Conditions: Urinary Tract Infections Cystitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2229
Healthy volunteers: no

Brief summary:
Study 310 is a clinical study which compares the effectiveness of oral sulopenem versus oral amoxicillin/clavulanate for the treatment of adult women with uncomplicated urinary tract infection.

Detailed description:
IT001-310 is a Phase 3, randomized, multicenter, double-blind, double dummy, controlled study to compare oral sulopenem etzadroxil/probenecid (oral sulopenem) to oral amoxicillin/clavulanate for the treatment of adult female patients with uncomplicated urinary tract infection. Approximately 1966 adult women with uncomplicated urinary tract infection will be randomized in a 1:1 fashion to receive either oral sulopenem etzadroxil/probenecid or oral amoxicillin/clavulanate twice daily for 5 days. The primary outcome measure for efficacy evaluation will be the overall success (combined clinical and microbiologic success) on Day 12 (± 1 day)/Test of Cure (TOC).

Arms:
arm 1: Sulopenem etzadroxil/probenecid 500 mg/500 mg PO twice daily for 5 days arm 2: Amoxicillin/clavulanate PO twice daily for 5 days

Interventions: intervention 1: Sulopenem etzadroxil/probenecid intervention 2: Amoxicillin/clavulanate
Intervention descriptions: intervention 1: Oral sulopenem twice daily for 5 days intervention 2: Oral Augmentin twice daily for 5 days

Protocol document:
Prot_000.pdf: 
Sulopenem etzadroxil 
 
Iterum Therapeutics International Limited 
Clinical Trial Protocol: IT001-310 
 
December 2022 
Confidential 
Page 1 of 84 
Clinical Trial Protocol: IT001-310 
Study Title: 
A prospective, Phase 3, randomized, multi-center, double-blind 
study of the efficacy, tolerability, and safety of oral sulopenem 
etzadroxil/probenecid versus oral amoxicillin/clavulanate for 
treatment of uncomplicated urinary tract infections (uUTI) in 
adult women. 
Study Number: 
IT001-310 
Study Phase: 
Phase 3 
Product Name: 
Sulopenem etzadroxil/probenecid tablets (500 mg/500 mg) 
IND Number: 
129,849 
EudraCT Number 
2017-003771-57 
Indication: 
Uncomplicated urinary tract infection 
Investigators: 
Multicenter 
Sponsor: 
Iterum Therapeutics International Limited 
Fitzwilliam Court, 1st Floor, Leeson Close 
Dublin 2, D02 YW24 
Ireland 
Sponsor Contact: 
Sailaja Puttagunta, MD 
Sponsor’s US Agent: Iterum Therapeutics US Limited 
20 Research Parkway, Suite A 
Old Saybrook, CT 06475 
Medical Monitors: 
Brian Murphy, MD and Phillip Cole, MD (Medpace) 
Steven I. Aronin, MD (Sponsor) 
 
Pharmacovigilance: 
Medpace Clinical Safety 
Medpace SAE reporting line – United States: 
Telephone: +1-800-730-5779, dial 3 or +1-513-579-9911, dial 3 
Fax: +1-866-336-5320 or +1-513-570-5196 
Email: medpace-safetynotification@medpace.com  
 
   Date 
Original Draft Protocol  
May 31, 2022 
Final Protocol 
July 7, 2022 
Amendment 1 
December 5, 2022 
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. 
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SYNOPSIS  
Sponsor: 
Iterum Therapeutics International Limited 
Name of Finished Product: 
Sulopenem etzadroxil/probenecid tablets (500 mg/500 mg) 
Study Title: 
A prospective, Phase 3, randomized, multi-center, double-blind study of the efficacy, 
tolerability, and safety of oral sulopenem etzadroxil/probenecid versus oral 
amoxicillin/clavulanate for treatment of uncomplicated urinary tract infections (uUTI) in adult 
women. 
Study Number: 
IT001-310 
Study Phase: Phase 3 
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Objective(s):  
Non-inferiority Trial: 
Objective 
Estimand/Endpoint 
Primary: 
To compare the overall response (clinical and 
microbiologic combined response) at Day 12 
(±1 day)/test of cure (TOC) of oral sulopenem 
etzadroxil/probenecid tablets (500 mg/500 
mg) versus oral amoxicillin/clavulanate (875 
mg/125 mg) tablets for the treatment of 
uncomplicated urinary tract infection in adult 
women. 
Primary Estimand: 
Endpoint of interest: Overall success 
at Day 12 (±1 day)/TOC (clinical and 
microbiologic combined) 
Intercurrent events: non-susceptibility 
or resistance to 
amoxicillin/clavulanate, use of rescue 
antibiotic, study discontinuation 
Population level summary of variable: 
Comparison of overall success rates 
between treatment groups 
Secondary: 
Secondary Endpoints: 
To evaluate the clinical efficacy at Day 12 
(±1 day)/TOC. 
Clinical cure (resolution of the 
symptoms of uUTI present at trial 
entry and no new uUTI symptoms) at 
Day 12 (±1 day)/TOC. 
To evaluate the rate of post-treatment 
asymptomatic bacteriuria at Day 12 (±1 
day)/TOC.  
Clinical cure (resolution of the 
symptoms of uUTI present at trial 
entry and no new uUTI symptoms) 
and microbiologic persistence (≥ 103 
CFU/mL of the baseline uropathogen) 
at Day 12 (±1 day)/TOC 
To evaluate the microbiologic efficacy at Day 
12 (±1 day)/TOC. 
Microbiologic eradication (<103 
CFU/mL of the baseline uropathogen) 
at Day 12 (±1 day)/TOC 
To further evaluate the safety profile of oral 
sulopenem etzadroxil/probenecid tablets (500 
mg/500 mg) when used for treatment of uUTI 
in adult women. 
Incidence of TEAEs through Day 28 
(±2 days); Changes from baseline in 
clinical laboratory tests at the Day 12 
(±1 day)/TOC visit; Changes from 
baseline in vital signs at the Day 5 (+1 
day)/EOT, and Day 12 (±1 day)/TOC 
visits 
Additional: 
Additional Endpoints: 
To evaluate the clinical efficacy at Day 5 (+1 
day) and Day 28 (±2 days). 
Clinical cure (resolution of the 
symptoms of uUTI present at trial 
entry and no new uUTI symptoms) at  
Day 5 (+1day) and Day 28 (±2 days). 
To evaluate the rate of post-treatment 
asymptomatic bacteriuria at Day 5 (+1 day) 
and Day 28 (±2 days).  
Clinical cure (resolution of the 
symptoms of uUTI present at trial 
entry and no new uUTI symptoms) 
and microbiologic persistence (≥ 103 
CFU/mL of the baseline uropathogen) 
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at Day 5 (+1 day) and Day 28 (±2 
days). 
To evaluate the microbiologic efficacy at Day 
5 (+1 day) and Day 28 (±2 days). 
Microbiologic eradication (<103 
CFU/mL of the baseline uropathogen) 
at Day 5 (+1 day) and Day 28 (±2 
days). 
To evaluate overall response at other relevant 
timepoints 
Overall success (clinical and 
microbiologic combined response) at 
Day 5 (+1 day) and Day 28 (±2 days) 
visits 
To evaluate the investigator determined 
clinical response 
Investigator determined clinical 
response (clinical success, failure, and 
indeterminate) at Day 5 (+1 day), Day 
12 (±1 day)/TOC, and Day 28 (±2 
days) 
To evaluate overall success, clinical success, 
and microbiologic success by key baseline 
pathogens 
Overall success, clinical success, and 
microbiologic success at Day 5 (+1 
day), Day 12 (±1 day)/TOC, and Day 
28 (±2 days) by key baseline pathogen 
 
Study Design:  
Sulopenem is an investigational thiopenem antibiotic being developed for treatment of 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 expected to be rapidly hydrolyzed to yield sulopenem, the active 
moiety.   
Sulopenem possesses potent activity against species of the Enterobacterales including those 
that encode Extended Spectrum β-lactamase (ESBL) or AmpC-type β-lactamases that confer 
resistance to third generation cephalosporins. Sulopenem etzadroxil is expected to be the first 
oral penem for uUTI on the market in the United States and Europe and will offer the option 
of treatment in the outpatient setting as well as intravenous (IV) to oral switch therapy for 
early discharge of patients hospitalized with serious, complicated infections.  Probenecid, co-
administered with the oral prodrug, in a bilayer tablet formulation, will reduce renal clearance 
and increase systemic exposure of the active moiety, sulopenem (CP-70,429).   
 
This trial is a prospective Phase 3, randomized, multicenter, double-blind, double dummy, 
controlled study to compare oral sulopenem etzadroxil/probenecid (oral sulopenem) to oral 
amoxicillin/clavulanate for the treatment of patients with uUTI.  Approximately 1966 adult 
women with uUTI will be randomized in a 1:1 fashion to receive either a bilayer tablet with 
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sulopenem etzadroxil/probenecid 500 mg/500 mg twice daily for 5 days or oral 
amoxicillin/clavulanate 875 mg/125 mg twice daily for 5 days.  
The primary outcome measure for efficacy evaluation will be the overall success (combined 
clinical and microbiologic success) on Day 12 (± 1 day)/TOC in the micro-MITT, micro-
MITTS and micro-MITTR populations.  
The micro-MITT population will be comprised of all randomized patients who received at 
least one dose of study drug and had ≥105 CFU/mL of a baseline pathogen (Enterobacterales 
or Staphylococcus saprophyticus only) isolated from a urine culture specimen taken at 
baseline, prior to initiation of study drug therapy. 
 
The primary comparison of the study is in the micro-MITT population (the combined 
population of patients with a positive baseline culture and without regard to 
amoxicillin/clavulanate susceptibility). These outcomes are most relevant to the practicing 
clinician who must choose empiric treatment of uUTI before culture results become available. 
From a regulatory perspective, these results will help put into context the outcomes in the 
culture and susceptibility- driven subpopulations. 
The primary comparisons for regulatory approval are in two mutually exclusive sub-
populations of the micro-MITT population defined by a baseline characteristic, the micro-
MITTS and micro-MITTR populations: 
 
• The micro-MITTS population: the subset of patients whose baseline pathogens are 
determined to be susceptible (MIC ≤ 8/4 mg/L) to the comparator study drug, 
amoxicillin/clavulanate. 
• The micro-MITTR population: the subset of patients whose baseline pathogen is 
determined to be non-susceptible [intermediate (MIC 16/8 mg/L) or resistant (MIC ≥ 
32/16 mg/L)] to the comparator study drug, amoxicillin/clavulanate. 
Amoxicillin/clavulanate breakpoints as per Clinical Laboratory Standards Institute (CLSI) 
(M100 Performance Standards for Antimicrobial Susceptibility Testing, 32nd edition).  
Study Population:  
A total enrollment of approximately 1966 patients is planned.   
Patients will be randomized using an Interactive Web Randomization System (IWRS) into the 
study, provided they have satisfied all patient selection criteria.    
Inclusion Criteria: 
1. Female patients ≥18 years of age with ≥24 hours and ≤96 hours of urinary symptoms 
attributable to a UTI  
2. Two of the following signs and symptoms of uUTI: urinary frequency, urinary 
urgency, pain or burning on micturition, suprapubic pain 
3. A mid-stream urine specimen with:  
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a. a machine-read dipstick positive for nitrite AND any positive leukocyte 
esterase 
OR,  
b. evidence of pyuria alone as defined by either: 
i. a machine-read dipstick positive for large leukocyte esterase OR  
ii. at least 10 white blood cells per cubic millimeter on microscopic 
analysis of unspun urine OR  
iii. White blood cell count ≥10 cells/HPF in the sediment of a spun urine 
4. Has given written informed consent to participate in the study 
Exclusion Criteria: 
1. Presence of signs and symptoms suggestive of acute pyelonephritis defined as: fever 
(temperature > 38° Celsius), chills, costovertebral angle tenderness, flank pain, nausea, 
and/or vomiting 
2. Receipt of antibacterial drug therapy potentially effective as treatment of uUTI within 
the prior 7 days 
3. Concurrent use of non-study treatments that would have a potential effect on outcome 
evaluations in patients with uUTI, including analgesics (e.g., non-steroidal anti-
inflammatory drugs, aspirin, paracetamol etc.), phenazopyridine, and cranberry 
products. Note: Patients can be included if these medications were previously taken 
and have ceased at the time of Screening onward.  
4. Any anatomical abnormality of the urinary tract, including surgically modified urinary 
tract anatomy, and obstructive uropathy due to nephrolithiasis, stricture, tumor, or 
fibrosis 
5. Ongoing urinary retention 
6. Neurogenic bladder 
7. Current resident of a long-term care facility 
8. Instrumentation of urinary tract in the previous 30 days 
9. An indwelling urinary catheter, ureteral stent or other foreign material in the urinary 
tract 
10. Any history of trauma to the pelvis or urinary tract 
11. Current urine culture, if available while evaluating eligibility, that is positive for more 
than 2 microorganisms regardless of colony count (contaminated), or confirms a fungal 
UTI 
12. Receiving hemodialysis, hemofiltration, peritoneal dialysis, or had a renal transplant 
13. Immunocompromised as evidenced by any of the following: 
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• Known HIV positive, with either a recent (in the past 6 months) AIDS-defining 
condition or a CD4 + T lymphocyte count <200/mm3  
• Known neutropenia (defined as absolute neutrophil count <1000 cells/mm3) 
• 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 
• Immunosuppressive therapy, including maintenance corticosteroid therapy 
(>40 mg/day equivalent prednisolone for 5 days or more in the 30 days prior to 
randomization) 
14. Known liver function abnormalities as defined by the following laboratory criteria: 
• ALT or AST > 3x upper limit of normal, and/or 
• Total bilirubin > 2x upper limit of normal 
15. Females of child-bearing potential who are unable to take adequate contraceptive 
precautions (refer to Sections 4.4 and 4.5), have a positive pregnancy test result within 
24 hours of study entry, are otherwise known to be pregnant, or are currently 
breastfeeding 
16. Poorly controlled Diabetes mellitus, including the presence of ketoacidosis and 
hyperosmolar hyperglycemia 
17. History of seizures 
18. History of blood dyscrasias 
19. History of uric acid kidney stones 
20. Acute (current) gouty arthritis 
21. Concomitant administration of valproic acid 
22. History of allergy or hypersensitivity to carbapenems, β-lactams or probenecid, as 
formulated with their excipients 
23. Unlikely to survive the 4-week study period or has a rapidly progressive or terminal 
illness, including septic shock, associated with a high risk of mortality 
24. The use of any other investigational drug in the 30 days prior to the first dose of study 
drug, or prior participation in any sulopenem clinical trial 
 
Urine samples, including results from urine tests, collected as part of routine standard of care, 
prior to obtaining informed consent, may be used to assess eligibility for enrollment into study 
and/or for baseline urine culture. 
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Test Product, Dose, and Mode of Administration:  
Patients will be randomized to receive either an oral bilayer tablet with sulopenem 
etzadroxil/probenecid 500 mg/500 mg PO twice daily for 5 days or oral 
amoxicillin/clavulanate 875 mg/125 mg PO twice daily for 5 days. 
Patients found to have pathogens isolated from urine cultures that are resistant to 
amoxicillin/clavulanate or carbapenems may be allowed to continue on study drug therapy to 
complete the 5-day duration of treatment based on clinical response and investigator 
judgement and are not required to receive alternative antibiotic therapy. 
Adjunctive Systemic Antibiotics (Rescue Therapy) 
In general, adjunctive systemic antibiotics are not allowed for patients enrolled in the study.  
At any time during the study period, and at the discretion of the principal investigator (PI), 
additional antibiotics—oral or IV, as appropriate—can be prescribed as rescue therapy, e.g., in 
the event of worsening signs and symptoms of uUTI, or if the patient develops fever and/or 
flank pain suggestive of upper urinary tract involvement. In the event that rescue therapy is 
prescribed, patient symptoms will be collected as an unscheduled event; such patients will be 
considered as treatment failures and will be asked to still complete all protocol-specified 
assessments through the Final Visit. Use of adjunctive antibiotics without clinical symptoms is 
strongly discouraged. 
Other Systemic Antibiotics: 
For Clostridioides difficile infections, metronidazole (IV or oral), vancomycin (oral or rectal), 
or fidaxomicin (oral) may be used in both treatment groups. Patients with a co-infection with a 
gram-positive uropathogen known or suspected to be resistant to study drugs are allowed to 
receive agents with narrow spectrum gram-positive coverage (such as oral linezolid) at the 
discretion of the investigator. 
Formulation and Packaging: 
Sulopenem etzadroxil treatment group:  The study drug will be supplied as a study kit 
containing one bottle with 10 bilayer tablets containing sulopenem etzadroxil/probenecid 500 
mg/500 mg and one blister wallet containing10 amoxicillin/clavulanate placebo capsules. 
Comparator treatment group:  The study drug will be supplied as a study kit containing one 
blister wallet containing 10 over-encapsulated amoxicillin/clavulanate 875 mg/125 mg tablets, 
and one bottle with 10 placebo tablets to match sulopenem etzadroxil/probenecid tablets.  
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Preparation and Dispensing: 
Each patient will receive a treatment kit containing one 5-day treatment course of either 
sulopenem etzadroxil/probenecid and placebo amoxicillin/clavulanate or placebo sulopenem 
etzadroxil/probenecid and amoxicillin/clavulanate. 
Administration: 
Patients randomized to the sulopenem treatment group will take one sulopenem 
etzadroxil/probenecid tablet and one placebo capsule twice daily for 5 days and those 
randomized to the amoxicillin/clavulanate treatment group will take one over-encapsulated 
amoxicillin/clavulanate tablet and one placebo tablet twice daily for 5 days (10 doses total 
over a 5-day period; if Dose 1 is taken in the evening of Day 1, Dose 10 will be taken in the 
morning of Day 6). The first dose of each medication will be administered under the 
supervision of study site personnel to help ensure compliance with dosing directions. 
Dosing with food:  
Food significantly increases bioavailability of sulopenem and consequently results in 
decreased rates of diarrhea. Therefore, dosing of oral sulopenem 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.  
Amoxicillin and clavulanate are well absorbed from the gastrointestinal tract after oral 
administration. Dosing in the fasted or fed state has minimal effect on the pharmacokinetics of 
amoxicillin. While amoxicillin/clavulanate can be given without regard to meals, absorption of 
clavulanate when taken with food is greater relative to the fasted state. Therefore, dosing of 
oral amoxicillin/clavulanate with food whenever possible is also recommended. 
Efficacy Assessments: 
 
The assessment of clinical response includes a review of the following symptoms at the 
Baseline, Day 5 (+1 day)/End of Treatment (EOT) visits, and the Day 12 (± 1 day)/TOC, and 
Day 28 (± 2 days) visits or at Premature Discontinuation: urinary frequency, urinary urgency, 
pain or burning on micturition, and suprapubic pain.  
Microbiologic response assessments will be made based on quantitative cultures performed on 
collected urine specimens at the Baseline, Day 5 (+1 day), Day 12 (± 1 day)/TOC, and Day 28 
(± 2 days) visits or at Premature Discontinuation. 
Results of susceptibility testing to differentiate between pathogens isolated at baseline and 
follow-up visits will be used in a sensitivity analysis to be specified in the statistical analysis 
plan (SAP); whole genome sequencing (WGS) may be performed if needed and results will be 
used in a sensitivity analysis to be specified in the SAP. 
 
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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 the Baseline visit, and a targeted exam 
will be conducted if needed (as determined by the investigator) at Day 5 (+1 day), Day 12 (± 1 
day)/TOC, Day 28 (± 2 days) visits or at Premature Discontinuation; vital signs will be 
collected at the Baseline visit, and at Day 5 (+1 day), and Day 12 (± 1 day)/TOC or Premature 
Discontinuation. Adverse events will be collected at every visit, beginning from the signing of 
Informed Consent. Clinical laboratory tests will be obtained at the Baseline visit, the Day 12 
(± 1 day)/TOC visit, in follow-up of any clinically significant laboratory findings, as well as at 
Premature Discontinuation.  
Statistical Methods:  
Sample Size Considerations:  
Study IT001-310 is designed to determine whether oral sulopenem is non-inferior to oral 
amoxicillin/clavulanate for the outcome measure of overall success (combined clinical and 
microbiologic success) at Day 12 (± 1 day)/TOC in both the micro-MITT and micro-MITTS 
populations and whether oral sulopenem is superior to oral amoxicillin/clavulanate for overall 
success at Day 12 (± 1 day)/TOC in the micro-MITTR population. The primary outcome 
measure of overall success (combined clinical and microbiologic success) is defined as 
resolution of the symptoms of uUTI present at trial entry with no new symptoms, and the 
demonstration that the bacterial pathogen found at trial entry is reduced to <103 CFU/mL on 
urine culture. 
The proposed sample size in the micro-MITTS population is 505 patients per arm (total 
sample size of 1010 patients) based on the method of Farrington and Manning. This assumes a 
non-inferiority margin of 10.0%, a power of 90%, a one-sided alpha level of 0.025, 60% 
overall success rate with amoxicillin/clavulanate and 60% overall success rate with sulopenem 
etzadroxil/probenecid. Assuming that 21% of the patients will have non-susceptible pathogens 
to amoxicillin/clavulanate and assuming 85% power to show superiority in the micro-MITTR 
population (micro-MITT=1278 patients), 67% of the randomized patients will meet criteria for 
inclusion into the micro-MITT population (MITT=1907 patients) and allowing for a dropout 
rate of 3%, the sample size for the ITT population is 1966. With 134 patients per treatment 
group in the micro-MITTR population, there is at least 85% power to show superiority at the 
one-sided 2.5% alpha level given a 51% and 33% overall success rate in the oral sulopenem 
and amoxicillin/clavulanate groups, respectively. With 1278 patients in the micro-MITT 
population, there is at least 95% power to show non-inferiority (non-inferiority margin of 
10.0%) at the one-sided alpha level of 0.025 with the treatment success rates of the oral 
sulopenem and amoxicillin/clavulanate groups assumed to be 58% in this population. 
To ensure that the point estimate of overall success (combined clinical and microbiologic 
success) used in the estimation of sample size, and the estimated eligibility rate, 
susceptibility rate, and rate of post-treatment asymptomatic bacteriuria is valid for this study, 
an interim analysis for sample size re-estimation will be performed when clinical and 
microbiologic response data at Day 12 (± 1 day)/TOC are available for approximately 50% 
of the patients (approximately 983 patients) (see Section 9.7). The FDA Guidance “Non-
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inferiority Clinical Trials” [FDA Guidance 2016] 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. The sample size of the study will be computed to 
ensure that there is sufficient power for determining whether oral sulopenem is NI to oral 
amoxicillin/clavulanate for the primary outcome measure in the micro-MITTS population. 
This will ensure that the study is sufficiently powered to test the primary endpoint in the 
micro-MITT and micro-MITTR populations as well. The sample size will not be decreased 
after the interim analysis.  In addition, the sample size may be increased based on a lower-
than-expected evaluability rate (i.e., percentage of the ITT population in the micro-MITT 
population), higher- than-expected rate of asymptomatic bacteriuria or lower than expected 
percentage of patients with a susceptible pathogen. The sample size re-estimation will be 
based on the blinded overall (not by treatment group) pooled data. If the aggregated overall 
success rate in the micro-MITTS population is higher than 70%, or if the aggregated rate of 
asymptomatic bacteriuria is significantly lower than anticipated, then a futility analysis may 
be conducted by the DMC to assess if the study should continue. Further details of how the 
DMC will decide to do the futility analysis, how the sponsor will be involved and how the 
analysis will be conducted will be provided in the SAP and the DMC charter. 
 
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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 oral sulopenem versus oral 
amoxicillin/clavulanate. Exploratory analyses may also be performed.  Listings of individual 
patient’s data will be produced. 
A comprehensive Statistical Analysis Plan (SAP) will be finalized and submitted to the FDA 
prior to the interim analysis.  
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Efficacy Analyses:   
Analysis of Primary Outcome Measure: 
The study is designed to determine whether oral sulopenem is NI to oral 
amoxicillin/clavulanate for the outcome measure of overall success (combined clinical and 
microbiologic success) at Day 12 (± 1 day)/TOC in the micro-MITT and micro-MITTS 
populations and whether oral sulopenem is superior to oral amoxicillin/clavulanate for overall 
success at Day 12 (± 1 day)/TOC in the micro-MITTR population.  
A patient will be defined as an overall success if the following criteria are met: 
• The patient is alive 
• The patient has received no rescue therapy for uUTI 
- 
If an antibiotic active against the urinary tract pathogen is given for other reasons, then 
the patient will be considered indeterminate 
• The patient has resolution of the symptoms of uUTI present at trial entry and no new uUTI 
symptoms (based on the Patient Symptom Assessment Questionnaire) 
• Urine culture taken on Day 12 (± 1 day)/TOC demonstrates <103 CFU/mL of the baseline 
uropathogen based on results of quantitative cultures performed on collected urine 
specimens.   
All other patients will be considered as failures unless data are unavailable to determine if 
the patient is a success or a failure. In this case, the patient will be considered as having an 
indeterminate response. Patients with an indeterminate response are included in the 
denominator for determination of the overall success rate. 
 
The number and percentage of patients with success, failure and indeterminate outcomes will 
be determined in each treatment group in the micro-MITT, micro-MITTS and micro-MITTR 
populations. For each analysis population, the observed difference in the percentage of 
patients with success at Day 12 (± 1 day)/TOC (oral sulopenem group minus the 
amoxicillin/clavulanate group) will be determined and a two-sided 95% confidence interval 
(CI) for the observed difference will be computed using the method proposed without 
stratification by Miettinen and Nurminen.  
The framework for the statistical hypothesis testing of the primary efficacy outcome, overall 
success (combined clinical and microbiological success) at Day 12 (± 1 day)/TOC, is defined 
below. 
 
