Clinical trial NCT03357614
Conditions: Complicated Urinary Tract Infections
Sponsor: Iterum Therapeutics, International Limited
Start date: 2018-09-18; Completion date: 2019-12-14
Enrollment: 1395 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a prospective, phase 3, randomized, multicenter, double-blind, double-dummy study to compare the efficacy and safety of sulopenem followed by sulopenem-etzadroxil/probenecid versus ertapenem followed by ciprofloxacin for the treatment of complicated urinary tract infections (cUTI) in adults.

Detailed description:

Arms: arm 1: Sulopenem 1000 mg IV once daily for a minimum of 5 days, followed by sulopenem-etzadroxil/probenecid 500 mg PO twice daily to complete 7-10 total days of treatment arm 2: Ertapenem 1000 mg IV once daily for a minimum of 5 days, followed by ciprofloxacin 500 mg PO twice daily or amoxicillin-clavulanate 500 mg PO twice daily to complete 7-10 total days of treatment
Interventions: intervention 1: Sulopenem intervention 2: Sulopenem-Etzadroxil/Probenecid intervention 3: Ertapenem intervention 4: Ciprofloxacin intervention 5: Amoxicillin-clavulanate
Intervention descriptions: intervention 1: Antibiotic therapy for complicated UTI intervention 2: Antibiotic therapy for complicated UTI intervention 3: Antibiotic therapy for complicated UTI intervention 4: Antibiotic therapy for complicated UTI intervention 5: Antibiotic therapy for complicated UTI

Protocol documents:
Prot_000.pdf: 
Sulopenem/Sulopenem etzadroxil 
 
Iterum Therapeutics International Limited. 
Clinical Trial Protocol: IT001-302 
 
June 2018 
Confidential 
Page 1 of 76 
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 
 
Iterum Therapeutics International Limited. 
Clinical Trial Protocol: IT001-302 
 
June 2018 
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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. 
 
 


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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 
 
 
 


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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: 
 

SAP_001.pdf: 
Statistical Analysis Plan: 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
Indication:
Complicated urinary tract infection
Study Statistician:
Michael Zelasky
Study Clinician:
Steven I. Aronin, M.D.
Sponsor:
Iterum Therapeutics International Limited
20 Research Parkway, Suite A
Old Saybrook, CT 06475
Final SAP Date:
September 25, 2019
Revised SAP Date:
February 11, 2020
Protocol Version:
January 16, 2020
Confidentiality Statement
This document is strictly confidential. It was developed by Iterum Therapeutics US Limited 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


Anita F Das
Digitally signed by Anita F Das 
DN: cn=Anita F Das, o, ou, 
email=adas@adstat.onmicrosoft.
com, c=US 
Date: 2020.02.12 12:57:12 -08'00'


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TABLE OF CONTENTS
 
TABLE OF CONTENTS............................................................................................................ 3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS............................................. 5 
1 
INTRODUCTION............................................................................................................. 7 
2 
STUDY DESIGN............................................................................................................... 7 
3 
STUDY OBJECTIVES..................................................................................................... 7 
3.1 
Primary Objective ................................................................................................. 7 
3.2 
Secondary Objectives ........................................................................................... 7 
4 
DEFINITION OF ANALYSIS POPULATIONS........................................................... 8 
4.1 
Intent-to-Treat (ITT)............................................................................................ 8 
4.2 
Modified Intent-to-Treat (MITT) ....................................................................... 8 
4.3 
Microbiological Modified Intent-to-Treat (micro-MITT or m-MITT)......... 8 
4.4 
Clinical Evaluable (CE) ......................................................................................... 8 
4.5 
Microbiological Evaluable (ME)......................................................................... 9 
4.6 
Safety ....................................................................................................................... 9 
4.7 
Determination of Inclusion in Analysis Populations................................... 10 
5 
DEFINITION OF OUTCOMES ................................................................................... 10 
5.1 
Overall Response................................................................................................... 10 
5.2 
Microbiologic Response........................................................................................ 11 
5.2.1 Baseline Pathogens................................................................................................ 11 
5.2.2 Post-Baseline Pathogens....................................................................................... 13 
5.3 
Patient-Determined Clinical Response (Clinical Response) ............................. 14 
5.4 
Investigator-Determined Clinical Response:...................................................... 15 
5.5 
Patient Symptom Assessment Questionnaire (PSAQ)....................................... 15 
5.6 
Other Signs and Symptoms.................................................................................. 16 
5.7 
Safety Outcome Measures.................................................................................. 16 
6 
STATISTICAL METHODS .......................................................................................... 16 
6.1 
Sample Size........................................................................................................... 16 
6.2 
Randomization ...................................................................................................... 17 
6.3 
Visit Windows........................................................................................................ 17 
6.4 
Microbiology Data ................................................................................................ 17 
6.5 
Handling of Missing Data..................................................................................... 18 
6.6 
Comments on Statistical Analysis........................................................................ 20 
7 
STATISTICAL ANALYSES ......................................................................................... 21 


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7.1 
Patient Disposition ................................................................................................ 21 
7.2 
Demographics and Baseline Characteristics ...................................................... 21 
7.2.1 
Baseline Microbiology.................................................................................. 22 
7.3 
Prior and Concomitant Medications................................................................... 22 
7.4 
Study Drug Exposure ........................................................................................... 23 
7.5 
Efficacy Analyses .................................................................................................. 23 
7.5.1 
Primary Efficacy Analysis.................................................................................... 23 
7.5.2 
Additional Analyses of the Primary Efficacy Outcome..................................... 24 
7.5.3 
Secondary Efficacy Analysis................................................................................ 26 
7.5.4 
Additional Efficacy Analyses ............................................................................... 26 
7.6 
Interim Analysis.................................................................................................... 31 
7.7 
Safety Analyses...................................................................................................... 32 
7.7.1 
Adverse Events...................................................................................................... 32 
7.7.1.1 Diarrhea Episodes................................................................................................. 32 
7.7.2 
Laboratory Values ................................................................................................ 33 
7.7.3 
Physical Examinations.......................................................................................... 34 
7.7.4 
Vital Signs.............................................................................................................. 34 
7.8 
Protocol Deviations............................................................................................... 35 
8 
DIFFERENCES WITH ANALYSES SPECIFIED IN THE PROTOCOL............... 36 
9 
REFERENCES................................................................................................................ 37 
Appendix A: Schedule of Activities ............................................................................. 38 
Appendix B: Criteria for Safety Values of Potential Clinical Concern........................ 40 
Appendix C: Method for Determination of Creatinine Clearance................................ 41 
Appendix D: Microbiology Rules for Determination of Final Pathogen ..................... 42 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
AE
Adverse Event
BMI
Body Mass Index
CE
Clinical Evaluable
CFU
Colony Forming Unit
CI
Confidence Interval
CRF
Case Report Form
CSR
Clinical Study Report
cUTI
Complicated Urinary Tract Infection
EOT
End of Treatment Visit
ESBL
Extended-6SHFWUXPȕ-Lactamases
FDA
Food and Drug Administration
FV
Final Visit
GCP
Good Clinical Practice
IA
Interim Analysis
ITT
Intent-to-Treat
IWRS
Interactive Web Response System
m-MITT
Microbiological Modified Intent-to-Treat
ME
Microbiological Evaluable
MedDRA
Medical Dictionary for Regulatory Activities
MG
Milligram
MIC
Minimum Inhibitory Concentration
micro-MITT
Microbiological Modified Intent-to-Treat
MITT
Modified Intent-to-Treat
NDA
New Drug Application


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PD
Pharmacodynamic
PK
Pharmacokinetic
PO
Orally
PSAQ
Patient Symptom Assessment Questionnaire
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
SE
standard error
Tfree>MIC
Time of free concentration above MIC
TOC
Test of Cure Visit
WHODRUG
World Health Organization (WHO) Drug Dictionary


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1
INTRODUCTION
This document presents the Statistical Analysis Plan (SAP) for the protocol IT001-302, “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.”  The 
statistical plan described is an a priori plan, and the analyses outlined here have not been 
conducted on the final and unblinded data prior to the preparation of this plan. This SAP 
summarizes the design and objectives of protocol IT001-302 and provides details of the 
definitions of analysis populations, derived variables, the outcome measures and statistical 
methodology that will be used to analyze the data from the study.
Any deviation from the planned analysis after unblinding will be documented in the clinical 
study report (CSR). This SAP is based on the most recent version of the final study protocol as 
noted on Page 1.
2
STUDY DESIGN
This prospective Phase 3, randomized, multicenter, double-blind, double dummy, controlled 
study compares intravenous sulopenem followed by oral sulopenem-etzadroxil with probenecid 
to intravenous ertapenem followed by oral ciprofloxacin or amoxicillin-clavulanate for the 
treatment of patients with complicated urinary tract infection (cUTI).  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.
The duration of treatment may be extended up to a total duration of 14 days for patients with 
bacteremia at baseline.
Visits occur on Day 1, Day 5, Day 10 (± 1 day), Day 21 (± 1 day) and Day 28 (± 3 days).  The 
Day 10 visit is the End of Therapy (EOT) visit, Day 21 is the Test of Cure (TOC) visit and Day 
28 is the Final Visit (FV) which is a phone call. 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.
3
STUDY OBJECTIVES
3.1
Primary Objective 
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 the TOC visit.
3.2
Secondary Objectives 
x
To compare the per-patient microbiologic response across treatment groups.


