................................................................... 38 
6 
STUDY PROCEDURES ................................................................................................ 38 
6.1 
Screening (Day -1) - Within 24 Hours Prior to First Dose ................................... 38 
6.1.1 
Treatment Period ......................................................................................... 38 
6.1.2 
Day 1 ........................................................................................................... 39 
6.1.3 
Day 5 ........................................................................................................... 39 
6.1.4 
Day 10 (± 1 day).......................................................................................... 39 
6.2 
Follow-up Period ................................................................................................... 40 
6.2.1 Day 21 (± 1 day) – (Test of Cure) ...................................................................... 40 
6.2.2 Day 28 (± 3 days) – Final Visit (Phone call) ...................................................... 40 
6.3 
Premature Discontinuation .................................................................................... 40 
6.3.1 
Premature Discontinuation from Study Drug Therapy ............................... 40 
6.3.2 
Premature Discontinuation from Study ....................................................... 41 
6.4 
Patient Withdrawal from Treatment or Study ....................................................... 41 
7 
ASSESSMENTS ............................................................................................................. 41 
7.1 
Safety ..................................................................................................................... 41 
7.1.1 
Physical Examination .................................................................................. 41 
7.1.2 
Vital Signs (Blood Pressure, Respiration Rate, Temperature and 
Pulse Rate)................................................................................................... 42 
7.1.3 
Clinical Laboratory Assays ......................................................................... 42 
7.1.4 
Clinically Significant Laboratory Tests ...................................................... 43 
7.2 
Efficacy ................................................................................................................. 43 
7.2.1 
Overall Response......................................................................................... 43 
7.2.2 
Microbiologic Response .............................................................................. 43 
7.2.3 
Patient-Determined Clinical Response........................................................ 44 
7.2.4 
Investigator Assessment of Clinical Outcome ............................................ 45 
7.2.5 
Patient Symptom Assessment Questionnaire (PSAQ) ................................ 45 
8 
ADVERSE EVENT REPORTING ................................................................................. 46 
8.1 
Adverse Events ...................................................................................................... 46 
8.2 
Reporting Period ................................................................................................... 46 
8.3 
Definition of an AE ............................................................................................... 46 
8.4 
Abnormal Test Findings ........................................................................................ 47 
8.5 
Serious Adverse Events (SAE) ............................................................................. 47 
8.6 
Hospitalization ...................................................................................................... 48 
8.7 
Severity Assessment .............................................................................................. 49 
8.8 
Causality Assessment ............................................................................................ 49 
8.9 
Exposure during Pregnancy .................................................................................. 50 
8.10 
Discontinuation from Study Drug Due to AEs (See also Patient Withdrawal, 
Section 6.4)............................................................................................................ 51 

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8.11 
Eliciting AE Information ....................................................................................... 51 
8.12 
Reporting Requirements ........................................................................................ 51 
8.12.1 
SAE Reporting Requirements ..................................................................... 51 
8.12.2 
Non-SAE Reporting Requirements ............................................................. 52 
8.12.3 
Sponsor Reporting Requirements to Regulatory Authorities ...................... 52 
9 
DATA ANALYSIS/STATISTICAL METHODS .......................................................... 52 
9.1 
Sample Size Determination ................................................................................... 52 
9.2 
Definition of Analysis Populations ....................................................................... 53 
9.3 
General Statistical Considerations ........................................................................ 54 
9.4 
Patient Characteristics ........................................................................................... 54 
9.5 
Efficacy Analysis .................................................................................................. 54 
9.5.1 
Analysis of Primary Outcome Measure ...................................................... 54 
9.5.1.1 
Additional Analyses of the Primary Efficacy Outcome .................... 55 
9.5.2 
Analysis of the Secondary Efficacy Outcome Measure .............................. 55 
9.5.3 
Analysis of Additional Efficacy Outcome Measures .................................. 56 
9.6 
Safety Analyses ..................................................................................................... 56 
9.7 
Interim Analysis .................................................................................................... 57 
9.8 
Handling of Missing Data ..................................................................................... 57 
10 QUALITY CONTROL AND QUALITY ASSURANCE .............................................. 58 
11 DATA HANDLING AND RECORD KEEPING ........................................................... 58 
11.1 
Case Report Forms / Electronic Data Record ....................................................... 58 
11.2 
Record Retention ................................................................................................... 59 
12 ETHICS ........................................................................................................................... 59 
12.1 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ............ 59 
12.2 
Ethical Conduct of the Study ................................................................................ 59 
12.3 
Patient Information and Consent ........................................................................... 60 
12.4 
Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP ... 60 
13 DEFINITION OF END OF STUDY .............................................................................. 60 
13.1 
End of Study in a Member State............................................................................ 60 
14 SPONSOR STUDY TERMINATION CRITERIA ........................................................ 61 
15 PUBLICATION OF STUDY RESULTS ....................................................................... 61 
15.1 
Communication of Results by Iterum ................................................................... 61 
15.2 
Publications by Investigators ................................................................................ 61 
16 REFERENCE LIST......................................................................................................... 63 
List of In-Text Tables 
Table 1. Sulopenem In-Vitro Susceptibility (2013-2015)…………………………………..20 

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LIST OF APPENDICES 
Appendix 1 
Schedule of Activities ..................................................................................... 64 
Appendix 2 
Microbiology ................................................................................................... 66 
Appendix 3 
Method for Determination of Creatinine Clearance/Renal Dose Adjustment 
Guidance.......................................................................................................... 68 
Appendix 4 
Population PK Sub-study ................................................................................ 69 
Appendix 5 
Criteria for Safety Values of Potential Clinical Concern ................................ 75 
Appendix 6 
Investigator’s Signature................................................................................... 76 
 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
AUC0-24 
Area under the curve from zero to 24 hours 
βhCG 
Beta Human Chorionic Gonadotropin 
BID 
Twice a day 
BUN 
Blood Urea Nitrogen 
Cmax 
Maximum concentration 
CA 
Community-acquired 
CBC 
Complete Blood Count 
CE 
Clinically Evaluable 
CI 
Confidence Interval 
cIAI 
Complicated intra-abdominal infection 
CLSI 
Clinical and Laboratory Standards Institute 
CrCl 
Creatinine Clearance 
CRE  
Carbapenem resistant Enterobacteriaceae 
CRF 
Case Report Form 
CTA 
Clinical Trial Application 
cUTI 
Complicated urinary tract infections 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
ECG 
Electrocardiogram 
E.coli 
Escherichia coli 
EIU 
Exposure in Utero 
EOT 
End of Treatment Visit 
EARS-NET 
European Antimicrobial Resistance Surveillance Network 
ESBL 
Extended Spectrum Beta-lactamase 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating Hormone 

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FV 
Final Visit 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl Transpeptidase 
GMP 
Good Manufacturing Practice 
hERG 
Human ether-a-go-go-related gene 
HIV 
Human Immunodeficiency Virus 
hs-CRP 
High-sensitivity C-reactive Protein 
IHMA 
International Health Management Associates 
ICH 
International Conference on Harmonisation 
ICF 
Informed Consent Form 
IRB/IEC 
Institutional Review Board /Independent Ethics Committee  
ITT 
Intent-to-Treat 
IUD 
Intrauterine Device 
IV 
Intravenous 
IWRS 
Interactive Web Response System  
LDH 
Lactate Dehydrogenase 
LTFU 
Lost to Follow-Up 
ME 
Microbiologically Evaluable 
MCI 
Minimal Inhibitory Concentration 
MITT 
Modified ITT (MITT) 
mMITT 
Microbiologic-MITT 
NI 
Non-inferior 
OSD 
Oral solid dose 
NOAEL 
No-observed-adverse-effect-level 
PBPs 
Penicillin-binding proteins 
PCS 
Potentially clinically significant 
PK 
Pharmacokinetic 
PK/PD 
Pharmacokinetic / Pharmacodynamic 
PSAQ 
Patient Symptom Assessment Questionnaire 
PO 
Oral Administration 

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PV 
Pharmacovigilance 
QTc 
QT corrected 
RBC 
Red Blood Cell  
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SmPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TOC 
Test of Cure 
TEAE 
Treatment Emergent Adverse Event 
Tmax 
Time to maximum concentration 
ULN 
Upper limit of normal 
USPI 
United State Prescribing Information 
uUTI 
Uncomplicated urinary tract infection 
WBC 
White Blood Cell 
2-EBA 
2-ethylbutryic acid 
 
 

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1 
INTRODUCTION 
1.1 
Indication 
Sulopenem is being studied for the treatment of the following indications: 
- 
Complicated and uncomplicated urinary tract infections 
- 
Complicated intra-abdominal infections 
1.2 
Background and Rationale 
β-lactam antimicrobials are widely recognized for their efficacy and low toxicity and form the 
cornerstone of therapy for the treatment of infections caused by gram-positive and gram-
negative bacteria.  However, extensive use of β-lactams during the past 50 years has resulted in 
the development of microbial resistance to these agents among clinically important bacteria.  
This resistance commonly takes the form of β-lactamase production, expression of porins in the 
bacterial outer membrane or alterations in penicillin-binding proteins (PBPs).  Such mechanisms 
have reduced the clinical utility of frequently prescribed β-lactams such as amoxicillin, 
amoxicillin plus clavulanate (a β-lactamase inhibitor), and cephalosporins.  The issue of 
resistance continues to drive the search for new compounds with increased stability and efficacy 
against resistant pathogens. 
The prevalence of infections caused by extended-spectrum β-lactamases (ESBL) producing 
Enterobacteriaceae has been increasing worldwide and includes both hospital acquired and 
community onset infections. An analysis of data reported from 2011 to 2014 to the National 
Healthcare Safety Network performed by the Centers for Disease Control in March 2016 
revealed that the proportion of E.coli resistant to extended-spectrum cephalosporins causing 
hospital-acquired infection was 13.4% nationally, with rates as high as 24% reported in some 
Northeastern, Southern and Western states.  The same analysis also demonstrated that over a 
third of E.coli isolates in 2014 were resistant to quinolones. Oral antibiotic treatment options are 
extremely limited for patients with these infections, resulting in lengthy hospital stays to 
facilitate administration of intravenous antibiotics. Data reported by the European Antimicrobial 
Resistance Surveillance Network (EARS-NET) in Europe demonstrate that the prevalence of 
quinolone resistant E.coli and E.coli resistant to third-generation cephalosporins is > 25%, and 
multi-drug resistant E.coli (resistant to third generation cephalosporins, aminoglycosides and 
quinolones) has increased to >10% in some southern and eastern European countries. 
Consequently, options for oral antibiotic step-down therapy for patients with resistant gram-
negative infections are limited.  
Sulopenem is a broad-spectrum thiopenem β-lactam antibiotic which is being developed for the 
treatment of infections caused by multi-drug resistant bacteria. Sulopenem possesses potent 
activity against species of the Enterobacteriaceae that encode ESBLs or AmpC-type β-
lactamases that confer resistance to third generation cephalosporins. The targeted gram-negative 
spectrum of sulopenem is balanced by its potent in vitro activity against anaerobic pathogens, 
which is similar to that of imipenem.  
An in-vitro susceptibility study of sulopenem was conducted in April 2016 utilizing 
contemporary clinical bacterial isolates from patients in the United States and Europe. Minimal 
inhibitory concentrations (MICs) of sulopenem and 18 comparators were determined against 
1,122 recent (2013-2015) clinical isolates following Clinical and Laboratory Standards Institute 

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(CLSI) guidelines.  The study collection included 872 aerobes (811 gram-negative, 61 gram-
positive) and 250 anaerobes.  Isolates were chosen randomly from the IHMA (International 
Health Management Associates, Inc., Schaumburg, IL) repository, which is a global collection 
of single patient clinical isolates.   For this study the selection of isolates focused on infection 
source (IAI and UTI) and region (US and Europe) for the inclusive years. Aerobes were tested 
by broth microdilution and anaerobes were tested by agar dilution. Results from this study 
presented below demonstrate that sulopenem retains potent in vitro activity against common 
pathogens implicated in urinary tract infections and intra-abdominal infections, including those 
that are caused by organisms that produce ESBLs. Carbapenem resistant Enterobacteriaceae 
(CRE) were excluded from the analysis shown below, but the MIC90 of Enterobacteriaceae 
remains at 0.25 µg/mL even if CRE are included, given that their overall prevalence is low (data 
on file). 
Table 1. Sulopenem In-Vitro Susceptibility (2013-2015) 
Organism Class 
N 
MIC50 
(µg/mL) 
MIC90 
(µg/mL) 
Enterobacteriaceae 
636 
0.03 
0.25 
E. coli                       ESBL negative 
169 
0.015 
0.03 
                                 ESBL positive 
20 
0.03 
0.06 
Klebsiella spp.         ESBL negative 
108 
0.03 
0.06 
                                 EBSL positive 
16 
0.03 
0.25 
P. mirabilis 
14 
0.12 
0.25 
E. aerogenes 
57 
0.06 
0.25 
C. koseri 
60 
0.03 
0.03 
S. marcescens 
55 
0.12 
0.5 
Gram-Negative Anaerobes 
121 
0.12 
0.25 
Staphylococcus saprophyticus 
31 
0.25 
0.25 
As in the case of most β-lactams, sulopenem is not active against methicillin-resistant 
staphylococci or MDR enterococci. Sulopenem also does not have activity against 
Pseudomonas aeruginosa, therefore its broad use for treating such cephalosporin-resistant 
hospital isolates should not select for resistant P. aeruginosa as can occur with imipenem and 
meropenem. 
Sulopenem (CP-70,429) is available as an intravenous formulation. Intravenous sulopenem was 
previously evaluated in Phase 1 and Phase 2 clinical studies in Japan in approximately 1476 
subjects, at doses up to 1 g BID administered intravenously over 3-14 days in the early 1990’s. 
Safety data collected from these trials regarding both adverse events as well as laboratory 
examinations provides support for the safety and tolerability of sulopenem in patients and its 
further development.   
Sulopenem and its oral pro-drug, sulopenem etzadroxil, have been studied in single and multiple 
dose Phase 1 studies, and the oral prodrug has been studied with and without co-administration 
of probenecid. One small Phase 2 study in patients with community acquired pneumonia was 
conducted, in which 35 adult patients were randomized to one of three treatment groups to 

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receive either: a single loading dose of intravenous (IV) sulopenem with switch to oral 
sulopenem etzadroxil, 4 dose minimum of IV sulopenem with switch to oral sulopenem 
etzadroxil, or ceftriaxone (IV) for a minimum of 2 doses, with step down to amoxicillin-
clavulanate. The cure rates in the clinically evaluable subjects in this study at TOC were 90%, 
88% and 63% in the single IV dose sulopenem, multiple IV dose sulopenem and ceftriaxone 
groups (IV), respectively. While these efficacy results were not statistically significant due to 
the small numbers enrolled, they provide encouraging support for further clinical testing in this 
indication.  Phase 2 studies in patients with urinary tract infection or intra-abdominal infection 
have not been conducted in the United States. 
Sulopenem-etzadroxil has minimal in vitro antibacterial activity.  Upon oral absorption, 
sulopenem-etzadroxil yields the active moiety sulopenem in addition to the non-active moieties 
formaldehyde and 2-ethylbutyric acid (2-EBA).  
The currently proposed study will compare the safety, tolerability and efficacy of sulopenem 
followed by sulopenem-etzadroxil with probenecid versus ertapenem followed by oral 
ciprofloxacin or amoxicillin-clavulanate for treatment of complicated urinary tract infection. 
1.2.1 
Safety data 
1.2.1.1 
Sulopenem-etzadroxil (PF-03709270; oral prodrug) 
Pre-clinical data 
The non-clinical program to assess toxicity of sulopenem-etzadroxil consisted of acute oral 
and repeat-dose toxicity studies, safety pharmacology studies, genetic toxicity assessments, 
and reproductive development toxicity studies in rats and rabbits.  Following oral 
administration of sulopenem-etzadroxil in rats and monkeys, circulating concentrations of 
sulopenem-etzadroxil were variable and minimal or below limits of quantitation, whereas 
significant levels of sulopenem and 2-EBA were present in whole blood. Effects observed in 
rats and monkeys from the repeat dose toxicology studies were generally consistent with those 
expected from the active moiety sulopenem. The no observed adverse effect level (NOAEL) in 
the rat is 100 mg/kg with a Cmax of 1.90 µg/mL and AUC of 7.24 µg•h/mL for sulopenem, and 
the NOAEL in the monkey is 50 mg/kg with a Cmax of 4.63 µg/mL and an AUC of 11.1 
µg•h/mL for sulopenem, respectively. Sulopenem-etzadroxil was negative in mutagenicity and 
in vivo clastogenicity tests but positive for clastogenic activity in human lymphocytes. 
Sulopenem-etzadroxil had no effects on male and female rat fertility and early embryonic 
development, and was not teratogenic to rats or rabbits. Developmental toxicity was observed 
in both rats and rabbits with the NOAEL being 100 mg/kg and 5 mg/kg, respectively, at doses 
where maternal toxicity was also observed. 