The primary comparison of the study is in the micro-MITT population (the combined 
population of patients with a positive baseline culture and without regard to 
amoxicillin/clavulanate susceptibility). These outcomes are most relevant to the practicing 
clinician who must choose empiric treatment of uUTI before culture results become available. 
From a regulatory perspective, these results will help put into context the outcomes in the 
culture and susceptibility- driven subpopulations. 
The primary comparisons for regulatory approval are in two mutually exclusive sub-
populations of the micro-MITT population defined by a baseline characteristic:  1) the micro-
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MITTS population (the subset of the micro-MITT population in which the baseline pathogen 
is determined to be susceptible to the comparator study drug, amoxicillin/clavulanate); and 2) 
the micro-MITTR population (the subset of the micro-MITT population in which the baseline 
pathogen is determined to be non-susceptible [intermediate (MIC 16/8 mg/L) or resistant 
(MIC ≥ 32/16 mg/L)] to the comparator study drug, amoxicillin/clavulanate).  
To control for inflation of the overall type I error rate, the hierarchical testing procedure of 
Westfall and Krishen (Westfall 2001) will be used to test the hypotheses of the primary 
efficacy outcome in these populations in the sequential order described below. Testing will 
proceed to the next comparison, only in the case where the null hypothesis in the previous 
comparison was rejected. When testing in a sequential manner with pre-planned testing, no 
adjustment to the alpha level is required  
(1) NI in the micro-MITT population.  For this population, a NI test of the overall success rate 
will be conducted.  The null and alternative hypotheses are the following: 
∆
−
≤
−
2
1
0 :
p
p
H
 and 
∆
−
>
−
2
1
:
p
p
H A
, 
where p1 is the primary efficacy outcome rate in the oral sulopenem group, p2 is the primary 
efficacy outcome rate in the amoxicillin/clavulanate group, and Δ is the non-inferiority margin 
of 10.0%. 
The NI 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% CI for the observed difference in the 
overall success rate (oral sulopenem group minus amoxicillin/clavulanate group).  The 
primary analysis is based on the CI computed using the method proposed without stratification 
by Miettinen and Nurminen, which corresponds to the p-value approach of the Farrington-
Manning test.  If the lower limit of the 95% CI for difference in success rates in the micro-
MITT population is greater than -10.0%, the null hypothesis will be rejected and the NI of oral 
sulopenem to amoxicillin/clavulanate will be concluded. 
 (2) NI in the micro-MITTS population OR superiority in the micro-MITTR population as 
described below: 
Micro-MITTS population: the subset of the micro-MITT population in which the baseline 
pathogen is determined to be susceptible to the comparator study drug, 
amoxicillin/clavulanate. For this population, a NI test of the overall success rate will be 
conducted. The null and alternative hypotheses are as follows:  
∆
−
≤
−
2
1
0 :
p
p
H
 and 
∆
−
>
−
2
1
:
p
p
H A
 
A 2-sided 95% CI for the observed treatment difference in success rates will be determined. If 
the lower bound of the 95% CI is greater than -10.0%, the null hypothesis will be rejected and 
the NI of oral sulopenem to amoxicillin/clavulanate in the micro-MITTS population will be 
concluded. 
Micro-MITTR population: the subset of the micro-MITT population in which the baseline 
pathogen is determined to be non-susceptible to the comparator study drug, 
amoxicillin/clavulanate. For this population, a superiority test will be conducted.  The null and 
alternative hypotheses are as follows: 
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2
1
0 :
p
p
H
=
 and 
2
1
:
p
p
H A
≠
 
A 2-sided 95% CI for the observed treatment difference in success rates will be determined 
using the method without stratification of Miettinen and Nurminen.  If the lower bound of the 
95% CI is greater than 0%, the null hypothesis will be rejected and superiority of oral 
sulopenem to amoxicillin/clavulanate will be concluded in the micro-MITTR population. 
Each of the 2 null hypotheses in this step will be tested at the 2.5% level and if either 
hypothesis is rejected, then testing will proceed to the next step. 
(3) Superiority test of overall success, 𝐻𝐻0: 𝑝𝑝1 = 𝑝𝑝2 and 𝐻𝐻𝐴𝐴: 𝑝𝑝1 ≠𝑝𝑝2, in the micro-MITT 
population. If the lower bound of the 95% CI (calculated for the hypothesis test in (1) is 
greater than 0%, the null hypothesis will be rejected and the superiority of oral sulopenem to 
amoxicillin/clavulanate in the micro-MITT population will be concluded. 
Analysis of Secondary Efficacy Outcome Measure: 
The number and percentage of patients in each treatment group with a clinical response of 
success, failure and indeterminate at Day 12 (±1 day)/TOC will be presented for the MITT, 
micro-MITT, micro-MITTS, and micro-MITTR populations. The number and percentage of 
patients in each treatment group with a clinical response of success and failure at Day 12 (±1 
day)/TOC will be presented for the CE and ME populations.  Two-sided 95% unstratified CIs 
will be constructed for the observed difference in the clinical success rates between the 
treatment groups for descriptive purposes; no conclusion of NI will be made. 
The number and percentage of patients in each treatment group with asymptomatic bacteriuria 
at Day 12 (±1 day)/TOC will be presented for the micro-MITT, micro-MITTS, micro-MITTR 
and ME populations. The difference in rate of asymptomatic bacteriuria (oral sulopenem group 
minus the amoxicillin/clavulanate group) will be determined and 2-sided 95% unstratified CIs 
will be constructed for the observed difference between the treatment groups for descriptive 
purposes; no conclusion of NI will be made. 
 
The number and percentage of patients in each treatment group with a microbiologic response 
of success, failure and indeterminate at Day 12 (±1 day)/TOC will be presented for the micro-
MITT, micro-MITTS, and micro-MITTR populations. The number and percentage of patients 
in each treatment group with a microbiologic response of success and failure at Day 12 (±1 
day)/TOC will be presented for the ME population.  Two-sided 95% unstratified CIs will be 
constructed for the observed difference in the microbiologic success rates between the 
treatment groups for descriptive purposes; no conclusion of NI will be made. 
 
Safety analyses will be conducted in the Safety population (all patients who received at least 
one dose of study drug) and will be summarized by treatment group.  Safety will be assessed 
through summaries of AEs, laboratory evaluations, and vital signs. 
 
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TABLE OF CONTENTS 
SYNOPSIS ........................................................................................................................... 2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................................ 20 
1 
INTRODUCTION ....................................................................................................... 23 
1.1 
Indication........................................................................................................... 23 
1.2 
Background and Rationale ................................................................................. 23 
1.2.1 
Safety data ............................................................................................... 28 
1.2.1.1 
Sulopenem etzadroxil (PF-03709270; oral prodrug) ........................ 28 
1.2.1.2 
Sulopenem (CP-70,429; Intravenous) ............................................. 29 
1.2.2 
Rationale for Study .................................................................................. 30 
1.2.3 
Dose Rationale ......................................................................................... 32 
2 
STUDY OBJECTIVES ............................................................................................... 33 
2.1 
Objectives .......................................................................................................... 33 
3 
STUDY DESIGN ........................................................................................................ 34 
3.1 
Investigational Study Medications ..................................................................... 35 
3.2 
Adjunctive Systemic Antibiotics ........................................................................ 35 
3.3 
Additional Non-Study Therapy Antibiotics ........................................................ 35 
4 
STUDY POPULATION SELECTION ........................................................................ 35 
4.1 
Inclusion Criteria ............................................................................................... 35 
4.2 
Exclusion Criteria .............................................................................................. 36 
4.3 
Randomization Criteria ...................................................................................... 37 
4.4 
Lifestyle Guidelines ........................................................................................... 37 
4.5 
Women of Child-Bearing Potential .................................................................... 38 
5 
STUDY TREATMENTS............................................................................................. 38 
5.1 
Allocation to Treatment ..................................................................................... 38 
5.2 
Drug Supplies .................................................................................................... 38 
5.2.1 
Formulation and Packaging ...................................................................... 38 
5.2.2 
Preparation and Dispensing ...................................................................... 39 
5.2.3 
Administration ......................................................................................... 39 
5.2.4 
Compliance .............................................................................................. 39 
5.3 
Drug Storage and Drug Accountability .............................................................. 40 
5.4 
Concomitant Medication(s), Adjunctive Therapy, and Non-drug Therapy .......... 40 
5.4.1 
Concomitant Medications ......................................................................... 40 
5.4.2 
Adjunctive Systemic Antibiotics (Rescue Therapy) .................................. 40 
5.4.3 
Additional Non-Study Therapy Antibiotics .............................................. 40 
6 
STUDY PROCEDURES ............................................................................................. 41 
6.1 
Screening (Day -1) - Within 24 Hours Prior to First Dose .................................. 41 
6.2 
Treatment Period ............................................................................................... 42 
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6.2.1 
Day 1 ....................................................................................................... 42 
6.2.2 
Day 5 (+ 1 day) (End of Treatment/EOT) ................................................. 42 
6.3 
Follow-up Period ............................................................................................... 42 
6.3.1 
Day 12 (± 1 day) (Test of Cure/TOC) ....................................................... 42 
6.3.2 
Day 28 (± 2 days) (Final Visit/FV) ........................................................... 43 
6.4 
Premature Discontinuation ................................................................................. 43 
6.5 
Patient Withdrawal from Treatment or Study ..................................................... 44 
7 
ASSESSMENTS ......................................................................................................... 44 
7.1 
Safety ................................................................................................................ 44 
7.1.1 
Physical Examination ............................................................................... 44 
7.1.2 
Vital Signs (Temperature, Blood Pressure, Pulse Rate, Respiratory Rate) . 44 
7.1.3 
Clinical Laboratory Assays ...................................................................... 44 
7.1.4 
Clinically Significant Laboratory Tests .................................................... 45 
7.2 
Efficacy ............................................................................................................. 45 
7.2.1 
Overall Response ..................................................................................... 45 
7.2.2 
Microbiologic........................................................................................... 46 
7.2.3 
Patient-Determined Clinical Response ...................................................... 46 
7.2.4 
Investigator Assessment of Clinical Response .......................................... 47 
7.2.5 
Patient Symptom Assessment Questionnaire (PSAQ) ............................... 47 
8 
ADVERSE EVENT REPORTING .............................................................................. 48 
8.1 
Adverse Events .................................................................................................. 48 
8.2 
Reporting Period ................................................................................................ 48 
8.3 
Definition of an AE............................................................................................ 48 
8.4 
Abnormal Test Findings..................................................................................... 49 
8.5 
Serious Adverse Events (SAE) ........................................................................... 49 
8.6 
Hospitalization ................................................................................................... 50 
8.7 
Severity Assessment .......................................................................................... 51 
8.8 
Causality Assessment......................................................................................... 51 
8.9 
Exposure during Pregnancy ............................................................................... 52 
8.10 
Discontinuation from Study Drug Due to AEs (See also Patient Withdrawal, 
Section 6.5)........................................................................................................ 53 
8.11 
Eliciting AE Information ................................................................................... 53 
8.12 
Reporting Requirements .................................................................................... 53 
8.12.1 
SAE Reporting Requirements ................................................................... 53 
8.12.2 
Non-SAE Reporting Requirements ........................................................... 54 
8.12.3 
Sponsor Reporting Requirements to Regulatory Authorities ..................... 54 
9 
DATA ANALYSIS/STATISTICAL METHODS ........................................................ 54 
9.1 
Sample Size Determination ................................................................................ 54 
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9.2 
Definition of Analysis Populations ..................................................................... 55 
9.3 
General Statistical Considerations ...................................................................... 56 
9.4 
Patient Characteristics ........................................................................................ 56 
9.5 
Efficacy Analysis ............................................................................................... 56 
9.5.1 
Analysis of Primary Outcome Measure .................................................... 56 
9.5.2 
Additional Analyses of the Primary Efficacy Outcome ............................. 58 
9.5.3 
Analysis of Secondary Efficacy Outcome Measure .................................. 58 
9.5.4 
Analyses of Additional Efficacy Outcome Measures ................................ 59 
9.6 
Safety Analyses ................................................................................................. 60 
9.7 
Interim Analysis ................................................................................................ 60 
9.8 
Handling of Missing Data .................................................................................. 61 
10 QUALITY CONTROL AND QUALITY ASSURANCE ............................................ 62 
11 DATA HANDLING AND RECORD KEEPING......................................................... 62 
11.1 
Case Report Forms / Electronic Data Record ..................................................... 62 
11.2 
Record Retention ............................................................................................... 62 
12 ETHICS ...................................................................................................................... 63 
12.1 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ............ 63 
12.2 
Ethical Conduct of the Study.............................................................................. 63 
12.3 
Patient Information and Consent ........................................................................ 63 
12.4 
Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP ... 64 
13 DEFINITION OF END OF STUDY ............................................................................ 64 
13.1 
End of Study in all Participating Countries......................................................... 64 
14 SPONSOR STUDY TERMINATION CRITERIA ...................................................... 64 
15 PUBLICATION OF STUDY RESULTS ..................................................................... 64 
15.1 
Communication of Results by Iterum ................................................................. 64 
15.2 
Publications by Investigators.............................................................................. 64 
16 REFERENCE LIST ..................................................................................................... 66 
APPENDIX 1 
   RATIONALE FOR AMOXICILLIN/CLAVULANATE AS 
COMPARATOR IN UNCOMPLICATED UTI TRIAL .............................................. 69 
APPENDIX 2 
 SCHEDULE OF STUDY ASSESSMENTS ............................................ 78 
APPENDIX 3 
 MICROBIOLOGY .................................................................................. 79 
APPENDIX 4 
CRITERIA FOR SAFETY LABORATORY VALUES OF POTENTIAL 
CLINICAL CONCERN .............................................................................................. 81 
APPENDIX 5 
 SUMMARY OF CHANGES ................................................................... 82 
Appendix 5.1 
 Amendment 1 ................................................................................ 82 
APPENDIX 6 INVESTIGATOR’S SIGNATURE .............................................................. 84 
 
 
 
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List of In-Text Tables 
Table 1   Sulopenem In-Vitro Susceptibility (2013-2015) .................................................... 25 
Table 2 Comparison of Optimal and Alternative Treatment Regimens, IDSA Guidelines .. 71 
Table 3   Resistance Rate for Baseline Pathogen(s), IT001-301 ........................................... 74 
Table 4   Overall Response at TOC by Stepdown Category, IT001-302, micro-MITT 
Population .................................................................................................... 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 daily 
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 
CFU 
Colony Forming Unit 
CLSI 
Clinical and Laboratory Standards Institute 
Cmax 
Maximum concentration 
 
 
CRE 
Carbapenem Resistant Enterobacterales  
CRF 
Case Report Form 
CTA 
Clinical Trial Application 
cUTI 
Complicated Urinary Tract Infection 
DMC 
Data Monitoring Committee 
EARS-NET 
European Antimicrobial Resistance Surveillance Network 
ECG 
Electrocardiogram 
E. coli 
Escherichia coli 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EIU 
Exposure in Utero 
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EOT 
End of Treatment Visit 
ESBL 
Extended Spectrum Beta-lactamase 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating Hormone 
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  
HPF 
High power field 
hs-CRP 
High-sensitivity C-reactive Protein 
ICH 
International Conference on Harmonisation 
ICF 
Informed Consent Form 
IDSA 
Infectious Disease Society of America 
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 
MedDRA 
Medical Dictionary of Regulatory Activities 
MIC 
Minimal Inhibitory Concentration 
MITT 
Modified ITT 
Micro-MITT 
Microbiologic-MITT 
Micro-MITTR 
Microbiologic-MITT Resistant 
Micro-MITTS 
Microbiologic-MITT Susceptible 
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NI 
Non-inferior/Non-inferiority 
NOAEL 
No Observed Adverse Effect Level 
PBP 
Penicillin-Binding Proteins 
PCS 
Potentially clinically significant 
PK 
Pharmacokinetic 
PK/PD 
Pharmacokinetic / Pharmacodynamic 
PO 
Per-oral 
PSAQ 
Patient symptom assessment questionnaire 
PT 
Preferred Term 
PV 
Pharmacovigilance 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
System organ class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TA 
Target Achievement 
TEAE 
Treatment Emergent Adverse Event 
TOC 
Test of Cure 
Tmax 
Time to maximum concentration 
USPI 
United States package insert 
uUTI 
Uncomplicated urinary tract infection 
WBC 
White Blood Cell 
WGS 
Whole genome sequencing 
2-EBA 
2-Ethylbutryic Acid 
 
 
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1 
INTRODUCTION 
1.1 Indication 
Sulopenem and/or sulopenem etzadroxil/probenecid (oral sulopenem) are being studied for the 
treatment of the following indications: 
- 
Uncomplicated urinary tract infections  
- 
Complicated 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-lactamase (ESBL) producing 
Enterobacterales 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. 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 E. coli resistant to third generation cephalosporins, aminoglycosides and 
quinolones has increased to >10% in some southern and eastern European countries.  
Oral antibiotic treatment options are extremely limited for patients with these multi-drug 
resistant infections, resulting in lengthy hospital stays to facilitate administration of intravenous 
antibiotics, even for those with uncomplicated infections. The currently available oral antibiotics 
with activity against ESBL producing organisms include nitrofurantoin, fosfomycin, quinolones, 
and trimethoprim-sulfamethoxazole. Nitrofurantoin and fosfomycin are only approved for the 
treatment of uncomplicated urinary tract infections in the United States, have rising rates of 
resistance and are associated with inferior efficacy [Munoz-Davila 2014; Schito 2009]. 
Resistance to trimethoprim-sulfamethoxazole is uniformly above 20% in the US. Increasing 
prevalence of resistance to quinolones and their propensity to cause collateral damage resulted in 
relegation of quinolones to second-line therapy by the Infectious Disease Society of America 
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(IDSA) for uUTI [Gupta 2011]. In a recent multicenter analysis of trends in resistance in >2.2 
million urinary Enterobacterales isolates from ambulatory patients in the United States (2011-
2020), resistance rates were 57.5%, 23.1%, 20.6%, and 20.2% for β-lactams, trimethoprim-
sulfamethoxazole, fluoroquinolones, and nitrofurantoin, respectively, and 6.9% had an ESBL-
producing phenotype [Dunne 2022]. Efficacy outcomes for patients treated with antibiotics  for 
uUTI caused by non-susceptible pathogens are not known, though a recent analysis of 4,792 
patients with 5,395 evaluable outpatient UTI episodes, 22% of patients received an antibiotic to 
which the pathogen was resistant in vitro, and those patients were almost twice as likely to 
require a second prescription (34% versus 19%) or be hospitalized (15% versus 8%) within 28 
days of the initial prescription fill compared to patients who received an antibiotic to which the 
pathogen was susceptible [Dunne 2022].  
 
The currently proposed study will compare the safety, tolerability, and efficacy of oral 
sulopenem versus oral amoxicillin/clavulanate for the treatment of uUTI in women. Sulopenem 
(CP-70,429) 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 Enterobacterales 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 
(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 (data on file). Carbapenem resistant 
Enterobacterales (CRE) were excluded from the analysis shown below, but the MIC90 of 
Enterobacterales remains at 0.25 µg/mL even if CRE are included, given that their overall 
prevalence is low (data on file). 
 
 
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Table 1   Sulopenem In-Vitro Susceptibility (2013-2015) 
Organism Class 
N 
MIC50 
(µg/mL) 
MIC90 
(µg/mL) 
Enterobacterales 
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 and some other non-lactose fermenting gram-negative organisms, 
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 1478 
subjects, at doses up to 1g BID administered intravenously over 3-14 days in the early 1990s. 
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 etzadroxil, the oral pro-drug of sulopenem, has minimal in vitro antibacterial activity. 
Upon oral absorption, sulopenem etzadroxil yields the active moiety sulopenem (CP-70,429) in 
addition to the non-active moieties formate and 2-ethylbutyric acid (2-EBA).  
Sulopenem etzadroxil has been studied in single and multiple dose Phase 1 studies, 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 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 patients in this study at TOC 
were 90%, 88% and 63% in the single IV dose sulopenem, multiple IV dose sulopenem and 
ceftriaxone (IV) groups, 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.   
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Sulopenem (IV) has been studied in Phase 3 studies in patients with cUTI, and cIAI, and oral 
sulopenem has been studied in a Phase 3 study in patients with uUTI, as well as step-down 
therapy in patients in the cUTI and cIAI studies. These studies were conducted in the United 
States and Eastern Europe. 
Study IT001-301: 
Study IT001-301 was a prospective, Phase 3, randomized, multi-center, double-blind, double-
dummy study of the efficacy, tolerability, and safety of oral sulopenem versus oral ciprofloxacin 
for treatment of uUTI in adult women. A total of 1,671 adult women with uUTI were 
randomized in a 1:1 fashion to receive either a bilayer tablet with sulopenem 
etzadroxil/probenecid 500  mg/500 mg twice daily for 5 days or oral ciprofloxacin 250 mg twice 
daily for 3 days.  
The primary efficacy endpoint for the population of patients with organisms non-susceptible to 
quinolones (micro-MITTR population) was overall response at the Day 12 (±1 day)/TOC Visit. 
Overall success was seen in 62.6% of patients in the sulopenem group and 36% of patients in the 
ciprofloxacin group (treatment difference 26.6%, 95% CI [15.1, 37.4]). The study demonstrated 
superiority of sulopenem to ciprofloxacin in the treatment of uUTI in the micro-MITTR 
population.  
In a second population of patients with organisms susceptible to quinolones (micro-MITTS 
population), oral sulopenem was not noninferior to ciprofloxacin for the primary endpoint of 
overall response.  The difference in overall success between the treatment groups in this 
population of patients was driven primarily by the rate of asymptomatic bacteriuria post-
treatment which was lower for patients receiving ciprofloxacin relative to those receiving 
sulopenem etzadroxil/probenecid.  
Overall response in the combined population of patients with a positive baseline culture and 
without regard to quinolone susceptibility, did not demonstrate a difference in treatment 
outcome.  
Overall, the safety profile for oral sulopenem compared with ciprofloxacin was consistent across 
patient populations. The most common adverse event seen in patients receiving oral sulopenem 
was diarrhea, which was mild and self-limited.  The rates of discontinuations from study drug 
and SAEs were low on both regimens and similar between the two groups. 
Study IT001-302: 
Study IT001-302 was a prospective, Phase 3, randomized, multi-center, double-blind, double-
dummy study of the efficacy, tolerability and safety of sulopenem IV followed by oral 
sulopenem versus ertapenem IV followed by oral ciprofloxacin or amoxicillin/clavulanate for 
treatment of cUTI in adults. A total of 1395 patients were enrolled in the study, randomly 
assigned in a 1:1 ratio to sulopenem 1000 mg IV once daily for 5 days followed by oral 
sulopenem 500 mg/500 mg twice daily to complete 7-10 total days of treatment (N = 697) 
or ertapenem 1000 mg IV once daily for 5 days followed by oral ciprofloxacin 500 mg 
twice daily to complete 7-10 total days of treatment (N = 698). Patients with a baseline 
pathogen non-susceptible to ciprofloxacin, but susceptible to amoxicillin/clavulanate, and who 
met criteria for oral step-down took amoxicillin/clavulanate 875 mg/125 mg twice daily instead 
of ciprofloxacin to complete the 7-10 total days of treatment. 
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In Study 302, the primary efficacy endpoint was overall response at the Day 21 (TOC) Visit in 
the micro-MITT population. Overall success was seen in 67.8% of patients in the sulopenem 
group and 73.9% of patients in the ertapenem group in the micro-MITT population (treatment 
difference -6.1%, 95% CI [-12.0, -0.1]); because the lower bound of the CI was less than the NI 
margin of -10, the study did not demonstrate noninferiority of sulopenem to ertapenem in the 
treatment of cUTI. 
Sulopenem was well-tolerated, with both the rate of discontinuations and the incidence of 
TEAEs similar to those of ertapenem. The rate of SAEs for patients on sulopenem was similar to 
that for patients on ertapenem. 
Study IT001-303: 
Study IT001-303 was a prospective Phase 3, double-blind, multicenter, randomized study of the 
efficacy and safety of sulopenem IV followed by oral sulopenem versus ertapenem followed by 
ciprofloxacin and metronidazole or amoxicillin/clavulanate for treatment of cIAI in adults.  A 
total of 674 patients were enrolled in the study, randomly assigned in a 1:1 ratio to sulopenem 
1000 mg IV once daily for 5 days followed by oral sulopenem 500 mg/500 mg twice daily 
to complete 7-10 total days of treatment (N = 338) or ertapenem 1000 mg IV once daily for 
5 days followed by oral ciprofloxacin 500 mg twice daily and metronidazole 500 mg four 
times daily to complete 7-10 total days of treatment (N = 336). Patients with a baseline 
pathogen non-susceptible to ciprofloxacin, but susceptible to amoxicillin/clavulanate, and who 
met criteria for oral step-down took amoxicillin/clavulanate 875 mg/125 mg twice daily instead 
of ciprofloxacin and metronidazole to complete the 7-10 total days of treatment. 
Clinical success was seen in 85.5% of patients in the sulopenem group and 90.2% of patients in 
the ertapenem group in the micro-MITT population (treatment difference -4.7%, 95% CI [-10.3, 
1.0]); the study thus narrowly missed its stated objective of demonstrating the noninferiority of 
sulopenem to ertapenem in the treatment of cIAI. In all other study populations—ITT, MITT, 
CE, and ME—the lower limit of confidence interval was above -10.0. These findings are in the 
context of regulatory criteria that vary from -10 to -12.5, depending on region, for this indication.   
 