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x
To compare the efficacy outcomes at relevant time points 
x
To assess the safety profile of treatment with each regimen. 
x
To assess the population PK profile of sulopenem IV and/or sulopenem-etzadroxil co-
administered with probenecid.
4
DEFINITION OF ANALYSIS POPULATIONS
4.1
Intent-to-Treat (ITT)  
The ITT population is comprised of all randomized patients regardless of whether or not the
patient received study drug.
4.2
Modified Intent-to-Treat (MITT)  
The MITT population will include all patients in ITT population who received at least a single 
dose of study medication and had the disease under study defined as having two of the five 
baseline cUTI symptoms listed in inclusion criteria #4.
4.3
Microbiological Modified Intent-to-Treat (micro-MITT or m-MITT)  
All MITT patients with a positive study entry urine culture within 48 hours prior to first dose
GHILQHGDV5 colony forming units (CFU)/mL of a uropathogen [Enterobacteriaceae only,
susceptible to sulopenem (MIC  1) and ertapenem (MIC  0.5)] and no more than 2 species 
of microorganisms identified in the study entry urine culture ZLWK5 (CFU)/ml (Wilson ML 
and Gaido L. Laboratory diagnosis of urinary tract infections in adult patients. Clin Infect Dis 
2004;38:1150-8) except in the situation where one of the organisms cultured from the urine is 
also isolated from blood cultures drawn at baseline. Patients with a study pathogen isolated 
from baseline blood cultures will be included in the m-MITT population regardless of the 
patient’s baseline urine culture result. See section 6.4 for further details on the use of lab 
results for determining eligibility for inclusion in the micro-MITT.
4.4
Clinical Evaluable (CE) 
Four CE populations will be defined based on the timing of the outcome assessment, CE-Day 
5, CE-EOT, CE-TOC and CE-FV.  The term “CE population” is used to refer to all. The CE 
population is a subset of the MITT population and follows the rules below.
a) Received all their protocol defined active study medication up to the timepoint of 
assessment (i.e., 5 days of IV for the day 5 visit and at least 7 days of therapy in a 
row for EOT, TOC and FV)
b) Met all inclusion and no exclusion criteria
c) Had no important protocol deviations that would affect the assessment of efficacy 
prior to the visit as indicated in the protocol deviation log (see section 7.8)
d) Had a patient-determined clinical response of success or failure (and not 
indeterminate) at Day 5, EOT or TOC visits (i.e., within the SAP defined allowed 
visit window), respectively.  


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e) Did not receive effective antibacterial drug therapy for cUTI for a continuous 
duration of more than 24 hours during the previous 72 hours prior to the initiation of
study therapy. 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.
f)
Did not receive any systemic antibiotic therapy (excluding linezolid, daptomycin, 
vancomycin, azithromycin, metronidazole, josamycin, macrolide, nifuratel,
tergynan, fluconazole, cystone, butoconazole nitrate, clindamycin hydrochloride, 
clotrimazole, tinidazole
and clarithromycin, as well as ‘antibiotics and 
chemotherapeutics for dermatological use’ and ‘ophthalmologicals' since they have 
no activity against the pathogens in the study) with potential activity against any of 
the uropathogens collected at baseline between the time of the baseline culture and 
the Day 5, EOT or TOC visits, respectively. This excludes the protocol defined study 
therapy and patients 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 (i.e., such as, but not limited to, linezolid, daptomycin or 
vancomycin).
g) Received appropriate adjunctive antibacterial coverage (i.e., such as, but not limited 
to, linezolid, daptomycin or vancomycin) if the patient had a culture-documented 
Enterococcus spp. or other gram-positive resistant pathogens (excluding S. 
saprophyticus) at baseline and has symptoms (PSAQ) at the post-baseline visit.
h) Site personnel involved in the assessment of efficacy parameters remained blinded 
to study treatment up to the time of the efficacy assessment.
i)
Patients who receive study drug therapy beyond the protocol treatment period (up to 
14 days) for patients with bacteremia at baseline) as a result of the investigator's 
assessment that additional drug therapy is needed for treatment of the underlying 
urinary tract infection will be defined as failures for patient determined clinical 
response at TOC. Thus, these patients will be included in the CE populations, if all 
other criteria are met.
4.5
Microbiological Evaluable (ME) 
All patients included in both the micro-MITT and CE populations at the Day 5 (ME-Day 5), 
Day 10 visit (ME-EOT; or Day 11-14 (± 1 day) for patients with bacteremia at baseline) and 
Day 21 visit (ME-TOC) and have an appropriately collected urine culture specimen and 
interpretable urine culture (lab culture result reportable by the lab) result at the Day 5, Day 10
(or Day 11-14 (± 1 day) for patients with bacteremia at baseline) and Day 21 visits (i.e., within 
the SAP defined allowed visit window), respectively.
4.6
Safety  
The safety population is comprised of all patients in ITT population who received any amount 
of study drug.


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4.7
Determination of Inclusion in Analysis Populations 
Inclusion into the ITT, MITT and Safety populations will be determined programmatically 
from the eCRF data and as needed by manual review by the sponsor.
Inclusion into the CE populations will be determined programmatically from the eCRF data 
and through a manual review conducted by the Sponsor. The Sponsor will review clinical data 
for determination of criteria used to assess inclusion in the CE populations. The Sponsor will 
be blinded to treatment assignment and will review the data concurrent with the conduct of the 
study. 
Inclusion into the Micro-MITT and ME populations will be determined programmatically and 
through a manual review conducted by the Sponsor.
5
DEFINITION OF OUTCOMES
5.1
Overall Response
The primary endpoint for the study is Overall Response at TOC.
A patient will be defined as a success at a given visit (Day 5, EOT and 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, benign 
prostatic hypertrophy, urethral stricture, chronic hydronephrosis, overactive bladder 
or certain other symptoms that were present before the cUTI event such as flank pain 
related to a recent procedure) do not need to be resolved.
- For certain patients PSAQ symptoms may not be relevant and therefore if missing 
will not be counted as an indeterminate outcome (e.g., patients with an indwelling 
urinary catheter or suprapubic catheter may not have symptoms of frequency, urgency 
or dysuria)
•
The patient has not received any non-study rescue antibacterial for cUTI (excluding 
linezolid, daptomycin, vancomycin, azithromycin, metronidazole, josamycin, 
macrolide, nifuratel, tergynan, fluconazole, cystone, butoconazole nitrate, 
clindamycin hydrochloride, clotrimazole, tinidazole and clarithromycin, as well as 
‘antibiotics and chemotherapeutics for dermatological use’ and ‘ophthalmologicals' 
since they have no activity against the pathogens in the study)
- If an antibiotic is given for other reasons then the patient will not be considered a 
non-responder for cUTI
•
The bactHULDOSDWKRJHQIRXQGDW5 CFU/ml in the trial entry urine cultures are
reduced to <103 CFU/mL in the urine culture taken at the specified study visit and the 
blood culture is eradicated or was presumed eradicated if one was present at baseline


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A patient will be defined as a failure if at least one of the following criteria is met:
•
Patient died due to cUTI
•
Patient received non-study antibacterial therapy for cUTI (excluding linezolid, 
daptomycin, vancomycin, azithromycin, metronidazole, josamycin, macrolide, 
nifuratel, tergynan, fluconazole, cystone, butoconazole nitrate, clindamycin 
hydrochloride, clotrimazole, tinidazole and clarithromycin, as well as ‘antibiotics and 
chemotherapeutics for dermatological use’ and ‘ophthalmologicals' since they have 
no activity against the pathogens in the study)
•
Patient does not have resolution or experiences worsening of symptoms of cUTI 
(dysuria, urinary frequency, urinary urgency, suprapubic pain, and flank pain or pelvic 
pain) present at trial entry and/or has new cUTI symptoms.
-
Baseline symptoms associated with anatomic abnormalities that predispose to 
cUTI (e.g., symptoms associated with the presence of an indwelling urinary 
catheter, benign prostatic hypertrophy, urethral stricture, chronic hydronephrosis, 
overactive bladder or certain other symptoms that were present before the cUTI 
event such as flank pain related to a recent procedure) do not need to be resolved.
-
For certain patients PSAQ symptoms may not be relevant and therefore if missing 
will not be counted as an indeterminate outcome (e.g., patients with an indwelling 
urinary catheter or suprapubic catheter may not have symptoms of frequency, 
urgency or dysuria)
•
7KHEDFWHULDOSDWKRJHQIRXQGDW5 CFU/ml in the trial entry urine culture is not 
reduced to <103 CFU/mL in the urine culture taken at the specified study visit or the 
blood culture is not eradicated if one was present at baseline
Patients will be defined to have an indeterminate outcome if any data needed to determine 
whether the outcome is success or failure are missing. For example, if the assessment of the 
UTI symptoms was not completed at TOC, the patient will be considered an indeterminate 
response for overall response at TOC (unless the urine FXOWXUHGHPRQVWUDWHV103 CFU/mL of 
the baseline uropathogen or the blood pathogen is not eradicated if one was present at baseline 
in which case the patient is a failure).  Patients who died due to other reasons than the cUTI
will have an indeterminate outcome.
5.2
Microbiologic Response
Per pathogen microbiologic response is assessed using the definitions listed below. It will be 
analyzed at each timepoint (Day 5, EOT and TOC).  It is assessed for each pathogen that a 
patient has at baseline.
Per patient microbiologic response is a patient level response determined by the outcome 
of all culture results at that visit.
Note, if a patient did not have a positive culture at baseline, they are not included in the 
micro-MITT or ME populations even if a pathogen is isolated post-baseline. 
5.2.1 Baseline Pathogens