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Previous human experience  
The sulopenem-etzadroxil studies have investigated the pharmacokinetics, safety and 
tolerability of single oral doses ranging from 400 mg to 8000 mg. The pharmacokinetics, 
safety and tolerability of multiple oral doses of sulopenem-etzadroxil at a dose of 2000 
mg BID for 10 days and 1200 mg plus 1000 mg probenecid BID for 10 days, 500 mg, 
1000 mg and 1500 mg BID for 7 days have also been investigated. 
Single doses of sulopenem-etzadroxil of 400 mg, 600 mg, 1000 mg, and 2000 mg 
produced an approximately linear increase in sulopenem mean exposure. The apparent 
terminal half- life of sulopenem was generally dose independent and ranged from 0.76 
hours to 1.10 hours. 
Mean time to observed maximum concentration (Tmax) was on average 1 hour for all 
doses. Neither sulopenem-etzadroxil nor formic acid has been detected in either plasma 
or whole blood following dosing with sulopenem etzadroxil. In addition, the levels of 2 
EBA were much lower (~1/20) than sulopenem concentrations. During the 
administration of multiple doses of sulopenem-etzadroxil for 10 days due to the short 
half-life of sulopenem-etzadroxil there is no accumulation on Day 10 of dosing.  
Sulopenem-etzadroxil doses of 2000 mg produced a mean sulopenem Cmax of 4.7 µg/mL 
and a mean AUClast of 13.1 h•µg/mL. Sulopenem systemic exposure parameters (Cmax 
and AUClast) following sulopenem-etzadroxil single doses ranging from 400 to 2000 
mg, increased in a dose-related manner. 
There is a significant effect of food (high fat meal) on the pharmacokinetic (PK) of 
sulopenem, given as sulopenem-etzadroxil orally. The mean AUCinf and Cmax increased 69% 
and 13.5% respectively, with a longer mean time above MIC of 1 µg/mL (1.91 hours).  
Mean t1/2 was similar between the fed and fasted states (0.98-1.14 hr). 
The concentrations of radioactivity in plasma and whole blood, the excretion of 
radioactivity and the metabolic pathways of [14C] sulopenem-etzadroxil have been 
determined in healthy male volunteers (N = 4) following single oral solution (2000 mg) 
administration. The majority of the radioactivity was excreted in the urine and feces (40.8 
and 44.3% respectively). Total mean recovery of radioactivity ranged from 80.2 to 95%.  
Overall sulopenem-etzadroxil was well tolerated in the Phase 1 program. The most 
common adverse events occurring in the program were diarrhea and abnormal urine odor. 
1.2.1.2 
Sulopenem (CP-70,429; Intravenous) 
Preclinical intravenous data 
In non-clinical evaluations of intravenous administration of sulopenem, the NOAEL in the 
2-week toxicity study in rats was 200 mg/kg with extrapolated AUC(0-tlast) of 50 µg•h/mL.  
NOAEL was based on increases in kidney and liver weights, erythema, and salivation at 
800 mg/kg.  
The NOAELs in the 4-week toxicity studies in rats and monkeys were both 60 mg/kg.  In 
rats, the NOAEL was based on a slight decrease in red blood cell (RBC) parameters and 
increases in liver, kidney, and cecum weights at ≥60 mg/kg.  In monkeys, the NOAEL was 
based on a decrease in RBC parameters and increased bilirubin at 200 mg/kg.  

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The NOAELs in the 3-month studies were 120 mg/kg in the rat; AUC(0-tlast) of 29.2 ug•hr/mL 
(AUC(0-tlast) represents 0-2 h), and 60 mg/kg in the monkey; AUC(0-tlast) of 49.2 ug•hr/mL; 
(AUC(0-tlast) represents 0-8 h).  The NOAEL in rats was based on adverse effects on body 
weight and food consumption, and slight decreases in RBC parameters at 600 mg/kg.  The 
NOAEL in monkeys was based on a positive Direct Coombs test result, decreases in RBC 
parameters, increased bilirubin, moribundity in 2 animals, bone marrow hyperplasia, and soft 
stools at 200 mg/kg.  
No change in heart rate or QTc was observed in a single-dose cardiovascular safety 
pharmacology study in anesthetized dogs up to 300 mg/kg, yielding an average blood level of 
258 µg/mL (total). Similarly, no change in heart rate or QTc was observed in the 
cardiovascular study in telemetry-implanted monkeys at 1000 mg/kg, yielding a blood 
concentration of 2270 µg/mL (total).    
In a safety pharmacology study evaluating the effect on the human ether-a-go-go-related 
gene (hERG) potassium channel, sulopenem inhibited the hERG current by approximately 
50% at the maximum concentration of 300 µM (105 µg/mL; free).  There were no changes in 
action potential duration in the in vitro Purkinje fiber assay at concentrations up to 300 µM 
(105 µg/mL; free).   
Previous human experience  
The pharmacokinetics and safety of sulopenem have been evaluated in Phase 1 single and 
multiple dose studies. Doses of 400 mg, 800 mg, 1600 mg, 2400 mg and 2800 mg of 
sulopenem were evaluated in a single dose ascending study, and doses of 800 mg infused 
over 3 hours, 1200 mg infused over 1 hour, 1200 mg infused over 2.5 hours, 1600 mg 
infused over 1.5 hours for 14 days and 2000 mg infused over 1.5 hours for 7 days were 
evaluated in a multiple dose study in healthy volunteers (8 subjects in each dose group). 
There were no deaths or serious adverse events (SAEs) in either study. One subject who 
received 1200 mg IV twice a day (BID) was discontinued on Day 4 from study drug therapy 
due to an adverse event (AE) of mildly increased troponin (0.107 ng/mL [normal limit 
<0.04 ng/mL]); the AE was reported to be resolved on Day 8. The most frequently reported 
AEs were gastrointestinal events (nausea, vomiting). Severe AEs included nausea and 
vomiting, and were reported only in the highest dose groups (>2000 mg), indicating that 
MTD had been reached. All AEs in the lower dose groups (<2000 mg) were considered mild 
to moderate in severity. No clinical laboratory abnormalities occurred that were considered to 
be clinically significant by the investigator. There were no vital signs or electrocardiogram 
(ECG) changes (including QTc interval changes) of clinical concern.  
Pharmacokinetic analysis revealed a dose proportional increase in Cmax and AUClast. The 
mean t ½ remained constant over the dose range. Following a 1 hour intravenous infusion, all 
doses higher than 400 mg produced mean concentrations above 1.0 μg/mL for > 3.3 hours, 
allowing for a twice daily dosing and potentially a single daily dose with a longer infusion 
duration.  
In healthy adults, intravenous sulopenem doses up to 1000 mg BID were studied in 3 small 
Phase 1 studies (two in Japan and one in the US) in the early 1990’s; Sulopenem was well 
tolerated.  The mean Cmax and AUCinf were 61.5 µg/mL and 51.9 µg•h/mL, respectively for a 
single 1000 mg dose infused over 30 minutes in the Japanese study.  The mean Cmax and 

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AUCinf were 69.8 µg/mL and 54.1 µg•h/mL, respectively, for a single 1000 mg dose infused 
over 10 minutes in the US study.  
The IV formulation of sulopenem was also investigated in four Phase 2 clinical efficacy 
studies in Japan in the early 1990s.  Fourteen hundred and seventy-six patients with hospital 
and community acquired infections were administered primarily 250 or 500 mg BID dosing 
regimens of IV sulopenem for 3 to 14 days.   
Complete information on sulopenem-etzadroxil and sulopenem is available in the 
Investigator Brochure. 
1.2.2 
Rationale for Study  
ß-lactam antimicrobials are widely recognized for their efficacy and low toxicity and form 
the cornerstone of therapy for the treatment of infections caused by gram-positive and gram-
negative bacteria. However, extensive use of ß-lactams during the past 50 years has resulted 
in the development of microbial resistance to these agents among clinically important 
bacteria. This resistance commonly takes the form of ß-lactamase production, development 
of porins or alterations in penicillin-binding proteins (PBPs). Such mechanisms have reduced 
the clinical utility of frequently prescribed ß-lactams such as amoxicillin, amoxicillin plus 
clavulanate (a ß-lactamase inhibitor), and cephalosporins. The issue of resistance continues 
to drive the search for new compounds with increased stability and activity against resistant 
pathogens. Nowhere is the importance of resistance more evident than among agents of the 
ß-lactam family.  
For Escherichia coli, ampicillin resistance has risen to ≥50% in high-risk populations, and 
resistance to third generation cephalosporins is now increasingly common in certain areas. 
Only through the recognition of factors associated with increasing resistance and the 
mechanisms responsible can strategies be designed for minimizing ß-lactam resistance. As 
antibiotic resistance leads to increased costs of treatment, increased morbidity as well as 
increased mortality, there is an unmet urgent medical need for antimicrobial agents that can 
be utilized in serious hospital and community infections, especially agents that can be 
delivered orally. 
The penems are considered to exhibit advantages to the ß-lactam class as they possess good 
antibacterial activity against gram-negative pathogens commonly responsible for a wide 
range of community and hospital infections, and are stable to many ß-lactamases. 
Sulopenem has in vitro activity against many common hospital pathogens, including 
extended spectrum ß-lactamase (ESBL) producing gram-negative pathogens (except 
Pseudomonas spp., Acinetobacter spp., Stenotrophomonas spp.), and anaerobes such as 
Bacteroides fragilis.  
Rationale for probenecid 
Probenecid has been shown in a dog model to increase the systemic exposure of a penem 
CP-65,207 (sulopenem is the S-isomer of CP-65,207) by about 2-fold, suggesting a role of 
active renal tubular secretion in drug elimination. Findings from a previous clinical 
pharmacokinetic study indicate that renal clearance accounts for a significant proportion 
(approximately 50%) of total clearance of sulopenem in healthy volunteers suggesting that 
probenecid could increase exposure and thus time over MIC for sulopenem.  Probenecid is 

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known to increase plasma levels of weak organic acids such as penicillins, cephalosporins, 
and other beta-lactam antibiotics, including penems, by competitively inhibiting their renal 
tubular secretion.  Probenecid has been used safely with other beta-lactam antibiotics, to 
either reduce dose or dosing frequency of beta-lactams when used to treat infectious diseases 
in human beings.  Please refer to the probenecid product label for more pharmacology 
information on probenecid. 
The pharmacokinetics, safety and tolerability of sulopenem-etzadroxil in combination with 
probenecid 1000 mg were evaluated in 6 subjects in Study A8811006. Escalating oral doses 
of sulopenem-etzadroxil (PF-03709270) administered with 1000 mg probenecid produced 
approximately proportional increases in systemic exposure of sulopenem over the dose range 
of 800 mg to 1200 mg. The combination of sulopenem etzadrozil 500 mg and probenecid 500 
mg was evaluated in a study, IT001-101. Results from this study were consistent with those 
observed in previous studies. 
Thus probenecid has the potential to be used as a PK booster with sulopenem etzadroxil, 
optimizing the time over MIC for any given sulopenem dose while minimizing the 
gastrointestinal exposure of the parent compound and subsequent gastrointestinal adverse 
events such as diarrhea.  
Rationale for dosing with food 
In a multiple dose (A8811003) study, at higher doses of sulopenem etzadroxil, there is a 
higher rate of gastrointestinal symptoms especially diarrhea in a fasted state.  It has therefore 
been postulated that if the fraction of sulopenem-etzadroxil absorbed, and bioavailability of 
sulopenem (the active moiety) can be increased, the gastrointestinal toleration and 
pharmacokinetics of the compound can be improved. 
In Study A8811008 there was an increase in relative bioavailability of sulopenem when 
sulopenem-etzadroxil was administered in the fed state (~82% increase in mean AUC).  In 
Study IT001-101, sulopenem-etzadroxil was evaluated in a fasted and fed state at a dose of 
500 mg BID. Results from this study indicate that food significantly increases bioavailability 
of sulopenem and consequently results in decreased rates of diarrhea. Therefore, dosing of 
oral sulopenem-etzadroxil with food whenever possible is recommended.  Since adequate 
target attainment appears to be achieved in the fasted state, inability to administer the dose 
with food should not preclude dosing. 
1.2.3 
Dose Rationale  
Sulopenem (IV) and Sulopenem-etzadroxil (Oral) 
Doses of sulopenem and sulopenem-etzadroxil were chosen by PK/PD modeling using a 
combination of (1) modeling (Naïve Pool analysis) of the sulopenem effect on net change in 
colony forming units (CFU) over 24 hours of clinically relevant organisms in an 
immunocompetent mouse thigh infection model, (2) defining targets of percent time above 
the MIC (T>MIC) for sulopenem from this mouse model, and (3) population PK modeling 
using nonlinear mixed effects models, generated from clinical data in multiple IV sulopenem 
and oral sulopenem-etzadroxil Phase 1 studies in healthy volunteers.  
Monte Carlo simulations were performed using the human population PK parameters for 
sulopenem-etzadroxil and mean pharmacodynamic parameters from murine thigh infection 

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model to determine % target achievement (TA) for the selected doses. A %TA of ≥90% was 
deemed desirable for selecting particular doses. The 1000 mg IV dose delivered over 3 hours 
and the 500 mg dose of sulopenem-etzadroxil co-administered with 500 mg of probenecid 
administered twice daily meets the criteria of %T>MIC for achieving 1-log kill in >90% of 
bacteria with MIC’s expected in this indication.  
Probenecid 
The maximum total daily dose of probenecid will be 1000 mg (500 mg BID) which is within 
the recommended dosage of 2000 mg daily in divided doses.  
Ertapenem 
The recommended dose of IV ertapenem in this study is 1000 mg administered over 30 
minutes and is consistent with the ertapenem USPI for treatment of urinary tract infections.  
Ciprofloxacin 
The recommended dose of oral ciprofloxacin in this study is 500 mg BID following an initial 
course of ertapenem IV to complete 7-10 days of therapy, consistent with the ciprofloxacin 
USPI and SmPC for treatment of urinary tract infections. 
Amoxicillin-clavulanate 
The recommended dose of oral amoxicillin-clavulanate in this study is 875 mg BID, 
consistent with the amoxicillin-clavulanate US FDA Package Insert and SmPC for severe 
infections. 
For the full prescribing information for probenecid and all comparator study drugs, please 
refer to respective local country product labels (USPI or SmPC). 
2 
STUDY OBJECTIVES 
2.1 
Objectives 
The primary objective of this study is to compare the efficacy of sulopenem IV followed by 
oral sulopenem-etzadroxil plus probenecid with ertapenem IV followed by oral ciprofloxacin 
or amoxicillin-clavulanate for the treatment of complicated urinary tract infection at Day 21 
(± 1day; TOC). 
The secondary objectives of this study are: 
• To compare the per-patient microbiologic response across treatment groups. 
• To compare the efficacy outcomes at relevant time points  
• To assess the safety profile of treatment with each regimen.  
• To assess the population PK profile of sulopenem and/or sulopenem-etzadroxil co-
administered with probenecid. 
3 
STUDY DESIGN 
This prospective, Phase 3, randomized, multicenter, double-blind, double dummy, controlled 
study compares IV sulopenem followed by oral sulopenem-etzadroxil with probenecid to IV 

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ertapenem followed by oral ciprofloxacin or amoxicillin-clavulanate for treatment of 
complicated urinary tract infection in adults. The site pharmacist will be unblinded in order 
to prepare the intravenous study medications and select the appropriate oral follow on 
therapy for patients randomized to the ertapenem regimen. Approximately 1156 adults with 
cUTI will be randomized in a 1:1 fashion to receive either IV sulopenem 1000 mg once daily 
for at least 5 days (5 doses) followed by sulopenem-etzadroxil 500 mg co-administered with 
oral probenecid 500 mg twice daily to complete a total of 7-10 days of treatment or 
ertapenem IV 1000 mg once daily for at least 5 days (5 doses) followed by oral ciprofloxacin 
500 mg or amoxicillin-clavulanate 875 mg twice daily to complete a total of 7-10 days of 
therapy. The dose of study drugs may be adjusted for patients with severe renal impairment 
(CrCl <30 mL/min) who are not on regular hemodialysis (see Appendix 3). 
Patients in the comparator treatment group with baseline pathogens non-susceptible to 
ciprofloxacin, but susceptible to amoxicillin-clavulanate, will be stepped-down to 
amoxicillin-clavulanate instead of ciprofloxacin, and those with baseline pathogens non-
susceptible to both ciprofloxacin and amoxicillin-clavulanate will need to continue on IV 
ertapenem for the entire duration of therapy.  
The total duration of therapy may be increased up to 14 days in both treatment groups for 
patients with bacteremia at baseline. 
The primary outcome measure for efficacy evaluation will be the resolution of the symptoms 
of cUTI present at trial entry (and no new symptoms) and the demonstration that the bacterial 
pathogen found at trial entry is reduced to <103 CFU/mL on urine culture on Day 21 (± 1 
day; TOC). 
See Appendix 1, Schedule of Activities table. 
3.1 
Investigational Study Medications 
Patients randomized to the sulopenem treatment group will receive 1000 mg of sulopenem 
IV for a minimum of 5 days, and sulopenem-etzadroxil 500 mg/probenecid 500 mg tablets to 
take twice daily to complete a total of 7-10 days of therapy in addition to placebo tablets to 
match ciprofloxacin or amoxicillin-clavulanate. Patients randomized to the comparator 
treatment group will receive ertapenem 1000 mg IV once daily for a minimum of 5 days 
followed by ciprofloxacin 500 mg or amoxicillin-clavulanate 875 mg tablets to take twice 
daily to complete a total of 7-10 days of therapy, in addition to placebo tablets to match 
sulopenem-etzadroxil placebo tablets. The dose of study drugs may be adjusted for renal 
function if needed (see Appendix 3). 
3.2 
Adjunctive Systemic Antibiotics 
None allowed 
3.3 
Additional, Non-Study Therapy Antibiotics 
For Clostridium difficile infections, metronidazole (IV or oral) or oral vancomycin may be 
used in both treatment groups. Patients with a co-infection with a gram-positive uropathogen 
resistant to study drugs are allowed to receive agents with narrow spectrum gram-positive 
coverage (ie, such as linezolid, daptomycin or vancomycin). 