Sulopenem was well-tolerated, with both the rate of discontinuations and the incidence of 
TEAEs similar to those of ertapenem. There were more SAEs on sulopenem, the difference 
primarily a consequence of an imbalance of SAEs related to intra-abdominal abscesses in the two 
treatment groups. 
Given the challenges that clinicians are now facing with resistance to commonly used antibiotics 
for uUTI, historical protocol designs used to introduce new antibiotics may not adequately 
address the relevance of the new agent. This protocol employs a novel design in an attempt to 
understand the activity of a new compound, sulopenem, relative to a standard-of-care, 
amoxicillin/clavulanate, in an era of significant antibacterial resistance to multiple standard-of-
care oral antibiotics. The activity of oral sulopenem will be compared to amoxicillin/clavulanate 
in patients with organisms susceptible to amoxicillin/clavulanate, to provide a quantitative 
estimate of relative activity established by non-inferiority testing as well as in patients with 
organisms that are resistant to amoxicillin/clavulanate through superiority testing. Further 
analyses examining outcomes in the as-randomized populations will attempt to define the 
relative activity of these two drugs without the benefit of culture results, the utility of which may 
be dependent on the actual findings in the different sub-populations. 
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Rationale for amoxicillin/clavulanate as the comparator: 
Amoxicillin/clavulanate was chosen as the comparator because it is an approved antibiotic for 
the indication of UTI [Augmentin USPI], it is listed as a treatment option in the IDSA Treatment 
Guideline [Gupta 2011], and as a β-lactam antibiotic, it is likely to have a similar effect to 
sulopenem on the urogenital microbiome, thus allowing for a fair comparison of efficacy.  The 
dose of amoxicillin/clavulanate (875 mg/125 mg PO twice daily) was chosen to justify the use of 
amoxicillin/clavulanate CLSI breakpoints for uncomplicated urinary tract infection (M100 
Performance Standards for Antimicrobial Susceptibility Testing, 32nd edition). See Appendix 1 
for further details on the rationale for using amoxicillin/clavulanate as the comparator.  
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. 
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 
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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 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. Of note, the 
incidence of loose stools/diarrhea was significantly lower in patients dosed with food. 
Oral sulopenem was safe and well-tolerated across the Phase 3 program in patients with uUTI 
(Study IT001-301), cUTI (Study IT001-302), and cIAI (IT001-303) (see details for individual 
studies above). 
1.2.1.2 
Sulopenem (CP-70,429; Intravenous) 
Preclinical 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.  The 
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 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.  
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).    
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In a safety pharmacology study evaluating the effect on the 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 
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) [Foulds 1991] 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 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. 
Doses of 400 mg, 800 mg, 1600 mg, 2400 mg and 2800 mg of IV 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 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 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.  
IV sulopenem was also investigated in four Phase 2 clinical efficacy studies in Japan in the early 
1990s.  Over fourteen hundred 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 oral sulopenem etzadroxil and IV sulopenem is available in the 
Investigator’s 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 
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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 being seen 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. Quinolone resistance and resistance to 
trimethoprim-sulfamethoxazole among Escherichia coli is now > 20% in the United States; 
likewise, nitrofurantoin resistance among Enterobacterales is near or above 20%.   
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 pneumococci and 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, and/or quinolone non-susceptible gram-negative 
pathogens (except Pseudomonas spp., and some other non-lactose fermenting gram-negative 
rods), and anaerobes.  
Rationale for probenecid 
Probenecid is known to increase plasma levels of weak organic acids such as penicillins, 
cephalosporins, and other β-lactam antibiotics, including penems, by competitively inhibiting 
their renal tubular secretion.  Probenecid has been used safely with other β-lactam antibiotics, to 
either reduce dose or dosing frequency of βbeta-lactams when used to treat infectious diseases in 
human beings.  
Probenecid has been shown in an animal 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.    
In a previous Phase 1 study (A8811007), the use of 500 mg and 1000 mg of probenecid was 
compared for its effect on the PK of sulopenem.  While the sulopenem AUC was significantly 
higher for the 1000 mg probenecid administration, the %Tfree >MIC was very similar, as 
anticipated, suggesting that the 500 mg of probenecid may provide sufficient extension of 
circulating sulopenem to achieve the PKPD objectives. The combination of oral sulopenem 
etzadroxil 500 mg and probenecid 500 mg was evaluated in a recently completed 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.  
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Probenecid may prolong or enhance the action of oral sulfonylureas and thereby increase the risk 
of hypoglycemia.  The concomitant administration of probenecid increases the mean plasma 
elimination half-life of a number of drugs which can lead to increased plasma concentrations.  
These include agents such as indomethacin, acetaminophen, naproxen, ketoprofen, 
meclofenamate, lorazepam, and rifampin.  The clinical significance of this observation has not 
been established.  Please see probenecid product label for more pharmacology information.  
Rationale for dosing with food 
In a multiple dose (A8811003) study, at higher doses of oral sulopenem etzadroxil, there was 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 (CP-70,429, 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 oral 
sulopenem etzadroxil was administered in the fed state (~82% increase in mean AUC).  In Study 
IT001-101, oral 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, an inability to administer the dose with food 
should not preclude dosing. 
1.2.3 
Dose Rationale  
Sulopenem etzadroxil  
Doses of oral 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 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 
model to determine % target achievement (TA) for the selected doses. A %TA of ≥90% was 
deemed desirable for selecting particular doses. The 500 mg dose of oral sulopenem etzadroxil 
co-administered with 500 mg of probenecid administered twice daily meets the criteria of 
%T>MIC for achieving 1-log kill in bacteria.  
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.  
Amoxicillin/clavulanate  
The FDA approved (NDA 50-720/S024) dose of 875/125 mg oral amoxicillin/clavulanate 
administered twice daily for 5 days for treatment of uncomplicated UTI, per the Augmentin 
USPI, will be used in this study. This dose was chosen to justify the use of 
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amoxicillin/clavulanate CLSI breakpoints for uncomplicated urinary tract infection (M100 
Performance Standards for Antimicrobial Susceptibility Testing, 32nd edition). 
For the full prescribing information for probenecid or amoxicillin/clavulanate, please refer to 
respective local country product labels. 
2 
STUDY OBJECTIVES 
 
2.1 
Objectives  
Non-inferiority Trial: 
Objective 
Estimand/Endpoint 
Primary: 
Primary Estimand: 
To compare the overall response (clinical and 
microbiologic combined response) at Day 12 
(±1 day)/test of cure (TOC) of oral sulopenem 
etzadroxil/probenecid tablets (500 mg/500 
mg) versus oral amoxicillin/clavulanate (875 
mg/125 mg) tablets for the treatment of 
uncomplicated urinary tract infection in adult 
women. 
Endpoint of interest: Overall success 
at Day 12 (±1 day)/TOC (clinical and 
microbiologic combined) 
Intercurrent events: non-susceptibility 
or resistance to 
amoxicillin/clavulanate, use of rescue 
antibiotic, study discontinuation 
Population level summary of variable: 
Comparison of overall success rates 
between treatment groups 
Secondary: 
Secondary Endpoints: 
To evaluate the clinical efficacy at Day 12 
(±1 day)/TOC. 
Clinical cure (resolution of the 
symptoms of uUTI present at trial 
entry and no new uUTI symptoms) at 
Day 12 (±1 day)/TOC. 
To evaluate the rate of post-treatment 
asymptomatic bacteriuria at Day 12 (±1 
day)/TOC.  
Clinical cure (resolution of the 
symptoms of uUTI present at trial 
entry and no new uUTI symptoms) 
and microbiologic persistence (≥ 103 
CFU/mL of the baseline uropathogen) 
at Day 12 (±1 day)/TOC 
To evaluate the microbiologic efficacy at Day 
12 (±1 day)/TOC. 
Microbiologic eradication (<103 
CFU/mL of the baseline uropathogen) 
at Day 12 (±1 day)/TOC 
To further evaluate the safety profile of oral 
sulopenem etzadroxil/probenecid tablets (500 
mg/500 mg) when used for treatment of uUTI 
in adult women. 
Incidence of TEAEs through Day 28 
(±2 days); Changes from baseline in 
clinical laboratory tests at the Day 12 
(±1 day)/TOC visit; Changes from 
baseline in vital signs at the Day 5 (+1 
day)/EOT and Day 12 (±1 day)/TOC 
visits 
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Additional: 
Additional Endpoints: 
To evaluate the clinical efficacy at Day 5 (+1 
day) and Day 28 (±2 days). 
Clinical cure (resolution of the 
symptoms of uUTI present at trial 
entry and no new uUTI symptoms) at 
Day 5 (+1day) and Day 28 (±2 days). 
To evaluate the rate of post-treatment 
asymptomatic bacteriuria at Day 5 (+1 day) 
and Day 28 (±2 days).  
Clinical cure (resolution of the 
symptoms of uUTI present at trial 
entry and no new uUTI symptoms) 
and microbiologic persistence (≥ 103 
CFU/mL of the baseline uropathogen) 
at Day 5 (+1 day) and Day 28 (±2 
days). 
To evaluate the microbiologic efficacy at Day 
5 (+1 day) and Day 28 (±2 days). 
Microbiologic eradication (<103 
CFU/mL of the baseline uropathogen) 
at Day 5 (+1 day) and Day 28 (±2 
days). 
To evaluate overall response at other relevant 
timepoints 
Overall success (clinical and 
microbiologic combined response) at 
Day 5 (+1 day) and Day 28 (±2 days) 
visits 
To evaluate the investigator determined 
clinical response 
Investigator determined clinical 
response (clinical success, failure, and 
indeterminate) at Day 5 (+1 day), Day 
12 (±1 day)/TOC, and Day 28 (±2 
days) 
To evaluate overall success, clinical success, 
and microbiologic success by key baseline 
pathogens 
Overall success, clinical success, and 
microbiologic success at Day 5 (+1 
day), Day 12 (±1 day)/TOC, and Day 
28 (±2 days) by key baseline pathogen 
3 
STUDY DESIGN 
Study IT001-310 is a prospective, Phase 3, randomized, multicenter, double-blind, double 
dummy, controlled study to compare oral sulopenem to oral amoxicillin/clavulanate for the 
treatment of patients with uUTI.  Approximately 1966 adult women with uUTI will be 
randomized in a 1:1 fashion to receive either oral sulopenem etzadroxil/probenecid 500 mg/500 
mg twice daily for 5 days or oral amoxicillin/clavulanate 875 mg/125 mg twice daily for 5 days. 
End of Therapy is defined as Day 5 (+ 1 day). The primary efficacy assessment will be overall 
response (combined clinical and microbiologic response [success, failure or indeterminate]) in 
the micro-MITT, micro-MITTS and micro-MITTR populations on Day 12 (± 1 day)/TOC. 
Secondary efficacy assessments will include the clinical response (success, failure, or 
indeterminate), and microbiologic response (success [eradication], failure [persistence or 
persistence with increasing MIC] or indeterminate) on Day 12 (± 1 day)/TOC. See Appendix 2, 
Schedule of Activities Table. 
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3.1 
Investigational Study Medications 
Patients will be randomized to receive either a bilayer tablet with sulopenem 
etzadroxil/probenecid 500 mg/500 mg PO twice daily for 5 days or amoxicillin/clavulanate 875 
mg/125 mg PO twice daily for 5 days. 
Sulopenem etzadroxil treatment group:  The study drug will be supplied as a study kit containing 
one bottle with 10 bilayer tablets containing sulopenem etzadroxil/probenecid 500 mg/500 mg 
and one blister wallet containing 10 amoxicillin/clavulanate placebo capsules. 
Comparator treatment group:  The study drug will be supplied as a study kit containing one 
blister wallet containing 10 over-encapsulated amoxicillin/clavulanate 875 mg/125 mg tablets, 
and one bottle with 10 placebo tablets to match sulopenem etzadroxil/probenecid tablets.  
3.2 
Adjunctive Systemic Antibiotics 
None allowed except as described in Section 5.4.2.    
3.3 
   Additional Non-Study Therapy Antibiotics 
For Clostridioides difficile infections, metronidazole (IV or oral), vancomycin (oral or rectal), or 
fidaxomicin (oral) may be used in both treatment groups. Patients with a co-infection with a 
gram-positive uropathogen known or suspected to be resistant to study drugs are allowed to 
receive agents with narrow spectrum gram-positive coverage (such as oral linezolid) at the 
discretion of the investigator. 
4 
STUDY POPULATION SELECTION 
Female patients who present with uUTI, defined by symptoms and a urinalysis suggestive of a 
uUTI per Section 4.1, 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. Female patients ≥18 years of age with ≥24 hours and ≤96 hours of urinary symptoms 
attributable to a UTI  
2. Two of the following signs and symptoms of uUTI:  urinary frequency, urinary urgency, 
pain or burning on micturition, suprapubic pain. 
3. A mid-stream urine specimen with:  
a. a machine-read dipstick positive for nitrite AND any positive leukocyte esterase 
OR,  
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b. evidence of pyuria alone as defined by either: 
i. a machine-read dipstick positive for large leukocyte esterase OR  
ii. at least 10 white blood cells per cubic millimeter on microscopic analysis 
of unspun urine OR  
iii. White blood cell count ≥10 cells/HPF in the sediment of a spun urine 
4. Has given written informed consent to participate in the study 
4.2 
Exclusion Criteria 
1. Presence of signs and symptoms suggestive of acute pyelonephritis defined as: fever 
(temperature > 38° Celsius), chills, costovertebral angle tenderness, flank pain, nausea, 
and/or vomiting 
2. Receipt of antibacterial drug therapy potentially effective as treatment of uUTI within the 
prior 7 days 
3. Concurrent use of non-study treatments that would have a potential effect on outcome 
evaluations in patients with uUTI, including analgesics (e.g., non-steroidal anti-
inflammatory drugs, aspirin, paracetamol etc.), phenazopyridine, and cranberry products. 
Note: Patients can be included if these medications were previously taken and have 
ceased at the time of Screening onward.   
4. Any anatomical abnormality of the urinary tract, including surgically modified urinary 
tract anatomy, and obstructive uropathy due to nephrolithiasis, stricture, tumor, or 
fibrosis 
5. Ongoing urinary retention 
6. Neurogenic bladder 
7. Current resident of a long-term care facility 
8. Instrumentation of urinary tract in the previous 30 days 
9. An indwelling urinary catheter, ureteral stent or other foreign material in the urinary tract 
10. Any history of trauma to the pelvis or urinary tract 
11. Current urine culture, if available while evaluating eligibility, that is positive for more 
than 2 microorganisms regardless of colony count (contaminated), or confirms a fungal 
UTI 
12. Receiving hemodialysis, hemofiltration, peritoneal dialysis, or had a renal transplant 
13. Immunocompromised as evidenced by any of the following: 
a. Known HIV positive, with either a recent (in the past 6 months) AIDS-defining 
condition or a CD4 + T lymphocyte count <200/mm3  
b. Known neutropenia (defined as absolute neutrophil count <1000 cells/mm3) 
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c. 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 
d. Immunosuppressive therapy, including maintenance corticosteroid therapy (>40 
mg/day equivalent prednisolone for 5 days or more in the 30 days prior to 
randomization) 
14. Known liver function abnormalities as defined by the following laboratory criteria: 
• ALT or AST > 3x upper limit of normal, and/or 
• Total bilirubin > 2x upper limit of normal 
15. Females of child-bearing potential who are unable to take adequate contraceptive 
precautions (refer to Sections 4.4 and 4.5), have a positive pregnancy test result within 24 
hours of study entry, are otherwise known to be pregnant, or are currently breastfeeding 
16. Poorly controlled Diabetes mellitus, including the presence of ketoacidosis and 
hyperosmolar hyperglycemia 
17. History of seizures 
18. History of blood dyscrasias 
19. History of uric acid kidney stones 
20. Acute (current) gouty arthritis 
21. Concomitant administration of valproic acid 
22. History of allergy or hypersensitivity to carbapenems, β-lactams or probenecid, as 
formulated with their excipients 
23. Unlikely to survive the 4-week study period or has a rapidly progressive or terminal 
illness, including septic shock, associated with a high risk of mortality 
24. The use of any other investigational drug in the 30 days prior to the first dose of study 
drug, or prior participation in any sulopenem clinical trial 
Urine samples, including results from urine tests, collected as part of routine standard of care, 
prior to obtaining informed consent, may be used to assess eligibility for enrollment into study 
and/or for baseline urine culture. 
4.3 
Randomization Criteria 
Patients will be randomized in a 1:1 ratio to oral sulopenem versus oral amoxicillin/clavulanate 
using an IWRS into the study provided they have satisfied all patient selection criteria.   
4.4 
Lifestyle 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. 
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4.5 
Women of Child-Bearing Potential 
If the patient is a woman of childbearing potential (women of child-bearing potential 
and peri-menopausal women include females <50 years of age or those ≥ 50 years of 
age who have been post-menopausal [amenorrheic] for < 2 years) , and not practicing 
abstinence, that patient is required to simultaneously use 2 effective contraceptive 
methods, from the following list of five: 
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 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 and documented in source. 
5 
STUDY TREATMENTS 
5.1 
Allocation to Treatment 
This is a randomized, double-blind, double dummy, controlled study comparing oral sulopenem 
with oral amoxicillin/clavulanate in the treatment of uUTI. Approximately 1966 patients will be 
randomized to receive either oral sulopenem twice daily for 5 days or oral 
amoxicillin/clavulanate twice daily for 5 days in a 1:1 allocation ratio using an IWRS. 
A patient will be eligible for randomization once it has been determined that the patient 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 site 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 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 treatment assignment associated with 
the patient entered into the IWRS. 
5.2 
Drug Supplies 
5.2.1 
Formulation and Packaging 
Sulopenem etzadroxil/probenecid treatment group:  The study drug will be supplied as a study 
kit containing one bottle with 10 bilayer tablets containing sulopenem etzadroxil/probenecid 500 
mg/500 mg and one blister wallet containing 10 amoxicillin/clavulanate placebo capsules. 
Patients found to have pathogens isolated from urine cultures that are resistant to 
amoxicillin/clavulanate or carbapenems, may be allowed to continue on study drug therapy to 
complete the 5-day duration of treatment based on clinical response and investigator judgement, 
and are not required to receive alternative antibiotic therapy. 
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Comparator treatment group:  The study drug will be supplied as a study kit containing one 
blister wallet containing 10 over-encapsulated amoxicillin/clavulanate 875 mg/125 mg tablets, 
and one bottle with 10 placebo tablets to match sulopenem etzadroxil/probenecid tablets.  
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 
All kits of study drug will be provided to the study site by Iterum Therapeutics. Dispensing of 
study medication will be done and documented in accordance with the treatment schedule as 
outlined in the study protocol.  Written dispensing instructions will be provided to each study site 
in a study pharmacy manual.     
5.2.3 Administration 
Patients randomized to the sulopenem treatment group will take one sulopenem 
etzadroxil/probenecid tablet and one placebo capsule twice daily for 5 days and those 
randomized to the amoxicillin/clavulanate treatment group will take one over-encapsulated 
amoxicillin/clavulanate tablet and one placebo tablet twice daily for 5 days (10 doses total over a 
5-day period; if Dose 1 is taken in the evening of Day 1, Dose 10 will be taken in the morning of 
Day 6). The first dose of each medication will be administered under the supervision of study 
site personnel to help ensure compliance with dosing directions. 
Study drug administration will be documented in accordance with the Pharmacy Manual.  
Dosing with food:  
Food significantly increases bioavailability of sulopenem and consequently results in decreased 
rates of diarrhea. Therefore, dosing of oral sulopenem 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.  
Amoxicillin and clavulanate are well absorbed from the gastrointestinal tract after oral 
administration. Dosing in the fasted or fed state has minimal effect on the pharmacokinetics of 
amoxicillin. While amoxicillin/clavulanate can be given without regard to meals, absorption of 
clavulanate when taken with food is greater relative to the fasted state. Therefore, dosing of oral 
amoxicillin/clavulanate with food whenever possible is also recommended. 
5.2.4 Compliance 
All patients should be informed that compliance with taking all oral medication as instructed is 
imperative.  
Patients will be asked to bring all study medication containers (used and unused) to the next 
scheduled study visit for drug accountability. The total amount of oral dosing completed 
(determined by tablet or capsule count from returned containers) will be recorded in the 
IWRS/EDC systems.  
A study-specific diary will be provided to every patient to capture compliance with study 
medications. 
A urine sample will be collected and frozen at the Day 5 visit which can be used to confirm 
compliance, safety, or efficacy assessments. 
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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, the IWRS 
will be used to document site standard accountability.  
At the end of the study, Iterum Therapeutics will provide instructions as to disposition of any 
unused investigational product including oral sulopenem and amoxicillin/clavulanate.  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 during the study, other than study drug, is considered 
concomitant medication.  All concomitant medications from Baseline (Day 1) through the Final 
Visit must be recorded in the patient's source record and on the Case Report Form (CRF). 
At each visit, the investigator/site designee will obtain information on any therapeutic 
interventions (e.g., 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, and any 
drugs that may be required for emergency treatments, must be recorded on the CRF.  Of note, the 
use of medications to alleviate UTI symptoms (such as analgesics [e.g., non-steroidal anti-
inflammatory drugs, aspirin, paracetamol etc.], phenazopyridine or cranberry products) is 
prohibited until after the Day 12 (± 1 day)/TOC visit. 
5.4.2 
Adjunctive Systemic Antibiotics (Rescue Therapy) 
In general, adjunctive systemic antibiotics are not allowed for patients enrolled in the study.  At 
any time during the study period, and at the discretion of the principal investigator (PI), 
additional antibiotics—oral or IV, as appropriate—can be prescribed as rescue therapy, e.g., in 
the event of worsening signs and symptoms of uUTI, or if the patient develops fever and/or flank 
pain suggestive of upper urinary tract involvement. In the event that rescue therapy is prescribed, 
patient symptoms will be collected as an unscheduled event; such patients will be considered as 
failures and will be asked to still complete all protocol-specified assessments through the Final 
Visit.  Use of adjunctive antibiotics without clinical symptoms is strongly discouraged. 
5.4.3 
Additional Non-Study Therapy Antibiotics 
Concomitant systemic antibacterials are prohibited during the study, up to the Day 28 (± 2 days) 
visit, with the following exceptions: 
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• For Clostridioides difficile infections, metronidazole (IV or oral), vancomycin (oral or 
rectal), or fidaxomicin (oral) may be used in both treatment groups. The Sponsor will not 
provide therapy for Clostridioides difficile infections. 
• Patients with a co-infection with a gram-positive uropathogen known or suspected to be 
resistant to study drugs are allowed to receive agents with narrow spectrum gram-positive 
coverage (such as oral linezolid) at the discretion of the investigator. The Sponsor will 
not provide therapy for co-infection with a gram-positive uropathogen resistant to study 
drugs.  
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. 
Urine samples, including results from urine tests, collected as part of routine standard of care, 
prior to obtaining informed consent, may be used to assess eligibility for enrollment into study 
and/or for baseline urine culture. 
The following screening procedures will be performed prior to randomization and study drug 
administration (Screening and Day 1 Visit will typically occur on the same calendar day): 
• Obtain signed informed consent 
• Review demographics and medical history 
• Review eligibility criteria 
• Review previous drug and non-drug treatments (defined as within the prior 30 days) 
• Review concomitant medications 
• Review adverse events occurring after signing the ICF 
• Targeted physical examination (including general appearance, examination of heart, 
lungs, abdomen, and extremities) 
• Vital signs (temperature, blood pressure, pulse rate, respiratory rate), height and weight 
• Perform urine pregnancy test on women of child-bearing potential, including peri-
menopausal women, and confirm negative result.  
• 
Women of child-bearing potential and peri-menopausal women include females 
<50 years of age or those ≥ 50 years of age who have been post-menopausal 
[amenorrheic] for < 2 years 
• Collect urine for urinalysis and urine culture and susceptibility 
• Blood for laboratory testing including hematology and chemistry studies 
• Banked serum and urine for retrospective safety and efficacy assessments 
 
 
To prepare for trial participation, patients will be instructed on the use of Lifestyle Guidelines 
and Concomitant Medications. 
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6.2 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 
 
6.2.1 
Day 1 
• 
Review concomitant medications and adverse events if Day 1 visit not on same day as 
Screening/Day -1 visit 
• 
Confirm eligibility if Day 1 visit not on same day as Screening/Day -1 visit 
• 
Randomize patient 
• 
Provide patient daily dosing diary along with instructions on how to complete 
• 
Have patient complete patient symptom assessment questionnaire 
• 
Administer the study medication as described in Section 5.2.3 
 