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Per Pathogen Microbiological Response 
for Pathogens from Urine
Definition 
Eradication 
A urine culture taken within 48 hours prior 
to randomization (baseline) and compared 
with the culture from the timepoint of 
analysis showed that the urine culture 
obtained at the relevant visit demonstrated 
<103 CFU/mL of the baseline uropathogen
(contaminated results are considered an 
eradication).
Persistence 
A uropathogen from urine present at 
EDVHOLQHJUHZDW3 CFU/mL at the 
timepoint of analysis.*
Persistence with increasing MIC 
A urine culture taken after at least 2 full days 
of treatment JUHZ3 CFU/mL of the 
EDVHOLQHXURSDWKRJHQDQGGLVSOD\HG-fold 
higher MIC to study drug received at the 
timepoint of analysis.
Indeterminate 
Patient was lost to follow-up or 
circumstances that precluded classification 
as an eradication, presumed eradication, 
persistence, presumed persistence or
persistence with increasing MIC.
* The genus/species and susceptibility profiles need to match. For the baseline and TOC visits, additional 
molecular testing by pulsed field gel electrophoresis (PFGE) or whole genome sequencing (WGS) may 
be performed for confirmation.
Per Pathogen Microbiological Response 
for Pathogens from Blood
Definition 
Eradication 
The last follow-up blood culture prior to the 
visit or at the visit is sterile (no growth).
Presumed Eradication
If follow-up blood cultures were not done 
for patients with bacteremia at baseline, and
the patient was assessed as a clinical cure at 
that visit based on the programmatic 
determination of clinical response.
Persistence 
The last follow-up blood culture prior to the 
visit or at the visit shows growth of the 
baseline pathogen.*
Presumed Persistence
If follow-up blood cultures were not done 
for patients with bacteremia at baseline, and
the patient was assessed as a clinical failure
at that visit based on the programmatic 
determination of clinical response.


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Persistence with increasing MIC 
Follow-up blood cultures taken after at least 2 
full days of treatment show growth of the 
same baseline pathogen displaying -fold 
higher MIC to study drug therapy.
Indeterminate 
Patient was lost to follow-up or 
circumstances that precluded classification 
as an eradication, presumed eradication, 
persistence, presumed persistence or
persistence with increasing MIC.
* The genus/species and susceptibility profiles need to match. For the baseline and TOC visits, additional 
molecular testing by pulsed field gel electrophoresis (PFGE) or whole genome sequencing (WGS) may 
be performed for confirmation.
A per pathogen microbiologic success for pathogens from the urine is defined as Eradication
(or presumed eradication, if applicable).  A pathogen failure is Persistence (or presumed 
persistence, if applicable) or Persistence with Increasing MIC. A per pathogen microbiologic 
success for pathogens from the blood are defined in the same way.
When pathogens from urine or blood are presented in the same table the individual per 
pathogen outcomes are combined into a single outcome where the worst outcome from urine 
or blood is used. The order from worst to best is Persistence with increasing MIC, Persistence, 
Presumed Persistence, Indeterminate, Presumed Eradication and then Eradication.
A per patient microbiologic success is defined as all pathogen responses (both urine and blood) 
for a patient are Eradication (or presumed eradication, if applicable).  A per patient 
microbiologic failure is one or more pathogens for a patient are Persistence (or presumed 
persistence, if applicable) or Persistence with increasing MIC. Otherwise, the patient will be 
indeterminate.
5.2.2 Post-Baseline Pathogens
For patients with a baseline pathogen meeting the micro-MITT criteria, the following post-
baseline pathogen definitions will be used.
Microbiologic response 
Definition 
Superinfection
A pathogen in the urine or blood not 
present at baseline grew with 5 CFU/mL 
from the first dose of study drug through 
the EOT visit in the setting of 
recurrent/persistent/new cUTI symptoms 
requiring non-study systemic antibacterial 
treatment* (patient-determined clinical 
failure at EOT).
New Infection
Isolation of a non-baseline pathogen in the 
urine or blood from a culture post-EOT visit 
with 5 CFU/mL in a patient with one or 
more cUTI signs/symptoms requiring new 
systemic antibacterial treatment* after the 


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EOT visit (patient-determined clinical 
failure post-EOT).
Recurrence
In a patient with clinical and 
microbiological success at EOT, isolation of 
a baseline pathogen in the urine or blood 
from a culture specimen with 5 CFU/mL 
post-EOT visit, along with new or 
recurrence of one or more cUTI
signs/symptoms requiring new systemic 
antibacterial treatment* after the EOT visit
(patient-determined clinical failure post-
EOT).
Colonization
Isolation of a micro-organism in the urine or 
blood after EOT in a patient without one or 
more signs and symptoms of cUTI and not 
requiring new systemic antibiotic therapy*
(patient-determined clinical success post-
EOT).
* excluding linezolid, daptomycin, vancomycin, azithromycin, metronidazole, josamycin, 
macrolide, nifuratel, tergynan, fluconazole, cystone, butoconazole nitrate, clindamycin 
hydrochloride, clotrimazole, tinidazole and clarithromycin, as well as ‘antibiotics and 
chemotherapeutics for dermatological use’ and ‘ophthalmologicals' since they have no activity 
against the pathogens in the study
5.3
Patient-Determined Clinical Response (Clinical Response)
A patient will be defined as a clinical success at a given timepoint (Day 5, EOT, TOC and FV)
if the following criteria are met (programmatically, based on the data on the eCRF): 
•
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,
benign prostatic hypertrophy, urethral stricture, chronic hydronephrosis, overactive 
bladder or certain other symptoms that were present before the cUTI event such as 
flank pain related to a recent procedure) do not need to be resolved.
- For certain patients PSAQ symptoms may not be relevant and therefore if missing 
will not be counted as an indeterminate outcome (e.g., patients with an indwelling 
urinary catheter or suprapubic catheter may not have symptoms of frequency, 
urgency or dysuria)
•
The patient has not received any non-study rescue antibacterial therapy for cUTI
(excluding linezolid, daptomycin, vancomycin, azithromycin, metronidazole, 
josamycin, macrolide, nifuratel, tergynan, fluconazole, cystone, butoconazole 
nitrate, clindamycin hydrochloride, clotrimazole, tinidazole and clarithromycin, as 


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well as ‘antibiotics and chemotherapeutics for dermatological use’ and 
‘ophthalmologicals' since they have no activity against the pathogens in the study)
prior to the visit
All other patients will be considered as failures unless data are unavailable to determine if the 
patient is a success or failure. In this case, the patient will be considered as having an 
indeterminate response. Patients who died due to reasons other than the cUTI will have an 
indeterminate outcome.
5.4
Investigator-Determined Clinical Response:
Investigators will use the definitions below to document clinical response, irrespective of 
microbiologic findings, at Day 5, EOT, TOC and FV or premature discontinuation:
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 are considered a failure: 
x
Death related to cUTI prior to Day 5, 
EOT, TOC and FV, respectively 
x
Persistence or progression of any pre-
therapy cUTI signs and symptoms or 
use of additional antibiotics for the 
current infection 
x
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:
x
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, 
EOT, TOC, or FV, respectively
x
Death prior to Day 5, EOT, TOC, or 
FV respectively, where cUTI was 
clearly noncontributory 
5.5
Patient Symptom Assessment Questionnaire (PSAQ)
Patients will report their UTI symptoms as no symptom, mild, moderate or severe and this will 
be recorded on the Patient Symptom Assessment Questionnaire (PSAQ). The symptoms are:
x
Burning (dysuria) when passing urine
x
Frequency of urination or going to the toilet very often


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x
Urgency of urination or a strong and uncontrollable urge to pass urine
x
Suprapubic pain (uncomfortable pressure) in the lower abdomen
x
Lower back/flank pain
x
Pelvic pain (uncomfortable pressure) in the pelvic area
If a symptom is mild, moderate or severe then patients will report the impact of the symptom 
on daily activities as not at all, not significantly bothersome, moderately bothersome or 
severely bothersome.
5.6
Other Signs and Symptoms
In addition to the signs and symptoms collected on the PSAQ, the following will be collected:
x
Rigors, chills or fever/hypothermia with temperature (oral, rectal, tympanic, temporal) 
>100.4ºF or 38ºC, or <95ºF or 35ºC
x
Nausea or vomiting
x
Costovertebral angle tenderness on physical examination
These symptoms plus the ones collected on the PSAQ will be used to create a supplementary 
clinical response which will be the same as patient-determined clinical response but with the 
added signs and symptoms. The supplementary clinical response will use nine symptoms, six 
from the PSAQ plus these three.
5.7
Safety Outcome Measures
The safety parameters include AEs, clinical laboratory evaluations and vital signs. Adverse 
Events will be coded using the Medical Dictionary of Regulatory Activities (MedDRA) 
Version 21.0 or higher to the System Organ Class and Preferred Term levels.
6
STATISTICAL METHODS
6.1
Sample Size 
The study is designed to determine whether sulopenem IV 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 original 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. 
The expected overall response rate is estimated from large randomized controlled trials in a 