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4 
STUDY POPULATION SELECTION 
Male or female patients who present with cUTI and who meet all of the inclusion and none 
of the exclusion criteria will be eligible for participation in this study. 
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom protocol treatment is considered 
appropriate.  All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether a particular patient is suitable for enrollment under this 
protocol. 
4.1 
Inclusion Criteria 
1. Adults ≥18 years of age with more than 24 hours of urinary symptoms attributable to 
a UTI  
2. Patient or the patient’s legally acceptable representative able to provide a signed 
written informed consent prior to any study-specific procedures. 
3. Clinically documented pyelonephritis or complicated urinary tract infection: 
a) Pyelonephritis with normal anatomy, OR 
b) Complicated UTI as defined by one or more of the following factors: 
i. 
The presence of an indwelling urethral catheter 
ii. 
>100 mL of residual urine after voiding 
iii. 
Neurogenic bladder 
iv. 
Obstructive uropathy due to nephrolithiasis, tumor or fibrosis 
v. 
Azotemia (blood urea nitrogen [BUN] > 20 mg/dL and BUN/creatinine 
ratio <15) due to intrinsic renal disease 
vi. 
Urinary retention in men possibly due to benign prostatic hypertrophy 
vii. 
Surgically modified or abnormal urinary tract anatomy 
4. At least two of the following signs or symptoms: 
a) Rigors, chills or fever/hypothermia with temperature (oral, rectal, tympanic, 
temporal) >100.4ºF or 38ºC, or <95ºF or 35ºC  
b) Flank pain or pelvic pain 
c) Nausea or vomiting 
d) Dysuria, urinary frequency or urinary urgency 
e) Costovertebral angle tenderness on physical examination 
5. A mid-stream urine specimen with: 
a) A machine-read dipstick positive for nitrite AND 
b) evidence of pyuria as defined by either: 
i. a machine-read dipstick positive for leukocyte esterase AND/OR 

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ii. at least 10 white blood cells per cubic millimeter on microscopic 
analysis of unspun urine AND/OR 
iii. White blood cell count ≥10 cells/HPF in the sediment of a spun urine 
4.2 
Exclusion Criteria 
1. Receipt of effective antibacterial drug therapy for cUTI for a continuous duration of 
more than 24 hours in the previous 72 hours prior to randomization.  
Patients who have objective documentation of clinical progression of cUTI while 
on antibacterial drug therapy, or patients who received antibacterial drugs for 
surgical prophylaxis and then develop cUTI, may be appropriate for enrollment. 
2. Subjects with an organism isolated from the urine within the last year known to be 
resistant to ertapenem  
3. Severe structural or functional urinary tract abnormality responsible for an intractable 
infection which in the opinion of the investigator would require > 10 days of therapy 
or post-treatment prophylaxis (eg. patients with chronic vesiculo-ureteral reflux). 
4. Uncomplicated UTI 
5. Patients with paraplegia/quadriplegia 
6. Hypotension with systolic blood pressure < 90 mm Hg 
7. Complicated UTI associated with complete obstruction, emphysematous 
pyelonephritis, known or suspected renal or perinephric abscess or expected to 
require surgical intervention (not placement of catheters, stents or nephrostomy tubes) 
to achieve cure 
8. Patients with a known history of myasthenia gravis 
9. Patients who require concomitant administration of tizanidine or valproic acid 
10. Patients with a history of allergy to carbapenems or quinolones or amoxicillin-
clavulanate or other beta-lactams, or hypersensitivity to probenecid 
11. Renal transplantation 
12. Patients requiring hemodialysis, hemofiltration or peritoneal dialysis 
13. Acute or chronic prostatitis 
14. High risk for cUTI caused by Pseudomonas spp. (eg,. history of prior UTI due to 
Pseudomonas species, recent steroid use  (>40 mg/day equivalent prednisolone for 5 
days or more in the 30 days prior to randomization), multiple sclerosis, chronic supra-
pubic catheter) 
15. Chronic indwelling catheters or stents (>2 weeks)  
16. Ileal loops or vesico-ureteral reflux 
17. Recent trauma to the pelvis or urinary tract within the prior 30 days 
18. History of seizures 

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19. Patients with a history of blood dyscrasias 
20. Patients with a history of uric acid kidney stones 
21. Patients with acute gouty attack 
22. Patients on chronic methotrexate therapy 
23. Females of child-bearing potential who are unable to take adequate contraceptive 
precautions (refer to Section 4.4.1), have a positive pregnancy test result within 24 
hours of study entry, are otherwise known to be pregnant, or are currently 
breastfeeding an infant. 
24. Male subjects who do not agree to use an effective barrier method of contraception 
(refer to Section 4.4.2) during the study and for 28 days after dosing 
25. Patients known to have a history of liver disease or neutropenia as defined by the 
following baseline laboratory criteria: 
• ALT or AST >3 X ULN 
• Total bilirubin >2 X ULN  
• Neutropenia (absolute neutrophil count <1000 cells/mm3) 
26. Patient participating in any other clinical study that involved the administration of an 
investigational medication at the time of presentation, during the course of the study, 
or who had received treatment with an investigational medication in the 30 days prior 
to study enrollment, or had previously been enrolled in this study or had been treated 
with sulopenem.  
27. Patient immunocompromised as evidenced by any of the following: 
a. Human immunodeficiency virus (HIV) infection, with either a recent (in the 
past 6 months) acquired immune deficiency syndrome-defining condition or a 
CD4 + T lymphocyte count <200/mm3  
b. Systemic or hematological malignancy requiring chemotherapeutic or 
radiation/immunologic interventions within 6 weeks prior to randomization or 
anticipated to begin prior to completion of study 
c. Immunosuppressive therapy, including maintenance corticosteroid therapy 
(>40 mg/day equivalent prednisolone for 5 days or more in the 30 days prior 
to randomization). 
28. Patient unlikely to comply with protocol e.g., uncooperative attitude, inability to 
return for follow-up visits, and unlikely to complete the study. 
29. Patient considered unlikely to survive the 4-week study period or has a rapidly 
progressive or terminal illness, including septic shock that was associated with a high 
risk of mortality. 
4.3 
Randomization Criteria 
Patients will be randomized in a 1:1 ratio to receive IV sulopenem followed by oral 
sulopenem-etzadroxil with probenecid versus IV ertapenem followed by oral ciprofloxacin or 
amoxicillin-clavulanate using an IWRS provided they have satisfied all patient selection 

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criteria.  The randomization schedule will be stratified by the type of infection 
(pyelonephritis vs cUTI without pyelonephritis). No more than 25% of patients may have 
received prior antibiotic therapy, and at least 30%, but no more than 70% of patients may 
have acute pyelonephritis. 
4.4 
Life Style Guidelines 
For the duration of the study, all female patients of child-bearing potential must agree to be 
strictly abstinent from sexual intercourse with any individual of the opposite sex, or to follow 
the following instructions for contraception. 
4.4.1 
Women of Child-Bearing Potential 
If the patient is a woman of childbearing potential, she and any male partner are required to 
simultaneously use 2 effective contraceptive methods, from the following list of 5: 
1. A barrier (condoms, diaphragm or cervical cap) with spermicide; 
2. A second, different barrier method (condoms, diaphragm or cervical cap); 
3. Oral or similar contraceptive, which includes, but is not limited to: injectable, implanted, 
or patch hormone therapy, and intrauterine device (IUD); 
4. Documented surgical sterilization at least 4 weeks prior to baseline; 
5. Partner vasectomy at least 6 months prior to baseline. 
She and any male partner must agree to continue all of these contraceptive methods until the 
last Study visit. Within these limits, the specific forms of contraception employed are left to 
the discretion of the patient, and/or the principal investigator, and/or the patient’s physician. 
4.4.2 
Males 
It is required that all male subjects use one of the following methods of contraception from 
the first dose of study medication and until 28 days after dosing: 
1. Abstinence 
2. Use of condom for males that have not been vasectomized for at least 6 months. 
Male subjects who have not had a vasectomy must use a condom.  In addition, such a male 
subject should be instructed that, unless his female partner has had a tubal ligation, 
hysterectomy, or bilateral oophorectomy or is post-menopausal, his female partner should 
use another form of contraception from the time of the first dose of study medication until 28 
days after dosing.  Such other forms of contraception include an IUD, spermicidal 
foam/gel/film/cream/suppository, diaphragm with spermicide, oral contraceptive, injectable 
progesterone, or subdermal implant. 
5 
STUDY TREATMENTS 
5.1 
Allocation to Treatment 
This is a randomized, double blind, double dummy study in which approximately 1156 
patients will receive either IV sulopenem followed by oral sulopenem-etzadroxil plus 

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probenecid or IV ertapenem followed by oral ciprofloxacin or amoxicillin-clavulanate in the 
treatment of cUTI. Randomization will be based on an IWRS-generated schedule in a 1:1 
allocation ratio. 
A patient will be eligible for randomization once it has been determined that he or she meets 
all inclusion criteria and has none of the exclusion criteria. On the day the patient is to 
receive the first dose of study drug, a designated member of the clinical pharmacy staff will 
contact the IWRS to obtain the study treatment assignment and dispense therapy accordingly. 
The IWRS will associate that patient with the next available treatment in the appropriate 
stratum on the randomization schedule.  The IWRS will then give the investigative site 
information which corresponds to study medication that has been previously shipped to the 
site and is in the site’s inventory ready to be dispensed. A patient is considered randomized 
when the site personnel receive the patient’s study randomization number from the IWRS. 
5.1.1 
Criteria for Switch from IV to Oral Therapy 
After 5 days (at least 5 administrations of IV therapy), patients who meet the following 
criteria will be switched to oral treatment: 
1. Patient can tolerate oral medications 
2. Clinical signs of infection such as fever and white blood cell count are 
improving; these signs of infection do not have to return to normal 
3. Clinical symptoms such as dysuria, suprapubic pain, and flank pain, if present 
at baseline, are improving. 
4. Baseline pathogen susceptible to the drugs included in the oral step-down 
regimen 
Those patients who do not meet the criteria for switch to oral treatment at Day 5 should 
continue with IV treatment.  The Investigator should continue to re-evaluate if the patient 
meets the criteria for switch to oral treatment on a daily basis.  The total study treatment 
should not exceed 10 days of treatment, with the exception of those patients with bacteremia, 
who can receive up to 14 days of treatment. 
5.2 
Drug Supplies 
5.2.1 
Formulation and Packaging 
Sulopenem treatment group: Sulopenem 1000 mg IV will be supplied as a single-use vial 
with lyophilized powder for injection.  The IV solution will be prepared for dosing by an 
unblinded pharmacist according to the dosing instruction provided by the sponsor.  The oral 
medications will be packaged in a suitable packaging container and provided to the sites.  
Comparator treatment group:  Ertapenem 1000 mg IV will be supplied as a single-use vial. 
The IV solution will be prepared for dosing by an unblinded pharmacist.  The oral 
medications will be packaged in a suitable packaging container and provided to the sites. 
Dosage and administration instructions will be provided in the pharmacy manual for 
preparation of doses using the sulopenem vials, comparator vials and saline solution for 
blinding. 

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All oral study drugs and placebos are matched for blinding. 
All supplies packed and labeled will be formally released in accordance with both Good 
Manufacturing Practice (GMP) and Good Clinical Practice (GCP) guidelines. 
5.2.2 
Preparation and Dispensing 
Sulopenem or ertapenem IV: Each dose of IV study medication will be prepared by an 
unblinded pharmacist or other qualified personnel at the site according to the dosing 
instructions provided by the sponsor.  Dosing and administration instructions will be 
provided in the pharmacy manual for preparation of doses of sulopenem and ertapenem.  
Sulopenem etzadroxil/probenecid or comparator OSD: All investigational product including 
supplies of the oral solid dose study drug will be provided to the study site by Iterum 
Therapeutics. Written study medication preparation and administration instructions will be 
provided to each study site in a study pharmacy manual.   
The pharmacy manual will contain detailed instructions for the preparation and 
administration of study medication.   
5.2.3 Administration 
Sulopenem arm:  
Patients with normal renal function: Patients randomized to the sulopenem treatment group 
will receive 1000 mg sulopenem IV infused over 3 hours, once daily for 5 days. For blinding 
purposes sulopenem will be co-administered with a 30-minute infusion of saline solution to 
simulate the comparator. 
After at least 5 days of intravenous therapy those patients with a baseline pathogen 
susceptible to ciprofloxacin and who meet criteria for oral step-down will take one 
sulopenem etzadroxil/probenecid tablet twice daily and one over-encapsulated placebo 
ciprofloxacin capsule twice daily to complete 7-10 total days of treatment. Patients with a 
baseline pathogen non-susceptible to ciprofloxacin but susceptible to amoxicillin-
clavulanate, and who meet criteria for oral step-down will take one sulopenem 
etzadroxil/probenecid tablet twice daily  and one over-encapsulated placebo amoxicillin-
clavulanate capsule twice daily to complete 7-10 total days of treatment. Patients with a 
baseline pathogen non-susceptible to ciprofloxacin and amoxicillin-clavulanate will receive a 
30 minute IV infusion of saline daily to match the comparator infusion and take one 
sulopenem etzadroxil/probenecid tablet twice daily to keep the blinding intact. The duration 
of treatment may be extended up to a total duration of 14 days for patients with bacteremia at 
baseline, although recent literature suggests that dosing beyond 10 days has been shown to 
have no additional value, especially in urinary tract infection [Chotiprasitsakul 2018; 
Canzoneri 2017]. 
Patients with severe renal impairment (CrCl <30mL/min): Patients with severe renal 
impairment randomized to the sulopenem treatment group will receive 250 mg sulopenem IV 
infused over 3 hours once daily for 5 days. For blinding purposes sulopenem will be co-
administered with a 30-minute infusion of saline solution to simulate the comparator. 
After at least 5 days of intravenous therapy those patients with a baseline pathogen 
susceptible to ciprofloxacin and who meet criteria for oral step-down will take one 
sulopenem etzadroxil/probenecid tablet twice daily and one over-encapsulated placebo 

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ciprofloxacin capsule approximately every 18 hours to complete 7-10 total days of treatment. 
Patients with a baseline pathogen non-susceptible to ciprofloxacin, and who meet criteria for 
oral step-down will receive a 30 minute IV infusion of saline daily to match the comparator 
infusion and will take one sulopenem etzadroxil/probenecid tablet twice daily to keep the 
blinding intact and complete 7-10 total days of treatment. . The duration of treatment may be 
extended up to a total duration of 14 days for patients with bacteremia at baseline, although 
recent literature suggests that dosing beyond 10 days has been shown to have no additional 
value, especially in urinary tract infection [Chotiprasitsakul 2018; Canzoneri 2017]. 
Comparator arm:  
Patients with normal renal function: Patients with normal renal function randomized to the 
comparator treatment group will receive 1000 mg of IV ertapenem infused over 30 minutes, 
once daily for 5 days. For blinding purposes comparator will be co-administered with a 3 
hour infusion of saline solution to simulate sulopenem IV. 
After at least 5 days of intravenous therapy those patients with a baseline pathogen that is 
susceptible to ciprofloxacin who meet criteria for oral step-down will take one placebo 
sulopenem etzadroxil/probenecid tablet twice daily and take one over-encapsulated 
ciprofloxacin capsule twice daily to complete 7-10 total days of treatment. Patients with a 
baseline pathogen non-susceptible to ciprofloxacin, but susceptible to amoxicillin-
clavulanate, and who meet criteria for oral step-down will take one placebo sulopenem 
etzadroxil/probenecid tablet twice daily and take one over-encapsulated amoxicillin-
clavulanate capsule twice daily to complete 7-10 total days of treatment.  
Patients with a baseline pathogen non-susceptible to ciprofloxacin and amoxicillin-
clavulanate will receive a 30 minute IV infusion of ertapenem daily and take one placebo 
sulopenem etzadroxil/probenecid tablet twice daily to keep the blinding intact; patients will 
not receive the placebo/active ciprofloxacin/amoxicillin-clavulanate.  
The duration of treatment may be extended up to a total duration of 14 days for patients with 
bacteremia at baseline, although recent literature suggests that dosing beyond 10 days has 
been shown to have no additional value, especially in urinary tract infection [Chotiprasitsakul 
2018; Canzoneri 2017]. 
Patients with severe renal impairment (CrCl <30mL/min): Patients with severe renal 
impairment randomized to the comparator treatment group will receive 500 mg of IV 
ertapenem infused over 30 minutes, once daily for 5 days. For blinding purposes comparator 
will be co-administered with a 3 hour infusion of saline solution to simulate sulopenem IV. 
After at least 5 days of intravenous therapy those patients with a baseline pathogen that is 
susceptible to ciprofloxacin who meet criteria for oral step-down will take one placebo 
sulopenem etzadroxil/probenecid tablet twice daily and take one over-encapsulated 
ciprofloxacin capsule approximately every 18 hours to complete 7-10 total days of treatment. 
Patients with a baseline pathogen non-susceptible to ciprofloxacin will need to remain on IV 
ertapenem 500 mg infused over 30 minutes once daily and take one placebo sulopenem 
etzadroxil/probenecid tablet twice daily to keep the blinding intact and complete 7-10 total 
days of treatment. . 
The duration of treatment may be extended up to a total duration of 14 days for patients with 
bacteremia at baseline, although recent literature suggests that dosing beyond 10 days has 