 
6.2.2 
Day 5 (+ 1 day) (End of Treatment/EOT) 
• Targeted physical examination, if required, based on patient’s symptoms (as 
determined by the investigator) 
• Vital signs (temperature, blood pressure, pulse rate, respiratory rate)  
• Bank urine for retrospective assessments 
• Collect urine for urinalysis and urine culture and sensitivity  
• Review concomitant medications 
• Assess symptoms by spontaneous reporting of adverse events and by asking the 
patients to respond to a non-leading question such as “How do you feel? 
• Confirm and document study medication compliance by pill count and patient daily 
dosing diary 
• Collect patient daily dosing diary and review for completeness 
• Have patient complete patient symptom assessment questionnaire 
• Investigator Assessment of Clinical Response (Section 7.2.4) 
6.3 
Follow-up Period  
6.3.1 
Day 12 (± 1 day) (Test of Cure/TOC) 
• Targeted physical examination, if required, based on patient’s symptoms (as 
determined by the investigator) 
• Vital signs (temperature, blood pressure, pulse rate, respiratory rate)  
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• Blood for laboratory testing (including hematology and chemistry studies) 
• Bank serum and urine for retrospective safety and efficacy assessments 
• Collect urine for urinalysis and urine culture and sensitivity  
• Review concomitant medications 
• Assess symptoms by spontaneous reporting of adverse events and by asking the 
patients to respond to a non-leading question such as “How do you feel? 
• Have patient complete patient symptom assessment questionnaire 
• Investigator Assessment of Clinical Response (Section 7.2.4) 
6.3.2 
Day 28 (± 2 days) (Final Visit/FV)  
• Targeted physical examination, if required, based on patient’s symptoms (as 
determined by the investigator) 
• 
Perform urine pregnancy test on women of child-bearing potential, 
including peri-menopausal women, and confirm negative result. 
Women of child-bearing potential and peri-menopausal women 
include females <50 years of age or those ≥ 50 years of age who 
have been post-menopausal [amenorrheic] for < 2 years 
• Collect urine for urinalysis, urine culture and sensitivity 
• Review concomitant medications 
• Assess symptoms by spontaneous reporting of adverse events and by asking the 
patients to respond to a non-leading question such as “How do you feel? 
• Have patient complete patient symptom assessment questionnaire  
• Investigator Assessment of Clinical Response (Section 7.2.4) 
6.4 
Premature Discontinuation 
• Targeted physical examination, if required, based on patient’s symptoms (as 
determined by the investigator) 
• Vital signs (temperature, blood pressure, pulse rate, respiratory rate)  
• Blood for laboratory testing including hematology and chemistry studies 
• Perform urine pregnancy test on women of child-bearing potential, 
including peri-menopausal women, and confirm negative result 
o Women of child-bearing potential and peri-menopausal women 
include females <50 years of age or those ≥ 50 years of age who have 
been post-menopausal [amenorrheic] for < 2 years 
• Collect urine for urinalysis and urine culture and sensitivity 
• Review concomitant medications 
• Assess symptoms by spontaneous reporting of adverse events and by asking the 
patients to respond to a non-leading question such as “How do you feel? 
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• Confirm and document study medication compliance by pill count and patient daily 
dosing diary 
• Have patient complete patient symptom assessment questionnaire 
• Investigator Assessment of Clinical Response (Section 7.2.4) 
6.5 
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 the final visit. 
For patients who withdraw from the study early, a Premature Discontinuation visit should be 
performed within 3 calendar days after decision to discontinue (Section 6.4 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.  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, 
examination of heart, lungs, abdomen, and extremities). A targeted physical exam may be 
conducted at any visit to address patient’s symptoms if needed (as determined by the 
investigator). 
7.1.2 
Vital Signs (Temperature, Blood Pressure, Pulse Rate, Respiratory Rate) 
Vital signs are performed at Baseline, Day 5 (+ 1 day), Day 12 (± 1 day)/TOC, or Premature 
Discontinuation. 
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 should 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 may be 
measured as an oral, rectal, tympanic (ear) or temporal temperature.  
7.1.3 
Clinical Laboratory Assays 
The following laboratory parameters will be measured:  
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• Hematology: Complete blood count (CBC), including white blood cell (WBC) and 
differential counts; at Baseline, Day 12 (± 1 day)/TOC or Premature Discontinuation 
• Serum Clinical Chemistry: AST, ALT, GGT, alkaline phosphatase, albumin, total and direct 
bilirubin, BUN or urea, creatinine, Na+, K+, Cl-, total CO2 (Bicarbonate), glucose, high 
sensitivity C-reactive protein (CRP) and LDH at Baseline, Day 12 (± 1 day)/TOC or 
Premature Discontinuation. 
• Urinalysis and urine culture and sensitivity at Baseline, Day 5 (+ 1 day), Day 12 (± 1 
day)/TOC and Day 28 (± 2 days) or Premature Discontinuation.  
 Susceptibility results of pathogens to amoxicillin/clavulanate and carbapenems from 
cultures obtained at Screening, EOT, and TOC should not be reported to 
sites/investigators until after the TOC visit, unless requested by the Principal 
Investigator and clinically warranted, so as not to influence the investigator’s decision 
to prescribe a rescue antibiotic in the case of presence of a non-susceptible pathogen. 
• Urine pregnancy test performed at the site for women of child-bearing potential, including 
peri-menopausal women; at Baseline and Day 28 (± 2 days)) or Premature Discontinuation. 
 Women of child-bearing potential and peri-menopausal women include females <50 
years of age or those ≥ 50 years of age who have been post-menopausal [amenorrheic] 
for < 2 years 
• Serum pregnancy test performed by laboratory at the discretion of the principal investigator  
• Serum and urine samples will be banked for retrospective safety and efficacy analyses as 
needed at Baseline, Day 5 [(+ 1 day); urine only], and Day 12 (± 1 day)/TOC. Banked 
serum and urine samples may be stored up to 10 years.  
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 
Overall Response (at a given Visit) is assessed using the definitions listed below: 
A patient will be defined as a success if the following criteria are met (programmatically, based 
on the data on the eCRF): 
• The patient is alive 
• The patient has received no rescue therapy for uUTI 
- 
If an antibiotic active against the urinary tract pathogen is given for other reasons, then 
the patient will be considered indeterminate 
• The patient has resolution of the symptoms of uUTI present at trial entry and no new uUTI 
symptoms (based on the Patient Symptom Assessment Questionnaire) 
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- 
Baseline symptoms associated with another known condition (e.g., overactive 
bladder) do not need to be resolved.  
• Urine culture demonstrates <103 CFU/mL of the baseline uropathogen based on results of 
quantitative cultures performed on collected urine specimens.  
Results of susceptibility testing to differentiate between pathogens isolated at baseline and 
follow-up visits will be used in a sensitivity analysis to be specified in the SAP; whole 
genome sequencing (WGS) of isolated organisms may be performed if needed and results will 
be used in a sensitivity analysis to be specified in the SAP. 
All other patients will be considered as failures unless data are unavailable to determine if the 
patient is a confirmed overall success or a failure. In this case, the patient will be considered as 
having an indeterminate response. Patients with an indeterminate response are included in the 
denominator for determination of the response rate. 
7.2.2 
Microbiologic 
Microbiologic Response is assessed using the definitions listed below: 
Microbiological 
response 
Definition 
Success  
The urine culture demonstrates <103 CFU/mL of the baseline 
uropathogen (also referred to as eradication) at the time-point of 
analysis, i.e., Day 5 (+ 1 day), Day 12 (± 1 day)/TOC, or Day 28 
(± 2 days) visit  
Persistence  
A uropathogen present at baseline grew at ≥103 CFU/mL at the 
time-point of analysis, i.e., Day 5 (+ 1 day), Day 12 (± 1 
day)/TOC, or Day 28 (± 2 days) visit 
Persistence with 
increasing MIC  
A urine culture taken after at least 2 full days of treatment grew 
≥103 CFU/mL of the baseline uropathogen and displayed ≥4-
dilutions higher MIC, as compared to baseline, to study drug 
received at the time-point of analysis, i.e., Day 5 (+ 1 day), Day 
12 (± 1 day)/TOC, or Day 28 (± 2 days) visit 
Indeterminate 
Patient was lost to follow-up or an assessment was not 
undertaken such that no urine culture was obtained (or culture 
results could not be interpreted for any reason) at the time-point 
of analysis, i.e., Day 5 (+ 1 day), Day 12 (± 1 day)/TOC, or Day 
28 (± 2 days) visit 
7.2.3 
Patient-Determined Clinical Response 
A patient will be defined as a clinical success if the following criteria are met (programmatically, 
based on the data on the eCRF): 
• The patient is alive 
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• The patient has received no rescue therapy for uUTI 
- 
If an antibiotic active against the urinary tract pathogen is given for other reasons, then 
the patient will be considered indeterminate 
• The patient has resolution of the symptoms of uUTI present at trial entry and no new uUTI 
symptoms (based on the Patient Symptom Assessment Questionnaire) 
- 
Baseline symptoms associated with another known condition (e.g., overactive bladder) do 
not need to be resolved 
All other patients will be considered as failures unless data are unavailable to determine if the 
patient is a success or a failure. In this case, the patient will be considered as having an 
indeterminate response. Patients with an indeterminate response are included in the denominator 
for determination of the response rate. 
7.2.4 
Investigator Assessment of Clinical Response 
Investigators will use the definitions below to document clinical response, irrespective of 
microbiologic findings, at Day 5 (+ 1 day), Day 12 (± 1 day)/TOC, Day 28 (± 2 days), or 
Premature Discontinuation: 
Clinical response 
Definition 
Clinical success 
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 to be considered as failure: 
Death related to uUTI prior to visit 
Persistence or progression of any pre-therapy uUTI 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 the visit 
Death prior to study visit, where uUTI 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.  PSAQ is administered on Day 1 (prior to first dose), Day 5 (+ 1 day)/EOT, 
Day 12 (± 1 day)/TOC, and Day 28 (± 2 days) visit, or Premature Discontinuation. In the 
event that rescue therapy is prescribed, patient symptoms will be collected as an unscheduled 
event.  
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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 (Medpace Safety).  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 sequelae 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 the Day 28 (± 2 days) (Final Visit).  
For SAEs, the reporting period to Iterum Therapeutics’ designated pharmacovigilance provider 
(Medpace Safety) 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 uUTI have not resolved from Baseline to such an extent that new antibiotics 
are needed for the infection under study 
• Development of new uUTI symptoms not present at Baseline 
• Follow up urine cultures do not reveal eradication of causative uropathogen  
Except for circumstances as defined above, examples of AEs include but are not limited to:   
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• 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 (not UTI)  
Additionally, they may include the signs or symptoms resulting from: 
• Drug overdose 
• Drug withdrawal 
• Drug abuse 
• Drug misuse  
• Drug interactions 
• Drug dependency 
• 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); 
• Requires inpatient hospitalization or prolongation of existing hospitalization; 
• Results in persistent or significant disability/incapacity; 
• Results in congenital anomaly/birth defect; 
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• 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 preexisting condition not associated with the development of a 
new AE or with a worsening of the preexisting 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 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. 
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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 patient'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 Section 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 
explanations 
• 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 
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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’ designated 
pharmacovigilance provider (Medpace Safety) on a 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 reporting of birth 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. 
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 
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(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 6.5) 
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’ designated 
pharmacovigilance provider (Medpace Safety) is to be notified within 24 hours of awareness of 
the event by the investigator electronically in the EDC system for the study. When the form in 
EDC is completed, Medpace Safety personnel will be notified electronically by the EDC system 
and will retrieve the form. If the event meets serious criteria and it is not possible to access the 
EDC system, send an email to Medpace Safety at medpace-safetynotifications@medpace.com or 
call the Medpace SAE reporting line (phone number listed below), and fax/email the completed 
paper SAE form to Medpace within 24 hours of awareness. When the EDC system becomes 
available, the SAE information must be entered within 24 hours of the system becoming 
available.  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 
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 
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investigator may be requested by Iterum Therapeutics’ designated pharmacovigilance provider 
(Medpace Safety) 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’ designated pharmacovigilance provider 
(Medpace Safety).  The information should be reported on an SAE/Pregnancy form and sent to 
Iterum Therapeutics’ designated pharmacovigilance provider (Medpace Safety). 
 
8.12.2 
Non-SAE Reporting Requirements 
All AEs/SAEs will be reported on the AE page(s) of the CRF.    Adverse events should be 
reported using concise medical terminology on the CRFs.  
8.12.3 
Sponsor Reporting Requirements to Regulatory Authorities 
Adverse event reporting, including reporting of Suspected, Unexpected Serious Adverse 
Reactions (SUSARs), will be carried out in accordance with applicable local regulations.  Death 
and life-threatening 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 oral sulopenem is NI to oral amoxicillin/clavulanate 
for the outcome measure of overall success (combined clinical and microbiologic success) at 
Day 12 (± 1 day)/TOC in both the micro-MITT and micro-MITTS populations and whether oral 
sulopenem is superior to oral amoxicillin/clavulanate for overall success at Day 12 (± 1 
day)/TOC in the micro-MITTR population. The primary outcome measure of overall success 
(combined clinical and microbiologic success) is defined as resolution of the symptoms of uUTI 
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 (microbiological success 
[eradication]). 
The proposed sample size in the micro-MITTS population is 505 patients per arm (total of 1010 
patients) based on the method of Farrington and Manning. This assumes a non-inferiority margin 
of 10.0%, a power of 90%, a one-sided alpha level of 0.025, 60% overall success rate with 
amoxicillin/clavulanate and 60% overall rate with sulopenem etzadroxil/probenecid.  Assuming 
that 21% of the patients will have non-susceptible pathogens and assuming 85% power to show 
superiority in the micro-MITTR population (micro-MITT=1278 patients), 67% of the 
randomized patients will meet criteria for inclusion into the micro-MITT population 
(MITT=1907 patients) and allowing for a dropout rate of 3%, the sample size for the ITT 
population is 1966. With 134 patients per treatment group in the micro-MITTR population, there 
is at least 85% power to show superiority at the one-sided 2.5% alpha level given a 51% and 
33% overall success rate in the oral sulopenem and amoxicillin/clavulanate groups, respectively. 
With 1278 patients in the micro-MITT population, there is at least 95% power to show non-
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inferiority (non-inferiority margin of 10.0%) at the one-sided alpha level of 0.025 with the 
treatment success rates of the oral sulopenem and amoxicillin/clavulanate groups assumed to be 
58% in this population.   
One blinded interim analysis for sample size re-estimation is planned (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 
medication. Patients will be analyzed according to the treatment to which they were 
randomized. 
3. Safety: randomized patients who received at least a single dose of study medication. 
Patients will be analyzed according to the treatment that they received. 
4. Micro-MITT: All MITT patients with a positive study entry urine culture defined as 
≥105 CFU/mL of a uropathogen (Enterobacterales or Staphylococcus saprophyticus only) 
and no more than 2 species of microorganisms identified in the study entry urine culture, 
regardless of colony count. 
5. Micro-MITTS: All micro-MITT patients with a baseline uropathogen susceptible 
(defined as MIC <8/4 mg/L) to the comparator drug, amoxicillin/clavulanate, and no 
baseline pathogen non-susceptible to amoxicillin/clavulanate. 
6. Micro-MITTR: All micro-MITT patients with a baseline uropathogen non-susceptible 
[intermediate (MIC 16/8 mg/L) or resistant (MIC ≥ 32/16 mg/L)] to the comparator drug, 
amoxicillin/clavulanate. 
7. Clinically Evaluable: Clinically Evaluable (CE) at the Day 5 (+1 day), Day 12 (±1 
day)/TOC, and Day 28 (±2 days) 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 SAP) 
b) Had no important protocol deviations that would affect the assessment of efficacy (to 
be defined in the SAP) 
c) Had a clinical outcome assessment at the relevant visit and the assessment was within 
the protocol allowed visit window.   
d) Had not received antibacterial drug therapy potentially effective as treatment of uUTI 
within 7 days prior to study entry 
e) Did not receive any antibiotic therapy with potential activity against any of the 
baseline uropathogens collected at Baseline between the time of the baseline culture 
and the Day 5 (+1 day) or Day 12 (±1 day)/TOC culture, respectively.  This excludes 
the protocol defined study therapy and patients who were considered clinical failures 
and required additional rescue 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 oral linezolid). 
8. Microbiologically evaluable (ME): all patients included in both the micro-MITT and 
CE populations at the Day 5 (+1 day) visit (ME-Day 5), Day 12 (±1 day)/TOC visit (ME-
Day 12) and at the Day 28 (±2 days) visit (ME-Day28) and have an appropriately 
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collected urine culture specimen and interpretable urine culture result at the Day 5 (+1 
day), Day 12 (±1 day)/TOC and Day 28 (±2 days) visits, respectively. 
Amoxicillin/clavulanate breakpoints as per CLSI (M100 Performance Standards for 
Antimicrobial Susceptibility Testing, 32nd edition). 
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 oral sulopenem treatment group and 
the amoxicillin/clavulanate treatment group. Exploratory analyses may also be performed. 
Listings of individual patient’s data will be produced.  
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 uUTI, microbiological assessment of the urine, and 
study drug administration will also be summarized.   
9.5 
Efficacy Analysis 
For all efficacy analyses, patient data will be analyzed in the treatment group to which the patient 
was randomized.   
9.5.1 
Analysis of Primary Outcome Measure 
The primary efficacy outcome is overall success (combined clinical and microbiologic success) 
at Day 12 (± 1 day)/TOC in the micro-MITT, micro-MITTS and micro-MITTR populations.  
Patients will be programmatically categorized as a success, failure, or indeterminate based on 
data in the eCRF and from the microbiology lab.  Patients with missing data or who are lost to 
follow-up are defined as indeterminate for the primary analyses and are included in the 
denominator for the calculation of the success rate. The number and percentage of patients with 
success, failure and indeterminate response will be determined in each treatment group in the 
micro-MITT, micro-MITTS and micro-MITTR populations.  
The primary comparison of the study is in the micro-MITT population (the combined population 
of patients with a positive baseline culture and without regard to amoxicillin/clavulanate 
susceptibility). These outcomes are most relevant to the practicing clinician who must choose 
empiric treatment of uUTI before culture results become available. From a regulatory 
perspective, these results will help put into context the outcomes in the culture and susceptibility- 
driven subpopulations. 
The primary comparisons for regulatory approval are in two mutually exclusive sub-populations 
of the micro-MITT population defined by a baseline characteristic, the micro-MITTS and micro-
MITTR populations. 
To control for inflation of the overall type I error rate, the hierarchical testing procedure of 
Westfall and Krishen (Westfall 2001) will be used to test the hypotheses of the primary efficacy 
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outcome in these populations in the sequential order described below. Testing will proceed to the 
next comparison, only in the case where the null hypothesis in the previous comparison was 
rejected. When testing in a sequential manner with pre-planned testing, no adjustment to the 
alpha level is required: 
(1) NI in the micro-MITT population.  For this population, a NI test of the overall success rate 
will be conducted.  The null and alternative hypotheses are the following: 
∆
−
≤
−
2
1
0 :
p
p
H
 and 
∆
−
>
−
2
1
:
p
p
H A
, 
where p1 is the primary efficacy outcome rate in the oral sulopenem group, p2 is the primary 
efficacy outcome rate in the amoxicillin/clavulanate group, and Δ is the non-inferiority margin of 
10.0%. 
The NI 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% CI for the observed difference in the overall 
success rate (oral sulopenem group minus amoxicillin/clavulanate group).  The primary analysis 
is based on the CI computed using the method proposed without stratification by Miettinen and 
Nurminen, which corresponds to the p-value approach of the Farrington-Manning test.  If the 
lower limit of the 95% CI for difference in success rates in the micro-MITT population is greater 
than -10.0%, the null hypothesis will be rejected and the NI of oral sulopenem to 
amoxicillin/clavulanate will be concluded. 
 (2) NI the micro-MITTS population OR superiority in the micro-MITTR population as 
described below: 
Micro-MITTS population: the subset of the micro-MITT population in which the baseline 
pathogen is determined to be susceptible to the comparator study drug, amoxicillin/clavulanate. 
For this population, a NI test of the overall success rate will be conducted. The null and 
alternative hypotheses are as follows:  
∆
−
≤
−
2
1
0 :
p
p
H
 and 
∆
−
>
−
2
1
:
p
p
H A
 
A 2-sided 95% CI for the observed treatment difference in success rates will be determined. If 
the lower bound of the 95% CI is greater than -10.0%, the null hypothesis will be rejected and 
the NI of oral sulopenem to amoxicillin/clavulanate in the micro-MITTS population will be 
concluded. 
Micro-MITTR population: the subset of the micro-MITT population in which the baseline 
pathogen is determined to be non-susceptible to the comparator study drug, 
amoxicillin/clavulanate. For this population, a superiority test will be conducted.  The null and 
alternative hypotheses are as follows: 
2
1
0 :
p
p
H
=
 and 
2
1
:
p
p
H A
≠
 
A 2-sided 95% CI for the observed treatment difference in success rates will be determined using 
the method without stratification of Miettinen and Nurminen.  If the lower bound of the 95% CI 
is greater than 0%, the null hypothesis will be rejected and superiority of oral sulopenem to 
amoxicillin/clavulanate will be concluded in the micro-MITTR population. 
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Each of the 2 null hypotheses in this step will be tested at the 2.5% level and if either hypothesis 
is rejected, then testing will proceed to the next step. 
(3) Superiority test of overall success, 𝐻𝐻0: 𝑝𝑝1 = 𝑝𝑝2 and 𝐻𝐻𝐴𝐴: 𝑝𝑝1 ≠𝑝𝑝2, in the micro-MITT 
population. If the lower bound of the 95% CI (calculated for the hypothesis test in (1) is greater 
than 0%, the null hypothesis will be rejected and the superiority of oral sulopenem to 
amoxicillin/clavulanate in the micro-MITT population will be concluded. 
 
9.5.2 
Additional Analyses of the Primary Efficacy Outcome 
Sensitivity analyses of the primary outcome will be conducted in the micro-MITT, micro-MITTS 
and micro-MITTR populations. An analysis will consider all patients who have missing data for 
the primary outcome (i.e., an indeterminate response) as successes.  A 2-sided 95% unstratified 
CI will be computed for the difference in the success rates between the treatment groups.  A 
sensitivity analysis applying multiple imputation methods for missing data will be conducted. A 
sensitivity analysis based on results of whole genome sequencing to confirm susceptibility 
testing results will also be conducted. An analysis of the overall response at Day 12 (±1 
day)/TOC may be performed after adjusting for covariates. 
Additional sub-group analyses, such as the effect of food or based on baseline variables 
including geographic region if applicable, may be conducted as exploratory analyses.  
9.5.3 
Analysis of Secondary Efficacy Outcome Measure 
The number and percentage of patients in each treatment group with a clinical response of 
success, failure and indeterminate at Day 12 (±1 day)/TOC will be presented for the MITT, 
micro-MITT, micro-MITTS, and micro-MITTR populations. The number and percentage of 
patients in each treatment group with a clinical response of success and failure at Day 12 (±1 
day)/TOC will be presented for the CE and ME populations.  Two-sided 95% unstratified CIs 
will be constructed for the observed difference in the clinical success rates between the treatment 
groups for descriptive purposes; no conclusion of NI will be made. 
The number and percentage of patients in each treatment group with asymptomatic bacteriuria at 
Day 12 (±1 day)/TOC will be presented for the micro-MITT, micro-MITTS, micro-MITTR and 
ME populations. The difference in rate of asymptomatic bacteriuria (oral sulopenem group 
minus the amoxicillin/clavulanate group) will be determined and 2-sided 95% unstratified CIs 
will be constructed for the observed difference between the treatment groups for descriptive 
purposes; no conclusion of NI will be made. 
 
The number and percentage of patients in each treatment group with a microbiologic response of 
success, failure and indeterminate at Day 12 (±1 day)/TOC will be presented for the micro-
MITT, micro-MITTS, and micro-MITTR populations. The number and percentage of patients in 
each treatment group with a microbiologic response of success and failure at Day 12 (±1 
day)/TOC will be presented for the ME populations.  Two-sided 95% unstratified CIs will be 
constructed for the observed difference in the microbiologic success rates between the treatment 
groups for descriptive purposes; no conclusion of NI will be made. 
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9.5.4 
Analyses of Additional Efficacy Outcome Measures 
The number and percentage of patients in each treatment group with a clinical response of 
success, failure and indeterminate at Day 5 (+1 day), and Day 28 (±2 days) will be presented for 
the MITT, micro-MITT, micro-MITTS, and micro-MITTR populations. The number and 
percentage of patients in each treatment group with a clinical response of success and failure at 
Day 5 (+1 day), and Day 28 (±2 days) will be presented for the CE and ME populations.  Two-
sided 95% unstratified CIs will be constructed for the observed difference in the clinical success 
rates between the treatment groups for descriptive purposes; no conclusion of NI will be made. 
The number and percentage of patients in each treatment group with asymptomatic bacteriuria at 
Day 5 (+1 day), and Day 28 (±2 days) will be presented for the micro-MITT, micro-MITTS, 
micro-MITTR and ME populations. The difference in rate of asymptomatic bacteriuria (oral 
sulopenem group minus the amoxicillin/clavulanate group) will be determined and 2-sided 95% 
unstratified CIs will be constructed for the observed difference between the treatment groups for 
descriptive purposes; no conclusion of NI will be made. 
 
The number and percentage of patients in each treatment group with a microbiologic response of 
success, failure and indeterminate at Day 5 (+1 day), and Day 28 (±2 days) will be presented for 
the micro-MITT, micro-MITTS, and micro-MITTR populations. The number and percentage of 
patients in each treatment group with a microbiologic response of success and failure at Day 5 
(+1 day), and Day 28 (±2 days) will be presented for the ME population.  Two-sided 95% 
unstratified CIs will be constructed for the observed difference in the microbiologic success rates 
between the treatment groups for descriptive purposes; no conclusion of NI will be made. 
The number and percentage of patients in each treatment group with an overall response of 
success, failure and indeterminate at Day 5 (+1 day), and Day 28 (±2 days) will be presented for 
the micro-MITT, micro-MITTS and micro-MITTR populations. The number and percentage of 
patients in each treatment group with an overall response of success and failure at Day 5 (+1 
day), Day 12 (±1 day)/TOC and Day 28 (±2 days) 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. 
Investigator determined clinical response (clinical success, failure and indeterminate) at the Day 
5 (+1 day), Day 12 (±1 day)/TOC, and Day 28 (±2 days) visits will be presented by treatment 
group for the MITT, micro-MITT, micro-MITTS, micro-MITTR, and the respective 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. 
A shift table of the severity of each uUTI symptom based on the Patient Symptom Assessment 
Questionnaire from baseline to Day 5 (+1 day), Day 12 (±1 day)/TOC, Day 28 (±2 days) and 
relevant unscheduled visits will be provided by treatment group for the micro-MITTS and micro-
MITTR populations. 
Overall success, clinical success, and microbiologic success at the Day 5 (+1 day), Day 12 (±1 
day)/TOC and Day 28 (±2 days) visits by baseline pathogen (key pathogens) will be summarized 
by treatment group in the micro-MITT, micro-MITTS, micro-MITTR and ME populations.  
The number and percentage of patients 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 
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Day 12 (±1 day)/TOC) will also be presented for the micro-MITT, micro-MITTS, micro-MITTR 
and ME populations. 
The number and percentage of patients 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 12 (±1 day)/TOC) and monomicrobial infection will also be presented for the micro-MITT, 
micro-MITTS, micro-MITTR and ME populations. 
An assessment of the impact of antibiotic therapy on the in vitro susceptibility of study 
uropathogens (Enterobacterales and S. saprophyticus) identified at baseline will be performed at 
the D12 (±1 day)/TOC and Day 28 (±2 days) visits in order to determine if study drug selected 
for organisms with higher MIC’s. 
An assessment of overall response by baseline uropathogen resistance class(es) will be presented 
in each treatment group for the micro-MITT, micro-MITTS, micro-MITTR and ME populations.  
Sub-group analyses, such as the effect of food, may be conducted for selected secondary safety 
and 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 regimen 
of study drug for their entire course of treatment will be analyzed in the group based on the 
regimen received. 
Adverse events will be coded using the Medical Dictionary of Regulatory Activities (MedDRA). 
Summary tables of treatment-emergent AEs (TEAEs) will be provided.  A TEAE is any AE that 
newly appeared or worsened in severity following initiation of study drug.  The incidence of 
TEAEs will be tabulated by system organ class (SOC) and preferred term (PT) for each 
treatment group, by SOC, PT and severity and by SOC, PT 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 the Baseline and Day 12 (± 1 day)/TOC 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 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 for 
the Baseline, Day 5 (+1 day), and Day 12 (± 1 day)/TOC study visits, as well as the change from 
baseline at the Day 5 (+1 day) and Day 12 (± 1 day)/TOC study visits.   
9.7 
Interim Analysis  
To ensure that the point estimate of overall success (combined clinical and microbiologic 
success) used in the estimation of sample size, and the estimated eligibility rate, susceptibility 
rate, and rate of post-treatment asymptomatic bacteriuria is valid for this study, an interim 
analysis for sample size re-estimation will be performed when clinical and microbiologic 
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response data at Day 12 (± 1 day)/TOC are available for approximately 50% of the patients 
(approximately 983 patients).  The FDA Guidance “Non-inferiority Clinical Trials” [FDA 
Guidance 2016] 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. The sample size of the study will be computed to ensure that there is sufficient power 
for determining whether oral sulopenem is NI to oral amoxicillin/clavulanate for the primary 
outcome measure in the micro-MITTS population. This will ensure that the study is sufficiently 
powered to test the primary endpoint in the micro-MITT and micro-MITTR populations as 
well. The sample size will not be decreased.  In addition, the sample size may be increased 
based on a lower-than-expected evaluability rate (i.e., percentage of the ITT population in the 
micro-MITT population), higher- than-expected rate of asymptomatic bacteriuria or lower than 
expected percentage of patients with a susceptible pathogen. The sample size re-estimation will 
be based on the blinded overall (not by treatment group) pooled data. 
The blinded interim analysis will proceed as follows: 
1. Determine the percentage of patients with a baseline pathogen (micro-MITT population) 
2. Determine the percentage of patients with a susceptible (to comparator study drug, 
amoxicillin/clavulanate) pathogen (micro-MITTS population) and a non-susceptible (to 
amoxicillin/clavulanate) pathogen (micro-MITTR population) 
3. Determine the overall success rate and overall rate of asymptomatic bacteriuria 
aggregated across treatment groups in the micro-MITTS population 
4. Determine if there is sufficient power (80-90%) in the micro-MITTS to show NI with 
the planned sample size based on the observed aggregated (across treatment groups) 
overall success rate and overall rate of asymptomatic bacteriuria 
a. If NO, then increase the sample size in the micro-MITTS population to have 
sufficient power, up to a maximum number of 2500 patients. 
5.  If the aggregated overall success rate in the micro-MITTS population is higher than 
70%, or if the aggregated rate of asymptomatic bacteriuria is significantly lower than 
anticipated, then a futility analysis may be conducted by the DMC to assess if the study 
should continue. Further details of how the DMC will decide to do the futility analysis, 
how the sponsor will be involved and how the analysis will be conducted will be 
provided in the SAP and the DMC charter. 
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 (primary) 
and microbiological response (secondary) is missing at the Day 12 (±1 day)/TOC (primary) and 
Day 28 (±2 days) (secondary) visit, the patient will be considered an indeterminate response. 
By definition, patients with an indeterminate response are included in the denominator in the 
micro-MITT population and thus, are analyzed in the same manner as failures in the primary 
and secondary analyses. Additional sensitivity analyses for handling missing data will be 
detailed in the SAP. Imputation may be performed to understand the impact of any imbalance 
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in indeterminate outcomes between treatment regimens. By definition, patients with missing 
data are excluded from the CE and ME 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.  
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. 
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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. 
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 
law.  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 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 
before any study-specific activity is performed.  The investigator will retain the original of each 
patient's signed consent form. 
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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 becomes 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 all Participating Countries 
End of Study in all participating countries is defined as the last patient’s Final Visit. 
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.  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 outlined 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 (eudract.ema.europa.eu) as 
applicable. 
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. 
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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. 
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 
Banerjee R and Johnson JR. A New Clone Sweeps Clean: the Enigmatic Emergence of 
Escherichia coli Sequence Type 131. AAC 2014:58:4997-5004. 
Brannon JR, Dunigan TL, Beebout CJ, et al. Invasion of vaginal epithelial cells by uropathogenic 
Escherichia coli. Nature Communications 2020;11:2803. 
Brumfitt W, and Hamilton-Miller JMT. Amoxicillin plus clavulanic acid in the treatment of 
recurrent urinary tract infections. Antimicrob Agents Chemother 1984;25(2):276-278. 
CLSI M100-ED32:2022 Performance Standards for Antimicrobial Susceptibility Testing, 32nd 
Edition. 
Cooper J, Raeburn AL, Brumfitt W, and Hamilton-Miller JMT. General practitioner study: 
Fosfomycin trometamol versus amoxycillin clavulanate in acute urinary tract infections. 
Chemother 1990:36(suppl 1):24-26. 
Critchley IA, Cotroneo N, Pucci MJ, Mendes R (2019) The burden of antimicrobial resistance 
among urinary tract isolates of Escherichia coli in the United States in 2017. PLoS ONE 14(12): 
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Dunne MW, Aronin SI, Yu KC, Watts JA, and Gupta V. A multicenter analysis of trends in 
resistance in urinary Enterobacterales isolates from ambulatory patients in the United States: 
2011-2020. BMC Infect Dis 2022;22:194. https://doi.org/10.1186/s12879-022-07167-y.  
 