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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 7.6); the sample size methodology used at this interim 
assessment may or may not include a continuity correction.
6.2
Randomization
Patients will be randomized in a 1:1 ratio to sulopenem IV followed by oral sulopenem-
etzadroxil plus probenecid or ertapenem IV followed by oral ciprofloxacin or amoxicillin-
clavulanate using an Interactive Web Randomization System (IWRS), 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. Once IWRS provides a randomization number, the patient is 
officially randomized.
6.3
Visit Windows
Visit windows are used in determining whether a patient will be included in the CE and ME 
populations at EOT and TOC.  If their assessments are out of window, they will not be included 
in that population.  
For the ITT, MITT and micro-MITT populations, patients are not dropped from the 
populations for assessments out of window.  The nominal visit from the eCRF is used to assign 
assessments to the appropriate time point for efficacy.
For laboratory and vital signs by-visit analyses, the value closest to the target date for the visit 
will be used in the analyses if more than one assessment was within the visit window (i.e., 
unscheduled assessments were obtained).  If two values are equidistant from the planned visit 
date, then the first value will be used.
Visit 
Window 
Day 5 
No window 
Day 10 - End of Treatment (EOT) 
or Day 11-14 for patients with 
bacteremia at baseline 
± 1 day 
Day 21 - Test of Cure (TOC) 
± 1 day 
Day 28 - Final Visit (FV) 
± 3 days 
6.4
Microbiology Data


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The following organisms will be considered a uropathogen for this study:
x
Monomicrobial or polymicrobial infections caused by:
o
Enterobacteriaceae
o
Enterococci
o
Pseudomonas aeruginosa
x
The micro-MITT population will only include patients with UTIs caused by 
Enterobacteriaceae (study uropathogens), susceptible to ertapenem with an MIC 
µg/mL and susceptible to sulopenem with an MIC µg/mL. Patients may have 
other non-Enterobacteriaceae uropathogens
The following normal flora are never a pathogen:
x
Corynebacterium spp.
x
S. epidermidis
x
S. aureus
x
S. saprophyticus
x
Bacillus spp.
x
Diphtheroids
x
Micrococcus spp.
x
Lactobacillus spp.
x
Viridans Streptococci
x
Group B Streptococci
x
Gardnerella vaginalis
x
Neisseria gonorrhoeae
x
Yeasts
All isolates will be assessed on a case-by-case basis via manual review of a spreadsheet by the 
Sponsor.  This could include isolates not listed above.  If needed, patient clinical and 
microbiological information (e.g., Gram stain, PFGE or other appropriate tests) 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.
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.
The microbiology rules for identification of pathogens are in appendix D.
6.5
Handling of Missing Data
Missing data will be handled as outlined below:
•
All missing and partial dates for events and assessments occurring after randomization 


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or for medications received after randomization will be queried for a value. If no value 
can be obtained, the dates or partial dates will remain missing, but the following actions 
will take place:
-
Adverse Events
•
If an adverse event is missing a start date, the adverse event will be treated 
as treatment-emergent.  
•
If the start date only contains the year, then if the year is prior to the year 
of first dose then the adverse event will not be treatment 
emergent. Otherwise, it will be treatment emergent unless it is possible to 
conclude that the stop date is prior to first dose (based on the available parts 
of stop date if it is partial).
•
If the start date only contains the year and month, then if the year/month 
combination is prior to the year/month combination of first dose then the 
adverse event will not be treatment emergent. Otherwise, it will be 
treatment emergent unless it is possible to conclude that the stop date is 
prior to first dose (based on the available parts of stop date if it is partial).
•
If the start date only contains the month and day, then if the month/day 
combination is prior to the month/day combination of first dose then the 
adverse event will not be treatment emergent. Otherwise, it will be 
treatment emergent unless it is possible to conclude that the stop date is 
prior to first dose (based on the available parts of stop date if it is partial).
•
Other partial start dates will be treated as treatment-emergent unless it is 
possible to conclude that the stop date is prior to first dose (based on the 
available parts of stop date if it is partial).
-
Prior/Concomitant Medications and Prior/Concomitant Antibiotic Therapy
•
If a concomitant drug is missing a start date and stop date, then the 
concomitant drug should be reported both as a prior and concomitant drug.
•
If the start date only contains the year and month, then if the year/month 
combination is after the year/month combination of first dose then the drug 
should be reported as concomitant only. Otherwise, it should be reported 
as both prior and concomitant unless it is possible to conclude that the stop 
date is prior to first dose (based on the available parts of stop date if it is 
partial). In this case it should be reported as prior only.
•
If the start date only contains the month and day, then if the month/day 
combination is after the month/day combination of first dose then the drug 
should be reported as concomitant only. Otherwise, it should be reported 
as both prior and concomitant unless it is possible to conclude that the stop 
date is prior to first dose (based on the available parts of stop date if it is 
partial). In this case it should be reported as prior only.
•
Other partial start dates will be treated as both prior and concomitant unless 
it is possible to conclude that the stop date is prior to first dose (based on 


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the available parts of stop date if it is partial). In this case it should be 
reported as prior only.
•
The severity and causality assessment for an AE cannot be missing. Missing data will 
be queried for a value.
•
For overall response, patients will be defined as an indeterminate if any data needed to 
determine whether a patient is a success or failure are missing unless, since this is a 
composite outcome, the data that is present shows the patient is a failure.
•
Except as specifically noted for preplanned imputation analyses, missing values for other 
individual data points (not described above) will remain as missing. Missing values will 
not be imputed and only observed values will be used in data analyses and presentations.
•
Where individual data points are missing, categorical data will be summarized based on 
reduced denominators (i.e., only patients with available data will be included in the 
denominators).
6.6
Comments on Statistical Analysis
The following general comments apply to all statistical analyses and data presentations:
•
Summaries will include frequency and percentages for categorical data; frequency and 
median for ordinal data; and number, mean, standard deviation, and median, 
minimum, maximum and quartiles for quantitative data.
•
Duration variables will be calculated using the general formula (end date - start date)+1.
•
If the reported value of a clinical laboratory parameter cannot be used in a statistical 
summary table (e.g., a character string is reported for a parameter of the numerical 
type), a coded value must be appropriately determined and used in the statistical 
analyses. In general, a value or lower and upper limit of normal range such as ‘<10’ or 
µ¶ZLOOEHWUHDWHGDVµ¶RUµ¶UHVSHFWLYHO\DQGDYDOXHVXFKDVµ!¶ZLOOEH
treated as ‘100’. However, the actual values as reported in the database will be 
presented in data listings.
•
Individual patient listings of all data represented on the eCRFs will be provided to 
facilitate the investigation of tabulated values and to allow for the clinical review of
all efficacy and safety parameters.
•
Version 9.4 (or higher) of SAS® statistical software package will be used to provide 
all summaries, listings, graphs, and statistical analyses.


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7
STATISTICAL ANALYSES
7.1
Patient Disposition
The number of patients included in each of the study populations (i.e., ITT, Safety, MITT, 
Micro-MITT, CE-Day 5, CE-EOT, CE-TOC, ME-Day 5, ME-EOT and ME-TOC) will be 
summarized by treatment group. A table and listing will be provided that details the reasons 
the patient is excluded from the population.
A listing will be provided of randomized patients who did not meet all inclusion/exclusion 
criteria. 
The frequency and percentage of patients completing the study, prematurely discontinuing 
from study drug, and prematurely discontinuing from the study will be presented for each 
treatment group and overall for each study population. Comparisons between treatment groups 
will be made using Fisher‘s exact test.
Reasons for premature discontinuation of study drug and/or withdrawal from the study as 
recorded on the eCRF will be summarized (frequency and percentage) by treatment group. 
A listing of all patients who prematurely discontinued from study drug or withdrew from the 
study will be presented, and the primary reason for premature discontinuation of study drug 
or withdrawal from the study will be provided.
A listing of deaths will be presented separately.
7.2
Demographics and Baseline Characteristics
Demographic data and baseline characteristics will be presented by treatment group in all study 
populations. A table will present the patient demographics (e.g., gender, age, ethnicity, race,
geographic region) and baseline characteristics (e.g., height, weight, BMI, diabetes status,
creatinine clearance). Differences between treatment groups will be analyzed using Fisher‘s 
exact test for dichotomous variables (gender, ethnicity, race, geographic region, diabetes
status, creatinine clearance as a categorical variable: <30, 30-60, 60) and the Wilcoxon Rank 
Sum test for continuous variables (age, BMI, creatinine clearance).
Medical history will be summarized based on body site/system category and treatment group.
Signs and symptoms at baseline as captured on the PSAQ and CRF (rigors / chills / 
temperature, nausea / vomiting, costovertebral angle tenderness) will be summarized by 
treatment group and compared using the Wilcoxon Rank Sum test for ordinal data.
The factors defining complicated UTI will be summarized by treatment group:
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