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been shown to have no additional value, especially in urinary tract infection [Chotiprasitsakul 
2018; Canzoneri 2017]. 
Study drug administration will be documented in accordance with the Pharmacy Manual.  
The site pharmacist will be unblinded in order to prepare the IV study medications and select 
the appropriate oral follow on therapy for patients randomized to the ertapenem regimen.  
Both Treatment Groups:  
In both treatment groups, patients found to have pathogens isolated from blood cultures that 
are resistant to carbapenems including ertapenem should be discontinued from study drug 
therapy, but should remain in the study and treated appropriately. Patients found to have 
pathogens isolated from urine cultures that are resistant to carbapenems including ertapenem, 
may be allowed to continue on study drug therapy based on clinical response and investigator 
judgement, and are not required to receive alternative antibiotic therapy. 
Dosing with food:  
Food significantly increases bioavailability of sulopenem and consequently results in 
decreased rates of diarrhea. Therefore, dosing of oral sulopenem-etzadroxil with food 
whenever possible is recommended.  Since adequate target attainment appears to be achieved 
in the fasted state, an inability to administer the dose with food should not preclude dosing. 
Dosing with food does not affect the overall absorption of ciprofloxacin and has a minimal 
effect on the pharmacokinetics of amoxicillin-clavulanate. 
5.2.4 Compliance 
All patients should be informed that compliance with taking all medication as instructed is 
imperative. Intravenous treatment will be administered under the supervision of investigative 
site personnel at a hospital or, for centers approved by the Sponsor to do so, in an outpatient 
infusion center, and infusion date, start and stop time will be documented on the CRF. 
Patients discharged on oral medication will be asked to bring all study medication bottles and 
blister packs (used and unused) to the next scheduled study visit for drug accountability. 
Patients will be asked to record oral dosing on a dosing record and bring it to the site at each 
visit. The total amount of oral dosing completed (determined by tablet count from returned 
bottles and blister packs) will be recorded on the CRF. Investigator site personnel will 
provide daily reminders to the study patients to ensure compliance in taking their daily study 
medication. 
5.3 
Drug Storage and Drug Accountability  
The investigator, or an approved representative, e.g., pharmacist/designee, will ensure that all 
investigational products are stored in a secured area, under recommended storage conditions, 
and in accordance with applicable regulatory requirements. To ensure adequate records, all 
study drugs will be accounted for by using site standard accountability form or forms 
provided by Iterum Therapeutics. In either case, the forms must identify the investigational 
product, including batch or code numbers, and account for its disposition on a patient-by-
patient basis, including specific dates and quantities. 

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At the end of the study, Iterum Therapeutics will provide instructions as to disposition of any 
unused investigational product including sulopenem, sulopenem etzadroxil, ertapenem, 
ciprofloxacin, amoxicillin-clavulanate, and probenecid.  If Iterum Therapeutics authorizes 
destruction at the study site, the investigator must ensure that the materials are destroyed in 
compliance with applicable environmental regulations, institutional policy, and any special 
instructions provided by Iterum Therapeutics.  Destruction must be adequately documented. 
 
5.4 
Concomitant Medication(s), Adjunctive Therapy and Non-drug 
Therapy 
5.4.1 
Concomitant Medications 
Any medication taken by the patient, other than study drug, is considered concomitant 
medication.  All concomitant medications from Screening (Day -1) through the Final Visit 
must be recorded in the patient's source record and on the CRFs. 
At each visit, the investigator/site designee will obtain information on any therapeutic 
interventions (e.g., drug and non-drug therapy, surgery, etc.) provided.  The use of any other 
investigational drug is prohibited and patients may not participate in any other studies 
involving marketed products concomitantly while in this study.  
The use of other (non-antibacterial) medications should be limited to those essential for the 
care of the patient.  All medications required by the patient to manage underlying illnesses, 
other than infection under study, and any drugs that may be required for emergency 
treatments must be recorded on the CRF.  
The bioavailability of ciprofloxacin is significantly reduced when co-administered with 
magnesium or aluminum containing antacids. As a result, co-administration of these antacids 
with study drug is not permitted.   
Dosing with food does not affect the overall absorption of ciprofloxacin and has a minimal 
effect on the pharmacokinetics of amoxicillin-clavulanate. 
5.4.2 
Concomitant Antibacterial Medications 
Concomitant systemic antibacterials are prohibited during the study, up to the Day 21 (± 
1day; TOC) visit, with the following exceptions: 
• 
Vancomycin oral 125 mg or 250 mg every 6 hours may be used in both treatment groups 
for the treatment of Clostridium difficile infections and may be continued as required 
throughout the duration of the study.  The Sponsor will not provide oral vancomycin. 
• 
Metronidazole IV or oral 500 mg every 8 hours may be used in both treatment groups for 
the treatment of Clostridium difficile infections and may be continued as required throughout 
the duration of the study.  The Sponsor will not provide metronidazole.  
• 
Patients with a co-infection with a gram-positive uropathogen resistant to study drugs are 
allowed to receive agents with narrow spectrum gram-positive coverage (ie, such as 
linezolid, daptomycin or vancomycin). The Sponsor will not provide any of these drugs. 

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5.4.3 
Adjunctive Antibacterial Therapy 
None allowed 
5.4.4 
Non-drug Adjunctive Therapy 
None allowed 
6 
STUDY PROCEDURES 
6.1 
Screening (Day -1) - Within 24 Hours Prior to First Dose 
The investigator (or an appropriate delegate at the investigator site) will obtain written 
informed consent from each patient prior to the initiation of any study related activities. Sites 
participating in the population PK sub-study should offer the PK sampling sub-study and 
obtain written consent from willing patients. PK sampling procedures are detailed in 
Appendix 4. 
The following procedures will be performed prior to randomization and study drug 
administration: 
• Demographics and medical history. 
• Targeted physical examination (including general appearance, assessment of mental 
status (alert and oriented x 3, or not), examination of heart, lungs, abdomen, and 
extremities) 
• Vital signs (temperature, blood pressure, pulse rate, respiratory rate) and height and 
weight 
• Blood for laboratory testing (including hematology and chemistry studies as well as 
urine or serum (βhCG) pregnancy test (women of child-bearing potential, including 
peri-menopausal women until FSH value is known); serum follicle stimulating hormone 
[FSH] for postmenopausal females <50 years of age or those ≥50 years of age who have 
been post- menopausal for <2 years.  
• Banked serum and urine for retrospective safety and efficacy assessments 
• Collect urine for urinalysis, urine gram stain, culture and susceptibility testing 
• Peripheral blood cultures from two separate sites 
• Review previous (defined as within the prior 30 days) drug and non-drug treatments 
• Administer and collect patient assessment questionnaire from patient  
• Adverse events occurring after signing of ICF 
• To prepare for trial participation, patients will be instructed on the use of Life Style 
Guidelines and Concomitant Medications. 
6.1.1 
Treatment Period  
For the study period described below, where multiple procedures are scheduled at the same 
time point(s) relative to dosing, the following chronology of events should be adhered to, 
where possible. 
• Blood pressure/pulse rate: obtain prior to blood specimen collection. 

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• Pharmacokinetic blood specimens: obtain at scheduled time. 
6.1.2 
Day 1 
The following activities will be completed: 
• Review concomitant medications 
• Administer the study medication as described in the Study Treatment Section 
(Administration Section) 
• Collect blood samples for PK analyses for patients in the PK sub-study (see Appendix 
4)  
• Assess symptoms by spontaneous reporting of adverse events and by asking the subjects 
to respond to a non-leading question such as “How do you feel? 
6.1.3 
Day 5 
• Targeted physical examination, if required, based on patient’s symptoms 
• Vital signs (temperature, blood pressure, pulse rate, respiratory rate) 
• Blood for laboratory testing (including hematology and chemistry studies) 
• Collect urine for urinalysis, urine culture and susceptibility testing 
• Administer the study medication as described in the Study Treatment Section 
(Administration Section) 
• Collect blood and urine samples for PK analyses for patients in the PK sub-study (see 
Appendix 4) on the day of switch to oral therapy, on or after Day 6 
• Review concomitant medications 
• Assess symptoms by spontaneous reporting of adverse events and by asking the subjects 
to respond to a non-leading question such as “How do you feel? 
• Administer and collect patient assessment questionnaire from patient  
• Investigator Assessment of Clinical Outcome (Section 7.2.4) 
6.1.4 
Day 10 (± 1 day)  
• Targeted physical examination, if required, based on patient’s symptoms 
• Vital signs (temperature, blood pressure, pulse rate, respiratory rate) 
• Blood for laboratory testing (including hematology and chemistry studies) 
• Banked serum and urine for retrospective safety and efficacy assessments 
• Collect urine for urinalysis, urine culture and susceptibility testing 
• Review concomitant medications 
• Check and document compliance with oral study medication 
• Assess symptoms by spontaneous reporting of adverse events and by asking the subjects 
to respond to a non-leading question such as “How do you feel? 
• Administer and collect patient assessment questionnaire from patient  
• Investigator Assessment of Clinical Outcome (Section 7.2.4) 

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Of note, for patients with bacteremia identified at Baseline, and with the total duration of 
therapy extended up to 14 days, this visit could occur on any day from Day 11 to Day 14 (±1 
day), to correspond with EOT.   
6.2 
Follow-up Period  
6.2.1 Day 21 (± 1 day) – (Test of Cure) 
• Targeted physical examination, if required, based on patient’s symptoms 
• Vital signs (temperature, blood pressure, pulse rate, respiratory rate) 
• Blood for laboratory testing (including hematology and chemistry studies), if needed, to 
follow up on abnormal laboratory results from Day 10 (± 1 day; or Day 11-14 (± 1 day) 
for patients with bacteremia at Baseline). 
• Collect urine for urinalysis, urine culture and susceptibility testing 
• Review concomitant medications 
• Assess symptoms by spontaneous reporting of adverse events and by asking the subjects 
to respond to a non-leading question such as “How do you feel? 
• Administer and collect patient assessment questionnaire from patient  
• Investigator Assessment of Clinical Outcome (Section 7.2.4) 
6.2.2 Day 28 (± 3 days) – Final Visit (Phone call) 
• Review concomitant medications 
• Assess symptoms by spontaneous reporting of adverse events and by asking the subjects 
to respond to a non-leading question such as “How do you feel?” 
• If patient reports any recurrence of UTI symptoms, patients must return to provide a 
urine specimen for urinalysis, urine culture and susceptibility 
• Complete patient assessment questionnaire  
• Investigator Assessment of Clinical Outcome (Section 7.2.4) 
6.3 
Premature Discontinuation  
6.3.1 
 Premature Discontinuation from Study Drug Therapy 
• Targeted physical examination, if required, based on patient’s symptoms 
• Vital signs (temperature, blood pressure, pulse rate, respiratory rate) 
• Collect urine for urinalysis, urine culture and susceptibility testing 
• Review concomitant medications 
• Check and document compliance with oral study medication, if applicable 
• Assess symptoms by spontaneous reporting of adverse events and by asking the subjects 
to respond to a non-leading question such as “How do you feel? 
• Administer and collect patient assessment questionnaire from patient 
• Investigator Assessment of Clinical Outcome (Section 7.2.4) 

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6.3.2 
 Premature Discontinuation from Study 
• Targeted physical examination, if required, based on patient’s symptoms 
• Vital signs (temperature, blood pressure, pulse rate, respiratory rate) 
• Blood for laboratory testing (including hematology and chemistry studies) 
• Urine or serum (βhCG) pregnancy test (women of child-bearing potential, including 
peri- menopausal women until FSH value is known) 
• Collect urine for urinalysis, urine culture and susceptibility testing 
• Review concomitant medications 
• Assess symptoms by spontaneous reporting of adverse events and by asking the subjects 
to respond to a non-leading question such as “How do you feel? 
• Administer and collect patient assessment questionnaire from patient 
• Investigator Assessment of Clinical Outcome (Section 7.2.4) 
6.4 
Patient Withdrawal from Treatment or Study 
Patients may withdraw from the study or study drug at any time at their own request, or they 
may be withdrawn at any time at the discretion of the investigator or sponsor for safety, 
behavioral, or administrative reasons.  If a patient does not return for a scheduled visit, every 
effort should be made to contact the patient.  In any circumstance, every effort should be 
made to document patient outcome, if possible.  If the patient withdraws or is withdrawn 
from study drug treatment, the investigator should inquire about the reason for withdrawal, 
request the patient to return for all protocol-specified assessments, if possible, and follow-up 
with the patient regarding any unresolved AEs through Day 28 (+/- 3 days). 
For patients who withdraw from the study early, a Premature Discontinuation visit (Day 10 
[± 1 day] visit if still on study drug therapy) should be performed within 3 calendar days after 
decision to discontinue (Section 6.3) and no further visits are required. 
If the patient withdraws from the study, and also withdraws consent for disclosure of future 
information, no further study-specific evaluations should be performed, and no additional 
data should be collected, though ongoing laboratory assessment with specimens already 
collected will continue.  The sponsor may retain and continue to use any data collected 
before such withdrawal of consent. 
7 
ASSESSMENTS 
7.1 
Safety 
7.1.1 
Physical Examination 
A targeted physical examination will be performed at Baseline (including general 
appearance, assessment of mental status (alert and oriented x 3, or not), examination of heart, 
lungs, abdomen, and extremities). A targeted physical exam may be conducted at any visit to 
address patient’s symptoms if needed. 

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7.1.2 
Vital Signs (Blood Pressure, Respiration Rate, Temperature and 
Pulse Rate) 
Vital signs are performed at Baseline, Day 5, Day 10 (± 1 day; or Day 11-14 (± 1 day) for 
patients with bacteremia at Baseline), Day 21 (± 1 day; TOC), and premature discontinuation 
from study drug therapy or study. 
Blood pressure will be measured and recorded to the nearest mm Hg.  All blood pressure 
measurements should be taken at rest.  The same size blood pressure cuff will be used to 
measure blood pressure each time.  When the timing of these measurements coincides with a 
blood collection, blood pressure and pulse rate are to be obtained first.  Temperature will be 
measured as an oral, rectal, tympanic (ear) or temporal temperature.  
7.1.3 
Clinical Laboratory Assays 
The following laboratory parameters will be measured: 
• Hematology: Complete blood count (CBC), including white blood cell (WBC) and 
differential counts; at Baseline, Day 5, Day 10 (± 1 day; or Day 11-14 (± 1 day) for 
patients with bacteremia at Baseline), and premature discontinuation from study. 
• Serum Clinical Chemistry: AST, ALT, GGT, alkaline phosphatase, albumin, bilirubin, 
BUN or urea, creatinine, Na+, K+, Cl-, total CO2 (bicarbonate), glucose, and LDH at 
Baseline, Day 5, Day 10 (± 1 day; or Day 11-14 (± 1 day) for patients with bacteremia 
at Baseline), and premature discontinuation from study. 
• Urinalysis and urine culture at Baseline, Day 5, Day 10 (± 1 day; or Day 11-14 (± 1 day) 
for patients with bacteremia at Baseline), and Day 21 (± 1 day; TOC) and premature 
discontinuation from study drug therapy or study. 
• Urine gram stain at Baseline 
• Plasma sampling for PK analyses on Day 1; Plasma and urine sampling for PK analyses 
on the day of oral switch 
• Peripheral blood cultures at Baseline. If positive, blood cultures should be repeated 
immediately (no later than 24 hours after notification) until negative. 
• Pregnancy Test (women of child-bearing potential)/serum FSH (to confirm 
postmenopausal status for women <50 years of age or those ≥50 years of age who have 
been post-menopausal for <2 years): Urine or serum (βhCG) only at Baseline/Day 1; 
urine (βhCG) at premature discontinuation from study; FSH at Baseline only, as needed. 
Pregnancy test at Baseline should also be performed on peri-menopausal women until 
FSH value is available. 
• In addition, blood and urine samples at Baseline and Day 10 (± 1 day; or Day 11-14 (± 1 
day) for patients with bacteremia at Baseline) will be banked for retrospective safety and 
efficacy analyses (for example, measure hemoglobin A1c [HbA1c] to assess diabetic 
status) if needed. Banked urine specimens may be used to document compliance with 
study drug therapy is identified. 
 