Dunne MW, Puttagunta S, Aronin SI, Brossette S, Murray J, Gupta V. Impact of empirical 
antibiotic therapy on outcomes of outpatient urinary tract infection due to nonsusceptible 
Enterobacterales. Microbiology Spectrum 2022;10(1):e02359-21. 
 
Edowik Y, Caspari T, Williams HM. The Amino Acid Changes T55A, A273P and R277C in the 
Beta-Lactamase CTX-M-14 Render E. coli Resistant to the Antibiotic Nitrofurantoin, a First-
Line Treatment of Urinary Tract Infections. Microorganisms. 2020; 8(12). 
 
Foulds G, Knirsch A, Lazar J, et al. Pharmacokinetics of the penem CP 65,207 and its separate 
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Forrest A, Nix DE, Ballow CH, Goss TF, Birmingham MC, Schentag JJ. AAC 1993;37:1073-
1081. 
Gupta K, Hooton TM, Naber KG, Wullt B, Colgan R, Miller LG, Moran GJ, Nicolle LE, Raz R, 
Schaeffer AJ, Soper DE; Infectious Diseases Society of America; European Society for 
Microbiology and Infectious Diseases. International clinical practice guidelines for the treatment 
of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious 
Diseases Society of America and the European Society for Microbiology and Infectious 
Diseases. Clin Infect Dis. 2011 Mar 1;52(5):e103-20. doi: 10.1093/cid/ciq257. PMID: 21292654.  
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Gurwith MJ, Stein GE, and Gurwith D. Prospective comparison of amoxicillin-clavulanic acid 
and cefaclor in treatment of uncomplicated urinary tract infections. Antimicrob Agents 
Chemother 1983;24(5):716-719. 
 
Hooten TM, Scholes D, Gupta K, Stapleton AE, Roberts PL, Stamm WE. Amoxicillin-
clavulanate vs ciprofloxacin for the treatment of uncomplicated cystitis in women. A randomized 
trial. JAMA 2005; 293:949-955. 
Hooton TM, Roberts PL, Stapleton AE. Cefpodoxime vs ciprofloxacin for short-course treatment 
of acute uncomplicated cystitis. A Randomized Trial. JAMA 2012;307:583-589. 
Huttner A, et al. Effect of 5-day nitrofurantoin vs single-dose fosfomycin on clinical resolution 
of uncomplicated lower urinary tract infection in women. JAMA. 2018;319(17):1781-1789. 
doi:10.1001/jama.2018.3627. 
 
Kaye KS, et al. Effect of Meropenem-Vaborbactam vs Piperacillin-Tazobactam on Clinical Cure 
or Improvement and Microbial Eradication in Complicated Urinary Tract Infection: The 
TANGO I Randomized Clinical Trial. JAMA 2018;319(8):788-799. doi: 
10.1001/jama.2018.0438. PMID: 29486041; PMCID: PMC5838656. 
 
Kaye KS, Gupta V, Mulgirigama A, Joshi AV, Scangarella-Oman NE, Yu K, Ye G, Mitrani-
Gold FS. Antimicrobial Resistance Trends in Urine Escherichia coli Isolates From Adult and 
Adolescent Females in the United States From 2011 to 2019: Rising ESBL Strains and Impact on 
Patient Management. Clin Infect Dis. 2021 Dec 6;73(11):1992-1999. doi: 10.1093/cid/ciab560. 
PMID: 34143881; PMCID: PMC8664433. 
Lan KKG, and Wittes, J. The B-value: A tool for monitoring data. Biometrics 1988; 44: 579-585 
 
Le VVH, Rakonjac J (2021) Nitrofurans: Revival of an “old” drug class in the fight against 
antibiotic resistance. PLoS Pathog 17(7): e1009663. https://doi.org/10.1371/journal. 
ppat.1009663 
 
Martinez-Casanova J, Gomez-Zorilla S, Prim N, et al. Risk Factors for Amoxicillin-Clavulanate 
Resistance in Community-Onset Urinary Tract Infections Caused by Escherichia coli or 
Klebsiella pneumoniae: The Role of Prior Exposure to Fluoroquinolones. Antibiotics 2021, 10, 
582. 
Mehta CR and Pocock SJ. Adaptive increase in sample size when interim results are promising: 
A practical guide with examples. Statist. Med. 2011, 30 3267–3284. 
Munoz-Davila MJ. Role of old antibiotics in the era of antibiotic resistance. Antibiotics 2014; 
3:39-48. 
National Institute for Health and Care Excellence. Urinary tract infection (lower): antimicrobial 
prescribing guideline. Evidence review for NICE Guideline. October 2018. 
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Paterson DL. "Collateral damage" from cephalosporin or quinolone antibiotic therapy. Clin 
Infect Dis 2004; 38(Suppl. 4):S341–5. 
 
Ramphal R, Ambrose PG. Extended-spectrum b-lactamases and clinical outcomes: current data. 
Clin Infect Dis 2006; 42(Suppl. 4):S164–72. 
 
Sanchez GV, Master RN, Karlowsky JA, Bordon JM. In vitro antimicrobial resistance of urinary 
Escherichia coli isolates among U.S. outpatients from 2000 to 2010. Antimicrob Agents 
Chemother 2012; 56:2181–3. 
 
Schito GC, Naber KG, Botto H, Palou J, Mazzei T, Gualco L, Marchese A. The ARESC study: 
an international survey on the antimicrobial resistance of pathogens involved in uncomplicated 
urinary tract infections. Int J Antimicrob Agents. 2009 Nov;34(5):407-13. doi: 
10.1016/j.ijantimicag.2009.04.012. Epub 2009 Jun 7. PMID: 19505803. 
 
Thomas-White K, Forster SC, Kumar N, et al. Culturing of female bladder bacteria reveals an 
interconnected urogenital microbiota. Nature Communications 2018;9:1557 DOI: 
10.1038/s41467-018-03968-5. 
US Department of Health and Human Services.  Non-inferiority Clinical Trials to Establish 
Effectiveness.  Guidance for Industry.  Washington, DC:  US Food and Drug Administration; 
Clinical/Medical. November 2016. 
 
Wagenlehner FM, 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):754762; 
https://doi.org/10.1093/cid/ciw378. 
Wagenlehner FME, et al. Once-Daily Plazomicin for Complicated Urinary Tract Infections. N 
Engl J Med 2019;380:729-40. DOI: 10.1056/NEJMoa1801467. 
 
Westfall PH, Krishen A. Optimally weighted, fixed sequence and gatekeeper multiple testing 
procedures. Journal of Statistical Planning and Inference 2001; 99:25-40. 
Zhanel GG, et al. In vitro activity of sulopenem and comparative agents against bacterial 
pathogens isolated from Canadian patients with urinary tract infections: CANWARD 
surveillance study 2014-2020. Poster presentation World Microbe Forum, June 2021. 
 
 
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APPENDIX 1    RATIONALE FOR AMOXICILLIN/CLAVULANATE AS 
COMPARATOR IN UNCOMPLICATED UTI TRIAL 
Amoxicillin/clavulanate is an oral antibacterial combination consisting of the semisynthetic 
antibiotic amoxicillin and the β-lactamase inhibitor, clavulanate (the potassium salt of clavulanic 
acid). The formulation of amoxicillin and clavulanic acid protects amoxicillin from degradation 
by β-lactamase enzymes and effectively extends the antibiotic spectrum of amoxicillin to include 
many bacteria normally resistant to amoxicillin and other β-lactam antibiotics. 
Amoxicillin/clavulanate has activity against gram-positive and gram-negative aerobes and 
anaerobes, including the following Enterobacterales responsible for the majority of cases of 
uUTI: E. coli, Klebsiella species, and Proteus mirabilis. FDA-approved indications for 
amoxicillin/clavulanate include treatment of urinary tract infections, lower respiratory tract 
infections, otitis media, sinusitis, and skin and skin structure infections [Augmentin USPI]. 
Amoxicillin/clavulanate is also approved in Europe for the treatment of UTI and is still the most 
prescribed antimicrobial (in 26.5% of the cases) to treat community-onset UTI in some European 
countries [Martinez-Casanova 2021]. 
Amoxicillin/clavulanate was chosen as the comparator for Study IT001-310 because it is an 
approved antibiotic for the indication of urinary tract infection [Augmentin USPI], it is 
considered as a treatment option for acute uUTI in the IDSA Treatment Guideline [Gupta 2011], 
and as a β-lactam antibiotic, it is likely to have a similar effect to sulopenem on the female 
urogenital microbiome, thus allowing for a fair comparison of efficacy. The dose of 
amoxicillin/clavulanate (875 mg/125 mg PO twice daily) was chosen to justify the use of 
amoxicillin/clavulanate CLSI breakpoints for uncomplicated urinary tract infection (M100 
Performance Standards for Antimicrobial Susceptibility Testing, 32nd edition).    
1. Per the approved label [Augmentin USPI], amoxicillin/clavulanate is an approved antibiotic 
for the indication of urinary tract infection. 
‘Indication:  
Urinary Tract Infections – caused by β-lactamase–producing strains of E. coli, 
Klebsiella spp., and Enterobacter spp.  
While AUGMENTIN is indicated only for the conditions listed above, infections caused 
by ampicillin-susceptible organisms are also amenable to treatment with AUGMENTIN 
due to its amoxicillin content; therefore, mixed infections caused by ampicillin-
susceptible organisms and β-lactamase–producing organisms susceptible to 
AUGMENTIN should not require the addition of another antibiotic.’ 
 
‘Dosage Adults: The usual adult dose is one 500-mg tablet of AUGMENTIN every 12 
hours or one 250-mg tablet of AUGMENTIN every 8 hours. For more severe infections 
and infections of the respiratory tract, the dose should be one 875-mg tablet of 
AUGMENTIN every 12 hours or one 500-mg tablet of AUGMENTIN every 8 hours.’  
 
Based on the Guidance for “Non-inferiority clinical trials to establish effectiveness” 
amoxicillin/clavulanate is therefore an approved agent to use as a comparator in a noninferiority 
trial for patients with urinary tract infection.  
2. Amoxicillin/clavulanate is listed as a treatment option in the IDSA Treatment Guidelines 
[Gupta, 2011]. 
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‘β-Lactam agents, including amoxicillin/clavulanate, cefdinir, Cefaclor, and 
cefpodoxime-proxetil, in 3-7-day regimens are appropriate choices for therapy when 
other recommended agents cannot be used (B -1). Other β-lactams, such as cephalexin, 
are less well studied but may also be appropriate in certain settings (B-III).’ 
It is important to understand that the IDSA Treatment Guidelines were last updated in 2010 
(published in 2011). At that time, the authors aimed to balance issues of in vitro resistance and 
collateral damage (a term describing ecological adverse effects of antimicrobial therapy, such as 
the selection of drug-resistant organisms and colonization or infection with multidrug-resistant 
organisms) when making their recommendations for optimal and alternative treatment options.  
At that time, rising rates of resistance to quinolones and trimethoprim-sulfamethoxazole (TMP-
SMX) had been shown for outpatient urinary isolates 2000-2010 [Sanchez 2012], and increased 
collateral damage was found to be associated with broad-spectrum cephalosporins and 
quinolones [Paterson 2004; Ramphal 2006]. As shown in the Table below, pivmecillinam, a β-
lactam, had the lowest estimated clinical and microbiological efficacy of all the optimal and 
alternative treatment agents in the IDSA Guideline, yet it was listed as an optimal choice given 
its low resistance rates and low propensity to cause collateral damage.  Other β-lactams were 
listed as alternative agents, yet their estimated clinical and microbiologic efficacy was higher 
than pivmecillinam and comparable to fosfomycin, both listed as optimal agents.  High 
resistance rates were noted for β-lactams, specifically ampicillin and amoxicillin, and high 
propensity to cause collateral damage was noted, specifically for broad-spectrum cephalosporins.  
Ciprofloxacin had one of the highest efficacy rates observed, an estimated clinical and 
microbiological efficacy of 90% and 91%, respectively, but was listed as an alternative agent due 
to rising resistance rates and its high propensity to cause collateral damage.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 2 
Comparison of Optimal and Alternative Treatment Regimens, IDSA Guidelines 
Antibiotic / 
Class 
 
 
Dose 
Estimated 
clinical 
efficacy, 
Mean % 
(range) 
Estimated 
microbiolo
gical 
efficacy 
Mean %, 
(range) 
Efficacy 
Comments 
Estimated 
E. coli 
Resistanc
e Rate, 
2011 
Resistance 
Comments 
Propensity to 
Cause Collateral 
Damage 
Optimal Treatment Options 
Nitrofurantoin 
100 mg 
BID x 5-7d 
93 (84-95) 
88 (86-92) 
Efficacy 
comparable 
to 3 days of 
TMP-SMX 
1.6-4.8% 
Minimal 
resistance 
Minimal propensity 
for collateral 
damage 
TMP-SMX 
160/800 
mg BID x 
3d 
93 (90-
100) 
94 (91-
100) 
Favorable 
efficacy as 
assessed in 
numerous 
clinical 
trials 
24.2-
27.7% 
Appropriate 
choice if local 
resistance rates of 
uropathogens 
causing acute 
uncomplicated 
cystitis do not 
exceed 20% 
Has been 
demonstrated to 
significantly affect 
the normal fecal 
flora, but generally 
not thought to have a 
propensity for 
collateral damage 
Fosfomycin 
3 gm single 
dose sachet 
91 (NA) 
80 (78-83) 
Appears to 
have 
inferior 
efficacy 
compared 
with 
standard 
short-
course 
regimens  
1.9% (ex-
US data) 
Minimal 
resistance 
Minimal propensity 
for collateral 
damage 
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Pivmecillinam  400 mg 
BID x 3-7d 
73 (55-82) 
79 (74-84) 
May have 
inferior 
efficacy 
compared 
with other 
available 
therapies 
4.2% (ex-
US data) 
Minimal 
resistance  
Minimal propensity 
for collateral 
damage 
Alternative antimicrobial choices 
Quinolones 
Dose varies 
by agent; 
3-d 
regimen 
90 (85-98) 
91 (81-98) 
Highly 
efficacious 
17.1–26% 
Rising rates of 
resistance 
Propensity for 
collateral damage 
β-lactams 
Dose varies 
by agent; 
3-5d 
regimen 
89 (79-98) 
82 (74-98) 
Generally, 
have 
inferior 
efficacy 
43.4-
50.3% 
High rates of 
resistance for 
ampicillin and 
amoxicillin 
Propensity for 
broad-spectrum 
cephalosporins to 
cause collateral 
damage 
Source: Schito 2009; Gupta 2011; Sanchez 2012; Kaye 2021; Dunne 2022 
 
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The IDSA Treatment Guideline specifically warned against the empiric use of TMP-SMX for 
acute cystitis if local resistance rates of uropathogens causing acute uncomplicated cystitis 
exceeded 20%. Due to the resistance rates at the time, a similar recommendation was not 
made for other agents, but it has since become a common clinical practice to apply this 20% 
threshold to local resistance data in order to guide empiric therapy for patients with acute 
uncomplicated cystitis.   
 
Since the 2011 IDSA Treatment Guidelines were written, resistance rates have exceeded or 
approached the 20% threshold for quinolones and nitrofurantoin, respectively. For 
nitrofurantoin, resistance to E. coli is approximately 4%, but nitrofurantoin resistance rates 
for Enterobacterales other than E. coli are markedly elevated (88-100% for Proteus mirabilis, 
58-63.0% for Klebsiella pneumoniae, and approximately 57% for all other Enterobacterales) 
making the empirical use of this agent problematic [Huttner 2018, Zhanel 2021, Dunne 
2022].  
 
Rising nitrofurantoin resistance rates are likely a direct consequence of increased 
nitrofurantoin utilization in response to high TMP-SMX and quinolone resistance rates.  In 
one United Kingdom location, the authors believe that increased exposure of E. coli to 
nitrofurantoin resulted in the emergence of a mutated version of the ESBL CTX-M-14 
enzyme. When this mutated CTX-M-14 enzyme was recombinantly overexpressed in a 
laboratory strain of E. coli, a strain emerged that was hyper-resistant to nitrofurantoin while 
retaining β-lactam resistance [Edowik 2021].  Given that globally CTX-M-14 is one of the 
predominant ESBL types [Banerjee 2014], over time with continued E. coli exposure to 
nitrofurantoin, selection for this nitrofurantoin-resistant mutant is likely [Le 2021].  
 
To add to the complexity, there has been a rapid increase in both the rate of ESBL-producing 
pathogens, and the rate of co-resistance to two or more standard agents [Critchley 2019, 
Kaye 2021, Dunne 2022].   
 
Resistance rates for amoxicillin/clavulanate are not provided in the IDSA Guidelines.  As 
shown in Table 3 below, based on the results of Study IT001-301, the expected rate of 
resistance to amoxicillin/clavulanate is less than to quinolones and TMP-SMX, and 
comparable to nitrofurantoin. These findings, in conjunction with what is known about 
clinical response, microbiologic response, and propensity to cause collateral damage for 
uUTI patients treated with amoxicillin/clavulanate, support the use of amoxicillin/clavulanate 
as a safe and effective comparator in a non-inferiority uUTI trial. 
 
 
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Table 3   Resistance Rate for Baseline Pathogen(s), IT001-301  
Antibiotic/Class 
Resistance Rate 
n (%) 
N=1071 
Amoxicillin/clavulanate 
205 (19.1) 
Nitrofurantoin 
192 (17.9) 
Trimethoprim-sulfamethoxazole  
338 (31.6) 
Ciprofloxacin  
293 (27.4) 
Source: IT001-301 CSR; posthoc Table 198 
 
While amoxicillin/clavulanate is listed as a treatment option in the 2011 IDSA Guidelines, 
and the document provides useful historical information to help guide the management of 
patients with suspected and confirmed acute uncomplicated cystitis, the Guidelines are 
outdated, not based on efficacy alone, and cannot be relied upon to steer the choice of a 
comparator agent for a non-inferiority trial in uUTI in 2022.     
 
A more recent antimicrobial prescribing guideline for lower UTI from the National Institute 
for Health and Care Excellence published in October 2018 indicates that the efficacy of β-
lactams is not significantly different than that compared to nitrofurantoin, trimethoprim-
sulfamethoxazole or quinolones based on a large meta-analysis of randomized controlled 
trials [NICE Guideline 2018]. 
 
3. Availability of data regarding the degree of asymptomatic bacteriuria: 
 
In Study IT001-301, sulopenem was not non-inferior to ciprofloxacin in patients whose 
baseline uropathogen was susceptible to ciprofloxacin.  The difference in response rates was 
driven almost exclusively by a greater proportion of asymptomatic patients with the baseline 
uropathogen isolated at the test of cure visit in patients who received sulopenem. The 
presence of asymptomatic bacteriuria a week or more after completing therapy was not 
associated with a higher rate of clinical relapse, making it likely that the presence of 
pathogens in the urine culture was not a reflection of incomplete eradication of the offending 
baseline organism and more likely due to recolonization of the bladder.   
A possible explanation why asymptomatic bacteriuria would occur sooner post-treatment for 
patients receiving sulopenem than for those receiving ciprofloxacin is that ciprofloxacin has a 
more significant impact on the vaginal flora than a β-lactam such as sulopenem, and that this 
effect on the vaginal flora affects the rate at which women recolonize the bladder. Similar 
observations have been made in two previous studies of the treatment of uncomplicated 
urinary tract infection and recently in a mouse model of urinary tract infection [Hooton 2005, 
Hooton 2012, Brannon 2020]. The area under the curve (AUC) of ciprofloxacin in plasma 
over 24 hours after a 250 mg bid dose is approximately 9.6 μg • h/mL [Cipro USPI]. An 
AUC24/MIC of approximately 125 is the ratio required for achieving clinical and 
microbiologic success with ciprofloxacin [Forrest 1993] and this ratio would be achieved for 
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organisms with an MIC of <0.06 µg/mL. Consistent with this potential effect, and assuming 
tissue concentrations are equal to plasma, a lower rate of asymptomatic bacteriuria was only 
seen in those ciprofloxacin-treated patients whose baseline uropathogen had an MIC of <0.06 
mg/mL. This effect would be relevant not for organisms residing in the urine as the urine 
concentrations of ciprofloxacin are significantly higher than plasma, but rather for those 
organisms in the colonizing flora of the perineum and vaginal mucosa, a potential source of 
organisms for recolonization of the bladder [Thomas-White 2018, Brannon 2020].  
 
This concentration dependent effect of ciprofloxacin on the vaginal flora would also carry 
with it the potential for selection of increasingly more resistant pathogens in the post-
treatment flora. In Study IT001-301, 35/415 (8.4%) patients without culture evidence of a 
ciprofloxacin resistant pathogen at baseline had a ciprofloxacin resistant pathogen in their 
urine culture post-treatment. More worrisome was that many of these ciprofloxacin resistant 
isolates also carried the blaCTX-M-15 extended spectrum β-lactamase resistance gene, a 
commonly circulating plasmid among E. coli [Banerjee 2014], making treatment in the future 
with either a quinolone or a β-lactam other than a penem less likely to be successful.  
 
While the antibiotic effect on a woman’s vaginal flora, and subsequently the rate of bladder 
recolonization, is likely a class effect, other host factors and mechanisms may be at play, and 
the association between specific antibiotics and post-treatment asymptomatic bacteriuria is 
not known. This makes it challenging to confidently choose a comparator in a noninferiority 
trail, as long as microbiologic outcome remains part of the primary endpoint.  It is reasonable 
to assume that a β-lactam comparator such as amoxicillin/clavulanate will have a similar 
effect to sulopenem on the urogenital microbiome, thus allowing for a fair comparison of 
efficacy.  Additional data from Study IT001-302 supports using amoxicillin/clavulanate as 
the comparator.  As shown in Table 4 below, in Study IT001-302, a higher incidence of 
asymptomatic bacteriuria was observed in complicated UTI patients receiving sulopenem.  
This difference in the proportion of patients with asymptomatic bacteriuria was observed 
primarily among the patients who had ciprofloxacin-susceptible uropathogens and, per 
protocol, received ciprofloxacin as step-down treatment.  Of the patients who received IV 
sulopenem and stepped down to oral sulopenem, 21.8% failed due to asymptomatic 
bacteriuria at TOC compared to just 4.7% of those who received IV ertapenem and stepped 
down to oral ciprofloxacin.  Of the patients with ciprofloxacin-nonsusceptible uropathogens, 
those in the ertapenem group, depending on their clinical status, either received their entire 
treatment course IV or were stepped down to amoxicillin/clavulanate.  The rate of 
asymptomatic bacteriuria as the reason for failure among these patients was similar to that of 
sulopenem patients, supporting the use of amoxicillin/clavulanate as the comparator in our 
planned uncomplicated UTI noninferiority trial. 
 