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vii.
Surgically modified or abnormal urinary tract anatomy
7.2.1 Baseline Microbiology
The microbiological assessment of the baseline urine and blood samples will be summarized 
by treatment group for the micro-MITT and ME populations. A frequency distribution of the 
result of the central lab’s Gram stain, including organism characteristics will be presented. The 
number and percentage of patients with no growth, contaminant and positive for a pathogen at 
5 CFU/ml and >103-<105 CFU/ml will also be presented.
The bacterial pathogens identified from the baseline urine cultures and blood cultures will be 
presented. The number and percentage of patients with a gram-positive pathogen and with a 
gram-negative pathogen will be presented by genus and species for the MITT, micro-MITT 
and ME populations. The same pathogen identified from both the blood and the culture of the 
infection site will be counted only once in the summary.
In addition, the number and 
percentage of patients with infections that are mono-microbial, poly-microbial, ESBL positive,
ESBL negative, quinolone positive, quinolone negative and ESBL+ and quinolone non-
susceptible pathogens (subjects with a resistant baseline pathogen that precludes oral step 
down).  If either the urine specimen or blood culture is ESBL positive, then the patient will be 
presented as ESBL positive; same for quinolone resistance.
A listing will be provided that includes all baseline and post-baseline isolates obtained from 
the urine specimens and whether or not the isolate is considered the pathogenic organism.
Several tables providing the frequency distribution of the minimum inhibitory concentrations 
(MIC) by treatment group and treatment groups combined will be provided for the micro-
MITT and the ME populations. Pathogens from urine specimen and blood cultures will be 
presented separately and combined.  All drugs in which MIC data is available will be 
presented.  These include the following.
•
The distribution of MIC to sulopenem, ertapenem, ciprofloxacin, amoxicillin-
clavulanate and other drugs for the baseline pathogens
•
MIC summary statistics (i.e., range, MIC50 and MIC90 for pathogens that have 10 or 
more occurrences) for the study pathogens.
7.3
Prior and Concomitant Medications
All medications taken within 30 days prior to the first dose of the study drug and through the 
FV visit will be recorded on the eCRF.  Medications will be summarized by WHODRUG 
(March 1, 2018 version or higher) ATC level 3 and generic medication name for all 
populations.  Patients will be counted only once for an ATC class and generic medication 
name.
Medications are considered prior if taken prior to the first dose of study drug or if their start 
date is unknown.  Medications are considered concomitant if taken on or after the first dose of 
study drug, or if their stop date is unknown or marked as continuing.
Tables will be provided for prior medications, all concomitant medications and concomitant 
antibacterial medications.  Concomitant medications and concomitant antibacterial 
medications will be present in several tables of medications taken from study start to each visit 


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(e.g., concomitant medications taken from study start through EOT visit).  If a medication was 
taken during this interval, regardless if it was started in that interval, it will be counted.
A listing will be provided of all prior and concomitant medications.
7.4
Study Drug Exposure 
A dosing summary by treatment group will be presented for all study populations. The 
distribution of patients by the number of days on study drug therapy in each treatment group 
will be presented for overall dosing and separately by oral dosing only and IV dosing only.
For patients who step down to active sulopenem etzadroxil/probenecid, each tablet taken is 
considered a half day of therapy.  For patients who step down to active ciprofloxacin, each 
capsule taken is considered a half day of therapy.  For patients who step down to active 
amoxicillin-clavulanate, each capsule taken is considered a half day of therapy.
7.5
Efficacy Analyses
For all efficacy analyses, patient data will be analyzed in the treatment group to which the 
patient was randomized.  Patients who receive the study drug regimen other than the study 
drug regimen to which they were randomized are not included in the CE and ME populations 
by definition. 
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.
By definition, patients with an indeterminate response are included in the denominator for 
analyses in the ITT, MITT and micro-MITT populations, and are counted as failures.
For the ITT, MITT and micro-MITT populations, the proportion of successes is defined using 
the following formula:
Number of successes
Number of successes + Number of failures + Number of indeterminates
By definition, patients in the CE and ME populations must have sufficient information for 
determination of overall response. Thus, for the CE and ME populations, the proportion of 
successes is defined using the following formula:
Number of successes
Number of successes + Number of failures
7.5.1 Primary Efficacy Analysis
The primary outcome is based on overall response at the Day 21 (± 1 day; TOC) visit in the 
micro-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 


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each treatment group in each response category will be reported. The null and alternative 
hypothesis are the following: 
H0: P1 í32  -¨
H1: P1 – P2 > -¨
Where:
P1 = the primary efficacy outcome in the sulopenem IV/sulopenem-etzadroxil group,
P2 = the primary efficacy outcome in the ertapenem/oral ciprofloxacin or amoxicillin-
clavulanate group, 
¨ WKHQRQ-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 Z-
statistic. If the lower limit of the 95% CI for the difference in the micro-MITT population is 
greater than - 10%, the null hypothesis will be rejected and the non-inferiority of sulopenem
IV/sulopenem-etzadroxil to ertapenem/oral ciprofloxacin or amoxicillin-clavulanate will be 
concluded.
7.5.2 Additional Analyses of the Primary Efficacy Outcome
Subgroup Analyses
Infection Type (pyelonephritis vs cUTI without pyelonephritis)
Geographic Region (U.S. vs. non-U.S.)
Fed / Fasted State
Hypoalbuminemia
cUTI Diagnoses
Sensitivity Analyses
Adjustment for Stratification Factor of Infection Type
Patients not eligible to switch to oral therapy due to resistance to the oral agents 
(sulopenem, ciprofloxacin, amoxicillin/clavulanate) will be considered as 
failures
Missing Data / Indeterminates Equal Success
Multiple Imputation for Missing Data
An analysis of the primary endpoint where microbiologic eradication contributing 
to the overall response requires complete eradication defined as no growth 
(<100 CFU/mL) of the baseline pathogen on a follow-up urine culture at TOC.
Overall response defined by improvement of symptoms (instead of resolution) 
from baseline and no worse than mild and no new cUTI symptoms
Overall response defined by urgency and frequency are improved and no worse 
than mild and all other symptoms are resolved and no new cUTI symptoms
Optional Analysis - Patients with Enterobacteriaceae >105 CFU/mL as identified 
by either urine culture or a rapid PCR diagnostic test with an equivalent number 
of copies/ml will be included in the adjusted micro-MITT population
Optional Covariate Analysis


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A LOCF analysis will be conducted where overall response will be carried 
forward for patients who died, if there are enough deaths to justify the analysis. 
All primary analyses are done at TOC in the micro-MITT population
A two-sided 95% CI for the observed difference in the overall response rates will be calculated 
for each subgroup in the below subgroup analyses.
x
The primary efficacy outcome at TOC will be assessed within each baseline infection 
type (pyelonephritis vs cUTI without pyelonephritis) strata by treatment group. 
x
The primary efficacy outcome at TOC will also be assessed within each geographic 
region (U.S. vs. non-U.S.) by treatment group.
x
A subgroup analysis of the primary efficacy outcome by fed / fasted state will be 
conducted.  A patient will be considered fed if they took 100% of their doses in a fed 
state. If the patient did not take oral dosing they will be excluded from this analysis.  
Different proportions of doses taken in a fed state may be explored if the analysis 
suggests that the fed state is associated with outcome.
x
A subgroup analysis of the primary efficacy endpoint in those patients with and without 
hypoalbuminemia (serum albumin <2.0 g/dL) at baseline will be conducted.
x
As presently defined in the study protocol and case report form, 'cUTI without 
pyelonephritis' patients can have 'flank pain or pelvic pain' and 'costovertebral angle 
tenderness'.  An analysis of the primary endpoint will be performed with mutually 
exclusive subgroups of cUTI, specifically 'pyelonephritis', 'cUTI without 
pyelonephritis' and 'cUTI without pyelonephritis' but with evidence of pyelonephritis 
(i.e., 'flank pain or pelvic pain' and 'costovertebral angle tenderness').
Sensitivity analyses of the primary outcome will be conducted and a 2-sided 95% CI will be 
computed for the difference in the success rates between the treatment groups, unless stated 
otherwise.
x
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. 
x
A sensitivity analysis of the primary outcome at TOC will be conducted where patients 
not eligible to switch to oral therapy due to non-susceptibility to the oral agents 
(ertapenem, ciprofloxacin, amoxicillin/clavulanate) will be considered as failures
(patients treated with sulopenem who are non-susceptible to ertapenem and patients 
treated with ertapenem who are non-susceptible to both ciprofloxacin and 
amoxicillin/clavulanate will be considered failures). 
x
A sensitivity analysis will consider all patients who have missing data for the primary 
outcome (i.e., an indeterminate response) as successes.  
x
A sensitivity analysis applying multiple imputation methods for missing data will also 
be conducted.  The multiple imputation analysis assuming a monotone missing data 
pattern will be used to define the missing data (indeterminate response).  One hundred 


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datasets will be created using a logistic regression model with treatment, clinical 
response and microbiological response at EOT, baseline pathogen and possibly other 
variables included as predictive variables.
x
An analysis of the primary endpoint where microbiological eradication contributing to 
the overall response requires complete eradication defined as no growth (<100 
CFU/mL) of baseline pathogen on a follow-up urine culture at TOC.
x
An analysis will consider the primary outcome at TOC defined in section 5.1 except, 
improvement of symptoms (instead of resolution) from baseline and no worse than 
mild and no new cUTI symptoms.
x
An analysis will consider the primary outcome at TOC defined in section 5.1 except, 
urgency and frequency are improved and no worse than mild and all other symptoms 
are resolved and no new cUTI symptoms.
x
An optional analysis of the primary efficacy outcome measure will be conducted in an 
adjusted micro-MITT population utilizing results from both culture and rapid 
diagnostic testing.  ,QDGGLWLRQWRSDWLHQWVZLWK5 CFU/ml by culture, patients with 
baseline urine samples in which a study uropathogen is identified by rapid diagnostic 
WHVWLQJDQGDTXDQWLW\FRQVLVWHQWZLWK5 CFU/ml by culture will be included in the 
micro-MITT population. These patients may include those with a study uropathogen 
identified by culture with an organism burden of >103- <105CFU/ml or patients whose 
urine culture was missing at baseline but for whom a banked urine specimen was 
available for analysis.
x
An optional covariate exploratory analysis using logistic regression will be performed 
using baseline variables such as study drug, bacteremia at baseline, age, gender, race, 
E. coli at baseline, creatinine clearance, albumin, comorbidities, percentage of doses 
taken in fed state, diabetes and other variables if imbalances exist at baseline.   For the 
latter, baseline tables will be reviewed by Iterum prior to the covariate analysis.
Once the covariates are determined, a univariate logistic regression will be run for each 
covariate.  Covariates with a p-YDOXHZLOOEHXVHGLQDPXOWLYDULDWHDQDO\VLVZLWK
a stepwise selection method.  The alpha level for both entering and removing a 
covariate will be 0.10.
7.5.3 Secondary Efficacy Analysis
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 ertapenem group) will be determined and a 95% CI for the observed difference 
will be computed using a Z-statistic.
7.5.4 Additional Efficacy Analyses 
Analysis
Day 5
EOT
(Day 10)
TOC
(Day 21)
FV
(Day 28)