 

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7.1.4 
Clinically Significant Laboratory Tests 
Clinical laboratory tests may be repeated during the study if deemed necessary as part of 
routine practice based on investigator judgment.  All clinically significant abnormal 
laboratory test results occurring during the study will be repeated at appropriate intervals 
until they return either to baseline or to a level deemed acceptable by the investigator and the 
Iterum appointed medical monitor.   
7.2 
Efficacy 
7.2.1 
Overall Response 
A patient will be defined as a responder (programmatically, based on the data on the eCRF) 
at Day 5, Day 10 (± 1 day; or Day 11-14 (± 1 day) for patients with bacteremia at Baseline), 
and Day 21 (± 1day; TOC) if the following criteria are met: 
• The patient is alive 
• Resolution of dysuria, urinary frequency, urinary urgency, suprapubic pain, and 
flank pain or pelvic pain if present at trial entry and no new symptoms per the 
patient’s questionnaire 
- 
Baseline symptoms associated with anatomic abnormalities that predispose to 
cUTI (e.g., symptoms associated with the presence of an indwelling urinary 
catheter) do not need to be resolved. 
• The patient has received no rescue therapy for cUTI 
- 
If an antibiotic is given for other reasons then the patient will not be considered 
a non-responder for cUTI 
• The bacterial pathogen found at trial entry is reduced to <103 CFU/mL on urine 
culture taken at the specified study visit 
All other patients will be considered non-responders unless data are unavailable to determine 
if the patient is a responder or non-responder. In this case, the patient will be considered as 
having an indeterminate response. Deaths not due to cUTI will also be considered 
indeterminate. Patients with an indeterminate response are included in the denominator for 
determination of the response rate in the ITT populations. 
7.2.2 
Microbiologic Response 
Microbiologic Response is assessed at Day 5, Day 10 (± 1 day; or Day 11-14 (± 1 day) for 
patients with bacteremia at Baseline), and Day 21 (± 1day; TOC) using the definitions listed 
below: 

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Microbiological 
response 
Definition 
Eradication 
A urine culture taken within 48 hours prior to randomization 
(baseline) and compared with the culture from the Day 5 visit, 
Day 10 (± 1 day; or Day 11-14 (± 1 day) for patients with 
bacteremia at Baseline) visit, or Day 21 (± 1day; TOC) visit 
showed that the urine culture obtained at the relevant visit 
demonstrated <103 CFU/mL of the original uropathogen. For 
patients with bacteremia at Baseline, the follow-up repeat blood 
cultures are sterile. 
Persistence  
A uropathogen present at baseline grew at ≥103 CFU/mL at the 
time-point of analysis, i.e. Day 5, Day 10 (± 1 day; or Day 11-14 
(± 1 day) for patients with bacteremia at Baseline), or Day 21 (± 
1day; TOC). For patients with bacteremia at Baseline, follow-up 
blood cultures after 72 hours of treatment show growth of 
baseline pathogen.  
Persistence with 
increasing MIC  
A urine culture taken after at least 2 full days of treatment grew 
≥103 CFU/mL of the original uropathogen species and displayed 
≥4-fold higher MIC to study drug therapy after treatment with 
study therapy at Day 5, Day 10 (± 1 day; or Day 11-14 (± 1 day) 
for patients with bacteremia at Baseline), or Day 21 (± 1day; 
TOC) respectively. For patients with bacteremia at Baseline, 
follow-up blood cultures after 72 hours of treatment show growth 
of baseline pathogen and displayed ≥4-fold higher MIC to study 
drug therapy. 
Indeterminate 
Patient was lost to follow-up or an assessment was not 
undertaken such that no urine culture was obtained; culture is 
contaminated or culture results could not be interpreted for any 
reason, at either the Day 5, Day 10 (± 1 day; or Day 11-14 (± 1 
day) for patients with bacteremia at Baseline), or the Day 21 (± 
1day; TOC) visit 
 
7.2.3 
Patient-Determined Clinical Response 
A patient will be defined as a clinical success (programmatically, based on the data on the 
eCRF) at Day 5, Day 10 (± 1 day; or Day 11-14 (± 1 day) for patients with bacteremia at 
Baseline), and Day 21 (± 1day; TOC) if the following criteria are met: 
• The patient is alive 
• Resolution of dysuria, urinary frequency, urinary urgency, suprapubic pain, and 
flank pain or pelvic pain if present at trial entry and no new symptoms  

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- 
Baseline symptoms associated with anatomic abnormalities that predispose to 
cUTI (e.g., symptoms associated with the presence of an indwelling urinary 
catheter) do not need to be resolved. 
• The patient has received no rescue therapy for cUTI 
- 
If an antibiotic is given for other reasons then the patient will not be considered 
a non-responder for cUTI 
If data are unavailable to determine if the patient is a cure or a failure the outcome will be 
considered indeterminate. Deaths not due to cUTI will also be considered indeterminate. 
Patients with an indeterminate response are included in the denominator for determination of 
the response rate in the ITT populations. 
7.2.4 
Investigator Assessment of Clinical Outcome 
Investigators will use the definitions below to document clinical response irrespective of 
microbiologic findings at Day 5, Day 10 (± 1 day; or Day 11-14 (± 1 day) for patients with 
bacteremia at Baseline), Day 21 (± 1day; TOC), FV, and premature discontinuation from 
study drug therapy or study: 
Clinical response 
Definition 
Clinical cure 
All pre-therapy signs and symptoms of the index infection had resolved such 
that no additional antibiotics were required 
Clinical failure 
Patients who met any one of the criteria below were considered as failure: 
Death related to cUTI prior to Day 5, Day 10 (± 1 day;(or Day 11-14 (± 1 day) 
for patients with bacteremia at Baseline), Day 21 (± 1day; TOC), or FV, 
respectively 
Persistence or progression of any pre-therapy cUTI signs and symptoms or 
use of additional antibiotics for the current infection 
Patient previously met criteria for failure and received rescue antibiotics  
Indeterminate 
Data not available for evaluation of efficacy for any reason, including but not 
limited to: 
Patient lost to follow-up or assessment not undertaken such that a 
determination of clinical response could not be made at either the Day 5, Day 
10 (± 1 day; or Day 11-14 (± 1 day) for patients with bacteremia at Baseline), 
Day 21 (± 1day; TOC), or FV visit 
Death prior to Day 5, Day 10 (± 1 day; or Day 11-14 (± 1 day) for patients with 
bacteremia at Baseline)),Day 21 (± 1day; TOC), or FV assessments, 
respectively, where cUTI was clearly noncontributory 
7.2.5 
Patient Symptom Assessment Questionnaire (PSAQ) 
Patients will score their UTI symptoms and record them on a Patient Symptom Assessment 
Questionnaire. 

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8 
ADVERSE EVENT REPORTING 
8.1 
Adverse Events 
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections.  
For all AEs, the investigator must pursue and obtain adequate information both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as a 
serious AE (SAE) requiring immediate notification to Iterum Therapeutics designated 
pharmacovigilance provider.  For all AEs, sufficient information should be obtained by the 
investigator to determine the causality of the AE.  The investigator is required to assess 
causality.  All AEs will be followed up by the investigator until the event or its sequel resolve 
or stabilize at a level acceptable to the investigator, and Iterum concurs with that assessment. 
8.2 
Reporting Period 
Adverse events will be collected from the time that the patient provides informed consent 
through Final Visit.  
For SAEs, the reporting period to Iterum Therapeutics begins from the time that the patient 
provides informed consent, which is obtained prior to the patient’s participation in the study, 
i.e., prior to undergoing any study-related procedure and/or receiving investigational product, 
through the Final Visit.  Any SAE occurring any time after the reporting period must be 
promptly reported if a causal relationship to investigational product is suspected.  
All AEs should be recorded on the CRF if they occur from the time the patient provides 
informed consent through Final Visit. 
8.3 
Definition of an AE 
An AE is any untoward medical occurrence in a clinical investigation patient administered a 
product or medical device, unless the event is captured in the study endpoint, as defined 
below; the event need not necessarily have a causal relationship with the treatment or usage.   
An event would be considered as adequately captured in the study endpoint if it is accurately 
and fully represented by a protocol-defined reason for clinical failure (other than mortality) 
or relapse.  Such an event should not be reported as an adverse event unless it is a serious 
adverse event as defined in this protocol.   
Events represented by the study endpoints, which would not be considered AEs, include all 
of the following: 
• Symptoms of cUTI have not resolved from Baseline to such an extent that new 
antibiotics are not needed for the infection under study 
• Development of new cUTI symptoms not present at Baseline 
• Follow up urine cultures do not reveal eradication of causative uropathogen  

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Except for circumstances as defined above, examples of AEs include but are not limited to:   
• Abnormal test findings (see Section 8.4); 
• Clinically significant symptoms and signs; 
• Changes in physical examination findings; 
• Hypersensitivity to study drugs; 
• Progression/worsening of underlying disease.  
Additionally, they may include the signs or symptoms resulting from: 
• Drug overdose; 
• Drug withdrawal; 
• Drug abuse; 
• Drug misuse;  
• Drug interactions; 
• Drug dependency; 
• Extravasation of study drug; 
• Exposure during Pregnancy. 
8.4 
Abnormal Test Findings 
An abnormal objective test finding (e.g., an abnormal liver function test result) should be 
reported as an AE only if the following conditions apply:  
• Test result is associated with accompanying symptoms and/or signs, constituting a 
clinical syndrome (e.g., abnormal liver function test results, jaundice, and hepatic 
tenderness suggesting a diagnosis of hepatitis), and/or 
• Test result requires medical/surgical intervention, and/or 
• Test result leads to a change in study dosing or withdrawal from the study, significant 
additional concomitant drug treatment, or other therapy. 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
define the abnormal objective test finding as an AE.  Any abnormal test result that is 
determined to be an error does not require reporting as an AE.  Additional diagnostic testing 
and /or medical/surgical interventions that occur as a result of an adverse event due to an 
abnormal lab test finding should be noted in the CRF.  
8.5 
Serious Adverse Events (SAE) 
An SAE or serious adverse drug reaction is any untoward medical occurrence at any dose 
that: 
• Results in death; 
• Is life-threatening (immediate risk of death); 

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• Requires inpatient hospitalization or prolongation of existing hospitalization; 
• Results in persistent or significant disability/incapacity; 
• Results in congenital anomaly/birth defect; 
• Is assessed as being a medically important event based on medical and scientific 
judgment.  Such medically important events may not be immediately life-threatening or 
result in death or hospitalization, but may jeopardize the patient and may require medical 
or surgical intervention to prevent one of the above outcomes.  Examples of such events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or 
the development of drug dependency or drug abuse. 
8.6 
Hospitalization 
Adverse events associated with hospitalization or prolongations of hospitalization are 
considered serious.  Admission also includes transfer within the hospital to an acute/intensive 
care unit (e.g., from the psychiatric wing to a medical floor, medical floor to a coronary care 
unit, neurological floor to a tuberculosis unit). 
Hospitalization does not include the following: 
• Rehabilitation facilities; 
• Hospice facilities; 
• Respite care (e.g., caregiver relief); 
• Skilled nursing facilities; 
• Nursing homes; 
• Routine emergency room evaluation; 
• Same day surgeries (as outpatient/same day/ambulatory procedures). 
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include:  
• Admission for treatment of a pre-existing condition not associated with the development 
of a new AE or with a worsening of the pre-existing condition (e.g., for work-up of 
persistent pre-treatment laboratory abnormality); 
• Social admission (e.g., patient has no place to sleep); 
• Administrative admission (e.g., for yearly physical exam); 
• Protocol-specified admission during a study (e.g., for a procedure required by the study 
protocol); 
• Optional admission not associated with a precipitating clinical AE (e.g., for elective 
cosmetic surgery).  Pre-planned treatments or surgical procedures should be noted in the 
baseline documentation for the entire protocol and/or for the individual patient; 
• Admission exclusively for the administration of blood products. 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as an AE.  However, the medical condition for which the procedure was 

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performed should be reported if it meets the definition of an AE.  For example, an acute 
appendicitis that begins during the AE reporting period should be reported as the AE and the 
resulting appendectomy should be recorded as treatment of the AE. 
8.7 
Severity Assessment 
The investigator will use the adjectives MILD, MODERATE, or SEVERE to describe the 
maximum intensity of the AE.  For purposes of consistency, these intensity grades are 
defined as follows: 
• MILD:  Does not interfere with the patient's usual function. 
• MODERATE:  Interferes to some extent with the patient's usual function. 
• SEVERE:  Interferes significantly with the patient's usual function.  
Note the distinction between the severity and the seriousness of an adverse event.  A severe 
event is not necessarily a serious event.  For example, a headache may be severe (interferes 
significantly with subject's usual function) but would not be classified as serious unless it met 
one of the criteria for serious adverse events, listed above. 
8.8 
Causality Assessment 
The investigator’s assessment of causality must be provided for all AEs (serious and non-
serious); the investigator must record the causal relationship in the CRF, as appropriate, and 
report such an assessment in accordance with the serious adverse reporting requirements if 
applicable.  An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an AE.  
If the investigator does not know whether or not investigational product caused the event, 
then the event will be handled as “related to investigational product” for reporting purposes, 
as defined by the Sponsor (See 8.12 on Reporting Requirements).  If the investigator's 
causality assessment is "unknown but not related to investigational product", this should be 
clearly documented on study records.  Specifically, the investigator will choose whether the 
AE is unrelated, unlikely related, possibly related or probably related to the investigational 
product. 
In addition, if the investigator determines an SAE is associated with study procedures, the 
investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable. 
The Investigator will assess causality of the event in relation to study drugs based on the 
following defined criteria:  
• UNRELATED: No relationship between the event and medicinal product 
• UNLIKELY: Event or laboratory test abnormality, with a time to drug intake that makes 
a relationship improbable (but not impossible); Disease or other drugs provide plausible 
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• POSSIBLY: Event or laboratory test abnormality, with reasonable time relationship to 
drug intake; Could also be explained by disease or other drugs; Information on drug 
withdrawal may be lacking or unclear 
• PROBABLY: Event or laboratory test abnormality, with reasonable time relationship to 
drug intake; Unlikely to be attributed to disease or other drugs; Response to withdrawal 
clinically reasonable; Rechallenge not required 
8.9 
Exposure during Pregnancy 
For investigational products and for marketed products, an exposure during pregnancy (also 
referred to as exposure in-utero [EIU]) occurs if: 
1. A female becomes, or is found to be, pregnant either while receiving or having been 
directly exposed to (e.g., environmental exposure) the investigational product, or the 
female becomes, or is found to be, pregnant after discontinuing and/or being directly 
exposed to the investigational product (maternal exposure); 
2. A male has been exposed, either due to treatment or environmental exposure, to the 
investigational product prior to or around the time of his partner’s conception and/or is 
exposed during his partner’s pregnancy (paternal exposure). 
If any study patient or study patient’s partner becomes or is found to be pregnant during the 
study patient’s treatment with the investigational product, no further study drugs should be 
given and the investigator must submit this information to Iterum Therapeutics on a 
Pregnancy Form.  In addition, the investigator must submit information regarding 
environmental exposure to sulopenem in a pregnant woman (e.g., a nurse reports that she is 
pregnant and has been exposed to sulopenem by spillage) using the Pregnancy Form.  This 
reporting must be done irrespective of whether an AE has occurred and within 24 hours of 
awareness of the pregnancy.  The information submitted should include the anticipated date 
of delivery (see below for information related to induced termination of pregnancy). 
Follow-up is conducted to obtain pregnancy outcome information on all Pregnancy reports 
with an unknown outcome.  The investigator will follow the pregnancy until completion or 
until pregnancy termination (i.e., induced abortion) and then notify Iterum of the outcome.  
The investigator will provide this information as a follow up to the initial Pregnancy Form.  
The reason(s) for an induced abortion should be specified.  A Pregnancy report is not created 
when an ectopic pregnancy report is received since this pregnancy is not usually viable.  
Rather, an SAE case is created with the event of ectopic pregnancy. 
If the outcome of the pregnancy meets the criteria for immediate classification as an SAE 
(i.e., spontaneous abortion, stillbirth, neonatal death, or congenital anomaly [including that in 
an aborted fetus, stillbirth or neonatal death]), the investigator should follow the procedures 
for reporting SAEs. 
In the case of a live birth, the “normality” of the newborn can be assessed at the time of birth 
(i.e., no minimum follow-up period of a presumably normal infant is required before a 
Pregnancy Form can be completed).  The “normality” of an aborted fetus can be assessed by 
gross visual inspection, unless pre-abortion test findings are suggestive of a congenital 
anomaly. 