 
 
 
 
 
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Table 4   Overall Response at TOC by Stepdown Category, IT001-302, micro-MITT 
Population 
Outcome 
Sulopenem 
n (%) 
Ertapenem 
n (%) 
Difference (%), 
(95% CI) 
All patients 
Primary Endpoint:  Overall Success 
(TOC) 
301/444 (67.8) 
325/440 (73.9) 
-6.1 (-12.0, -0.1) 
Reason for failure:  Asymptomatic 
bacteriuria 
93 (20.9) 
59 (13.4) 
 
Patients with ciprofloxacin susceptible isolates by treatment regimen 
 
Sulopenem IV / 
oral Sulopenem 
 n (%) 
Ertapenem IV / oral 
ciprofloxacin 
n (%) 
 
Overall Success 
168/248 (67.7) 
186/215 (86.5) 
-18.8 (-26.1, -
11.0) 
Reason for failure:  Asymptomatic 
bacteriuria 
54 (21.8) 
10 (4.7) 
 
 
Sulopenem IV 
Ertapenem IV (n=26) 
or 
Ertapenem IV / oral 
Amoxicillin/clavulanate 
(n=6) 
 
Overall Success 
19/34 (55.9) 
17/32 (53.1) 
2.8 (-20.9, 26.2) 
Reason for failure:  Asymptomatic 
bacteriuria 
7 (20.6) 
7 (21.9) 
 
Patients with ciprofloxacin non-susceptible isolates by treatment regimen 
 
Sulopenem IV 
only or Sulopenem 
IV / Sulopenem-
Etzadroxil + 
Probenecid 
n (%) 
Ertapenem IV only or 
Ertapenem IV / 
Amoxicillin/clavulanate 
n (%) 
 
Overall Success 
114/162 (70.4) 
122/193 (63.2) 
7.2 (-2.7, 16.8) 
Reason for failure:  Asymptomatic 
bacteriuria 
32 (19.8) 
42 (21.8) 
 
Source: IT001-302 CSR 
 
Further support for the degree and rate of post-treatment asymptomatic bacteria being a class 
effect comes from the fact that efficacy rates for sulopenem in IT001-302 are consistent with 
those seen for other IV penems in recent cUTI trials where step-down to an oral agent was 
not allowed [Wagenlehner 2016, Kaye 2018, Wagenlehner 2019]. These approved penems 
have proven to be effective life-saving drugs. 
 
In conclusion, amoxicillin/clavulanate is an appropriate comparator for our proposed non-
inferiority trial in patients with uUTI. It is an FDA-approved agent for the treatment of UTI, 
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there is support for its use in the IDSA Treatment Guidelines and the 2018 NICE Guidelines, 
and of the potential oral comparator agents, it has a predictable impact on the female 
urogenital microbiome.  Amoxicillin/clavulanate breakpoints as per CLSI (M100 
Performance Standards for Antimicrobial Susceptibility Testing, 32nd edition). 
 
REFERENCES: 
See Reference List in Section 16 above. 
 
   
 
 
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APPENDIX 2  
SCHEDULE OF STUDY ASSESSMENTS 
 
SCREENING TREATMENT PERIOD 
FOLLOW-UP PERIOD 
 
Protocol Activity 
D-1 to D1  
 
Baseline 
D13 
D5 
(+ 1 day)  
EOT 
D12 
(± 1 day) 
TOC 
D28 
(± 2 days) 
FV 
Premature Study 
Discontinuation 
Informed Consent 
X 
 
 
 
 
 
Medical History and 
Demographics 
X 
 
 
 
 
 
Targeted Physical 
Examination 
X 
 
X1 
X1 
X1 
X1 
Vital Signs 
X 
 
X 
X 
 
X 
Hematology 
X 
 
 
X 
 
X 
Serum Chemistry 
X 
 
 
X 
 
X 
Pregnancy testing2 
X 
 
 
 
X 
X 
Banked serum sample 
X 
 
 
X 
 
 
Banked urine sample 
X 
 
X 
X 
 
 
Urinalysis 
X 
X 
X 
X 
X 
Urine Culture and 
sensitivity  
X 
 
X 
X 
X 
X 
Previous Drug and 
Non-drug Treatments 
X 
 
 
 
 
 
Concomitant 
Medications 
 
X 
X 
X 
X 
X 
Provide daily dosing 
diary  
 
X 
 
 
 
 
Collect daily dosing 
diary  
 
 
X 
 
 
X 
Study Drug 
Treatment 
 
X  (BID x 10 doses total) 
 
 
 
Study Drug 
Compliance Check 
 
 
X 
 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
Patient Symptom 
Assessment 
Questionnaire 
(PSAQ) 
 
X 
X 
X 
X 
X 
Investigator 
Assessment of 
Clinical Response  
 
 
X 
X 
X 
X 
 
Schedule of Activities Footnotes: 
1 If needed, based on symptoms, as determined by the investigator 
2 Baseline and Day 28 (±2 days) or Premature Discontinuation: Pregnancy test (women of childbearing potential and peri-menopausal women, defined 
as women < 50 years of age or those ≥ 50 years of age who have been post-menopausal for < 2 years) should be performed as required by the 
protocol 
3 Day 1 and Screening are generally on the same day 
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APPENDIX 3  
MICROBIOLOGY 
Method of Collection of Urine Specimens: 
To obtain a clean catch sample of urine from a female patient and avoid specimen 
contamination, 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. Urine samples should be collected by clean-catch midstream. Details 
of appropriate methodology for urine sample collection, handling, and storage 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. 
If feasible, urine specimens should be collected 4 hours after the last void. 
Culture and Susceptibility testing  
All gram-negative pathogens and S. saprophyticus will be tested by the Central laboratory for 
antimicrobial susceptibility.  
The Central laboratory should retain all isolates until the end of the study, if possible. 
Additional samples for culture may be requested if the Central laboratory does not receive a 
viable culture.  
Susceptibility results of pathogens to amoxicillin/clavulanate and carbapenems from cultures 
obtained at Screening, EOT, and TOC should not be reported to sites/investigators until after 
the TOC visit, unless requested by the Principal Investigator and clinically warranted, so as 
not to influence the investigator’s decision to prescribe a rescue antibiotic in the case of 
presence of a non-susceptible pathogen. 
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 urine culture specimen: 
• Monomicrobial or polymicrobial infections caused by: 
• Enterobacterales 
• Enterococci  
• Pseudomonas aeruginosa  
• S. saprophyticus 
The micro-MITT population for this study will only include patients with uUTI 
caused by Enterobacterales and/or S. saprophyticus. 
• Even if the organism was isolated from an acceptable urine culture specimen, the 
following are never a pathogen for this study: 
• Corynebacterium spp. 
• S. epidermidis 
• S. aureus 
• Bacillus spp. 
• Diphtheroids 
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• Micrococcus spp. 
• Lactobacillus spp. 
• Viridans Streptococci 
• Group B Streptococci 
• Gardnerella vaginalis 
• Neisseria gonorrhoeae 
• Yeasts 
• A study urine culture positive for more than 2 species of microorganisms, regardless 
of colony count, will be considered contaminated. 
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 will be used to assist 
in determining if the isolate 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 
Enterobacterales, Streptococci and methicillin-susceptible Staphylococcus aureus is ≤ 0.5 
µg/mL. Tentative 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 4 
CRITERIA FOR SAFETY LABORATORY 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 
Alkaline 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 
 
 
Albumin 
<0.8 times the lower 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 5  
SUMMARY OF CHANGES 
Appendix 5.1 
 
Amendment 1 
Minor editorial revisions that have been made for ease of reading, formatting, spelling, 
grammar, and consistency are not included in this summary of changes. 
 
Section 
Change 
Study Population 
Selection (Section 4, 
page 35) 
Female patients who present with uUTI, defined by symptoms and a urinalysis 
suggestive of a uUTI per Section 4.1positive for pyuria, and who meet all of the 
inclusion and none of the exclusion criteria will be eligible for participation in 
this study. 
Rationale: To align with changes made to Section 4.1 below. 
Inclusion Criteria 
(Synopsis and Section 
4.1, page 35) 
1. Female patients ≥18 years of age with ≥24 hours and ≤96 hours of 
urinary symptoms attributable to a UTI  
2. Two of the following signs and symptoms of uUTI: urinary frequency, 
urinary urgency, pain or burning on micturition, suprapubic pain 
3. A mid-stream urine specimen with:  
a. 
a machine-read dipstick positive for nitrite AND any positive 
leukocyte esterase 
OR 
b. evidence of pyuria alone as defined by either: 
i. a machine-read dipstick positive for large leukocyte 
esterase OR  
ii. at least 10 white blood cells per cubic millimeter on 
microscopic analysis of unspun urine OR  
iii. White blood cell count ≥10 cells/HPF in the sediment 
of a spun urine 
4. Has given written informed consent to participate in the study 
 
Rationale: To optimize enrollment of patients with the disease under study and 
to increase successful collection of a positive urine culture for >100,000 
CFU/mL of a uropathogen. 
Women of Child-
Bearing Potential 
(Section 4.5, page 38) 
She 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 and documented in source. 
Rationale: To improve clarity regarding site documentation of forms of 
contraception for women of child-bearing potential.  
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Administration 
(Synopsis and Section 
5.2.3, page 39) 
Patients randomized to the sulopenem treatment group will take one sulopenem 
etzadroxil/probenecid tablet and one placebo capsule twice daily for 5 days and 
those randomized to the amoxicillin/clavulanate treatment group will take one 
over-encapsulated amoxicillin/clavulanate tablet and one placebo tablet twice 
daily for 5 days (10 doses total over a 5-day period; if Dose 1 is taken in the 
evening of Day 1, Dose 10 will be taken in the morning of Day 6). The first dose 
of each medication will be administered under the supervision of study site 
personnel to help ensure compliance with dosing directions. 
Study drug administration will be documented in accordance with the Pharmacy 
Manual.  
Rationale: To improve clarity regarding administration of study medications. 
Appendix 2 (page 78) 
Study Drug Treatment         X (BID x 10 doses totalfor 5 days) 
Rationale: To improve clarity regarding administration of study medications. 
 
3Day 1 and Screening are generally on the same day. 
Rationale: To improve clarity regarding timing of Day 1 in relation to Screening 
activities. 
Appendix 4 (page 81) 
Calcium                             <0.9 or >1.1 times the limits of the reference range  
Rationale: To clarify list of safety laboratory tests being performed. 
 
 
 
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APPENDIX 6 INVESTIGATOR’S SIGNATURE 
Study Title: 
A prospective, Phase 3, randomized, multi-center, double-blind 
study of the efficacy, tolerability, and safety of oral sulopenem 
etzadroxil/probenecid versus oral amoxicillin/clavulanate for 
treatment of uncomplicated urinary tract infections (uUTI) in adult 
women. 
Study Number: 
IT001-310 
Final Date: 
 
Amendment 1 
Date: 
July 7, 2022 
 
December 5, 2022 
 
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: 
 
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SAP_001.pdf: 
 
Version 1.2 
 
Statistical Analysis Plan: IT001-310 
 
 
 
 
Study Title: 
A prospective, Phase 3, randomized, multi-center, double-blind study of 
the 
efficacy, 
tolerability, 
and 
safety 
of 
oral 
sulopenem 
etzadroxil/probenecid versus oral amoxicillin/clavulanate for treatment of 
uncomplicated urinary tract infections (uUTI) in adult women. 
Study Number: 
IT001-310 
Study Phase: 
Phase 3 
Product Name: 
Sulopenem etzadroxil/probenecid tablets (500 mg/500 mg) 
Indication: 
Uncomplicated urinary tract infection 
Sponsor: 
Iterum Therapeutics International Limited  
Study Statistician: 
Jayanti Gupta, PhD 
Study Clinician: 
Steven I. Aronin, MD 
 
 
Initial SAP Date: 
June 30, 2023 
Revised SAP Date: 
August 25, 2023 
Final SAP Date: 
January 10, 2024 
 
 
 
 
 
 
 
 
 
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 
 
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. 


 
Version 1.2 
 
Date: 
SIGNATURE PAGE 
 
 
Study Title: 
A prospective, Phase 3, randomized, multi-center, double-blind 
study of the efficacy, tolerability, and safety of oral sulopenem 
etzadroxil/probenecid versus oral amoxicillin/clavulanate for 
treatment of uncomplicated urinary tract infections (uUTI) in adult 
women. 
Study Number: 
IT001-310 
 
 
I have read this document and confirm that to the best of my knowledge it accurately describes 
the statistical analysis plan for the study. 
 
 
 
Prepared by:   
 
  
 
Name: Jayanti Gupta, PhD 
Title: Consultant Biostatistician 
Iterum Therapeutics 
 
 
 
Approved by: ___________________________________              Date: ____________________ 
Name: Steven I. Aronin, MD 
Title: Senior VP and Head Clinical Development 
Iterum Therapeutics 
January 10, 2024
January 10, 2024


Sulopenem etzadroxil/probenecid tablets  
 
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Statistical Analysis Plan: IT001-310 
 
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TABLE OF CONTENTS 
 
TABLE OF CONTENTS ......................................................................................................... 2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................... 4 
1. 
INTRODUCTION............................................................................................................. 6 
2. 
STUDY DESIGN ............................................................................................................... 6 
3. 
STUDY OBJECTIVES ..................................................................................................... 6 
3.1 
Primary Objective ................................................................................................. 6 
3.2 
Secondary Objectives ........................................................................................... 6 
3.3 
Additional Objectives ........................................................................................... 6 
4. 
DEFINITION OF ANALYSIS POPULATIONS ........................................................... 7 
4.1 
Intent-to-Treat (ITT) ............................................................................................ 7 
4.2 
Modified Intent-to-Treat (MITT) ....................................................................... 7 
4.3 
Microbiological Modified Intent-to-Treat (micro-MITT) .............................. 7 
4.4 
Clinically Evaluable (CE) ...................................................................................... 7 
4.5 
Microbiologically Evaluable (ME) ...................................................................... 9 
4.6 
Safety ..................................................................................................................... 10 
4.7 
Determination of Inclusion in Analysis Populations ................................... 10 
5. 
DEFINITION OF ENDPOINTS ................................................................................... 10 
5.1 
Overall Response................................................................................................. 10 
5.2 
Microbiologic Response ..................................................................................... 11 
5.3 
Patient-Determined Clinical Response (Clinical Response) ...................... 13 
5.4 
Asymptomatic Bacteriuria ................................................................................ 14 
5.5 
Investigator-Determined Clinical Response.................................................. 14 
5.6 
Patient Symptom Assessment Questionnaire (PSAQ) ................................. 14 
5.7 
Safety Endpoints .................................................................................................. 15 
6. 
ESTIMANDS ................................................................................................................... 15 
7. 
STATISTICAL METHODS .......................................................................................... 15 
7.1 
Sample Size ........................................................................................................... 15 
7.2 
Randomization .................................................................................................... 16 
7.3 
Visit Windows ...................................................................................................... 16 
7.4 
Microbiology Data ............................................................................................... 17 
7.5 
Handling of Missing Data ................................................................................... 18 
7.6 
Comments on Statistical Analysis .................................................................... 19 
8. 
STATISTICAL ANALYSES ......................................................................................... 20 
8.1 
Patient Disposition ............................................................................................. 20 


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8.2 
Demographics and Baseline Characteristics ................................................. 20 
8.3 
Baseline Microbiology ........................................................................................ 21 
8.4 
Prior and Concomitant Procedures ................................................................. 21 
8.5 
Prior and Concomitant Medications ............................................................... 21 
8.6 
Study Drug Exposure .......................................................................................... 22 
8.7 
Efficacy Analyses ................................................................................................. 22 
8.8 
Interim Analysis .................................................................................................. 31 
8.9 
Safety Analyses .................................................................................................... 32 
8.10 
Protocol Deviations ............................................................................................ 35 
9. 
CHANGES FROM ANALYSES SPECIFIED IN THE PROTOCOL ...................... 35 
10. REFERENCES ................................................................................................................ 37 
11. APPENDICES ................................................................................................................. 38 
APPENDIX A:  SCHEDULE OF ACTIVITIES .......................................................... 38 
APPENDIX B: CRITERIA FOR SAFETY VALUES OF POTENTIAL CLINICAL 
CONCERN ................................................................................................... 39 
APPENDIX C: METHOD FOR DETERMINATION OF CREATININE 
CLEARANCE............................................................................................... 40 
APPENDIX D: IT001-310 MICROBIOLOGY RULES FOR DETERMINATION OF 
FINAL PATHOGEN .................................................................................... 41 


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Statistical Analysis Plan: IT001-310 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Transaminase 
ATC 
Anatomical Therapeutic Chemical 
BID 
bis in die (Twice a Day) 
BMI 
Body Mass Index 
BPM 
Beats Per Minute 
BUN 
Blood Urea Nitrogen 
CE 
Clinically Evaluable 
CFU 
Colony Forming Unit 
CI 
Confidence Interval 
Cr 
Creatinine 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
dL 
Deciliter 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic Acid 
e-CRF 
Electronic Case Report Form 
EOT 
End of Treatment Visit 
ESBL 
Extended-Spectrum-β-Lactamases 
FDA 
Food and Drug Administration 
FV 
Final Visit 
GFR 
Glomerular Filtration Rate 
GGT 
Gamma Glutamyltransferase 
Hg 
Mercury 
HPF 
High Power Field 
IA 
Interim Analysis 
ITT 
Intent-to-Treat 
IWRS 
Interactive Web Response System 
Kg 
Kilogram 
LLN 
Lower Limit of Normal 
ME 
Microbiological Evaluable 


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MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligram 
MIC 
Minimum Inhibitory Concentration 
micro-MITT 
Microbiological Modified Intent-to-Treat 
micro-MITTR 
Microbiological Modified Intent-to-Treat Resistant 
micro-MITTS 
Microbiological Modified Intent-to-Treat Susceptible 
MITT 
Modified Intent-to-Treat 
MM 
Millimeter 
NI 
Non-inferiority or Non-inferior 
NTF 
Nitrofurantoin 
PCR 
Polymerase Chain Reaction 
PFGE 
Pulsed Field Gel Electrophoresis 
PSAQ 
Patient Symptom Assessment Questionnaire 
QNS 
Quinolone Non-Susceptible 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SE 
Standard Error 
TEAE 
Treatment Emergent Adverse Event 
TOC 
Test of Cure Visit 
ULN 
Upper Limit of Normal 
uUTI 
Uncomplicated Urinary Tract Infection 
WBC 
White Blood Cell 
WGS 
Whole Genome Sequencing 
WHODRUG 
World Health Organization (WHO) Drug Dictionary 


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1. 
INTRODUCTION 
This document presents the Statistical Analysis Plan (SAP) for the protocol IT001-310, “A 
prospective, Phase 3, randomized, multi-center, double-blind study of the efficacy, tolerability, 
and safety of oral sulopenem etzadroxil/probenecid versus oral amoxicillin/clavulanate for 
treatment of uncomplicated urinary tract infections (uUTI) in adult women”.  The statistical plan 
described is an a priori plan, and the unblinded analyses outlined here have not been conducted 
prior to the preparation of this plan. This SAP summarizes the design and objectives of protocol 
IT001-310 and provides details of the definitions of analysis populations, the endpoints and 
statistical methodology that will be used to analyze the data from the study. 
Any deviation from the planned analysis will be documented in the clinical study report (CSR). 
This SAP is based on study protocol Amendment 1 dated December 5, 2022. 
 
2. 
STUDY DESIGN 
This trial is a prospective Phase 3, randomized, multicenter, double-blind, double dummy, 
controlled 
study 
to 
compare 
oral 
sulopenem 
etzadroxil/probenecid 
to 
oral 
amoxicillin/clavulanate for the treatment of patients with uUTI.  Approximately 1966 adult 
women with uUTI are to be randomized in a 1:1 fashion to receive either an oral bilayer tablet 
with sulopenem etzadroxil/probenecid 500 mg/500 mg twice daily for 5 days or oral 
amoxicillin/clavulanate 875 mg/125 mg twice daily for 5 days. 
Visits occur on Screening (Day -1 to Day 1, within 24 hours of first dose), Day 5 (+ 1 day), Day 
12 (± 1 day), and Day 28 (± 2 days). The Day 5 visit is the End of Treatment (EOT) visit, Day 
12 is the Test of Cure (TOC) visit, and Day 28 is the Final Visit (FV). The schedule of activities 
at each visit is provided in Appendix A. 
 
3. 
STUDY OBJECTIVES 
3.1 Primary Objective 
To compare the overall response (clinical and microbiologic combined response) of oral 
sulopenem etzadroxil/probenecid versus oral amoxicillin/clavulanate for the treatment of uUTI 
in adult women at the primary timepoint, Day 12 (± 1 day)/TOC. 
3.2 Secondary Objectives 
• To evaluate the clinical efficacy at Day 12 (±1 day)/TOC 
• To evaluate the microbiologic efficacy at Day 12 (±1 day)/TOC 
• To further evaluate the safety profile of oral sulopenem etzadroxil/probenecid tablets 
when used for treatment of uUTI in adult women 
3.3 Additional Objectives 
• To evaluate the clinical efficacy at Day 5 (+1 day) and Day 28 (±2 days) 
• To evaluate the rate of post-treatment asymptomatic bacteriuria at Day 5 (+1 day), Day 
12 (±1 day)/TOC and Day 28 (±2 days) 


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• To evaluate the microbiologic efficacy at Day 5 (+1 day) and Day 28 (±2 days) 
• To evaluate overall response at other relevant timepoints 
• To evaluate the investigator determined clinical response 
• To evaluate overall success, clinical success, and microbiologic success by key baseline 
pathogens 
 
4. 
DEFINITION OF ANALYSIS POPULATIONS 
The definitions of the analysis populations included in this study are as follows: 
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 includes all patients in the ITT population who received at least a single 
dose of study medication.  
4.3 Microbiological Modified Intent-to-Treat (micro-MITT) 
The micro-MITT population includes all MITT patients with a positive study entry urine culture 
defined as ≥105 colony forming units (CFU)/mL of a uropathogen (Enterobacterales only) and no 
more than 2 species of microorganisms identified in the study entry urine culture, regardless of 
colony count.  
4.3.1 Susceptible (micro-MITTS) 
All micro-MITT patients with a baseline uropathogen susceptible (defined as MIC ≤ 8/4 
mg/L) to the comparator drug, amoxicillin/clavulanate, and no baseline pathogen non-
susceptible to amoxicillin/clavulanate. If a patient has 2 uropathogens at baseline, both need 
to be susceptible. 
4.3.2 Resistant (micro-MITTR) 
All micro-MITT patients with a baseline uropathogen non-susceptible (defined as 
intermediate (MIC ≥ 16/8 mg/L) or resistant (MIC ≥ 32/16 mg/L)) to the comparator drug, 
amoxicillin/clavulanate.  
4.4 Clinically Evaluable (CE) 
Three CE populations are defined based on the timing of the outcome assessment, CE-EOT, CE-
TOC and CE-FV. The term “CE population” is used to refer to all CE populations. CE is a subset 
of MITT and follows the rules below. 
a. Received at least 80% of their active study medication up to the timepoint of assessment 
unless a failure at the time of discontinuing study drug due to insufficient therapeutic 
effect or need for concomitant systemic antibacterial therapy 
b. Met the following inclusion criteria:  


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Inclusion Criterion 1. Female patients ≥18 years of age with ≥24 hours and ≤96 hours 
of urinary symptoms attributable to a UTI  
Inclusion Criterion 2. Two of the following signs and symptoms of uUTI: urinary 
frequency, urinary urgency, pain or burning on micturition, suprapubic pain;  
Inclusion Criterion 3 (if randomized under protocol dated Dec 5, 2022). A mid-stream 
urine specimen with:  
i. 
a machine-read dipstick positive for nitrite and any positive leucocyte esterase or 
ii. 
evidence of pyuria as defined by either: 
a. a machine-read dipstick positive for large leukocyte esterase OR 
b. at least 10 white blood cells per cubic millimeter on microscopic analysis 
of unspun urine OR 
c. White blood cell count >10 cells/HPF in the sediment of a spun urine  
Inclusion Criterion 3 (if randomized under protocol dated July 7, 2022). A mid-stream 
urine specimen with evidence of pyuria as defined by either:  
i. 
a machine-read dipstick positive for leucocyte esterase OR 
ii. 
at least 10 white blood cells per cubic millimeter on microscopic analysis of 
unspun urine OR 
iii. 
White blood cell count >10 cells/HPF in the sediment of a spun urine 
and did not meet any of the following exclusion criteria:  
Exclusion Criterion 1. Presence of signs and symptoms suggestive of acute 
pyelonephritis defined as: fever (temperature > 38° Celsius), chills, costovertebral 
angle tenderness, flank pain, nausea, and/or vomiting  
Exclusion Criterion 2. Receipt of antibacterial drug therapy potentially effective as 
treatment of uUTI within the prior 7 days (note, this will be checked against both the 
inclusion/exclusion and the prior concomitant medication eCRF pages)  
Exclusion Criterion 3. Patients requiring concurrent use of non-study treatments that 
would have a potential effect on outcome evaluations in patients with uUTI, including 
analgesics (e.g., non-steroidal anti-inflammatory drugs, aspirin, paracetamol etc.), 
phenazopyridine, and cranberry products  
Exclusion Criterion 4. Any anatomical abnormality of the urinary tract, including 
surgically modified urinary tract anatomy, and obstructive uropathy due to 
nephrolithiasis, stricture, tumor or fibrosis 
Exclusion Criterion 5. Ongoing urinary retention 
Exclusion Criterion 6. Neurogenic bladder 
Exclusion Criterion 9. Patients with an indwelling urinary catheter, ureteral stent or 
other foreign material in the urinary tract 
Exclusion Criterion 10. Any history of trauma to the pelvis or urinary tract 
Exclusion Criterion 11. Patient's current urine culture, if available while evaluating 


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eligibility, that is positive for more than 2 microorganisms regardless of colony count 
or patient has a confirmed fungal UTI  
Exclusion Criterion 16. Patients with poorly controlled diabetes mellitus, including 
the presence of ketoacidosis and hyperosmolar hyperglycemia 
Note: Fulfillment of inclusion and exclusion criteria is based on version of protocol 
that subject was randomized under. 
c. Had no major protocol deviations that would affect the assessment of efficacy prior to the 
visit as indicated in the protocol deviation log (see Section 8.10)  
d. Had a patient-determined clinical response of success or failure (and not indeterminate) 
at the timepoint of the visit (i.e., within the SAP defined allowed visit window) 
e. For CE-EOT and CE-TOC, did not receive any systemic antibiotic therapy with potential 
activity against any of the uropathogens collected at baseline, between the time of the 
baseline culture and the EOT or TOC visits, respectively. This excludes the protocol 
defined study therapy and patients who were considered clinical failures and required 
additional antibiotic therapy and patients who received a rescue antibiotic to which the 
baseline pathogen was found to be non-susceptible by susceptibility testing performed by 
the central laboratory. Patients with 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 oral linezolid, daptomycin and vancomycin).  
For CE-FV, did not receive any antibiotic therapy with potential activity against any of 
the baseline uropathogen(s) collected at baseline through FV, except resuming oral 
antibiotic prophylaxis therapy after the Day 12 urine culture was obtained. This does not 
include antibiotic therapy taken for the treatment of uUTI by patients who were 
considered investigator-assessed clinical failures.  
f. Received appropriate adjunctive antibacterial coverage (i.e., such as linezolid, 
daptomycin or vancomycin) if the patient had a culture-documented Enterococcus spp. or 
other gram-positive resistant pathogens at baseline and has symptoms at the post-baseline 
visit.  
g. Site personnel involved in the assessment of efficacy parameters remained blinded to 
study treatment up to the time of the efficacy assessment.  
h. Patients who receive study drug therapy beyond the protocol defined number of 10 doses 
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 Microbiologically Evaluable (ME) 
All patients included in both the micro-MITT and CE populations at the Day 5 visit (ME-EOT), 
Day 12 visit (ME-TOC) and at the Day 28 visit (ME-FV) and have an appropriately collected 
urine culture specimen and interpretable urine culture result at the Day 5, Day 12 and Day 28 
visits (i.e., within the SAP defined allowed visit window), respectively.  
4.5.1 Susceptible (ME-S) 


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All ME patients with a baseline uropathogen susceptible (defined as MIC ≤ 8/4 mg/L) to the 
comparator drug, amoxicillin/clavulanate, and no baseline pathogen non-susceptible 
(defined as intermediate [MIC 16/8 mg/L] or resistant [MIC ≥ 32/16 mg/L]) to 
amoxicillin/clavulanate. If a patient has 2 uropathogens at baseline, both need to be 
susceptible. 
4.5.2 Resistant (ME-R) 
All ME patients with a baseline uropathogen non-susceptible (defined as intermediate [MIC 
16/8 mg/L] or 
resistant [MIC ≥ 32/16 mg/L]) to the comparator drug, 
amoxicillin/clavulanate.  
 