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Overall Response
Micro-MITT
ME
Micro-MITT
ME
Micro-MITT#
ME
Overall Response by Baseline 
Pathogens
Micro-MITT
ME
Micro-MITT
ME
Micro-MITT
ME
Overall Response by MIC
Micro-MITT
ME
Overall Response by Combination of 
Antibiotic Resistance Classes
Micro-MITT
ME
Micro-MITT
ME
Micro-MITT
ME
Overall Response by Assessment 
Day*
Overall Response with Requirement 
that Failure is Both Symptoms and a 
3DWKRJHQ&)8P/
Micro-MITT
ME
Micro-MITT
ME
Micro-MITT
ME
Overall Response by Step Down 
Category
Micro-MITT
ME
Micro-MITT
ME
Micro-MITT
ME
Microbiologic Response
Micro-MITT
ME
Micro-MITT
ME
Micro-
MITT##
ME
Per Pathogen Microbiologic 
Response from Urine, Blood and 
Combined
Micro-MITT
ME
Micro-MITT
ME
MITT
Micro-MITT
ME
Microbiologic Response by ESBL 
Positive and ESBL Negative
Micro-MITT
ME
Micro-MITT
ME
Micro-MITT
ME
Per Pathogen Microbiologic 
Response by MIC
Micro-MITT
ME
Microbiologic Response for 
Complete Eradication
Micro-MITT
ME
Micro-MITT
ME
Micro-MITT
ME
Microbiologic Response for 
Complete Eradication by Baseline 
Pathogens
Micro-MITT
ME
Micro-MITT
ME
Micro-MITT
ME
Microbiologic Response for Post-
Baseline Pathogens
Micro-MITT
ME
Micro-MITT
ME
Patient Determined Clinical Response
ITT
MITT
Micro-MITT
CE
ME
ITT
MITT
Micro-MITT
CE
ME
ITT
MITT
Micro-MITT
CE
ME
ITT
MITT
Micro-MITT
CE
Patient Determined Clinical Response 
by Baseline Pathogen
Micro-MITT
ME
Micro-MITT
ME
Micro-MITT
ME
Micro-MITT
Patient Determined Clinical Response 
by ESBL Positive and ESBL 
Negative
Micro-MITT
ME
Micro-MITT
ME
Micro-MITT
ME
Micro-MITT
Patient Determined Clinical Response 
defined by improvement of symptoms 
(instead of resolution) from baseline 
and no worse than mild and no new 
cUTI symptoms
ITT
MITT
Micro-MITT
CE
ME
Patient Determined Clinical Response 
defined by urgency and frequency are 
improved and no worse than mild and 
all other symptoms are resolved and 
no new cUTI symptoms
ITT
MITT
Micro-MITT
CE
ME
Investigator-Determined Clinical 
Response
ITT
MITT
Micro-MITT
CE
ITT
MITT
Micro-MITT
CE
ITT
MITT
Micro-MITT
CE
ITT
MITT
Micro-MITT
CE


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ME
ME
ME
Patient Symptom Assessment 
Questionnaire
ITT
MITT
Micro-MITT
CE
ME
ITT
MITT
Micro-MITT
CE
ME
ITT
MITT
Micro-MITT
CE
ME
ITT
MITT
Micro-MITT
CE
Patient Symptom Assessment 
Questionnaire – Shift Table of 
Severity
ITT
MITT
Micro-MITT
CE
ME
ITT
MITT
Micro-MITT
CE
ME
ITT
MITT
Micro-MITT
CE
ME
ITT
MITT
Micro-MITT
CE
Patient Symptom Assessment 
Questionnaire – Kaplan-Meier Plot 
for Time to Resolution of All 
Symptoms*
Patient Symptom Assessment 
Questionnaire – Severity by 
Bothersome Questions
ITT
MITT
Micro-MITT
CE
ME
ITT
MITT
Micro-MITT
CE
ME
ITT
MITT
Micro-MITT
CE
ME
ITT
MITT
Micro-MITT
CE
Patient Symptom Assessment 
Questionnaire – Sensitivity Analysis 
using bothersome questions
ITT
MITT
Micro-MITT
CE
ME
ITT
MITT
Micro-MITT
CE
ME
ITT
MITT
Micro-MITT
CE
ME
ITT
MITT
Micro-MITT
CE
Other Signs & Symptoms (rigors / 
chills / temperature, nausea / 
vomiting, costovertebral angle 
tenderness)
ITT
MITT
Micro-MITT
CE
ME
ITT
MITT
Micro-MITT
CE
ME
ITT
MITT
Micro-MITT
CE
ME
Supplementary Clinical Response
ITT
MITT
Micro-MITT
CE
ME
ITT
MITT
Micro-MITT
CE
ME
ITT
MITT
Micro-MITT
CE
ME
# Primary Endpoint
## Secondary Endpoint
* Overall response by assessment day (not grouped by visit) and Kaplan-Meier Plot of time to resolution of 
all PSAQ symptoms are not done at individual visits and will be done in the MITT and micro-MITT
populations.
Overall Response
The number and percentage of patients in each treatment group with an overall response of 
success, failure and indeterminate at Day 5 and EOT will be presented for the micro-MITT
population (note, overall response at TOC in the micro-MITT population is the primary 
endpoint). The number and percentage of patients in each treatment group with an overall 
response of success and failure at Day 5, EOT and TOC will be presented for the ME 
population.  Two-sided 95% unstratified CIs will be constructed for the observed difference 
in the overall success rates between the treatment groups for descriptive purposes; no 
conclusion of NI will be made. Note, overall response is not analyzed in the ITT, MITT and 
CE populations because these populations do not require a baseline pathogen.
Overall response at Day 5, EOT and TOC by baseline pathogen (key pathogens and species 
such as E. coli, Klebsiella species and Proteus species) will be summarized by treatment group 


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in the micro-MITT and ME populations.
Confidence intervals at the genus level will be 
provided.
Overall response by ertapenem MIC and sulopenem MIC for baseline pathogens will be 
provided for TOC visit.
Overall response by combination of antibiotic resistance classes will be provided.  The classes 
will be ESBL status, quinolone non-susceptible (QNS), TMP-SMX resistant, non-susceptible 
to at least 2 classes of antibacterials (MDR – quinolones, TMP-SMX and beta-lactams), 
resistance to all three classes (quinolones, TMP-SMX and beta-lactams) and combinations of 
these resistant classes.
Ceftriaxone will serve as the reference drug for ESBL status, 
ciprofloxacin will serve as the reference drug for the quinolone class, and ampicillin will serve 
as the reference drug for the beta-lactam class. Resistance to a class means resistance to the 
reference drug in that class. A second table will be provided for resistance to oral drugs 
(ciprofloxacin, 
TMP-SMX, 
nitrofurantoin, 
ampicillin, 
amoxicillin-clavulanate 
and 
fosfomycin).  Multi-drug resistance will not be included in this table. However, multi-drug 
resistance will be explored for the primary endpoint in other ways.
Summary tables will be provided comparing the treatment groups by day the overall 
assessment was made.  For example, if patient’s EOT assessment was conducted on day 4 then 
they would be analyzed in the day 4 table.  A figure of overall response by day of assessment 
will be provided too. 
Overall response with failure defined as the patient has both symptoms and a pDWKRJHQ
CFU/mL will be presented for micro-MITT and ME.
Overall response by the IV/Oral treatment regimen they took (e.g., ertapenem IV only, 
ertapenem IV followed by ciprofloxacin, etc.) and what they were supposed to take per 
susceptibility data (e.g., ciprofloxacin susceptible, ciprofloxacin resistant/intermediate and 
amoxicillin/clavulanate, etc.) will be provided.
Microbiologic Response
The number and percentage of patients in each treatment group with a per patient
microbiologic response of success, failure (persistence and persistence with increasing MIC) 
and indeterminate at Day 5 and EOT will be presented for the micro-MITT population (note, 
microbiologic response at TOC in the micro-MITT population is the secondary endpoint). The 
number and percentage of patients in each treatment group with a per patient microbiologic 
response of success and failure at Day 5, EOT and TOC will be presented for the ME 
population.  Two-sided 95% unstratified CIs will be constructed for the observed difference 
in the overall success rates between the treatment groups for descriptive purposes; no 
conclusion of NI will be made.
Per pathogen microbiologic response at Day 5, EOT and TOC by baseline pathogen will be 
summarized by treatment group in the micro-MITT and ME populations separately for urine 
and blood, and then combined. Confidence intervals at the genus level will be provided.
Microbiologic response by ESBL positive and ESBL negative at Day 5, EOT and TOC will 
be summarized by treatment group in the micro-MITT and ME populations.
Per pathogen microbiologic response by ertapenem MIC and sulopenem MIC for individual 
pathogens will be provided for TOC visit.