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Additional information about pregnancy outcomes that are classified as SAEs follows:  
• “Spontaneous abortion” includes miscarriage and missed abortion. 
• All neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, any infant death after 1 month that the investigator 
assesses as possibly related to the exposure during pregnancy to the investigational 
medication should be reported. 
Additional information regarding the exposure during pregnancy may be requested by the 
investigator.  Further follow-up of birth outcomes will be handled on a case-by-case basis 
(e.g., follow-up on preterm infants to identify developmental delays).  In the case of paternal 
exposure, the investigator must obtain permission from the patient’s partner in order to 
conduct any follow-up or collect any information. 
8.10 Discontinuation from Study Drug Due to AEs (See also Patient 
Withdrawal, Section 6.4) 
Discontinuation from study drug due to an AE should be distinguished from discontinuation 
due to insufficient response, according to the definition of AE noted earlier, and recorded on 
the appropriate AE CRF page.   
When a patient discontinues study drug due to an SAE, the SAE must be reported in 
accordance with the reporting requirements defined below. 
8.11 Eliciting AE Information 
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study patient through the Final Visit.  In addition, each study patient will be questioned 
about the occurrence of any AEs. 
8.12 Reporting Requirements 
Each AE is to be assessed to determine if it meets the criteria for an SAE.  If an SAE occurs 
that is considered by the investigator or the Sponsor to be at least possibly related to study 
drug, expedited reporting will follow local and international regulations, as appropriate. 
8.12.1 
SAE Reporting Requirements 
If an SAE or exposure during pregnancy occurs, Iterum Therapeutics (PSI 
Pharmacovigilance) is to be notified within 24 hours of awareness of the event by the 
investigator on an SAE form or Pregnancy form.  If the SAE is fatal or life-threatening, 
notification to Iterum must be made immediately, irrespective of the extent of available event 
information.  This timeframe also applies to additional new information (follow-up) on 
previously forwarded SAE reports as well as to the initial and follow-up reporting of 
Pregnancy cases.   
In the rare instance that the investigator does not become aware of the occurrence of an SAE 
immediately (e.g., if an outpatient study patient initially seeks treatment elsewhere), the 

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investigator is to report the event within 24 hours after learning of it and document the time 
of his/her first awareness of the AE. 
For all SAEs and pregnancies, the investigator is obligated to pursue and provide information 
to Iterum in accordance with the timeframes for reporting specified above.  In addition, an 
investigator may be requested by Iterum Therapeutics to obtain specific additional follow-up 
information in an expedited fashion.  This information may be more detailed than that 
captured on the SAE form.  In general, this information may include hospital discharge 
summary, laboratory test and X-ray results.  Information on other possible causes of the 
event, such as concomitant medications and illnesses must be provided.  In the case of a 
patient death, a summary of available autopsy findings must be submitted as soon as possible 
to Iterum Therapeutics.  The information should be reported on an SAE/Pregnancy form and 
sent to the PSI Pharmacovigilance. 
8.12.2 
Non-SAE Reporting Requirements 
All AEs will be reported on the AE page(s) of the CRF.  Please note that while all AEs are 
reported on the AE page of the CRF, there is an additional form used for collection of SAE 
information, as described in Section 8.12.1, which is not the same as the AE CRF.  When the 
same data are collected, the two forms must be completed in a consistent manner.  For 
example, the same AE term should be used on both forms.  Adverse events should be 
reported using concise medical terminology on the CRFs as well as on the form for collection 
of SAE information.  The information on the AE CRF and the SAE form must be the same 
and will be reconciled at defined periods throughout the study to ensure that they do. 
8.12.3 
Sponsor Reporting Requirements to Regulatory Authorities 
Adverse event reporting, including reporting of suspected serious unexpected adverse 
reactions, will be carried out in accordance with applicable local regulations.  Death and life-
threatening Suspected, Unexpected Serious Adverse Reactions (SUSARs) are subject to 
expedited reporting within a 7 calendar day (life-threatening and fatal) or 15 calendar day (all 
other SUSARs) timeframe. 
9 
DATA ANALYSIS/STATISTICAL METHODS 
9.1 
Sample Size Determination 
The study is designed to determine whether IV sulopenem followed by sulopenem-etzadroxil 
co-administered with probenecid is NI to IV ertapenem followed by oral ciprofloxacin or 
amoxicillin-clavulanate for the outcome measure of overall response, defined as resolution of 
the symptoms of cUTI present at trial entry (and no new symptoms) such that no new 
antibiotics are required (clinical success), and the demonstration that the bacterial pathogen 
found at trial entry is reduced to <103 CFU/mL on urine culture (microbiological success). 
The proposed sample size for the ITT population is 1156 patients.  This ITT sample size 
estimate is based on the assumption that 80%, or 924 patients, of this ITT population will 
be m-MITT evaluable.  The sample size of the m-MITT population is 462 patients per arm 
based on a continuity-corrected Z-test with unpooled variance. This 924 m-MITT sample 
size assumes a non-inferiority margin of 10%, a power of 90%, a one-sided alpha level of 
0.025 and a 70% overall responder rate in both treatment groups.  

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The expected overall response rate is estimated from large randomized controlled trials in a 
similar cUTI patient population [Wagenlehner 2015, Wagenlehner 2016]. In those studies, 
the estimated response rate for the proposed primary efficacy outcome measure of overall 
response (combined clinical and microbiologic response) at TOC in the m-MITT 
population was 70%. The aggregate blinded response rate will be assessed when 
approximately 60% of the subjects have been randomized and have efficacy outcome data 
at TOC available. If the aggregate response rate at that point is <70%, or if the evaluability 
rate (proportion of ITT subjects included in the m-MITT population) is <80%, the sample 
size may be increased to maintain a power of 90%.  See Section 9.7. 
9.2 
Definition of Analysis Populations 
1. Intent-to-Treat (ITT): all randomized patients regardless of whether or not the 
patient received study drug 
2. Modified ITT (MITT): randomized patients who received at least a single-dose of 
study drug to which they were randomized 
3. Safety: randomized patients who received any amount of study drug 
4. Microbiologic-MITT (m-MITT): All MITT patients with a positive study entry 
urine culture defined as ≥105 CFU/mL of a uropathogen (Enterobacteriaceae only) 
and no more than 2 species of microorganisms identified in the study entry urine 
culture, regardless of colony count, except in the situation where one of the organisms 
cultured from the urine is also isolated from blood cultures drawn at baseline. 
5. Clinically evaluable: Clinically evaluable (CE) at the Day 5, Day 10 (± 1 day; or 
Day 11-14 (± 1 day) for patients with bacteremia at Baseline), and Day 21 (± 1day; 
TOC) visits population:  
All patients who were included in the MITT population and:  
a) Received a minimum number of days of study drug (to be defined in the 
Statistical Analysis Plan [SAP]) 
b) Had no important protocol deviations that would affect the assessment of 
efficacy (to be defined in the SAP) 
c) Had an outcome assessment of clinical cure or failure (and not indeterminate) 
at the Day 5, Day 10 (± 1 day; or Day 11-14 (± 1 day) for patients with 
bacteremia at Baseline), or Day 21 (± 1day; TOC) visits (and within the 
protocol allowed visit window), respectively.   
d) Receipt of effective antibacterial drug therapy for cUTI for a continuous 
duration of more than 24 hours during the previous 72 hours. Patients who 
have objective documentation of clinical progression of cUTI while on 
antibacterial drug therapy, or patients who received antibacterial drugs for 
surgical prophylaxis and then develop cUTI, may be appropriate for inclusion. 
e) Did not receive any non-study antibiotic therapy with potential activity against 
any of the baseline uropathogens collected at screening between the time of 
the baseline culture and the Day 5, Day 10 (± 1 day; or Day 11-14 (± 1 day) 
for patients with bacteremia at Baseline), or Day 21 (± 1day; TOC) culture, 
respectively.  This excludes the protocol defined study therapy and patients 

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who were considered clinical failures and required additional antibiotic 
therapy.  Patients with a coinfection with a gram-positive uropathogen 
resistant to study drugs are allowed to receive agents with narrow spectrum 
gram-positive coverage (ie, such as linezolid, daptomycin or vancomycin)  
6. Microbiologically evaluable (ME): all patients included in both the m-MITT and 
CE populations at the Day 5 visit (ME-Day5), Day 10 (± 1 day; or Day 11-14 (± 1 
day) for patients with bacteremia at Baseline)visit (ME- EOT) and at the Day 21 (± 
1day; TOC) visit (ME-TOC) and have an appropriately collected urine culture 
specimen and interpretable urine culture result at the Day 5, Day 10 (± 1 day; or Day 
11-14 (± 1 day) for patients with bacteremia at Baseline), and Day 21 (± 1day; TOC) 
visits, respectively.  
9.3 
General Statistical Considerations 
Descriptive statistics, including the numbers and percentages for categorical variables, and 
the numbers, means, standard deviations, medians, minimums, and maximums for 
continuous variables will be provided. All comparisons will be for the sulopenem treatment 
group and the comparator treatment group. Exploratory analyses may also be performed. 
Listings of individual patient’s data will be produced. A comprehensive SAP will be 
finalized prior to the interim analysis. 
9.4 
Patient Characteristics 
Enrollment, protocol deviations, discontinuations from the study drug and withdrawal from 
the study will be summarized by treatment group.  Demographics (age, race, sex), medical 
history, baseline assessment of the symptoms of cUTI, microbiological assessment of the 
urine and blood, and study drug administration (compliance with drug regimen and 
separately for IV and oral medication and total duration of study drug, duration of IV and 
oral medication) will also be summarized.  Differences between treatment groups will be 
analyzed using the chi-square or Fisher’s exact test for dichotomous variables and the 
Wilcoxon Rank Sum test for ordinal variables and continuous variables.  
9.5 
Efficacy Analysis 
For all efficacy analyses, patient data will be analyzed in the treatment group to which the 
patient was randomized.  Unless otherwise stated, patients who were randomized to the 
wrong infection type (pyelonephritis vs cUTI without pyelonephritis) stratum will be 
analyzed in the stratum to which they were randomized. 
9.5.1 
Analysis of Primary Outcome Measure 
The primary outcome is overall response at the Day 21 (± 1 day; TOC) visit in the m-MITT 
population. Patients will be programmatically categorized as a responder, non-responder, or 
indeterminate response. Patients with missing data or who are lost to follow-up are defined as 
indeterminate for the primary analysis and are included in the denominator for the calculation 
of overall response rate. Thus, patients with an indeterminate outcome are considered non-
responders for the primary analysis. The number and percentage of patients in each treatment 

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group in each response category will be reported. The null and alternative hypothesis are the 
following:  
H0: P1 − P2 ≤ -∆ 
H1: P1 – P2 > -∆ 
Where: 
P1 = the primary efficacy outcome in the sulopenem/sulopenem-etzadroxil group, 
P2 = the primary efficacy outcome in the ertapenem/oral ciprofloxacin or amoxicillin-
clavulanate group,  
∆ = the non-inferiority margin. 
The non-inferiority hypothesis test is a 1-sided hypothesis test performed at the 2.5% level of 
significance. This is based on the lower limit of the 2-sided 95% confidence interval (CI) for 
the observed difference in the overall success rate (sulopenem treatment group minus the 
ertapenem treatment group). The primary analysis is based on a CI computed using a 
continuity-corrected Z-statistic. If the lower limit of the 95% CI for the difference in the m-
MITT population is greater than - 10%, the null hypothesis will be rejected and the non-
inferiority of sulopenem/sulopenem-etzadroxil to ertapenem/oral ciprofloxacin or 
amoxicillin-clavulanate will be concluded.  
9.5.1.1 
Additional Analyses of the Primary Efficacy Outcome 
The primary efficacy outcome will be assessed within each baseline infection type 
(pyelonephritis vs cUTI without pyelonephritis) strata by treatment group. For each infection 
type stratum, a two-sided 95% CI for the observed difference in the overall response rates in 
the m-MITT population will be calculated. A sub-group analysis of the primary efficacy 
outcome in those patients with and without hypoalbuminemia (serum albumin <2.5 g/dL) at 
baseline will be conducted. Additional sub-group analyses, such as geographic region and the 
effect of food, may be conducted as exploratory analyses. 
Sensitivity analyses of the primary outcome will be conducted. An adjusted analysis (95% CI 
will be adjusted for the stratification factor of infection type using the stratified method of 
Miettinen and Nurminen) will be provided for the difference in the overall response rate 
between the two treatment groups. Cochran-Mantel-Haenszel weights will be used for the 
stratum weights in the calculation of the CI. Another sensitivity analysis of the primary 
endpoint at Day 21 (± 1day; TOC) will be conducted where patients in the comparator 
treatment group who have resistant baseline pathogens that preclude a step-down to an oral 
antibiotic regimen will be considered as failures. 
9.5.2 
Analysis of the Secondary Efficacy Outcome Measure 
The number and percentage of patients with a per-patient microbiologic response of 
eradication, persistence, persistence with increasing MIC, and indeterminate at the Day 21 (± 
1 day; TOC) visit will be determined in each treatment group in the m-MITT population. The 
observed difference in percentage of patients with a microbiologic eradication (sulopenem 
group minus the ertapenem group) will be determined and a 95% CI for the observed 
difference will be computed using a continuity corrected Z-statistic. 

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9.5.3 
Analysis of Additional Efficacy Outcome Measures 
The number and percentage of subjects in each treatment group with an overall response of 
responder, non-responder, and indeterminate (by definition subjects with an indeterminate 
response are excluded from the CE and ME populations) will be presented for the following 
time points and analysis populations: 
• 
Day 21 (± 1day; TOC) in the CE-TOC and ME-TOC populations 
• 
Day 10 (± 1 day; or Day 11-14 (± 1 day) for patients with bacteremia at Baseline) in the 
m-MITT, CE-EOT and ME-EOT populations 
• 
Day 5 in the m-MITT, CE-Day5 and ME-Day5 populations 
Two-sided 95% unstratified CIs will be constructed for the observed difference in the overall 
responder rates between the treatment groups for descriptive purposes; no conclusion of NI 
will be made. 
The number and percentage of subjects in each treatment group with a microbiologic 
response of eradication, persistence, persistence with increasing MIC, and indeterminate (by 
definition subjects with an indeterminate response are excluded from the ME populations) 
will be presented for the following time points and analysis populations: 
• 
Day 21 (± 1day; TOC) in the ME-TOC populations 
• 
Day 10 (± 1 day; or Day 11-14 (± 1 day) for patients with bacteremia at Baseline) in the 
m-MITT and ME-EOT populations 
• 
Day 5 in the m-MITT and ME-Day5 populations 
Two-sided 95% unstratified CIs will be constructed for the observed difference in the 
microbiologic eradication rates between the treatment groups for descriptive purposes.  
The number and percentage of subjects in each treatment group with a microbiologic 
response of complete eradication defined as no growth of baseline pathogen on a follow-up 
urine culture at Day 21 (± 1day; TOC) will also be presented for the m-MITT and ME-TOC 
populations. 
Investigator determined clinical response (clinical cure, failure and indeterminate) at the Day 
5, Day 10 (± 1 day; or Day 11-14 (± 1 day) for patients with bacteremia at Baseline), and 
Day 21 (± 1day; TOC) visits will be presented by treatment group for the m-MITT and CE 
populations.  Two-sided 95% unstratified CIs will be constructed for the observed difference 
in the clinical cure rates between the treatment groups for descriptive purposes. 
Overall response and microbiologic eradication at the Day 21 (± 1day; TOC) visit by 
baseline pathogen (key pathogens) will be summarized by treatment group in the m-MITT 
and ME-TOC populations.  
Sub-group analyses, such as infection type, geographic region and the effect of food, may be 
conducted for selected secondary efficacy outcomes as exploratory analyses. 
9.6 
Safety Analyses 
Safety will be assessed through summaries of AEs, clinical laboratory tests and vital signs.  
All safety analyses will be based on the Safety population.  Patients who receive the wrong 

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regimen of study drug for their entire course of treatment will be analyzed in the group based 
on the regimen received. 
Summary tables of treatment-emergent AEs (TEAEs) will be provided.  A TEAE is any AE 
that newly appeared, increased in frequency, or worsened in severity following initiation of 
study drug.  The incidence of TEAEs will be tabulated by system organ class and preferred 
term for each treatment group, and by severity and relationship to treatment.  Tables of 
TEAEs leading to study drug discontinuation, withdrawal from the study or an SAE will be 
provided.  AEs occurring prior to the first dose of study drug (AEs are recorded from the 
time of informed consent) will be provided in a listing. 
Descriptive statistics summarizing central laboratory data (hematology and chemistry) will 
be presented for all study visits.  The change from baseline to each post-baseline visit and to 
the overall worst post-baseline value will also be summarized by treatment group.  
Laboratory values will be classified as potentially clinically significant (PCS) and the number 
and percentage of patients with a PCS lab value will be summarized by visit and treatment 
group.  Descriptive statistics of the vital signs will be presented by treatment group and study 
visit, as well as the change from baseline at each study visit.   Vital signs will also be 
classified as PCS and number and percentage of patients with a PCS vital sign will be 
summarized. 
Sub-group analyses, such as the effect of food, may be conducted for selected safety 
outcomes as exploratory analyses. 
9.7 
Interim Analysis  
In order to ensure that the point estimate of overall response (combined clinical and 
microbiologic response) used in the estimation of sample size is valid for this study, an 
interim analysis for sample size re-estimation will be performed when response data at Day 
21 (± 1 day; TOC) are available for approximately 60% of the patients (692 patients).  The 
FDA Guidance “Non-inferiority Clinical Trials” [FDA Guidance 2010] notes that such a 
sample size re-estimation if based on the blinded overall response rates is not only 
acceptable but is advisable.  The interim analysis will involve a sample size re-estimation to 
either confirm the initial sample size estimate is adequate or increase the sample size 
(number of randomized patients) to ensure the study has adequate power for determining 
whether the sulopenem regimen is NI to the comparator treatment regimen for the primary 
outcome measure. In addition, the sample size may be increased based on a lower than 
expected evaluability rate. The sample size re-estimation will be based on the blinded 
overall (not by treatment group) outcome rate and evaluability rate and will be conducted 
by an independent, blinded statistician. A Data Monitoring Committee (DMC) will be 
provided the results of the interim analysis by the independent, blinded statistician and 
make a recommendation regarding changes to the sample size.  A detailed DMC charter 
will be developed which outlines the analyses to be completed, statistical rules, the potential 
changes to the sample size, and the recommendations that can be made to the Sponsor. 
9.8 
Handling of Missing Data 
Details of the handling of missing data will be provided in the SAP.  For the primary and 
secondary efficacy analyses, if any data field needed to determine overall response 