4.6 Safety 
The safety population is comprised of all patients in the ITT population who received at least one 
dose of study medication.  
4.7 Determination of Inclusion in Analysis Populations 
Inclusion into the ITT, MITT and Safety populations will be determined programmatically from 
the e-CRF data and as needed by manual review.  
Inclusion into the CE populations will be determined programmatically from the e-CRF 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, micro-MITTS, micro-MITTR, ME, ME-S and ME-R populations 
will be determined programmatically and through a manual review conducted by the Sponsor.  
 
5. 
DEFINITION OF ENDPOINTS 
5.1 Overall Response 
The primary endpoint in the study is overall success (combined clinical and microbiologic) at 
TOC. 
A patient will be defined as a success at a given timepoint (EOT, TOC and FV) if the following 
criteria are met (programmatically, based on the data on the e-CRF):  
• The patient is alive 
• The patient has received no non-study antibacterial therapy for uUTI. (Note: If an 
antibiotic is started after a visit, then for that visit’s assessment the patient will be 
considered as not having received non-study antibiotic therapy) 
o If an antibiotic active against the urinary tract pathogen is given for non-uUTI 
reasons and the baseline pathogen is susceptible to the antibiotic, then the patient 
will be considered indeterminate 
• The patient has resolution of the symptoms of uUTI present at trial entry and no new UTI 


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symptoms (based on the Patient Symptom Assessment Questionnaire (PSAQ)). Missing 
answers to PSAQ severity questions are treated as missing, thus the outcome will be 
indeterminate.  
o Baseline symptoms associated with another known condition (e.g., overactive 
bladder) do not need to be resolved. 
• The patient’s urine culture demonstrates <103 CFU/mL of each of the baseline study 
uropathogens based on results of quantitative cultures performed on the urine sample 
collected at the visit. If the urine culture is contaminated (defined in Appendix D), 
baseline pathogen(s) is/are considered eradicated. 
A patient will be defined as a failure if at least one of the following criteria is met: 
• Patient died due to uUTI 
• Patient received non-study antibacterial therapy for uUTI.  
• Patient has no resolution or has worsening of symptoms of uUTI present at trial entry 
and/or has new uUTI symptoms. Missing answers to PSAQ severity questions are treated 
as missing, thus the outcome will be indeterminate.  
• The patient’s urine culture at the visit demonstrates ≥103 CFU/mL of any of the baseline 
study uropathogens.  
Patients will be defined to have an indeterminate outcome if any data needed to determine 
whether the outcome is success or failure are missing. Patients with missing answers to PSAQ 
severity questions will be considered as indeterminate for overall response at TOC (unless the 
urine culture demonstrates ≥103 CFU/mL of the baseline uropathogen, then the patient is a 
failure). Patients who died due to other reasons than the uUTI will have an indeterminate 
outcome. If an antibiotic that is active against the urinary tract pathogen based on susceptibility 
results is given for non-uUTI reasons, then the patient will be considered indeterminate. If urine 
culture data at TOC is missing, the patient will be considered as indeterminate for overall 
response at TOC (unless the PSAQ response at TOC shows failure, then the patient is a failure). 
Patients with an indeterminate response are included in the denominator for determination of the 
response rate. 
5.2 Microbiologic Response 
Per pathogen microbiologic response is assessed using the definitions listed below. It will be 
analyzed at each timepoint (EOT, TOC and FV). It is assessed for each study uropathogen that a 
patient has at baseline.  
Per patient microbiologic response is a patient level response determined by the outcome of all 
baseline study uropathogens, and will be analyzed at each timepoint (EOT, TOC and FV).  
Note, if a patient did not have a positive culture at baseline, she is 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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Microbiologic 
response 
Definition 
Eradication 
(success) 
The urine culture demonstrates <103 CFU/mL of the baseline study 
uropathogen at the timepoint of analysis (contaminated results are 
considered a negative culture and therefore an eradication) 
Persistence  
A study uropathogen present at baseline grew at ≥103 CFU/mL at the time-
point of analysis*  
Persistence with 
increasing MIC  
A urine culture taken after at least 2 full days of treatment grew 
≥103 CFU/mL of the baseline study uropathogen and displayed ≥ 4-
dilutions higher MIC, as compared to baseline, to study drug received at 
the timepoint of analysis (i.e., when a post-baseline study uropathogen 
displays a MIC of >2 mg/L when the baseline MIC was 0.12 mg/L). 
Indeterminate 
Patient was lost to follow-up or an assessment was not undertaken such 
that no urine culture was obtained (or culture results could not be 
interpreted for any reason) at the timepoint of analysis  
* The genus and species need to match. Additional molecular testing by pulsed field gel electrophoresis (PFGE), 
polymerase chain reaction (PCR) or whole genome sequencing (WGS) may be performed to be used as sensitivity 
analysis of the primary endpoint  
 
A per pathogen microbiologic success is termed as ‘eradication’. A pathogen failure is termed as 
‘persistence’ or ‘persistence with increasing MIC’.  
A per patient microbiologic success is when all pathogen responses for a patient are ‘eradication’. 
A per patient microbiologic failure is when one or more pathogens for a patient are ‘persistence’ 
or ‘persistence with increasing MIC’. Otherwise, the patient will have an indeterminate outcome. 
5.2.2 
Post-Baseline Pathogens 
For patients with a baseline study uropathogen, the following outcomes based on post-baseline 
uropathogens will be determined. 
 
 
 
 
 
 


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Microbiologic 
response 
Definition 
Superinfection 
A uropathogen not present at baseline grew with ≥105 CFU/mL from the 
first dose of study drug through the EOT visit in the setting of 
recurrent/persistent/new uUTI symptoms requiring non-study systemic 
antibacterial treatment (patient determined clinical failure at EOT) 
New Infection  
Isolation of a non-baseline pathogen from a culture post-EOT visit from a 
urine culture specimen with ≥105 CFU/mL in a patient with one or more 
new uUTI signs/symptoms requiring new systemic antibacterial treatment 
after the EOT visit (patient determined clinical failure post-EOT) 
Recurrence  
In a patient with clinical and microbiologic success at EOT, isolation of a 
baseline study pathogen from a urine culture specimen with ≥105 CFU/mL 
post-EOT visit, along with new or recurrence of one or more uUTI 
signs/symptoms requiring new systemic antibacterial treatment after the 
EOT visit (patient determined clinical failure post-EOT)  
Colonization 
Isolation of a pathogen from the urine culture after EOT in a patient without 
one or more signs and symptoms of uUTI and not requiring new systemic 
antibiotic therapy (patient determined clinical success post-EOT)  
 
5.3 Patient-Determined Clinical Response (Clinical Response) 
A patient will be defined as a clinical success at a given timepoint (EOT, TOC and FV) if the 
following criteria are met (programmatically, based on the data on the eCRF):  
• The patient is alive 
• The patient has received no non-study antibacterial therapy for uUTI. (Note: If an 
antibiotic is started after a visit, then for that visit’s assessment the patient will be 
considered as not having received antibiotic therapy) 
o If an antibiotic active against the urinary tract pathogen is given for non-uUTI 
reasons and the baseline pathogen is susceptible to the antibiotic, then the patient 
will be considered indeterminate 
• The patient has resolution of the symptoms of uUTI present at trial entry and no new 
uUTI symptoms (based on the Patient Symptom Assessment Questionnaire). Missing 
answers to PSAQ severity questions are treated as missing thus the outcome will be 
indeterminate.  
o Baseline symptoms associated with another known condition (e.g., overactive 
bladder) do not need to be resolved.  
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 uUTI will have an 


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indeterminate outcome. If an antibiotic active against the urinary tract pathogen is given for non-
uUTI reasons and the baseline pathogen is susceptible to the antibiotic, then the patient will be 
considered indeterminate. Patients with missing answers to PSAQ severity questions will be 
treated as indeterminate.  
5.4 Asymptomatic Bacteriuria 
A patient will be defined to have asymptomatic bacteriuria at a given timepoint (EOT, TOC and 
FV) if both of the following criteria are met: 
• The patient is a clinical success (as defined in Section 5.3) 
• The patient is a microbiologic failure (as defined in Section 5.2.1) 
5.5 Investigator-Determined Clinical Response 
Investigators will use the definitions below to document clinical response, irrespective of 
microbiologic findings, at EOT, TOC, FV or premature discontinuation: 
 
Clinical response 
Definition 
Clinical success 
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 as failures: 
• Death related to uUTI prior to EOT, TOC and FV, respectively 
• Persistence or progression of any pre-therapy uUTI 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 
EOT, TOC or FV, respectively 
• Death prior to EOT, TOC or FV, respectively, where uUTI was 
clearly non-contributory 
 
5.6 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:  
• Pain (uncomfortable pressure) in the lower abdomen/pelvic area 
• Burning (dysuria) when passing urine  


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• Frequency of urination or going to the toilet very often  
• Urgency of urination or a strong and uncontrollable urge to pass urine  
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. 
5.7 Safety Endpoints 
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 
24.1 or higher to the System Organ Class and Preferred Term levels. 
 
6. 
ESTIMANDS 
Estimands are defined for the primary objective of the study. 
• Target population: There are 3 populations in which the primary objective will be 
assessed: the micro-MITT, micro-MITTS and micro-MITTR populations. 
• Endpoint of interest: Overall success at TOC 
• Intercurrent events: The following intercurrent events could impact the assessment of 
overall response in each of the target populations: 
o Patient receives non-study antibacterial therapy for uUTI (ie, rescue therapy). This 
is handled as a composite variable and is incorporated into the definition of the 
endpoint.  
o Patient receives anti-bacterial therapy that is active against the urinary tract 
pathogen for non-uUTI reasons. This is handled as a composite variable and is 
incorporated into the definition of the endpoint. 
o Missing or incomplete assessment of uUTI symptoms at TOC for any reason 
including study discontinuation. This is handled as a composite variable and is 
incorporated into the definition of the endpoint. 
o No urine culture was obtained or culture results could not be interpreted at TOC. 
This is handled as a composite variable and is incorporated into the definition of 
the endpoint. 
o Death due to reasons other than uUTI. This is handled as a composite variable and 
is incorporated into the definition of the endpoint. 
• Population-level summary: Difference in rates of overall response between oral 
sulopenem etzadroxil/probenecid and oral amoxicillin/clavulanate 
 
7. 
STATISTICAL METHODS 
7.1 Sample Size 
The study is designed to determine whether oral sulopenem etzadroxil/probenecid is non-inferior 


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(NI) to oral amoxicillin/clavulanate for the outcome measure of overall success (combined 
clinical and microbiologic success) at Day 12 (± 1 day)/TOC in both the micro-MITT and micro-
MITTS populations and whether oral sulopenem is superior to oral amoxicillin/clavulanate for 
overall success at Day 12 (± 1 day)/TOC in the micro-MITTR population. The primary outcome 
measure of overall success (combined clinical and microbiologic success) is defined as resolution 
of the symptoms of uUTI 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 
(microbiological success [eradication]).  
The proposed sample size in the micro-MITTS population is 505 patients per arm (total of 1010 
patients) based on the method of Farrington and Manning. This assumes a non-inferiority margin 
of 10.0%, a power of 90%, a one-sided alpha level of 0.025, 60% overall success rate with 
amoxicillin/clavulanate and 60% overall success rate with sulopenem etzadroxil/probenecid. 
Assuming that 21% of the patients will have non-susceptible pathogens and assuming 85% power 
to show superiority in the micro-MITTR population (micro-MITT=1278 patients), 67% of the 
randomized patients will meet criteria for inclusion into the micro-MITT population 
(MITT=1907 patients) and allowing for a dropout rate of 3%, the sample size for the ITT 
population is 1966. With 134 patients per treatment group in the micro-MITTR population, there 
is at least 85% power to show superiority at the one-sided 2.5% alpha level given a 51% and 33% 
overall success rate in the oral sulopenem and amoxicillin/clavulanate groups, respectively. With 
1278 patients in the micro-MITT population, there is at least 95% power to show non-inferiority 
(non-inferiority margin of 10.0%) at the one-sided alpha level of 0.025 with the treatment success 
rates of the oral sulopenem etzadroxil/probenecid and amoxicillin/clavulanate groups assumed 
to be 58% in this population.  
One blinded interim analysis for sample size re-estimation is planned (See Section 8.8). 
7.2 Randomization 
Patients will be randomized in a 1:1 ratio to sulopenem etzadroxil/probenecid versus 
amoxicillin/clavulanate using an Interactive Web Randomization System (IWRS), provided they 
have satisfied all patient selection criteria. Once IWRS provides a randomization number, the 
patient is officially randomized. 
7.3 Visit Windows 
Visit windows are used in determining whether a patient will be included in the CE and ME 
populations at EOT, TOC or FV. If their assessments are out of window, they will not be included 
in that population. If the data for a visit is collected on 2 separate days (i.e., partly on a scheduled 
visit and partly on an unscheduled visit), then the data from both days will be considered provided 
the days are within the prescribed window for that visit.  
For safety 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. 
The following visit windows will be used for analysis conducted using CE and ME populations 
and safety data described above. The date of PSAQ assessment and the date of urine specimen 
sample collection will be used to determine CE and ME populations. 


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Visit 
Window 
Day 5 – End of Treatment (EOT) 
+ 1 day 
Day 12 – Test of Cure (TOC) 
± 1 day 
Day 28 – Final Visit (FV) 
± 2 days 
 
For the ITT 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.  If the data for a visit is collected on 2 separate days (i.e., partly on a scheduled visit and 
partly on an unscheduled visit), then the data from the unscheduled visit will be considered 
provided the days are within the prescribed broader windows for that visit as below. For missed 
nominal visits or missed assessments at nominal visits, data from the closest unscheduled/early 
termination visits will be used provided unscheduled /early termination assessment day falls in 
the window provided below.  
Window for unscheduled visits for ITT analysis: 
 
Visit 
 Time interval (Days)*  
Day 5 – End of Treatment (EOT) 
5 - 7 
Day 12 – Test of Cure (TOC) 
8 - 20 
Day 28 – Final Visit (FV) 
21 - 35 
* The one closest to the target date for the visit will be used in the analyses if more than one unscheduled assessments 
are within the window. If two visits are equidistant from the target visit date, then the first one will be used 
7.4 Microbiology Data 
The following organisms will be considered a uropathogen for this study: 
• Monomicrobial or polymicrobial infections caused by:  
o Enterobacterales  
o Enterococci  
o Pseudomonas aeruginosa  
o S. saprophyticus  
• The micro-MITT population will only include patients with uUTIs caused by the 
following (study pathogens): Enterobacterales.  
The following normal flora are never a pathogen:  
• Corynebacterium spp.  
• Staphylcoccus epidermidis  
• Stayplococcus aureus  


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• Bacillus spp.  
• Diphtheroids  
• Micrococcus spp.  
• Lactobacillus spp.  
• Viridans Streptococci  
• Group B Streptococci  
• Gardnerella vaginalis  
• Neisseria gonorrhoeae  
• Yeasts 
All isolates will be assessed on a case-by-case basis via manual review by the Sponsor. This 
could include isolates not listed above. If needed, patient’s clinical and microbiological 
information will be used to assist in determining if the isolate is a pathogen. Appendix D provides 
the microbiology rules for determination of final pathogen. 
7.5 Handling of Missing Data 
Missing data will be handled as outlined below: 
• All missing and partial dates for events and assessments occurring after randomization 
or for medications received after randomization will be queried for a value. If no value 
can be obtained, missing 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, and 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, and 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). 
• 
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). 
• 
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 treatment-emergent AE 
(TEAE). 
- 
Prior/Concomitant Medications and Prior/Concomitant Antibiotic Therapy 


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• 
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 if the year is prior to the year 
of first dose then the drug should be reported as prior. Otherwise, it should 
be reported as 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). 
• 
If the start date only contains the year and month, and 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. 
• 
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 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 endpoint, the data that is present shows the patient is a failure.  
• For overall response, sensitivity analyses will be performed considering different 
imputations techniques for missing response data. These are described in Section 8.7.2. 
• Except as specifically noted for pre-planned 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). 
7.6 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, median, minimum, 
maximum and quartiles for quantitative data. 
• Duration variables will be calculated using the general formula: (end date - start date) 
+1 for end dates after first dose and (end date - start date) for end dates before first dose. 
• 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 ‘≤ 5’ will be 


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treated as ‘10’ or ‘5’ respectively, and a value such as ‘>100’ will be 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. 
 
8. 
STATISTICAL ANALYSES 
The tables to be presented for each population are specified in the subsections below. All tables 
specified for the micro-MITT population will also be presented for the micro-MITTS and micro-
MITTR populations. All tables specified for the ME population will also be presented for the 
ME-S and ME-R populations.  
8.1 Patient Disposition 
The number of patients included in each of the study populations (i.e., ITT, Safety, MITT, micro-
MITT, micro-MITTS, micro-MITTR, CE-EOT, CE-TOC, CE-FV, ME-EOT, ME-TOC and ME-
FV) will be summarized by treatment group. A table and listing will be provided that details the 
reasons the patient is excluded from each 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 the ITT, MITT, micro-MITT, micro-MITTS, micro-MITTR and Safety 
populations.  
Reasons for premature discontinuation of study drug and/or withdrawal from the study as 
recorded on the e-CRF 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. 
8.2 Demographics and Baseline Characteristics 
Demographic data and baseline characteristics will be presented by treatment group for the ITT, 
MITT and micro-MITT populations. A table will present the patient demographics (e.g., sex, age, 
age group [<65, ≥65 years], ethnicity, race) and baseline characteristics (height, weight, BMI as 
both a continuous variable and categorized BMI [<25, 25-30, >30], diabetes status 
[present/absent] and creatinine clearance as both a continuous variable and categorized creatinine 
clearance [<60 mL/min, ≥60 mL/min]).  
Differences between treatment groups will be analyzed using Fisher’s exact test for dichotomous 
variables (sex, age group, ethnicity, race, categorized BMI, diabetes status and categorized 
creatinine clearance) and the Wilcoxon Rank Sum test for continuous variables (age, height, 


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weight and BMI).  
Medical history will be summarized based on System Organ Class/Preferred term and treatment 
group for the ITT population.  
Patient-determined symptoms and bothersome symptoms as captured on the PSAQ at baseline 
will be summarized by treatment and compared using Fisher’s exact test. 
Note: The p-values from the tests at baseline are provided to assess overall baseline comparability 
and should be interpreted with caution. 
8.3 Baseline Microbiology 
A frequency distribution of the result of the urine cultures, including organism characteristics 
will be presented for the ITT, MITT and micro-MITT populations. The number and percentage 
of patients with no growth, contaminant and positive for a pathogen will also be presented. 
The bacterial pathogens identified from the baseline urine culture will be presented. The number 
and percentage of patients with isolated pathogens will be presented by genus and species for the 
MITT, micro-MITT and ME populations. In addition, the number and percentage of patients with 
mono-microbial and poly-microbial infections as well as ESBL positive and negative infections 
will be provided. 
Tables will be provided for a summary of pathogens at baseline and the distribution of pathogens 
by culture concentration at baseline for the micro-MITT populations. 
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 both treatment groups combined will be provided for the micro-
MITT and the ME populations. These include the following: 
• The distribution of MIC to sulopenem etzadroxil/probenecid, amoxicillin/clavulanate, 
meropenem, ciprofloxacin, ertapenem, nitrofurantoin, trimethoprim-sulfamethoxazole, 
cefazolin, ceftriaxone and fosfomycin 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: Enterobacterales  
8.4 Prior and Concomitant Procedures 
All non-drug interventions received prior to randomization as well as those received during the 
study (up through FV) will be recorded on the e-CRF. The percentage of patients who received 
prior and concomitant non-drug interventions will be presented by treatment group for the ITT 
and micro-MITT populations. 
A listing will be provided of all prior and concomitant non-drug interventions. 
8.5 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 e-CRF. Medications will be summarized by WHODRUG (March 
2022 version or higher) highest ATC level and generic medication name for the ITT and micro-
MITT populations. Patients will be counted only once for an ATC class and generic medication 


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name.  
Medications are considered prior if taken prior to the first dose of study drug. Medications are 
considered concomitant if taken on or after the first dose of study drug or if marked as continuing. 
For missing or incomplete start or stop dates, refer to rules in Section 7.5.  
Tables will be provided for prior medications, all concomitant medications, concomitant anti-
inflammatory and analgesic medications and concomitant antibacterial medications. 
Concomitant medications and concomitant antibacterial medications will be presented in several 
tables of medications taken from study start to each visit (e.g., 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. 
8.6 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. Each tablet or capsule taken is considered a half day of therapy. 
 
8.7 Efficacy Analyses 
For all efficacy analyses, patients will be analyzed in the treatment group to which they were 
randomized. By definition, patients who receive the study drug regimen other than the regimen 
to which they were randomized are not included in the CE and ME populations.  
For the ITT, MITT and micro-MITT populations, patients with an indeterminate response are 
included in the denominator for computing the proportion of success. The proportion of success 
is defined using the formula: 
(Number of successes)/(Number of successes + Number of failures
+ Number of indeterminates) 
 
For the CE and ME populations, patients must have sufficient information for determining 
success or failure. The proportion of success is defined using the formula: 
(Number of successes)/(Number of successes + Number of failures) 
 
8.7.1 
Primary Efficacy Analysis 
The primary efficacy endpoint is the outcome of overall success (combined clinical and 
microbiologic success) at TOC in each of the micro-MITT, micro-MITTS and micro-MITTR 
populations.  
Patients will be programmatically categorized as a success, failure or indeterminate based on the 
data in the e-CRF and from the microbiology lab. The number and percentage of patients with 
success, failure and indeterminate response will be determined in each treatment group in the 
micro-MITT, micro-MITTS and micro-MITTR populations. 
The primary comparison of the study is in the micro-MITT population (the combined population 


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of patients with a positive baseline culture and without regard to amoxicillin/clavulanate 
susceptibility). These outcomes are most relevant to the practicing clinician who must choose 
empiric treatment of uUTI before culture results become available, hence these results will help 
put into context the outcomes in the culture and susceptibility-driven sub-populations. 
To control for the inflation of the overall type I error rate, the hierarchical testing procedure of 
Westfall and Krishen (Westfall 2001) will be used to test the hypotheses of the primary efficacy 
outcome in these populations in the sequential order described below. Testing will proceed to the 
next comparison, only in the case where the null hypothesis in the previous comparison was 
rejected. When testing in a sequential manner with pre-planned hierarchy, no adjustment to the 
alpha level is required. 
(1) NI in the micro-MITT population:  
For this population, a NI test of the overall success rate will be conducted. The null and alternative 
hypotheses are the following: 
H0 : p1 − p2 ≤ −∆ and H1 : p1 − p2  > −∆ , 
where p1 is the overall success rate in the sulopenem etzadroxil/probenecid treatment group, p2  is 
the overall success rate in the amoxicillin/clavulanate group, and Δ is the non-inferiority margin 
of 10%.  
The NI 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% CI for the observed difference in the overall 
success rates (oral sulopenem etzadroxil/probenecid group minus amoxicillin/clavulanate group). 
The primary analysis is based on the CI computed using the method proposed without 
stratification by Miettinen and Nurminen, which corresponds to the p-value approach of the 
Farrington-Manning test. If the lower limit of the 95% CI for difference in success rates in the 
micro-MITT population is greater than -10%, the null hypothesis will be rejected and the NI of 
oral sulopenem etzadroxil/probenecid to amoxicillin/clavulanate will be concluded and testing 
will proceed to the next step. 
(2) NI in the micro-MITTS population OR superiority in the micro-MITTR population as 
described below: 
Micro-MITTS population: For this population, a NI test of the overall success rate will be 
conducted. The null and alternative hypotheses are the following: 
H0 : p1 − p2 ≤ −∆ and H1 : p1 − p2  > −∆ , 
where p1 is the overall success rate in the sulopenem etzadroxil/probenecid treatment group, p2  is 
the overall success rate in the amoxicillin/clavulanate group, and Δ is the non-inferiority margin 
of 10%. The NI hypothesis test is a 1-sided hypothesis test performed at the 2.5% level of 
significance. A 2-sided 95% CI for the observed treatment difference in success rates will be 
determined using the method without stratification of Miettinen and Nurminen. If the lower 
bound of the 95% CI is greater than -10%, the null hypothesis will be rejected and the NI of oral 
sulopenem etzadroxil/probenecid to amoxicillin/clavulanate in the micro-MITTS population will 
be concluded. 
Micro-MITTR population: For this population, a superiority test will be conducted. The null and 
alternative hypotheses are the following: 


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H0 : p1 = p2 and H1 : p1 ≠ p2 
A 2-sided 95% CI for the observed treatment difference in success rates will be determined using 
the method without stratification of Miettinen and Nurminen. The 1-sided p-value corresponding 
to the lower bound of the 95% CI will be reported. If the lower bound of the 95% CI is greater 
than 0%, the null hypothesis will be rejected and superiority of oral sulopenem 
etzadroxil/probenecid to amoxicillin/clavulanate will be concluded in the micro-MITTR 
population. 
If either of these 2 null hypotheses is rejected, then testing will proceed to the next step. 
(3) Superiority in the micro-MITT population 
The null and alternative hypotheses are: H0 : p1 = p2 and H1 : p1 ≠ p2.  
The 1-sided p-value corresponding to the lower bound of the 95% CI calculated for the hypothesis 
test in (1) will be reported. If the lower bound of the 95% CI (for the hypothesis test in (1)) is 
greater than 0%, the null hypothesis will be rejected and the superiority of oral sulopenem 
etzadroxil/probenecid to amoxicillin/clavulanate in the micro-MITT population will be 
concluded.  
 