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The number and percentage of patients in each treatment group with a microbiologic response 
of complete eradication defined as no growth (<102 CFU/mL) of baseline pathogen on a 
follow-up culture at Day 5, EOT and TOC will also be presented for the micro-MITT and ME 
populations and by baseline pathogen. The EMA analysis dataset will include a supportive 
analysis in which <102 CFU/mL at TOC are required in the micro-MITT population.
Additionally, rows for microbiologic response <103, <104 and <105 will be displayed.
Microbiological categories for pathogens identified after baseline assessment are 
superinfection, colonization, new infection and relapse/recurrence. The number and 
percentage of patients with a superinfection, colonization, new infection and recurrence will 
be presented by treatment group. A listing will be provided that presents the patients with a 
superinfection, colonization, new infection and recurrence including the pathogen.
Patient Determined Clinical Response
The number and percentage of patients in each treatment group with a patient-determined 
clinical response of success, failure and indeterminate at Day 5, EOT, TOC and FV will be 
presented for the micro-MITT, MITT and ITT populations. The number and percentage of 
patients in each treatment group with a patient-determined clinical response of success and 
failure at Day 5, EOT, TOC and FV will be presented for the CE and ME populations (there 
isn’t an ME population for FV since it was a phone call visit).  Two-sided 95% unstratified 
CIs will be constructed for the observed difference in the overall success rates between the 
treatment groups for descriptive purposes; no conclusion of NI will be made.
Patient determined clinical response will also be presented by baseline pathogen and by ESBL 
positive/negative for Day 5, EOT, TOC and FV in each treatment group for all populations.
Confidence intervals at the genus level will be provided.
Patient determined clinical response defined by improvement of symptoms (instead of 
resolution) from baseline and no worse than mild and no new cUTI symptoms will also be 
presented for Day 5, EOT and TOC in each treatment group for all populations.
Patient determined clinical response defined by urgency and frequency are improved and no 
worse than mild and all other symptoms are resolved and no new cUTI symptoms will also be 
presented for Day 5, EOT and TOC in each treatment group for all populations.
Investigator-Determined Clinical Response
Investigator-determined clinical response (clinical success, failure and indeterminate) at the 
Day 5, EOT, TOC and FV visits will be presented by treatment group for the micro-MITT, 
MITT, ITT, CE and ME 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.
Patient Symptom Assessment Questionnaire
A table of the severity of each cUTI symptom based on the PSAQ to Day 5, EOT, TOC and 
FV will be provided by treatment group for all populations.
A shift table of the severity of each cUTI symptom based on the PSAQ from baseline to Day 
5, EOT, TOC and FV will be presented by treatment group for the micro-MITT, MITT, ITT, 


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CE and ME populations.
Kaplan-Meier plots for time to resolution of all PSAQ symptoms will be provided for the 
MITT and micro-MITT populations.  Patients will be censored at time of taking non-study 
antibacterial therapy for cUTI, lost to follow-up or at the end of the study if the symptoms 
have not resolved.
A two-way table for each symptom will be provided by treatment group with severity of the 
symptom as rows and the bothersome responses as columns for Day 5, EOT and TOC in the 
micro-MITT, MITT, ITT, CE and ME populations.  
An additional analysis will then be performed in which “negative symptoms” will be defined 
as not at all or not significantly bothersome for mild symptoms.  These negative symptoms 
will be counted as ‘no symptom’.
Supplementary Clinical Response
The other signs and symptoms (rigors / chills / temperature, nausea / vomiting, costovertebral 
angle tenderness) will be added to the PSAQ signs and symptoms to create a supplementary 
clinical response which will be the same as patient-determined clinical response but with the 
added signs and symptoms.
The number and percentage of patients in each treatment group with a supplementary clinical 
response of success, failure and indeterminate at Day 5, EOT and TOC will be presented for 
the micro-MITT, MITT and ITT populations. The number and percentage of patients in each 
treatment group with a supplementary clinical response of success and failure at Day 5, EOT 
and TOC will be presented for the CE and ME populations.  Two-sided 95% unstratified CIs 
will be constructed for the observed difference in the overall success rates between the 
treatment groups for descriptive purposes; no conclusion of NI will be made.
7.6
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.


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7.7
Safety Analyses
All safety analyses will be conducted in the Safety population. Patients who receive the wrong 
study drug for their entire course of treatment will be analyzed in the group based on the drug 
received. Safety parameters include AEs, clinical laboratory parameters and vital signs. For 
each safety parameter, the last assessment made before the first dose of study drug will be used 
as the baseline for all analyses.
7.7.1 Adverse Events
Verbatim descriptions of AEs will be coded using Version 21.0 or higher of MedDRA. 
Summary tables will be provided for all treatment-emergent AEs (TEAEs). An AE is defined
as any untoward medical occurrence in a clinical investigation patient administered a product 
or medical device, unless the event is captured in the study outcome, as defined below; the 
event need not necessarily have a causal relationship with the treatment or usage. A TEAE is 
any AE that newly appeared, increased in frequency, or worsened in severity following 
initiation of study drug (on or after start date and time of first dose). All AEs (including non-
TEAEs), serious TEAEs, and TEAEs leading to study drug discontinuation will be provided 
in listings by treatment group, site, patient, verbatim term, MedDRA system organ class and 
preferred terms, onset and resolution date, seriousness flag, intensity, relationship to study 
drug, action taken and outcome.
An overall summary of AEs will include number of patients who experienced at least one AE 
of the following categories: any AE, any TEAE, any drug-related TEAE defined as possibly 
or probably related to study drug, any serious TEAE, any drug-related SAE, any SAE leading 
to death, any TEAE leading to premature discontinuation of study drug or study, and any SAE 
leading to premature study drug discontinuation.
The number and percentage of patients reporting a TEAE in each treatment group will be 
tabulated by system organ class and preferred term for all TEAEs. TEAEs will also be 
summarized separately by system organ class, preferred term, and intensity (mild, moderate, 
and severe); and by system organ class, preferred term, and [unrelated (unrelated or unlikely) 
or related (possibly or probably)] to IV and oral study drug. The incidence of all TEAEs that 
occur in at least 1% and 2% of patients in either treatment group will be summarized separately 
by preferred term and treatment group, sorted by decreasing frequency in the Sulopenem 
group. A table will provide all SAEs (through FV) by system organ class and preferred term. 
For all analyses of TEAEs, if the same AE (based on preferred term) is reported for the same 
patient more than once, the AE is counted only once for that preferred term and at the highest 
intensity and strongest relationship to study drug.
The incidence of treatment emergent adverse events by system organ class, preferred term will 
also be presented by gender, race (list all categories collected) and age DQG.
Analysis of the distribution of the duration of each adverse event as well as an overall mean 
adverse event duration in days for each treatment regimen will be presented. If the AE is still 
ongoing at the last visit, it will be censored at the last visit.
If an AE starts on the same day that dosing is initiated, and the start time of the AE is missing 
then the AE is considered TEAE.
7.7.1.1 Diarrhea Episodes


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Diarrhea episodes will be collected on the adverse event page and include verbatim terms 
diarrhea and loose or watery stools.  An AE event will be captured each day there is an episode.  
If there are multiple episodes on a day, the number of episodes will be captured in the verbatim 
term with an ‘X’ followed by the number of episodes (e.g., X3).
Clinically significant diarrhea is defined as having three or more episodes of diarrhea 
(preferred term which will included loose or watery stools verbatim terms) in one day or 
having two or more episodes of diarrhea per day for two consecutive days.
The number and percentage of treatment emergent episodes of clinically significant diarrhea
and number and percentage of subjects with treatment emergent clinically significant episodes 
of diarrhea will be summarized by severity level and drug relatedness. If severity level differs 
or drug relatedness differs across days, then the worst severity or the worst drug-relatedness 
will be used. The duration of treatment emergent clinically significant episodes (i.e., the 
number of days that diarrhea lasts) will also be summarized. The number of treatment 
emergent clinically significant episodes and the number of subjects with clinically significant 
episodes of diarrhea will be analyzed by fed / fasted state. If the patient did not take oral 
dosing they will be excluded from this analysis.  Only AEs that occur while taking oral dosing 
will be analyzed.
The following bar charts will be provided for diarrhea episodes:
x
Duration of Diarrhea 
x
Number of Episodes of Diarrhea by Study Day
x
Percent of Subjects with Diarrhea by Study Day
x
Duration of Clinically Significant Diarrhea 
x
Number of Episodes of Clinically Significant Diarrhea by Study Day
x
Percent of Subjects with Clinically Significant Diarrhea by Study Day
7.7.2 Laboratory Values
Several analyses of the laboratory data will be presented. Both local and central labs were 
performed.  Only the central lab data will be summarized.  However, if a central lab value is 
missing the local lab value will be used for the summary table. A listing will contain all lab 
data from both local and central labs.
For descriptive statistics of actual values and the change from baseline, values obtained from 
local laboratories will be normalized against the central laboratory normal ranges according to 
the following formula (Karvanen):
where s = the individual local laboratory value normalized against the central laboratory 
normal range; x = the original individual laboratory value; Ux is the upper limit of the normal 
range for an individual laboratory parameter; Us is the upper limit of the laboratory normal 
range for that laboratory parameter from the common source.