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(primary) and microbiological response (secondary) is missing at the Day 21 (± 1day; TOC) 
visit, the patient will be considered an indeterminate response. By definition, patients with 
an indeterminate response are included in the denominator in the m-MITT population and 
thus, are analyzed in the same manner as non-responders (primary) and persistence 
(secondary).   Additional sensitivity analyses for handling missing data will be detailed in 
the SAP. Imputation may be performed to understand the impact of any imbalance in 
indeterminate outcomes between treatment regimens. By definition, patients with missing 
data are excluded from the CE populations. 
10 QUALITY CONTROL AND QUALITY ASSURANCE 
During study conduct, Iterum or its agent will conduct periodic monitoring visits to ensure 
that the protocol and GCPs are being followed.  The monitors may review source documents 
to confirm that the data recorded on CRFs are accurate.  The investigator and institution will 
allow Iterum monitors or its agents and appropriate regulatory authorities direct access to 
source documents to perform this verification. 
The study site may be subject to review by the institutional review board (IRB)/independent 
ethics committee (IEC), and/or to quality assurance audits performed by Iterum, or 
companies working with or on behalf of Iterum, and/or to inspection by appropriate 
regulatory authorities. 
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process. 
11 DATA HANDLING AND RECORD KEEPING 
11.1 Case Report Forms / Electronic Data Record 
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study. 
A CRF is required and should be completed for each included patient.  The completed 
original CRFs are the sole property of Iterum and should not be made available in any form 
to third parties, except for authorized representatives of Iterum or appropriate regulatory 
authorities, without written permission from Iterum. 
The investigator has ultimate responsibility for the accuracy, authenticity, and timely 
collection and reporting of all clinical, safety, laboratory data entered on the CRFs and any 
other data collection forms.  The CRFs must be signed by the investigator or by an 
authorized staff member to attest that the data contained on the CRFs are true.  Any 
corrections to entries made in the CRFs and source documents must be dated, initialed and 
explained (if necessary) and should not obscure the original entry.  
In most cases, the source documents are the hospital's or the physician's patient chart.  In 
these cases, data collected on the CRFs must match the data in those charts.  
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigator’s site as well as at Iterum and 

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clearly identify those data that will be recorded in the CRF, and for which the CRF will stand 
as the source document. 
11.2 Record Retention 
To enable evaluations and/or audits from regulatory authorities or Iterum, the investigator 
agrees to keep records, including the identity of all participating patients (sufficient 
information to link records, e.g., CRFs and hospital records), all original signed informed 
consent forms, copies of all CRFs, SAE forms, source documents, and detailed records of 
treatment disposition, and adequate documentation of relevant correspondence (e.g., letters, 
meeting minutes, telephone call reports).  The records should be retained by the investigator 
according to ICH, local regulations, or as specified in the Clinical Study Agreement, 
whichever is longer. 
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (e.g., retirement, relocation), Iterum should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Iterum, such as another 
investigator, another institution, or to Iterum.  The investigator must obtain Iterum's written 
permission before disposing of any records, even if retention requirements have been met. 
12 ETHICS 
12.1 Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent forms, and other relevant documents, 
e.g., recruitment advertisements, if applicable, from the IRB/IEC.  All correspondence with 
the IRB/IEC should be retained in the Investigator File.  Copies of IRB/IEC approvals should 
be forwarded to Iterum. 
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the investigator must notify the IRB/IEC and Iterum in writing immediately after 
the implementation. 
12.2 Ethical Conduct of the Study 
The study will be conducted in accordance with the Declaration of Helsinki on Ethical 
Principles for Medical Research Involving Human Patients, adopted by the General 
Assembly of the World Medical Association (2013).  
In addition, the study will be conducted in accordance with the protocol, the International 
Conference on Harmonisation (ICH) guideline on Good Clinical Practice (GCP), and 
applicable local regulatory requirements and laws. 

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12.3 Patient Information and Consent 
All parties will ensure protection of patient personal data and will not include patient names 
on any sponsor forms, reports, publications, or in any other disclosures, except where 
required by laws.  In case of data transfer, Iterum will maintain high standards of 
confidentiality and protection of patient personal data. 
The informed consent form must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements. 
The informed consent form used in this study, and any changes made during the course of the 
study, must be prospectively approved by both the IRB/IEC and Iterum before use. 
The investigator must ensure that each study patient, or his/her legally acceptable 
representative, is fully informed about the nature and objectives of the study and possible 
risks associated with participation.  The investigator, or a person designated by the 
investigator, will obtain written informed consent from each patient or the patient's legally 
acceptable representative before any study-specific activity is performed.  The investigator 
will retain the original of each patient's signed consent form. 
12.4 Reporting of Safety Issues and Serious Breaches of the Protocol 
or ICH GCP 
In the event of any prohibition or restriction imposed (i.e., clinical hold) by an applicable 
Competent Authority in any area of the World, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the 
investigational product, Iterum should be informed immediately.   
In addition, the investigator will inform Iterum immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of. 
13 DEFINITION OF END OF STUDY 
13.1 End of Study in a Member State 
End of Trial in a Member State of the European Union is defined as the time at which it is 
deemed that sufficient patients have been recruited and have completed the study as stated 
in the regulatory application (i.e., Clinical Trial Application [CTA]) and ethics application 
in the Member State. Poor recruitment (recruiting less than the anticipated number in the 
CTA) by a Member State is not a reason for premature termination but is considered a 
normal conclusion to the study in that Member State. 
End of Study in all Participating Countries 
End of Study in all participating countries is defined as the last patient’s Final Visit. 

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14 SPONSOR STUDY TERMINATION CRITERIA 
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/IEC, drug safety problems, or at the discretion of Iterum.  In 
addition, Iterum retains the right to discontinue development of sulopenem at any time. 
If a study is prematurely terminated, Iterum will promptly notify the investigator and the 
investigator must also inform the IRB/IEC.  After notification, the investigator must contact 
all participating patients and the hospital pharmacy (if applicable) within 90 days.  
Investigator must also inform the IRB/IEC.  As directed by Iterum, all study materials must 
be collected and all CRFs completed to the greatest extent possible. 
15 PUBLICATION OF STUDY RESULTS 
Publication of study results is discussed in the Clinical Study Agreement. 
15.1 Communication of Results by Iterum 
Iterum fulfills its commitment to publicly disclose the results of studies through registration 
and posting of the results of this study on clinicaltrials.gov and EudraCT.   
15.2 Publications by Investigators 
Iterum has no objection to publication by the Investigator of any information collected or 
generated by the Investigator, whether or not the results are favorable to the Investigational 
Drug.  However, to ensure against inadvertent disclosure of Confidential Information or 
unprotected Inventions, the Investigator will provide Iterum an opportunity to review any 
proposed publication or other type of disclosure before it is submitted or otherwise disclosed. 
The Investigator will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc.) to Iterum 
at least 30 days before they are submitted for publication or otherwise disclosed.  If any 
patent action is required to protect intellectual property rights, the Investigator agrees to 
delay the disclosure for a period not to exceed an additional 60 days. 
The Investigator will, on request, remove any previously undisclosed Confidential 
Information (other than the study results themselves) before disclosure. 
If the study is part of a multi-center study, the Investigator agrees that the first publication is 
to be a joint publication covering all centers.  However, if a joint manuscript has not been 
submitted for publication within 12 months of completion or termination of the study at all 
participating sites, the Investigator is free to publish separately, subject to the other 
requirements of this section. 
For all publications relating to the study, the Institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors. 

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Publication of study results is also provided for in the Clinical Study Agreement between 
Iterum and the Institution.  In this section entitled Publications by Investigators, the defined 
terms shall have the meanings given to them in the Clinical Study Agreement. 
 

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16 REFERENCE LIST 
Canzoneri C, Akhavan B, Tosur Z, et al. Follow-up blood cultures in gram-negative 
bacteremia: are they needed? Clinical Infectious Diseases 2017; 65 (11):1776-9 
Chotiprasitsakul D, Han J, Cosgrove S, et al. Comparing the outcomes of adults with 
Enterobacteriaceae bacteremia receiving short-course versus prolonged-course antibiotic 
therapy in a multicenter, propensity score-matched cohort. Clinical Infectious Diseases 2018; 
66 (2):172-7 
Complicated Urinary Tract Infections: Developing Drugs for Treatment. Guidance for 
Industry. U.S. Department of Health and Human Services. Food and Drug Administration 
Center for Drug Evaluation and Research (CDER). February 2015. 
Committee for Medicinal Products for Human Use (CHMP). Guideline on the evaluation of 
medicinal products indicated for treatment of bacterial infections. 15 December 2011. 
CPMP/EWP/558/95 rev 2. 
Wagenlehner F, Sobel J, Newell P, et al. Ceftazidime-avibactam versus doripenem for the 
treatment of complicated urinary tract infections including acute pyelonephritis: 
RECAPTURE, a Phase 3 randomized trial program. Clinical Infectious Diseases 2016; 63 
(6):754-62 
Wagenlehner F, Umeh O, Steenbergen J, et al. Ceftolozane-tazobactam compared with 
levofloxacin in the treatment of complicated urinary-tract infections, including 
pyelonephritis: a randomized, double-blind, phase 3 trial (ASPECT-cUTI). Lancet 2015; 
385:1949-56. 
 

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APPENDIX 1  
SCHEDULE OF ACTIVITIES 
 
SCREENING 
TREATMENT PERIOD 
FOLLOW-UP PERIOD 
 
 
Protocol Activity 
D-1 to D1 
 
Baseline 
 D1 
 D5  
 
On Treatment 
D105 
(± 1 day) 
 D21 
(± 1 day) 
TOC 
 D286 
(± 3 days)  
FV (phone 
call) 
Premature 
Discontinuation 
Study 
Drug7 
Study 
Informed Consent 
X 
 
 
 
 
 
 
 
Medical History and 
Demographics 
X 
 
 
 
 
 
 
 
Targeted Physical 
Examination1 
X 
 
X1 
X1 
X1 
 
X1 
X1 
Vital Signs 
X 
 
X 
X 
X 
 
X 
X 
Hematology 
X 
 
X 
X 
X2 
 
 
X 
Serum Chemistry 
X 
 
X* 
X 
X2 
 
 
X 
Pregnancy testing 
X 
 
 
 
 
 
 
X 
Banked serum sample 
X 
 
 
X 
 
 
 
 
Banked urine sample 
X 
 
 
X 
 
 
 
 
Urinalysis 
X 
X 
X 
X 
 
X 
X 
Urine Gram stain 
X 
 
 
 
 
 
 
Urine Culture  
X 
 
X 
X 
X 
 
X 
X 
Peripheral Blood 
cultures3 
X 
 
 
 
 
 
 
 
Plasma and urine PK 
sampling for sulopenem4 
 
X4 
 
 
 
 
 
 
Previous Drug and Non-
drug Treatments 
X 
 
 
 
 
 
 
 
Concomitant 
Medications 
 
X 
X 
X 
X 
X 
X 
X 
Treatment  
 
X (each day for 7-10 days; may be 
extended to 14 days for patients 
with bacteremia at baseline) 
 
 
 
 
Compliance check with 
oral therapy  
 
 
 
X 
 
 
X 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
Patient Symptom 
Assessment 
Questionnaire 
X 
 
X 
X 
X 
X 
X 
X 
Investigator assessment 
of clinical response 
 
 
X 
X 
X 
X 
X 
X 
Schedule of Activities Footnotes: 
1 Post-baseline, to be done if needed, based on symptoms 
2     As needed to follow up on abnormal labs from Day 10 (± 1 day; or Day 11-14 (± 1 day) for patients with bacteremia at Baseline) 
3    Blood cultures should be drawn at Baseline (prior to study drug treatment) from 2 different anatomical sites and not through an existing 
intravascular line. If positive, blood cultures should be repeated immediately (no later than 24 hours after notification) until negative. 

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4     Refer to Appendix 4.  In the subset of patients enrolled in the PK sub-study, collect plasma for PK analysis 2 hours and 4 hours post-dose 
on Day 1; collect plasma for PK analysis 2 hours, 4 hours and 6 hours post-dose after first oral dose. Analysis to be performed only on 
samples collected from patients in the sulopenem treatment group. Patients will empty their bladder just prior to initiation of oral dosing 
on the day of the oral switch and a 1 ml aliquot from this urine will be frozen. 1 ml aliquots of urine from the following intervals after 
administration of the first dose of oral study drug after IV to oral switch: 0-2 hours, 2-4 hours, 4-6 hours, 6-8 hours, and 8-12 hours, may 
be collected and frozen for PKPD assessments. 
5     For patients with bacteremia at baseline whose duration of therapy is extended up to 14 days, the EOT visit should occur on Day 11-14 (± 
1 day) correlating with their EOT, instead of on Day 10. This visit should include collection of a urine specimen for urinalysis and urine 
culture, review of concomitant medications, compliance check with oral therapy, adverse events, PSAQ, and investigator assessment. 
6     Patients should return to provide a urine specimen for urinalysis, urine culture and susceptibility in case of relapse of urinary symptoms 
7   Visit to be completed within 3 days of discontinuation from study drug therapy 
*  If estimated CrCl is abnormal at Baseline, a repeat serum creatinine must be obtained at Day 5 in order to re-evaluate the CrCl and 
determine the appropriate oral or IV therapy. 
 
 
 

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APPENDIX 2  
MICROBIOLOGY 
Method of Collection of Urine Specimens: 
To obtain a clean catch sample of urine from a patient, a thorough cleansing of the 
periurethral area is essential before specimen collection. Clean the area with a disinfectant, 
and make all efforts to avoid any contact until urination is complete. Details of appropriate 
methodology for urine sample collection will be provided in the laboratory manual. 
All patients should void the first part of the specimen into the toilet, then collect the 
remainder of the specimen in a sterile container. Urine samples for routine culture must be 
transported in the urine transport tubes provided by the Sponsor. 
Urine samples should be collected by clean-catch midstream, from a newly-inserted Foley 
catheter (no bag specimens allowed), bladder needle aspiration, or ureter aspiration. 
Patients with indwelling urinary catheters: If a patient had an indwelling bladder catheter in 
place for >24 hours prior to screening, it needs to be removed or replaced prior to the 
collection of the screening urinalysis and urine culture, unless removal or replacement was 
considered unsafe or was contraindicated due to a recent procedure or urological condition. It 
is recommended that specimens be obtained by sampling through the catheter port using 
aseptic technique or, if a port is not present, puncturing the catheter tubing with a needle and 
syringe. In a symptomatic patient, this should be done immediately prior to initiating 
antimicrobial therapy. Culture specimens should not be obtained from the drainage bag. 
Culture and Susceptibility testing  
All gram-negative pathogens will be tested locally for antimicrobial susceptibility, as 
appropriate.  
The local laboratory should retain all isolates until the end of the study, if possible, or until 
confirmation of a viable organism is received from the central laboratory. Back-up cultures 
will be requested when the central laboratory does not receive a viable culture, or recovers an 
organism different from the one recorded by the local laboratory.  
Gram-staining of material from the site of infection  
One slide for Gram-stain is to be prepared from each specimen obtained from the urine at 
baseline. The slide is to be stained, read and retained by the local laboratory and sent to the 
central laboratory for rereading and confirmation if needed.  
Organisms considered as pathogens 
For the purpose of this study protocol, the following organisms will always be considered a 
pathogen when isolated from an acceptable culture specimen: 
• Monomicrobial or polymicrobial infections caused by: 
• Enterobacteriaceae 
• Enterococci  
• Pseudomonas aeruginosa 

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The micro-MITT population for this study will only include patients with UTIs caused by 
Enterobacteriaceae. 
• Even if the organism was isolated from an acceptable culture specimen, the following 
are never a pathogen: 
• Corynebacterium spp. 
• S. epidermidis 
• S. aureus 
• S. saprophyticus 
• Bacillus spp. 
• Diphtheroids 
• Micrococcus spp. 
• Lactobacillus spp. 
• Viridans Streptococci 
• Group B Streptococci 
• Gardenerella vaginalis 
• Neisseria gonorrhoeae 
• Yeasts 
All isolates not defined above will be assessed on a case-by-case basis via manual review by 
the Sponsor. If needed, patient clinical and microbiological information (e.g., Gram stain) 
will be used to assist in determining if the isolate is a pathogen. All organisms isolated from a 
blood culture will be reviewed by the Sponsor to determine if the organism is a pathogen. 
Based on the results of in vitro testing, animal studies, PK/PD modeling, surveillance 
programs and clinical trial data, a provisional breakpoint for susceptibility of sulopenem to 
Enterobacteriaceae, Streptococci and methicillin-susceptible Staphylococcus aureus is ≤ 0.5 
µg/mL. Disc diffusion interpretive criteria are available for sulopenem. A detailed 
description of the relevant microbiology data is available in the investigator brochure. 
 