For regulatory approval, the primary comparisons are in two mutually exclusive sub-populations 
of the micro-MITT population defined by a baseline characteristic, the micro-MITTS and micro-
MITTR populations. To control for the inflation of the overall type I error rate, the following 
hierarchical testing procedure will be used to test the hypotheses of the primary efficacy outcome 
in these populations in the sequential order described below. Testing will proceed to the next 
comparison, only in the case where the null hypothesis in the previous comparison was rejected. 
When testing in a sequential manner with pre-planned hierarchy, no adjustment to the alpha level 
is required. 
(1) NI in the micro-MITTS population OR superiority in the micro-MITTR population as 
described below: 
Micro-MITTS population: For this population, a NI test of the overall success rate will be 
conducted. The null and alternative hypotheses are the following: 
H0 : p1 − p2 ≤ −∆ and H1 : p1 − p2  > −∆ , 
where p1 is the overall success rate in the sulopenem etzadroxil/probenecid treatment group, p2  is 
the overall success rate in the amoxicillin/clavulanate group, and Δ is the non-inferiority margin 
of 10%. The NI hypothesis test is a 1-sided hypothesis test performed at the 2.5% level of 
significance. A 2-sided 95% CI for the observed treatment difference in success rates will be 
determined using the method without stratification of Miettinen and Nurminen. If the lower 
bound of the 95% CI is greater than -10%, the null hypothesis will be rejected and the NI of oral 
sulopenem etzadroxil/probenecid to amoxicillin/clavulanate in the micro-MITTS population will 
be concluded. 
Micro-MITTR population: For this population, a superiority test will be conducted. The null and 
alternative hypotheses are the following: 
H0 : p1 = p2 and H1 : p1 ≠ p2 


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A 2-sided 95% CI for the observed treatment difference in success rates will be determined using 
the method without stratification of Miettinen and Nurminen. The 1-sided p-value corresponding 
to the lower bound of the 95% CI will be reported. If the lower bound of the 95% CI is greater 
than 0%, the null hypothesis will be rejected and superiority of oral sulopenem 
etzadroxil/probenecid to amoxicillin/clavulanate will be concluded in the micro-MITTR 
population. 
If either of these 2 null hypotheses is rejected, then testing will proceed to the next step. 
(2) Superiority in the micro-MITT population 
The null and alternative hypotheses are: H0 : p1 = p2 and H1 : p1 ≠ p2.  
A 2-sided 95% CI for the observed treatment difference in success rates will be determined using 
the method without stratification of Miettinen and Nurminen. The 1-sided p-value corresponding 
to the lower bound of the 95% CI will be reported. If the lower bound of the 95% CI is greater 
than 0%, the null hypothesis will be rejected and the superiority of oral sulopenem 
etzadroxil/probenecid to amoxicillin/clavulanate in the micro-MITT population will be 
concluded. 
 
The reasons for failure and indeterminate will be tabulated for the primary efficacy endpoint at 
TOC in each of the micro-MITT, micro-MITTS and micro-MITTR populations.  
 
 
8.7.2 
Additional Analysis of the Primary Efficacy Endpoint 
The following sensitivity analyses of the primary endpoint at TOC will be conducted and a 2-
sided 95% unstratified CI will be computed for the difference in success rates between the 
treatment groups in the micro-MITT population: 
• A sensitivity analysis will consider all patients who have missing data for the primary 
endpoint (i.e., an indeterminate response) as successes. 
• A sensitivity analysis applying multiple imputation methods for missing data will be 
conducted. The multiple imputation analysis assuming a monotone missing data pattern 
will be used to define the missing data (indeterminate response). 100 datasets will be 
created using a logistic regression model with treatment, clinical response and 
microbiologic response at EOT  as predictors. 
• An analysis will consider the primary endpoint at TOC defined in Section 5.1 except, 
improvement of symptoms (instead of resolution) from baseline and no worse than mild 
and no new uUTI symptoms. 
• An analysis will consider the primary endpoint at TOC defined in Section 5.1 except, 
urgency and frequency are improved and no worse than mild and all symptoms are 
resolved and no new uUTI symptoms. 
• An analysis will consider the primary endpoint at TOC where microbiologic response is 
determined by molecular testing by PFGE, PCR or whole genome sequencing (WGS) 
• An analysis will consider the primary endpoint at TOC with varying thresholds of urine 
culture concentration at TOC 


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• An optional covariate exploratory analysis using logistic regression will be performed 
using baseline variables such as study drug, age, race, E. coli at baseline, creatinine 
clearance, albumin, comorbidities (such as 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-value ≤0.10 will be used in a 
multivariate analysis with a stepwise selection method. The alpha level for both entering 
and removing a covariate will be 0.10. 
 
A subgroup analysis of the primary efficacy endpoint by fed/fasted state will be conducted. A 
patient will be considered fed if she took 100% of her doses in a fed state (took either snack or 
meal 2 hours before or 30 minutes after the dose), otherwise fasted. Different proportions of doses 
taken in a fed state may be explored if the analysis suggests that the fed state makes a difference. 
 
8.7.3 
Secondary Efficacy Analysis 
The following analyses will be performed for the secondary efficacy endpoints in the populations 
as defined below. Tables specified for the micro-MITT population will also be presented for the 
micro-MITTS and micro-MITTR populations. 
• The number and percentage of patients in each treatment group with a (patient-
determined) clinical response of success, failure and indeterminate at TOC will be 
presented for the ITT, MITT and micro-MITT populations. The number and percentage 
of patients in each treatment group with a clinical response of success and failure at TOC 
will be presented for the CE and ME populations. Two-sided 95% unstratified CIs will 
be constructed for the observed difference in the clinical success rates between the 
treatment groups. 
• The number and percentage of patients in each treatment group with a per patient 
microbiologic response of success (eradication), failure (persistence or persistence with 
increasing MIC) and indeterminate at TOC will be presented for the micro-MITT 
population. The number and percentage of patients in each treatment group with a per 
patient microbiologic response of success and failure at TOC will be presented for the 
ME population. Two-sided 95% unstratified CIs will be constructed for the observed 
difference in the microbiologic success rates between the treatment groups for descriptive 
purposes, no conclusion of NI will be made. 
8.7.4 
Additional Efficacy Analyses  
All efficacy tables below will be presented for the specified populations. Tables specified for the 
micro-MITT population will also be presented for the micro-MITTS and micro-MITTR 
populations. Tables specified for the ME population will also be presented for the ME-S and ME-
R populations.  
Analysis 
EOT (Day 5) 
TOC (Day 12) 
FV (Day 28) 
Overall response 
Micro-MITT  
ME 
Micro-MITT¹  
ME 
Micro-MITT  
ME 


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Overall response by baseline pathogen 
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 study day* 
 
 
 
Overall response with failure requiring both 
clinical and microbiological failure 
 
Micro-MITT  
ME 
 
Patient determined clinical response 
ITT 
MITT 
Micro-MITT 
CE 
ME 
ITT² 
MITT² 
Micro-MITT² 
CE² 
ME² 
ITT 
MITT 
Micro-MITT 
CE 
ME 
Patient determined clinical response by baseline 
pathogen 
Micro-MITT  
ME 
Micro-MITT  
ME 
Micro-MITT  
ME 
Patient determined clinical response by ESBL 
positive and ESBL negative 
Micro-MITT  
ME 
Micro-MITT  
ME 
Micro-MITT  
ME 
Patient determined clinical response by baseline 
culture density 
MITT 
MITT 
MITT 
Patient determined clinical response defined by 
improvement of symptoms (instead of resolution) 
from baseline and no worse than mild and no new 
uUTI 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 uUTI symptoms 
 
ITT 
MITT 
Micro-MITT 
CE 
ME 
 
Patient determined clinical response failure by 
symptoms and bothersome questions 
ITT 
MITT 
Micro-MITT 
CE 
ME 
ITT 
MITT 
Micro-MITT 
CE 
ME 
ITT 
MITT 
Micro-MITT 
CE 
ME 
Microbiologic response 
Micro-MITT  
ME 
Micro-MITT²  
ME² 
Micro-MITT  
ME 
Per pathogen microbiologic response 
Micro-MITT  
ME 
Micro-MITT  
ME 
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 
 
Asymptomatic bacteriuria 
Micro-MITT  
ME 
Micro-MITT  
ME 
Micro-MITT  
ME 
Investigator determined clinical response 
ITT 
ITT 
ITT 


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MITT 
Micro-MITT 
CE 
ME 
MITT 
Micro-MITT 
CE 
ME 
MITT 
Micro-MITT 
CE 
ME 
PSAQ – by each symptom and severity 
ITT 
MITT 
Micro-MITT 
CE 
ME 
ITT 
MITT 
Micro-MITT 
CE 
ME 
ITT 
MITT 
Micro-MITT 
CE 
ME 
PSAQ – Shift table of severity 
ITT 
MITT 
Micro-MITT 
CE 
ME 
ITT 
MITT 
Micro-MITT 
CE 
ME 
ITT 
MITT 
Micro-MITT 
CE 
ME 
PSAQ – Kaplan-Meier plot of time to resolution 
of all symptoms* 
 
 
 
PSAQ – Severity by bothersome questions 
ITT 
MITT 
Micro-MITT 
CE 
ME 
ITT 
MITT 
Micro-MITT 
CE 
ME 
ITT 
MITT 
Micro-MITT 
CE 
ME 
PSAQ – Sensitivity analysis using bothersome 
questions 
ITT 
MITT 
Micro-MITT 
CE 
ME 
ITT 
MITT 
Micro-MITT 
CE 
ME 
ITT 
MITT 
Micro-MITT 
CE 
ME 
1 Primary efficacy endpoint 
2 Secondary efficacy endpoint 
* Overall response by study 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 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 EOT and FV will be presented for the micro-MITT 
populations. The number and percentage of patients in each treatment group with an overall 
response of success and failure at EOT, TOC and FV will be presented for the 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. 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 EOT, TOC and FV by baseline pathogen (key pathogens and species such as 
E. coli, Klebsiella species and Proteus species) will be summarized by treatment group in the 
micro-MITT and ME populations. Confidence intervals at the genus level will be provided.  
Overall response by amoxicillin/clavulanate MIC and sulopenem MIC for baseline pathogens 
will be provided for TOC visit in the micro-MITT and ME populations.  
Overall response by combination of antibiotic resistance classes will be provided. The classes 


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will be  
• ESBL status,  
• quinolone non-susceptible (QNS),  
• TMP-SMX non-susceptible,  
• nitrofurantoin (NTF) non-susceptible, 
• non-susceptible to at least 3 classes of antibacterials (MDR) (e.g., -quinolones, TMP-
SMX and beta-lactams),  
• resistance to all four classes (quinolones, TMP-SMX, nitrofurantoin 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 cefazolin 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, 
amoxicillin/clavulanate, tetracycline 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 by the treatment group and by day the overall assessment was 
made. For example, if a patient’s EOT assessment was conducted on Day 6 then she would be 
analyzed in the Day 6 table. A figure of overall response by day of assessment will be provided.  
Overall response with failure defined as both clinical and microbiological failure will be 
presented for micro-MITT and ME populations. 
The reasons for overall non-response at EOT, TOC and FV and overall indeterminate at TOC 
will be summarized for the micro-MITT and ME populations. The uUTI signs and symptoms in 
patients who were clinical failures at TOC will be summarized for the micro-MITT populations. 
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 EOT 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 EOT and FV 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.  
Patient-determined clinical response will also be presented by baseline pathogen and by ESBL 
positive/negative at EOT, TOC and FV in each treatment group for all populations. Confidence 
intervals at the genus level will be provided.  


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Patient-determined clinical response defined by improvement of symptoms (instead of 
resolution) from baseline and no worse than mild and no new uUTI symptoms will be presented 
at 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 uUTI symptoms will be 
presented at TOC in each treatment group for all populations.  
Patient-determined clinical response failure by symptoms and bothersome questions will be 
presented at EOT, TOC and FV in each treatment group for all populations.  
The reasons for clinical non-response at EOT, TOC and FV will be summarized for all the 
populations. 
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 EOT and FV will be presented for the micro-MITT populations. The number and percentage 
of patients in each treatment group with a per patient microbiologic response of success and 
failure at EOT and FV will be presented for the ME population. The microbiologic response per 
patient with definition of success varying by threshold of CFU/ml at TOC will be presented for 
the ME population. Two-sided 95% unstratified CIs will be constructed for the observed 
difference in the microbiologic success rates between the treatment groups for descriptive 
purposes; no conclusion of NI will be made.  
Per pathogen microbiologic response at EOT, TOC and FV by baseline pathogen will be 
summarized by treatment group in the micro-MITT and ME populations. Confidence intervals at 
the genus level will be provided.  
Per pathogen microbiologic response by amoxicillin/clavulanate MIC and sulopenem MIC for 
individual pathogens will be provided for TOC visit in the micro-MITT population.  
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. 
The impact of antibiotic therapy on the in vitro susceptibility of study uropathogens identified at 
baseline will be assessed at TOC. The distribution of MICs to sulopenem will be plotted at 
screening and TOC for the micro-MITT population. The distribution of MICs to 
amoxicillin/clavulanate will be plotted at screening and TOC for the micro-MITT, micro-MITTS 
and micro-MITTR populations. 
Asymptomatic Bacteriuria 
The number and percentage of patients in each treatment group with asymptomatic bacteriuria at 
EOT, TOC and FV will be presented for the micro-MITT and ME populations. Two-sided 95% 


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unstratified CIs will be constructed for the observed difference in the rate of asymptomatic 
bacteriuria between the treatment groups for descriptive purposes; no conclusion of NI will be 
made.  
Investigator-Determined Clinical Response 
Investigator-determined clinical response (clinical success, failure and indeterminate) at the 
EOT, TOC and FV visits will be presented by treatment group for the ITT, MITT, micro-MITT, 
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. 
Investigator-determined clinical response rates will be presented by treatment group for key 
targeted baseline pathogens at EOT, TOC and FV visits for the micro-MITT and ME populations. 
The reasons for investigator non-response at EOT, TOC and FV will be summarized for all the 
populations. 
Patient Symptom Assessment Questionnaire 
A table of the severity of each uUTI symptom based on the PSAQ from baseline to EOT, TOC 
and FV will be provided by treatment group for all populations.  
A shift table of the severity of each uUTI symptom based on the PSAQ from baseline to EOT, 
TOC and FV will be provided by treatment group for all populations.  
Kaplan-Meier plots for time to resolution of all PSAQ symptoms will be provided for the micro-
MITT population, where patients will be censored at time of death and taking non-study 
antibacterial therapy for uUTI. Plots for time to resolution of all PSAQ symptoms will also be 
provided where deaths and use of non-study antibacterial therapy are considered as failure.  
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 EOT, TOC and FV in all 
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 for all visits and populations. The 
negative symptoms will be counted as no symptom. 
8.8 Interim Analysis 
To ensure that the point estimate of overall success (combined clinical and microbiologic 
success) used in the estimation of sample size, the estimated eligibility rate, susceptibility rate, 
and rate of post-treatment asymptomatic bacteriuria is valid for this study, an interim analysis for 
sample size re-estimation will be performed when clinical and microbiologic response data at 
TOC are available for 50% of the patients (approximately 983 patients). The FDA Guidance 
“Non-inferiority Clinical Trials to Establish Effectiveness” [FDA Guidance 2016] 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 


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patients) to ensure the study has adequate power for determining whether oral sulopenem 
etzadroxil/probenecid is NI to oral amoxicillin/clavulanate for the primary outcome measure in 
the micro-MITTS population. This will ensure that the study is sufficiently powered to test the 
primary endpoint in the micro-MITT. The sample size will not be decreased. In addition, the 
sample size may be increased based on a lower-than-expected evaluability rate (i.e., percentage 
of the micro-MITT population in the ITT population), lower-than-expected percentage of patients 
with a susceptible pathogen and a lower-than-expected overall success rate. The sample size re-
estimation will be based on the blinded overall (not by treatment group) pooled data. 
The blinded interim analysis will proceed as follows:  
(1) Determine the percentage of patients with a baseline pathogen ≥105 CFU/mL (micro-
MITT population), which is the micro-MITT eligibility rate 
(2) Determine the percentage of patients with a susceptible (to comparator study drug, 
amoxicillin/clavulanate) pathogen (micro-MITTS population) and a non-susceptible (to 
amoxicillin/clavulanate) pathogen (micro-MITTR population) at baseline 
(3) Determine the overall success rate and overall rate of asymptomatic bacteriuria at TOC 
aggregated across treatment groups in the micro-MITTS population  
(4) Determine if there is sufficient power (80-90%) in the micro-MITTS to show NI with the 
planned sample size based on the observed aggregated (across treatment groups) overall 
success rate  
a. If NO, then increase the sample size in the micro-MITTS population to have 
sufficient power.  
(5)  If the aggregated overall success rate in the micro-MITTS population is higher than 70%, 
or if the aggregated rate of asymptomatic bacteriuria is significantly lower than 
anticipated, then a futility analysis may be conducted to assess if the study should 
continue. The futility analysis will be done by computing the conditional power at the 
interim analysis, given the observed overall success rates in each treatment group in the 
micro-MITTS population. 
The (blinded) sample size re-estimation will be conducted by a blinded statistician and the 
(unblinded) futility analysis will be conducted by an independent, unblinded statistician. A Data 
Monitoring Committee (DMC) will be provided the results of the interim analysis to make a 
recommendation regarding changes to the sample size and if the study should continue. A 
detailed DMC charter will be developed to outline the analyses to be completed, statistical rules, 
potential changes to the sample size and the recommendations that can be made to the sponsor. 
8.9 Safety Analyses 
All safety analyses will be conducted in the Safety population. Patients who receive the wrong 
regimen of study drug for their entire course of treatment will be analyzed in the group based on 
the regimen 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. 


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8.9.1 
Adverse Events 
Verbatim descriptions of AEs will be coded using Version 24.1 or higher of MedDRA. Summary 
tables will be provided for all treatment-emergent AEs (TEAEs). A TEAE is defined as any AE 
that newly appeared 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 (drug-related 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, any TEAE 
leading to discontinuation from the 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 relationship (unrelated (unrelated or 
unlikely) or related (possibly or probably)) to the 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 
etzadroxil/probenecid 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 patient is counted only once for that preferred 
term and at the highest intensity and strongest relationship to study drug. 
Incidence of TEAEs by system organ class, preferred term will also be presented by race and age. 
Analysis of the distribution of the duration of select adverse events 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. 
8.9.2 
Laboratory Values 
Several analyses of the laboratory data will be presented. Central labs were used in the study. A 
listing will be provided containing all lab data. 
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): 
𝑠𝑠= 𝑥𝑥  𝑈𝑈_𝑠𝑠/𝑈𝑈_𝑥𝑥  
where s = the individual local laboratory value normalized against the central laboratory normal 
range; x = the original individual local laboratory value; 𝑈𝑈_𝑥𝑥 is the upper limit of the normal 
range for an individual laboratory parameter; − 𝑈𝑈_𝑠𝑠  is the upper limit of the laboratory normal 
range for that laboratory parameter from the common source. 
Descriptive statistics for chemistry and hematology values and the change from baseline will be 


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summarized for all study visits. The change from baseline 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. If a patient has a value below the lower limit and a value above the upper limit, 
then the worst value will be the one that is furthest away from its corresponding limit. See 
Appendix B. 
The number and percentage of patients in each treatment group with an elevated alanine 
aminotransferase (ALT) level (>3 x ULN, >5 x ULN, and >10 x ULN), an elevated aspartate 
transaminase (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 >3 x ULN that is associated 
with both an ALP <2 x ULN and an increase in bilirubin ≥ 2 x ULN.  
For “worst overall value” post-baseline analyses, all laboratory assessments including those 
obtained from unscheduled visits will be included. 
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). 
8.9.3 
Physical Examinations 
Detailed patient listings of all physical examination results will be provided.  
8.9.4 
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 
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. 


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8.10 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, other, etc. The deviations will be adjudicated as major or minor 
as per 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, typically major deviations, 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 use). 
9. 
CHANGES FROM ANALYSES SPECIFIED IN THE PROTOCOL 
The following is the list of changes in the analyses from what was planned in the protocol: 
• The following are additions or changes to the clinical evaluable definition: 
o The patient must meet certain inclusion and exclusion criteria 
o The patient must have received appropriate adjunctive antibacterial coverage if 
the patient had a culture-documented Enterococcus spp. or other gram-positive 
resistant pathogens at baseline and symptoms 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 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. 
• Only one micro-evaluable population is defined in the protocol. The SAP defines two: 
ME-S for micro-evaluable amoxicillin/clavulanate susceptible patients and ME-R for 
micro-evaluable amoxicillin/clavulanate resistant patients. 
• For microbiologic response, post baseline responses of superinfection, new infection, 
recurrence and colonization were added. 
• 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 uUTI symptoms 
o Overall response defined by urgency and frequency are improved and no worse 
than mild and all symptoms are resolved and no new uUTI symptoms 
o Overall response with varying thresholds of urine culture concentration at TOC 
o Covariate analysis 
• Based on feedback received from the FDA on 30 October 2023, Staphylococcus 
saprophyticus has been excluded from the list of qualifying uropathogens in the micro-
MITT population. 


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• Based on feedback received from the FDA on 30 October 2023, asymptomatic bacteriuria 
will be assessed as an additional or exploratory endpoint instead of a secondary endpoint 
in the study. 
 


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10. 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 to Establish Effectiveness. 
November 2016.  
(4) Guidance for Industry: Uncomplicated Urinary Tract Infections: Developing Drugs for 
Treatment. August 2019.  
(5) Guidance for Industry: Adaptive Design Clinical Trials for Drugs and Biologics. 
December 2019.  
(6) Guidance for Industry: E9(R1) Statistical Principles for Clinical Trials: Addendum: 
Estimands and Sensitivity Analysis in Clinical Trials. May 2021. 
(7) Karvanen J. The Statistical Basis of Laboratory Data Normalization. Drug Information 
Journal 2003; 37: 101–107.  
(8) Kundu MG, Samanta S, Mondal S. (2023). Review of calculation of conditional power, 
predictive power and probability of success in clinical trials with continuous, binary and 
time-to-event endpoints. DOI: https://doi.org/10.21203/rs.3.rs-930504/v2 
 
 


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11. APPENDICES 
 
APPENDIX A:  SCHEDULE OF ACTIVITIES 
 
 
SCREENING 
TREATMENT PERIOD FOLLOW-UP PERIOD 
 
Protocol Activity 
D-1 to D1  
 
Baseline 
D13 
D5 
(+ 1 day)  
EOT 
D12 
(± 1 day) 
TOC 
D28 
(± 2 days) 
FV 
Premature Study 
Discontinuation 
Informed Consent 
X 
 
 
 
 
 
Medical History and 
Demographics 
X 
 
 
 
 
 
Targeted Physical 
Examination 
X 
 
X1 
X1 
X1 
X1 
Vital Signs 
X 
 
X 
X 
 
X 
Hematology 
X 
 
 
X 
 
X 
Serum Chemistry 
X 
 
 
X 
 
X 
Pregnancy testing2 
X 
 
 
 
X 
X 
Banked serum sample 
X 
 
 
X 
 
 
Banked urine sample 
X 
 
X 
X 
 
 
Urinalysis 
X 
X 
X 
X 
X 
Urine Culture and 
sensitivity  
X 
 
X 
X 
X 
X 
Previous Drug and Non-
drug Treatments 
X 
 
 
 
 
 
Concomitant Medications 
 
X 
X 
X 
X 
X 
Provide daily dosing 
diary  
 
X 
 
 
 
 
Collect daily dosing diary 
 
 
X 
 
 
X 
Study Drug Treatment 
 
X (BID x 10 doses total) 
 
 
 
Study Drug Compliance 
Check 
 
 
X 
 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
Patient Symptom 
Assessment 
Questionnaire (PSAQ) 
 
X 
X 
X 
X 
X 
Investigator Assessment 
of Clinical Response  
 
 
X 
X 
X 
X 
 
Schedule of Activities Footnotes: 
1 If needed, based on symptoms, as determined by the investigator 
2     Baseline and Day 28 (±2 days) or Premature Discontinuation: Pregnancy test (women of childbearing potential and peri-menopausal women, defined as women < 50 
years of age or those ≥ 50 years of age who have been post-menopausal for < 2 years) should be performed as required by the protocol 
3   Day 1 and Screening are generally on the same day 
 
 
 


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APPENDIX B: 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 
Alkaline 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 
Albumin 
<0.8 times the lower 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 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. It will be computed 
programmatically as below. 
For females:  
GFR = [(140-age) * (Ideal body weight in kg) * 0.85] / (72 * Cr), for serum Cr reported 
as mg/dL  
GFR = [(140-age) * (Ideal body weight in kg) * 1.0455] / (Cr), for serum Cr reported as 
micromol/L  
 
Ideal body weight is calculated as:  
For females:  
If Height > 152.5 cm  
Ideal body weight (kg) = 45.4 + [(Height - 152.4) * 0.89]  
If Height < 152.5 cm  
Ideal body weight (kg) = 45.4 – [(152.4 – Height) * 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: IT001-310 MICROBIOLOGY RULES FOR DETERMINATION OF 
FINAL PATHOGEN 
 
Baseline Visit 
1. Baseline urine sample is submitted for culture to Central laboratory (IHMA) 
2. Quantitative urine culture using a 1 μL loop is performed on baseline urine sample by 
IHMA 
3. Baseline urine culture is reported as: 
a. No growth, 
b. Uropathogen present (‘uropathogen’ is defined in section 7.4 of the Statistical 
Analysis Plan), 
c. Urogenital flora present, or 
d. >3 organisms present (uropathogen, if present, non-predominant), indicating 
contamination at collection 
4. For the one or two uropathogen(s) identified in the baseline urine culture specimen [final 
pathogen(s)], IHMA will perform susceptibility testing using the susceptibility panel 
outlined in IHMA’s Study Specifications Document (SSD) 
  
Post-Baseline Visits 
1. Post-baseline urine sample is submitted for culture to Central laboratory (IHMA) 
2. Quantitative urine culture using both a 1 μL and a 10 μL loop is performed on post-
baseline urine sample by IHMA 
3. Post-baseline urine culture is reported as: 
a. No growth, 
b. Uropathogen present (‘uropathogen’ is defined in section 7.4 of the Statistical 
Analysis Plan), 
c. Urogenital flora present, or 
d. >3 organisms present (uropathogen, if present, non-predominant), indicating 
contamination at collection 
4. For the one or two uropathogen(s) identified in the post-baseline urine culture specimen 
[final pathogen(s)], IHMA will perform susceptibility testing using the susceptibility panel 
outlined in IHMA’s Study Specifications Document (SSD)