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Descriptive statistics for chemistry and hematology values and the change from baseline will 
be summarized for all study visits. The change from baseline to each post-baseline visit will 
also be summarized by treatment group and it will be calculated for each patient at the specified 
visit as the value at the specified visit minus the baseline value. 
Laboratory values will also be classified as of potential clinical concern. The number and 
percentage of patients with a laboratory value of potential clinical concern will be summarized 
by visit and treatment group and broken out by patients with normal and abnormal at baseline.  
Worst overall value for each test will be used for this table.  For a few tests, worst value can 
have both a low and a high value.  When calculating the worst overall value, use the highest 
value when dealing with ULN or a > sign or a >= sign and use the lowest value when dealing 
with LLN or a < sign or a <= sign. See appendix B.
The number and percentage of patients in each treatment group with an elevated ALT level 
(>3 x ULN, >5 x ULN, and >10 x ULN), an elevated AST level (>3 x ULN, >5 x ULN, and 
>10 x ULN) and an elevated bilirubin level (>1.5 x ULN and >2 x ULN) will be presented by 
study visit and any visit post-baseline. The denominator will be number of patients within
normal limits at baseline.
Tables will be provided for elevated ALT and AST levels (>ULN, >ULN to 3 x ULN, >3 x 
ULN to 5 x ULN, >5 x ULN to 10 x ULN, >10 x ULN to 20 x ULN, >20 x ULN) and elevated 
ALT and AST levels by normal and abnormal at baseline.  Additionally, shift tables will be 
provided for elevated ALT and AST levels (shift from baseline to each study visit for each of 
the cutoffs).
A listing of patients who meet the laboratory screening criteria for potential Hy‘s law cases 
will also be provided. The laboratory screening criteria for identification of potential Hy‘s law 
cases for further review are defined as any elevated ALT and/or AST of >3xULN that is 
associated with both an ALP<2xULN and an increase LQELOLUXELQ[8/1
For “worst overall value” post-baseline analyses, all laboratory assessments including those 
obtained from unscheduled visits will be included.  
For by-visit analyses, the value closest to the target date for the visit will be used in the analyses 
if more than one laboratory assessment was within the visit window (i.e., unscheduled 
assessments were obtained). If two values are equidistant from the planned visit date, then the 
first value will be used.
Detailed patient listings of all laboratory data collected during the study will be provided. 
Laboratory values outside normal limits will be identified in the patient data listings with flags 
for low (L) and high (H).
7.7.3 Physical Examinations
Detailed patient listings of all physical examination results will be provided. 
7.7.4 Vital Signs
Blood pressure (systolic and diastolic), respiration rate, pulse rate, and temperature will be 
summarized using descriptive statistics at each study visit by treatment group.  Descriptive 
statistics of the change from baseline will also be provided.  Change from baseline will be 
calculated for each patient at the specified visit as the value at the specified visit minus the 


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baseline value.  
Vital signs will also be classified as of potential clinical concern (Appendix B). The number 
and percentage of patients with a vital sign measurement of potential clinical concern will be
summarized by treatment group and broken out by patients with normal and abnormal at 
baseline.
For by-visit analyses, the value closest to the target date for the visit will be used in the analyses 
if more than one assessment was within the visit window (i.e., unscheduled assessments were 
obtained).  If two values are equidistant from the planned visit date, then the first value will 
be used.
7.8
Protocol Deviations
A listing of all protocol deviations will be provided. Deviations will also be reviewed by the 
Sponsor concurrent with the conduct of the study and categorized into general categories such
as: inclusion/exclusion criteria, study drug administration, informed consent, visit schedule, 
test and procedures, randomization error, and other. The deviations will be adjudicated as 
major or minor per the Iterum process. Major deviations are defined as departures from the
protocol that impact subject safety or data integrity. The number of patients with at least one 
protocol deviation and the number of patients with at least one deviation in each category will 
be presented by treatment group for the ITT population. They will also be presented by major 
/ minor classification.
Protocol deviations that impact the analyses will be noted by the clinical team so that the 
identified patients can be excluded from the appropriate CE population.  Most, if not all, 
protocol deviations impacting the analyses and requiring exclusion will be excluded 
automatically through programming of other CE criteria (e.g., outcome assessment done 
within window or concomitant antibiotic).


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8
DIFFERENCES WITH ANALYSES SPECIFIED IN THE PROTOCOL
The following is the list of differences between the current protocol and the SAP:
x
The following are additions or changes to the clinical evaluable definition:
o
The patient must meet all inclusion and none of exclusion criteria.
o
Received appropriate adjunctive antibacterial coverage (i.e., such as, but not 
limited to, linezolid, daptomycin or vancomycin) if the patient had a culture-
documented Enterococcus spp. or other gram-positive resistant pathogens 
(excluding S. saprophyticus) at baseline and has symptoms (PSAQ) at the post-
baseline visit.
o
Site personnel involved in the assessment of efficacy parameters must have 
remained blinded to study treatment up to the time of the efficacy assessment.
o
Patients who receive study drug therapy beyond the protocol treatment period 
as a result of the investigator's assessment that additional drug therapy is needed 
for treatment of the underlying cUTI infection will be defined as failures for 
patient determined clinical response at TOC. Thus, these patients will be 
included in the CE populations, if all other criteria are met.
x
For microbiologic response, post baseline responses of superinfection, new infection, 
colonization and recurrence were added.
x
The analysis of diarrhea has been added.
x
The following sensitivity analyses of the primary endpoint have been added:
o
Overall response defined by improvement of symptoms (instead of resolution) 
from baseline and no worse than mild and no new cUTI symptoms
o
Overall response defined by urgency and frequency are improved and no worse 
than mild and all other symptoms are resolved and no new cUTI symptoms
o
Missing Data / Indeterminates Equal Success
o
Multiple Imputation for Missing Data
o
Overall response defined by both urine and blood cultures
o
Patients with baseline urine samples in which a study uropathogen is identified 
by rapid diagnostic testing DQG DTXDQWLW\FRQVLVWHQWZLWK5 CFU/ml by 
culture will be included in the micro-MITT population. These patients may 
include those with a study uropathogen identified by culture with an organism 
burden of >103- <105 CFU/ml or patients whose urine culture was missing at 
baseline but for whom a banked urine specimen was available for analysis.
o
A LOCF analysis will be conducted where overall response will be carried 
forward for patients who died, if there are enough deaths to justify the analysis.
o
Covariate Analysis
o
cUTI baseline factors
o
Hypoalbuminemia


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9
REFERENCES
1. Farrington CP, Manning G. Test statistics and sample size formulae for comparative 
binomial trials with null hypothesis of non-zero risk difference or non-unity relative risk. 
Stat Med. 1990 Dec;9(12):1447–54.
2. Miettinen O, Nurminen M. Comparative analysis of two rates. Statistics in Medicine. 
1985;4(2):213-26.
3. Guidance for Industry: Non-Inferiority Clinical Trials. Draft. March 2010.
4. Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation. 
July 2009.
5. Guidance for Industry: Adaptive Design and Clinical Trials for Drugs and Biologics. 
Draft. March 2010.
6.
Karvanen J. The Statistical Basis of Laboratory Data Normalization. Drug Information 
Journal, Vol. 37, pp. 101–107, 2003.


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Appendix A: 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.
4  In the subset of patients enrolled in the PK sub-study, collect plasma for PK analysis 2 hours and 4 hours post-


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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 B: Criteria for Safety Values of Potential Clinical Concern
Hematology
Hemoglobin
<0.8 x baseline
Hematocrit
<0.8 x baseline
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
t10/HPF
Urine RBC
t50/HPF
Vital Signs
Pulse Rate
<40 or >130 bpm, when baseline resting heart rate is 60-120 bpm
Blood Pressure
Systolic t30 mm Hg change from baseline in same posture
Systolic <80 mm Hg
Diastolic t20 mm Hg change from baseline in same posture
Diastolic <50 mm Hg


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Appendix C: Method for Determination of Creatinine Clearance
Creatinine clearance should be determined by the method of Cockroft-Gault based on serum 
creatinine concentrations, using ideal body weight instead of actual weight.
For females:
GFR = [(140-age) * (Ideal body wt in kg) * 0.85] / (72 * Cr), for serum Cr reported as 
mg/dl
GFR = [(140-age) * (Ideal body wt in kg) * 1.0455] / (Cr), for serum Cr reported as 
micromol/L
Ideal body weight is calculated as:
For females: 
If H > 152.5 cm
Ideal body weight (kg) = 45.4 + [(H-152.4) * 0.89]
If H < 152.5 cm
Ideal body weight  (kg) = 45.4 – [(152.4 – H)* 0.89]
Reference: Gault MH, Longerich LL, Harnett JD, Wesolowski C (1992). "Predicting glomerular function from 
adjusted serum creatinine". Nephron. 62 (3): 249–56


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Appendix D: Microbiology Rules for Determination of Final Pathogen
Urine Culture
1.
Baseline urine sample is submitted for culture to Local/Regional Lab 
2.
All pathogens identified at the local/regional lab will be considered as part of the baseline urine culture 
result.
a. Uropathogens as defined in section 6.4 will be sent to IHMA for confirmation and IHMA 
confirmation will be final  
b. Non-uropathogens not sent to IHMA or isolates not available for confirmation at IHMA will remain 
as identified by the local lab.
3.
If Local/Regional Lab’s urine culture yields >2 micro-organisms in a quantity of >105 CFU/mL, this 
will be considered as “contaminated.”
Blood Culture
1.
Baseline blood sample is submitted for culture to Local/Regional Lab
a.
If Local/Regional Lab’s blood culture is “no growth”, then the Local/Regional Lab’s result is 
accepted as final
b.
If Local/Regional Lab’s blood culture yields an organism(s), the isolate(s) is forwarded to IHMA 
for confirmation
i.
The result of IHMA’s testing of this isolate(s) will be accepted as the final result
c.
If Local/Regional Lab’s isolate(s) is lost or dies in transit then the Local/Regional Lab’s pathogen 
identification will be accepted as the final result.