 
 

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APPENDIX 3 
METHOD FOR DETERMINATION OF CREATININE 
CLEARANCE/RENAL DOSE ADJUSTMENT 
GUIDANCE 
Creatinine clearance should be determined by the method of Cockroft-Gault based on serum 
creatinine concentrations obtained at Baseline, using ideal body weight instead of actual 
weight. 
For females: 
GFR = [(140-age) * (Ideal body wt in kg) * 0.85] / (72 * Cr) 
For males: 
GFR = [(140-age) * (Ideal body wt in kg)] / (72 * Cr) 
Ideal body weight is calculated as: 
For females:  
If height (H) > 152.5 cm 
Ideal body weight = 45.4 + [(H-152.4) * 0.89] 
If H < 152.5 cm 
Ideal body weight = 45.4 – [(152.4 – H) * 0.89] 
For males: 
If H > 152.5 cm 
Ideal body weight = 50 + [(H-152.4) * 0.89]  
If H < 152.5 cm 
Ideal body weight = 50 – [(152.4 – H) * 0.89] 
In order to determine the need to adjust the dose and/or dosing interval of IV study therapy to 
be administered, the patient’s estimated CrCl should be calculated using the most recent 
serum creatinine value obtained at the local laboratory. If estimated CrCl is abnormal at 
Baseline, a repeat serum creatinine must be obtained at Day 5 in order to re-evaluate the CrCl 
and determine the appropriate oral or IV therapy. 
Dose adjustments for each of the study drugs based on estimated CrCl are outlined below. 
Study Drug 
CrCl ≥30 mL/min 
CrCl <30 mL/min 
Sulopenem IV 
1000 mg QD 
250 mg QD 
Ertapenem IV 
1000 mg QD 
500 mg QD 
Ciprofloxacin 
500 mg BID 
500 mg every 18 hours 
Amoxicillin-clavulanate 
875 mg BID 
- 

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APPENDIX 4  
POPULATION PK SUB-STUDY 
1 INTRODUCTION 
This study will be conducted within the context of an ongoing Phase 3 sulopenem clinical 
trial in order to generate confirmatory data for the population PK profile of both the IV 
and oral pro-drug regimens of sulopenem. 
1.1 Overall Study Design and Plan 
This protocol appendix describes the plan for collection, processing and analysis 
of population PK samples collected within Study IT001-302. 
At selected IT001-302 study sites, randomized patients will also be asked to provide 
plasma samples for population PK, according to the schedule noted below. Samples will 
be collected from subjects in both treatment arms. Urine samples will also be collected 
and analyzed (details to be provided in a study Laboratory Manual, if needed). The study 
will remain blinded, regardless of whether or not any individual patient chooses to 
participate in the population PK sampling. 
See Schedule of Events Table in Section 6. 
1.2 Rationale for Study Design and Control Group 
Population PK sample requires sampling from an adequate number of patients and must 
necessarily be done in the setting of a therapeutic clinical trial. The number of subjects and 
samples, and the sampling schedule has been determined using accepted population PK 
principles. A subset of the treatment population is needed for the study to meet its 
objectives; thus this study will be conducted at a subset of sites selected for their ability 
and willingness to collect and process the additional plasma and urine samples. 
2 STUDY PROCEDURES 
2.1 Study Population 
Patients at selected investigational sites who meet the inclusion criteria and none of 
the exclusion criteria for study IT001-302 will be eligible for participation in this 
study. 
This study can fulfill its objectives only if appropriate patients are enrolled. All relevant 
medical and non-medical conditions should be taken into consideration when deciding 
whether a particular patient is suitable for enrollment in this sub-study. 
2.2 Inclusion Criteria 
Each patient must meet the following criteria to be enrolled in this study. 
• Patient is randomized into study IT001-302 

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• Patient has given informed consent to participate in the population PK sampling 
2.3 Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from the study. 
• Patients who are not participating in clinical study IT001-302 
• Patients in study IT001-302 who have not received study treatment 
2.4 Pharmacokinetic Assessments 
A blood sample will be collected at the following time points: 
• Two hours (+/- 30 minutes) after end of Day 1 infusion 
• Four hours (+/- 2 hours) after end of Day 1 infusion 
• Two hours (+/- 1 hour) after end of administration of first dose of oral study drug after 
IV to oral switch 
• Four hours (+/- 2 hours) after end of administration of first dose of oral study drug after 
IV to oral switch 
• Six hours (+/- 2 hours) after end of administration of first dose of oral study drug after 
IV to oral switch 
4 mL of blood will be collected at each time point in Gray top Sodium Fluoride (2.5 
mg/mL)/Potassium Oxalate (2 mg/mL) tubes (BD part#368587).  
The labels for all biological sample collection and storage containers will contain, at a 
minimum, the subject’s number, study number, collection date and collection time. 
Additional details are provided in the Study Laboratory Manual. 
Urine samples for PK analysis will be collected at the following timepoints: 
• 
Prior to initiation of oral dosing on the day of the oral switch on Day 1 
• 
At the following intervals after completion of dosing of administration of the first 
dose of oral study drug after IV to oral switch: 0-2 hours, 2-4 hours, 4-6 hours, 6-8 
hours, and 8-12 hours. 
The timing of sampling may be adjusted in some patients, but the total number of 
samples will remain the same. 
3. PLANNED STATISTICAL METHODS 
3.1 General Considerations 
The statistical methods for analysis of clinical data are described in detail in the protocol 
for the primary study. Relevant clinical data, including baseline and demographic data 
and data on clinical outcomes will be excerpted from the primary database for use in the 
PK/PD analyses. Missed collections or collection times out of window will not be noted 
as deviations to the primary study protocol. 

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3.2 Sample Size Considerations 
For this class of drugs, the pharmacokinetic-pharmacodynamic (PK-PD) index which 
best describes efficacy is the time of free concentration of sulopenem above MIC 
(T>MIC). Therefore, the sparse pharmacokinetic (PK) sampling strategy chosen for this 
study are the times which are most informative of the T>MIC. The optimal times at 
which the five samples should be drawn, in hours after the beginning of the first infusion 
are as follows (the acceptable sampling window is provided in parentheses): 2 (1.5-2.5) 
and 4 (2-6); and after the first dose of oral medication, are as follows: 2 (1-3), 4 (2-6), 
and 6 (4-8). 
The PK samples will be used to identify potential covariate patient factors that influence 
PK as well to quantify PK/PD relationships. The intention is to gather quality PK-PD 
data in several studies and to pool the concentration and effect data to achieve 
reasonable precision. Therefore, as many subjects as possible should be studied during 
this trial. It has been determined that up to 125 sulopenem-treated patients will have 
pharmacokinetic samples drawn in this study.  
4 
PK SAMPLE HANDLING AND ANALYSIS 
Detailed instructions for the collection, processing, storage and shipment of samples will 
be provided in the study Laboratory Manual. 
4.1 
Sample Collection and Processing 
• Blood samples for PK analysis of sulopenem levels will be collected via direct 
venipuncture using 4 mL Gray top Sodium Fluoride (2.5 mg/mL)/Potassium Oxalate 
(2 mg/mL) tubes (BD part#368587). 
• Immediately after the sample is drawn, the tube must be mixed gently by inversion 8 
to 10 times and placed on ice. 
• The samples will be centrifuged at 2500 g for 10 minutes at 4ºC within 60 minutes of 
collection to achieve a clear plasma layer over the red cells.  
• The plasma will be immediately separated into two 0.5 ml aliquots, transferred into 1.8 
mL NUNC Cryovials and stored at approximately -70ºC or -20ºC within 60 minutes of 
collection. Samples may only be stored at -20ºC for a maximum of 5 days. Samples 
stored at -20ºC must be shipped on dry ice for -70ºC storage prior to the 7 day expiry. 
• The time of the sampling as well as the time when the dose was administered prior to 
the sampling will be noted in the CRF. 
 
4.2  Urine Sample Collection and Processing 
• 
Patients will be instructed to void in study-provided containers over each collection 
interval. 
• 1 mL of urine will be collected at each time point and placed into two separate 1.8 mL 
NUNC Cryovials and stored at approximately -70ºC within 90 minutes of the end of 
collection.  

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• 
Samples may only be stored at -20ºC for a maximum of 5 days. Samples 
stored at -20ºC must be shipped on dry ice for -70ºC storage prior to the 7 
day expiry. 
4.3 
Transport of Samples 
The clinical staff will inventory the samples which are to be shipped to the central lab for 
accessioning and storage. The central lab will ship samples to the bioanalytic lab for 
measurement of sulopenem concentrations. Each shipment will contain a complete set of 
samples. 
For sample shipment, the samples will be packed in ample dry ice within a 
Styrofoam container to ensure the samples will remain frozen for at least 72 hours 
and shipped via express delivery to the central lab. Written notification of sample 
shipment will be communicated to the bioanalytical facility and Sponsor. The 
samples will be tracked to assure arrival in a safe and timely manner. 
The shipment will be accompanied by logs showing the name of the study drug product, 
the protocol number, and the subjects and samples included in the shipment. 
Documentation noting the conditions of the samples upon arrival at the central lab and 
the bioanalytical laboratory will be forwarded to the Sponsor/and or Representative. 
The detailed instructions for collection, processing and shipping the urine PK samples will be 
provided to the site in a Laboratory Manual. 
4.4 
Bioanalytical Sample Analyses 
The sulopenem concentrations will be measured in plasma and urine samples collected from 
patients in the sulopenem treatment group using validated bioanalytical methods and 
according to the Bioanalytical Laboratory’s Standard Operating Procedures and FDA 
Guidances. The sulopenem urine concentrations may be measured in urine samples 
collected from patients in the sulopenem treatment group using a validated bioanalytical 
method and according to the Bioanalytical Laboratory’s Standard Operating Procedures and 
FDA Guidances. 
4.5 
Bioanalytical Methodology 
A full validation of a sensitive assay for the appropriate analytes in each biological 
matrix, including precision, accuracy, reproducibility, limit of quantitation, recovery, and 
selectivity will be completed and approved prior to sample analysis. The bioanalytical 
summary report will include the stability of the frozen samples, and a summary of the 
standard curves and quality control samples. 
4.6 
Patient Withdrawal 
Patients may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety, 
behavioral, or administrative reasons 

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4.7 
Handling Dropout and Withdrawn Subjects 
Samples from subjects will be analyzed by the bioanalytical laboratory and concentration 
data will be included in the pharmacokinetic and statistical analyses if the subject 
completes the study. 
Samples from subjects who choose to discontinue their participation in the study without 
submitting a written request to withdraw consent or are dropped by the Investigator(s) or 
the Sponsor may be analyzed and included in the pharmacokinetic and statistical analyses, 
if pharmacokinetic parameters can be estimated using the remaining data points, or if 
requested by the Sponsor.  Unanalyzed samples from subjects who submit a written 
request to withdraw consent authorization from the study will not be analyzed. 
4.8 
Final Integrated Report 
A final report will be issued by the Sponsor after it has been reviewed and released by a 
quality assurance specialist, and this report will be appended to the clinical study report 
for the primary study. Where applicable, it will contain a narrative description of the 
clinical, bioanalytical, pharmacokinetic, and statistical procedures used during the 
conduct of the study.  Appropriate tables and graphs will be created to summarize the 
data. 
The regulatory agency for submission will include the U.S. Food and Drug 
Administration and other Health Agencies, as deemed appropriate for the purpose of 
study conduct or product registration. 
5 PHARMACOKINETIC AND STATISTICAL DATA ANALYSES 
Pharmacokinetic and statistical analyses will be performed for sulopenem plasma and urine 
data. PKPD assessments may also be performed utilizing sulopenem urine concentration 
and urine bactericidal activity data.  
Data from subjects with missing concentration values (missed blood draws, lost 
samples, samples unable to be quantitated) may be used if pharmacokinetic 
parameters can be estimated using the remaining data points. 
5.1 
Pharmacokinetic Data Analyses 
PK-PD analyses will include all patients who are clinically and/or microbiologically 
evaluable and for whom sulopenem concentration-time data are available. An estimate of 
sulopenem PK parameters will be derived for every patient who undergoes PK sampling. 
This will be accomplished by fitting the population PK model developed for sulopenem 
using the data from patients from multiple Phase 1 studies to the sulopenem concentration-
time data. The PK PD index (T>MIC) will be calculated. The PK-PD index data as well as 
patient demographics and outcome information may also be pooled with other Phase 3 
studies of sulopenem for the conduct of the population PK and PK-PD analyses. The 
results of the PK-PD analysis may be reported separate from the clinical study report. 
6 SCHEDULE OF EVENTS 

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Evaluation 
Baseline 
Day 1 
Day 6-14: IV to Oral Switch 
 
Within 24 
hours 
prior to 
first dose 
Dose Day 1a Sample 1 
2 hr ± 
0.5 hrb 
Sample 2 
4 hrs 
±2 hrsb 
First dose of 
oral 
medication 
Sample 3 
2 hrs ± 
1 hr 
Sample 4 
4 hrs ± 
2 hrs 
Sample 5 
6 hrs ± 
2 hrs 
Informed Consent 
X 
 
 
 
 
 
 
 
Study drug dose 
 
X 
 
 
X 
 
 
 
Plasma PK sample 
collection 
 
 
X 
X 
 
X 
X 
X 
Urine PK sample 
collectionc 
 
 
 
 
Xc 
 
 
 
a      Study "Day" is calendar day beginning with Day 1, the calendar day the first infusion of study medication is started. 
b      All times from end of study drug infusion. 
c     Patients will empty their bladder just prior to initiation of oral dosing on the day of the oral switch and a 1 mL aliquot 
from this urine will be frozen. One mL aliquots of urine from the following intervals after administration of the first dose 
of oral study drug after IV to oral switch: 0-2 hours, 2-4 hours, 4-6 hours, 6-8 hours, and 8-12 hours, may be collected and 
frozen for PKPD assessments. The timing of sampling may be adjusted in some patients, but the total number of samples 
will remain the same. 
 
 

Sulopenem/Sulopenem etzadroxil 
 
Iterum Therapeutics International Limited. 
Clinical Trial Protocol: IT001-302 
 
June 2018 
 
Confidential 
Page 75 of 76 
APPENDIX 5 
CRITERIA FOR SAFETY VALUES OF POTENTIAL 
CLINICAL CONCERN 
Hematology 
 
Hemoglobin 
<0.8 times the lower limit of the reference range 
Leukocytes 
<1.5 or >20 x 103/mm3 
Platelets 
<75 or >700 x 103/mm3 
Chemistry 
 
Total bilirubin 
>2 times the upper limit of the reference range 
Direct bilirubin 
>2 times the upper limit of the reference range 
AST 
>3 times upper limit of the reference range 
ALT 
>3 times upper limit of the reference range 
GGT 
>3 times upper limit of the reference range 
Alk Phosphatase 
>3 times upper limit of the reference range 
Creatinine 
>1.5 times upper limit of the reference range 
BUN/Urea 
>1.3 times upper limit of the reference range 
Sodium 
<0.95 or >1.05 times the limits of the reference range 
Potassium 
<0.9 or >1.1 times the limits of the reference range 
Calcium 
<0.9 or >1.1 times the limits of the reference range 
Albumin 
<0.8 times the lower limit of the reference range 
Total protein 
<0.8 times the lower limit of the reference range 
Creatine Kinase 
>3.0 times upper limit of the reference range 
Urinalysis 
 
Urine WBC 
≥10/HPF 
Urine RBC 
≥50/HPF 
Vital Signs 
 
Pulse Rate 
<40 or >130 bpm, when baseline resting heart rate is 60-120 bpm 
Blood Pressure 
Systolic ≥30 mm Hg change from baseline in same posture 
 
Systolic <80 mm Hg 
 
Diastolic ≥20 mm Hg change from baseline in same posture 
 
Diastolic <50 mm Hg 
 
 
 

Sulopenem/Sulopenem etzadroxil 
 
Iterum Therapeutics International Limited. 
Clinical Trial Protocol: IT001-302 
 
June 2018 
 
Confidential 
Page 76 of 76 
APPENDIX 6  
INVESTIGATOR’S SIGNATURE 
Study Title: 
A prospective, Phase 3, randomized, multi-center, double-blind, 
double dummy study of the efficacy, tolerability and safety of 
intravenous sulopenem followed by oral sulopenem-etzadroxil 
with probenecid versus intravenous ertapenem followed by oral 
ciprofloxacin or amoxicillin-clavulanate for treatment of 
complicated urinary tract infections in adults. 
Study Number: 
IT001-302 
Final Date: 
June 4, 2018 
 
I have read the protocol described above.  I agree to comply with all applicable regulations 
and to conduct the study as described in the protocol.  I understand the study protocol and 
will conduct the study according to the procedures therein and according to the principles of 
good clinical practice. 
 
Name: 
 
 
 
 
 
 
 
 
 
 
 
Signature: 
 
Date: