Clinical trial NCT03354598
Conditions: Uncomplicated Urinary Tract Infections
Sponsor: Iterum Therapeutics, International Limited
Start date: 2018-08-01; Completion date: 2020-01-20
Enrollment: 1671 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a prospective, Phase 3, randomized, multi-center, double-blind study of the efficacy, tolerability, and safety of oral sulopenem-etzadroxil/probenecid versus oral ciprofloxacin for treatment of uncomplicated urinary tract infection (uUTI) in adult women

Detailed description:

Arms: arm 1: Sulopenem-etzadroxil/probenecid 500 mg PO twice daily for 5 days arm 2: Ciprofloxacin 250 mg PO administered twice daily for 3 days
Interventions: intervention 1: Sulopenem-Etzadroxil/Probenecid intervention 2: Ciprofloxacin
Intervention descriptions: intervention 1: Treatment of uncomplicated urinary tract infection intervention 2: Treatment of uncomplicated urinary tract infection

Protocol documents:
Prot_000.pdf: 
PF-03709270 
 
Iterum Therapeutics US Limited. 
Clinical Trial Protocol: IT001-301 
 
March 2018 
Confidential 
Page 1 of 71 
Clinical Trial Protocol: IT001-301 
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 ciprofloxacin for treatment of 
uncomplicated urinary tract infections in adult women. 
Study Number: 
IT001-301 
Study Phase: 
Phase 3 
Product Name: 
sulopenem etzadroxil/probenecid (PF-03709270/probenecid) 
IND Number: 
129,849 
EudraCT Number 
2017-003771-57 
Indication: 
Uncomplicated urinary tract infection 
Investigators: 
Multicenter 
Sponsor: 
Iterum Therapeutics US Limited 
Sponsor Contact: 
Sailaja Puttagunta 
Sponsor’s Legal 
Representative: 
Iterum Therapeutics US Limited 
20 Research Parkway, Suite A 
Old Saybrook, CT 06475 
Medical Monitor: 
Steven Aronin, M.D 
Email: saronin@iterumtx.com  
 
 
Pharmacovigilance 
Contact 
PSI Pharmacovigilance 
Email: SafetyDesk@psi-cro.com 
 
 
 
 
Date 
Original Draft Protocol  
August 1, 2017 
Revised Draft Protocol 
December 22, 2017 
Final Protocol 
March 06, 2018 
 
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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Clinical Trial Protocol: IT001-301 
 
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SYNOPSIS 
Sponsor: 
Iterum Therapeutics US Limited 
Name of Finished Product: 
Sulopenem etzadroxil/probenecid (PF-03709270/probenecid) 
 
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 ciprofloxacin for 
treatment of uncomplicated urinary tract infections (uUTI) in adult women. 
Study Number: 
IT001-301 
Study Phase: Phase 3 
Primary Objective(s):  
To compare the overall response of oral sulopenem etzadroxil/probenecid versus oral 
ciprofloxacin for the treatment of uncomplicated urinary tract infection in adult women at the 
primary time-point.  
Secondary Objective(s):  
a) To compare the overall response (clinical and microbiologic combined response) at other 
relevant time-points. 
b) To compare the microbiologic efficacy across treatment groups.  
c) To compare the clinical efficacy outcomes of oral sulopenem etzadroxil/probenecid 
versus oral ciprofloxacin at other relevant time points  
d) To compare the safety profile of treatment with oral sulopenem etzadroxil/probenecid 
versus oral ciprofloxacin for treatment of uncomplicated urinary tract infection in adult 
women.  
e) To assess the population PK profile of oral sulopenem etzadroxil/probenecid. 
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 Enterobacteriaceae including those 
that encode Extended Spectrum Beta-lactamase (ESBL) or AmpC-type β-lactamases that confer 
resistance to third generation cephalosporins. Sulopenem etzadroxil is expected to be the first 


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oral penem on the market in the United States and Europe and will offer the option of treatment 
in the outpatient setting as well as 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 prospective Phase 3, randomized, multicenter, double-blind, controlled study compares oral 
sulopenem etzadroxil/probenecid to oral ciprofloxacin for the treatment of patients with uUTI.  
Approximately 1,128 adult women with uUTI will be randomized in a 1:1 fashion to receive 
either a bilayer tablet with sulopenem etzadroxil 500 mg/probenecid 500 mg twice daily for 5 
days or oral ciprofloxacin 250 mg twice daily for 3 days.  
The primary outcome measure for efficacy evaluation will be the overall success (combined 
clinical and microbiologic success) on Day 12 (± 1 day).  
For the primary efficacy evaluations, these percentages will be compared in two subsets of the 
microbiologic-modified intent to treat population (micro-MITT): 1) where the baseline pathogen 
is determined to be susceptible (ciprofloxacin MIC ≤ 1 mg/L) to the comparator study drug, 
ciprofloxacin (micro-MITTS population), and 2) where the baseline pathogen is determined to 
be non-susceptible/resistant (ciprofloxacin MIC ≥ 2 mg/L; includes strains with intermediate 
susceptibility and resistance to ciprofloxacin) to the comparator study drug, ciprofloxacin 
(micro-MITTR population). 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 (Enterobacteriaceae and Staphylococcus saprophyticus only) isolated from a urine 
culture specimen taken at baseline, prior to initiation of study drug therapy.  
Study Population:  
A total of approximately 1,128 patients are planned. The sample size may be adjusted at the 
blinded interim analyses (one at 33% of planned sample size and the other at 66% of planned or 
original sample size) if the baseline assumptions for overall success rate, evaluability rate and 
susceptibility rate are not met, which, specifically, are an overall success rate of 79%, the 
proportion of ITT patients eligible to be included in the micro-MITT population of 80%, and a 
susceptibility rate of 80%. The sample size may also be adjusted at an unblinded interim analysis 
(66% of randomized patients) based on the conditional power analysis in the micro-MITTR 
population. 
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, gross hematuria 
3. A mid-stream urine specimen with:  
a. a dipstick analysis positive for nitrite  


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AND, in the same urine specimen 
b. evidence of pyuria as defined by either: 
i. 
a dipstick analysis positive for leukocyte esterase AND/OR  
ii. 
at least 10 white blood cells per cubic millimeter on microscopic analysis 
of unspun urine AND/OR  
iii. 
White blood cell count ≥10 cells/HPF in 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 3 days, unless the recovered pathogen demonstrates resistance to the initial 
antibiotic (other than quinolone or penem antibiotics) and clinical symptoms persist 
3. Causative uropathogen for the presenting illness known to be resistant to a carbapenem 
4. 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  
5. Patients with ileal loops or urinary stoma 
6. Patients with an indwelling urinary catheter in the previous 30 days 
7. Patients with paraplegia 
8. Patients who are likely to receive ongoing antibacterial drug prophylaxis after treatment 
of uUTI (e.g., patients with vesico-ureteral reflux) 
9. Any history of trauma to the pelvis or urinary tract 
10. Patient's urine culture results, if available at study entry, identify more than 2 
microorganisms regardless of colony count or patient has a confirmed fungal UTI 
11. Patient is receiving hemodialysis, peritoneal dialysis or had a renal transplant 
12. Creatinine clearance <50 mL/min as calculated by Cockcroft and Gault equation 
(Appendix 3) 
13. Patient known to be immunocompromised (e.g. absolute neutrophil count [ANC] < 500 
cells/mm3, human immunodeficiency virus (HIV) infected patients with a CD4 cell count 
< 200 cells/mm3, patients with a bone marrow/organ transplant in the 3 months prior to 
study enrollment, patients receiving oral steroids > 20 mg prednisolone per day [or 
equivalent] or receiving immunosuppressant drugs after bone marrow/organ 


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transplantation) 
14. Patients known to have a history of liver disease as defined by the following laboratory 
criteria: 
• ALT or AST > 3 X Upper Limit of Normal 
• Total bilirubin > 1.5 X Upper Limit of Normal 
15. Patients who are pregnant 
16. Patients with uncontrolled Diabetes mellitus (defined as the presence of ketoacidosis, 
hyperosmolar hyperglycemia, random or fasting serum glucose ≥ 250 mg/dL at 
screening) 
17. History of seizures 
18. Patients with a history of blood dyscrasias 
19. Patients with a history of uric acid kidney stones 
20. Patients with acute gouty attack 
21. Patients on chronic methotrexate therapy 
22. Patients with a known history of myasthenia gravis 
23. Patients who require concomitant administration of tizanidine or valproic acid 
24. Patients with a history of allergy or hypersensitivity to carbapenems, β-lactams, 
quinolones or probenecid, as formulated with their excipients 
25. Patient is considered 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 
26. 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 
Test Product, Dose, and Mode of Administration:  
Patients will be randomized to receive either a bilayer tablet with sulopenem etzadroxil 500 
mg/probenecid 500 mg PO twice daily for 5 days or oral ciprofloxacin 250 mg PO twice daily 
for 3 days. 
Other Systemic Antibiotics: 
For Clostridium difficile infections, metronidazole (IV or oral) or oral vancomycin may be used 
in both treatment groups. Patients with a co-infection with a gram-positive uropathogen resistant 
to study drugs are allowed to receive agents with narrow spectrum gram-positive coverage (such 
as oral linezolid). 


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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 500 mg/probenecid 500 mg 
and one blister pack with 6 ciprofloxacin placebo capsules. 
Comparator treatment group:  The study drug will be supplied as a study kit containing one 
blister pack with 6 over-encapsulated ciprofloxacin 250 mg tablets, and one bottle with 10 
placebo bilayer tablets to match sulopenem etzadroxil/probenecid tablets.  
Preparation and Dispensing: 
Each patient will receive a kit containing one 5 day treatment course of either sulopenem 
etzadroxil/probenecid and placebo ciprofloxacin or placebo sulopenem etzadroxil/probenecid 
and ciprofloxacin. 
Administration: 
Patients will take one tablet from the kit bottle twice daily (sulopenem etzadroxil/probenecid or 
placebo) for 5 days and they will take one capsule from the blister pack twice daily (over-
encapsulated ciprofloxacin or placebo capsules) for 3 days. The first dose of each medication 
will be administered under the supervision of study site personnel to help ensure compliance 
with dosing directions. 
Efficacy Assessments: 
The assessment of clinical response includes a review of the following symptoms at the 
Baseline, Day 3, Day 5 (± 1 day), Day 12 (± 1 day), and Day 28 (± 2 days) visits or at premature 
discontinuation: urinary frequency, urinary urgency, pain or burning on micturition, suprapubic 
pain and gross hematuria.  
Microbiologic response assessments will be made based on quantitative cultures performed on 
collected urine specimens at the Baseline, Day 3, Day 5 (± 1 day), Day 12 (± 1 day), and Day 28 
(± 2 days) visits or at premature discontinuation. 
 
Other Assessments: 
Plasma samples for population PK evaluations will be collected in a subset of patients at 
selected study sites. 
 
Safety Assessments: 
Safety will be assessed by means of vital signs, collection of adverse events and clinical 
laboratory tests.  
Physical examination will be performed at the Baseline visit, and a targeted exam will be 
conducted if needed at Day 3, Day 5 (± 1 day), Day 12 (± 1 day), 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) 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 and at the Day 12 (± 1 day) visit, in follow-up of any clinically 
significant laboratory finding, as well as at premature discontinuation.  


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Statistical Methods:  
Sample Size Considerations:  
The study is designed to determine whether oral sulopenem etzadroxil/probenecid is non-inferior 
to oral ciprofloxacin for the outcome measure of overall success (combined clinical and 
microbiologic success) at Day 12 (± 1 day) in the micro-MITTS population and/or whether oral 
sulopenem etzadroxil/probenecid is superior to oral ciprofloxacin for overall success at Day 12 
(± 1 day) 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 352 patients per arm (total sample 
size of 704 patients) based on the method of Farrington and Manning. This assumes a non-
inferiority margin of 10%, a power of 90%, a one-sided alpha level of 0.025 and a 79% 
treatment success rate. With 99 patients per treatment group in the micro-MITTR population, 
there is 90% power to show superiority given a 75% and 52% overall success rate in the 
sulopenem etzadroxil/probenecid and ciprofloxacin groups, respectively. Assuming that 80% of 
the randomized patients will meet criteria for inclusion into the micro-MITT population (902 
patients), the sample size for the ITT population is 1,128. 
Two blinded interim analyses for sample size re-estimation, based on the pooled, blinded overall 
response as defined in the primary endpoint, will be conducted when 33% and 66% of the 
patients (approximately 372 and 745 patients, respectively) have clinical and microbiologic 
response data available (see  Section 9.7) to assess overall success and evaluability rates. As 
indicated in the draft FDA Guidance “Adaptive Design and Clinical Trials for Drugs and 
Biologics”, no statistical adjustment is required when a blinded analysis is completed of the 
overall event rate.  Thus, the one-sided alpha level used for the sample size calculation is 0.025. 
The final sample size may be revised based on the observed overall success rate, the evaluability 
rate (proportion of MITT patients with a baseline pathogen) and the proportion of the micro-
MITT population with a susceptible pathogen at the blinded interim analysis, to maintain a 
power of 90%. 
An additional unblinded interim analysis for sample size re-estimation based on conditional 
power will be conducted when 66% of patients have clinical and microbiologic response data 
available to assess overall success rates in the micro-MITTR population (patients with a 
pathogen non-susceptible to comparator agent, ciprofloxacin). The alpha level does not need to 
be adjusted if the hypothesis test is not completed due to futility based on a conditional power of 
<40%.  


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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 etzadroxil/probenecid 
versus oral ciprofloxacin. Exploratory analyses may also be performed.  Listings of individual 
patient’s data will be produced. 
A comprehensive Statistical Analysis Plan (SAP) will be finalized prior to the interim analysis. 
Efficacy Analyses:   
The study is designed to determine whether oral sulopenem etzadroxil/probenecid is NI to oral 
ciprofloxacin for the outcome measure of overall success (combined clinical and microbiologic 
success) at Day 12 (± 1 day) in the micro-MITTS population and/or whether oral sulopenem 
etzadroxil/probenecid is superior to oral ciprofloxacin for overall success at Day 12 (± 1 day) 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) demonstrates <103 CFU/mL of the baseline 
uropathogen  
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-MITTS population and the micro-MITTR 
population. For each analysis population, the observed difference in the percentage of patients 
with success at Day 12 (± 1 day) (sulopenem etzadroxil/probenecid group minus the 
ciprofloxacin 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), is defined below. 
The primary comparisons for regulatory approval are in two mutually exclusive populations 
defined by a baseline characteristic: 1) the 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, ciprofloxacin); and 2) the micro-MITTR population (the subset of the 


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micro-MITT population in which the baseline pathogen is determined to be non-susceptible 
{defined as MIC ≥2 mg/L; includes pathogens with intermediate susceptibility [2 mg/L] and 
resistance [≥4 mg/L]} to the comparator study drug, ciprofloxacin).  
• NI test of overall success in the micro-MITTS population: the NI hypothesis test is a one-
sided hypothesis test performed at the 2.5% level of significance. If the lower limit of the 
95% CI for the difference in success rates in the micro-MITTS population is greater than   -
10% the NI of sulopenem etzadroxil/probenecid to the ciprofloxacin group will be 
concluded.  
• Superiority test of overall success in the micro-MITTR population: the superiority 
hypothesis test is based on the lower limit of the two-sided 95% CI for the difference in 
success rates.  If the lower limit of the CI is greater than 0, sulopenem etzadroxil/probenecid 
will be considered superior to ciprofloxacin. 
If either NI is declared for the primary comparison in the micro-MITTS population or if 
superiority is established in the micro-MITTR population, then an NI test of overall success 
followed by a superiority test of overall success (if the null hypothesis is rejected for the NI test) 
in the micro-MITT population will be conducted. When testing in a sequential manner with pre-
planned testing, no adjustment to the alpha level is required.  
 
The number and percentage of patients with a microbiologic eradication, persistence, or 
persistence with increasing MIC at the Day 12 (±1 day) visit in each treatment group in the 
microbiologic evaluable (ME-Day 12) population will be determined. The observed difference 
in percentage of patients with a microbiologic eradication (sulopenem etzadroxil/probenecid 
group minus the ciprofloxacin group) will be determined and a 2-sided unstratified 95% CI for 
the observed difference will be computed using the method of Miettinen and Nurminen. 
 
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. 
 
Date of Original Approved Protocol:  062 March 2018 
Date of Most Recent Protocol Amendment (if applicable):  NA 
Prepared in:  Microsoft Word 2016 


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TABLE OF CONTENTS 
SYNOPSIS ................................................................................................................................ 2 
LIST OF IN-TEXT TABLES .................................................................................................. 13 
LIST OF IN-TEXT FIGURES ................................................................................................ 13 
LIST OF APPENDICES ......................................................................................................... 13 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ......................................... 14 
1 
INTRODUCTION ........................................................................................................... 17 
1.1 
Indication ............................................................................................................... 17 
1.2 
Background and Rationale..................................................................................... 17 
1.2.1 
Safety data ................................................................................................... 20 
1.2.1.1 
Sulopenem etzadroxil (PF-03709270; oral prodrug) ......................... 20 
1.2.1.2 
Sulopenem (CP-70,429; Intravenous) ............................................... 21 
1.2.2 
Rationale for Study ...................................................................................... 22 
1.2.3 
Dose Rationale ............................................................................................. 24 
2 
STUDY OBJECTIVES ................................................................................................... 25 
2.1 
Objectives .............................................................................................................. 25 
3 
STUDY DESIGN ............................................................................................................ 25 
3.1 
Investigational Study Medications ........................................................................ 26 
3.2 
Adjunctive Systemic Antibiotics ........................................................................... 26 
3.3 
Additional Non-Study Therapy Antibiotics .......................................................... 26 
4 
STUDY POPULATION SELECTION ........................................................................... 26 
4.1 
Inclusion Criteria ................................................................................................... 26 
4.2 
Exclusion Criteria .................................................................................................. 27 
4.3 
Randomization Criteria.......................................................................................... 28 
4.4 
Life Style Guidelines ............................................................................................. 29 
4.5 
Women of Child-Bearing Potential ....................................................................... 29 
5 
STUDY TREATMENTS ................................................................................................ 29 
5.1 
Allocation to Treatment ......................................................................................... 29 
5.2 
Drug Supplies ........................................................................................................ 30 
5.2.1 
Formulation and Packaging ......................................................................... 30 
5.2.2 
Preparation and Dispensing ......................................................................... 30 
5.2.3 
Administration ............................................................................................. 30 
5.2.4 
Compliance .................................................................................................. 30 
5.3 
Drug Storage and Drug Accountability ................................................................. 31 
5.4 
Concomitant Medication(s), Adjunctive Therapy, and Non-drug Therapy .......... 31 
5.4.1 
Concomitant Medications ............................................................................ 31 
5.4.2 
Concomitant Antibacterial Medications ...................................................... 32 
5.4.3 
Adjunctive Antibacterial Therapy ............................................................... 32 


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5.4.4 
Non-drug Adjunctive Therapy ..................................................................... 32 
6 
STUDY PROCEDURES ................................................................................................. 32 
6.1 
Screening (Day -1) - Within 24 Hours Prior to First Dose .................................... 32 
6.2 
Treatment Period ................................................................................................... 33 
6.2.1 
Day 1............................................................................................................ 33 
6.2.2 
Day 3............................................................................................................ 33 
6.2.3 
Day 5 (± 1 day) (End of Treatment/EOT) ................................................... 34 
6.3 
Follow-up Period ................................................................................................... 34 
6.3.1 
Day 12 (± 1 day) (Test of Cure/TOC) ......................................................... 34 
6.3.2 
Day 28 (± 2 days) (Final Visit/FV) ............................................................. 34 
6.4 
Premature Discontinuation .................................................................................... 35 
6.5 
Patient Withdrawal from Treatment or Study ....................................................... 35 
7 
ASSESSMENTS ............................................................................................................. 36 
7.1 
Safety ..................................................................................................................... 36 
7.1.1 
Physical Examination .................................................................................. 36 
7.1.2 
Vital Signs (Temperature, Blood Pressure, Pulse Rate, Respiratory Rate) . 36 
7.1.3 
Clinical Laboratory Assays ......................................................................... 36 
7.1.4 
Clinically Significant Laboratory Tests ....................................................... 37 
7.2 
Efficacy .................................................................................................................. 37 
7.2.1 
Overall Response ......................................................................................... 37 
7.2.2 
Microbiologic .............................................................................................. 37 
7.2.3 
Patient-Determined Clinical Response ........................................................ 38 
7.2.4 
Investigator Assessment of Clinical Response ............................................ 38 
7.2.5 
Patient Symptom Assessment Questionnaire (PSAQ) ................................ 39 
8 
ADVERSE EVENT REPORTING ................................................................................. 39 
8.1 
Adverse Events ...................................................................................................... 39 
8.2 
Reporting Period .................................................................................................... 39 
8.3 
Definition of an AE ............................................................................................... 40 
8.4 
Abnormal Test Findings ........................................................................................ 40 
8.5 
Serious Adverse Events (SAE) .............................................................................. 41 
8.6 
Hospitalization ....................................................................................................... 41 
8.7 
Severity Assessment .............................................................................................. 42 
8.8 
Causality Assessment ............................................................................................ 42 
8.9 
Exposure during Pregnancy ................................................................................... 43 
8.10 
Discontinuation from Study Drug Due to AEs (See also Patient Withdrawal, 
Section 6.5) ............................................................................................................ 44 
8.11 
Eliciting AE Information ....................................................................................... 45 
8.12 
Reporting Requirements ........................................................................................ 45 
8.12.1 
SAE Reporting Requirements ..................................................................... 45 


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8.12.2 
Non-SAE Reporting Requirements ............................................................. 45 
8.12.3 
Sponsor Reporting Requirements to Regulatory Authorities ...................... 46 
9 
DATA ANALYSIS/STATISTICAL METHODS........................................................... 46 
9.1 
Sample Size Determination ................................................................................... 46 
9.2 
Definition of Analysis Populations........................................................................ 47 
9.3 
General Statistical Considerations ......................................................................... 49 
9.4 
Patient Characteristics ........................................................................................... 49 
9.5 
Efficacy Analysis ................................................................................................... 49 
9.5.1 
Analysis of Primary Outcome Measure ....................................................... 49 
9.5.1.1 
Additional Hypothesis Testing of the Primary Outcome Measure .... 50 
9.5.1.2 
Additional Analyses of the Primary Efficacy Outcome .................... 51 
9.5.2 
Analysis of Secondary Efficacy Outcome Measure .................................... 51 
9.5.3 
Analysis of Additional Efficacy Outcome Measures .................................. 51 
9.6 
Safety Analyses ..................................................................................................... 52 
9.7 
Interim Analysis .................................................................................................... 53 
9.8 
Handling of Missing Data...................................................................................... 54 
10 QUALITY CONTROL AND QUALITY ASSURANCE .............................................. 55 
11 DATA HANDLING AND RECORD KEEPING ........................................................... 55 
11.1 
Case Report Forms / Electronic Data Record ........................................................ 55 
11.2 
Record Retention ................................................................................................... 55 
12 ETHICS ........................................................................................................................... 56 
12.1 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ............. 56 
12.2 
Ethical Conduct of the Study ................................................................................. 56 
12.3 
Patient Information and Consent ........................................................................... 56 
12.4 
Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP .... 57 
13 DEFINITION OF END OF STUDY ............................................................................... 57 
13.1 
End of Study in all Participating Countries ........................................................... 57 
14 SPONSOR STUDY TERMINATION CRITERIA ......................................................... 57 
15 PUBLICATION OF STUDY RESULTS ........................................................................ 57 
15.1 
Communication of Results by Iterum .................................................................... 57 
15.2 
Publications by Investigators ................................................................................. 58 
16 REFERENCE LIST ......................................................................................................... 59 
 


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LIST OF IN-TEXT TABLES 
Table 1   Sulopenem In-Vitro Susceptibility (2013-2015) ...................................................... 18 
 
LIST OF IN-TEXT FIGURES 
LIST OF APPENDICES 
Appendix 1 
Schedule of Activities ...................................................................................... 60 
Appendix 2 
Microbiology ................................................................................................... 61 
Appendix 3 
Method for Determination of Creatinine Clearance ........................................ 63 
Appendix 4 
Patient Symptom Assessment Questionnaire (PSAQ) .................................... 64 
Appendix 5 
Population PK Substudy .................................................................................. 65 
Appendix 6 
Criteria for Safety Values of Potential Clinical Concern ................................ 70 
Appendix 7    Investigator’s Signature .................................................................................... 71 
 
 


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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 
 
BID 
Beta Human Chorionic Gonadotropin 
 
Twice daily 
 
BUN 
Blood Urea Nitrogen 
Cmax 
Maximum concentration 
CA 
Community-acquired 
CBC 
Complete Blood Count 
CE 
Clinically Evaluable 
CI 
 
cIAI 
 
CFU 
 
CLSI 
 
Cmax 
 
Confidence Interval 
 
Complicated Intra-Abdominal Infection 
 
Colony Forming Unit 
 
Clinical and Laboratory Standards Institute 
 
Maximum concentration 
CrCl 
 
CRE 
Creatinine Clearance 
 
Carbapenem Resistant Enterobacteriaceae  
 
CRF 
Case Report Form 
CTA 
 
cUTI 
 
DMC 
 
Clinical Trial Application 
 
Complicated Urinary Tract Infection 
 
Data Monitoring Committee 
EARS-NET 
 
ECG 
 
European Antimicrobial Resistance Surveillance Network 
 
Electrocardiogram 
 


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E.coli 
Escherichia coli 
EIU 
 
EOT 
 
ESBL 
Exposure in Utero 
 
End of Treatment Visit 
 
Extended Spectrum Beta-lactamase 
 
FDA 
 
FSH  
 
Food and Drug Administration 
 
Follicle-stimulating Hormone  
 
FV  
Final Visit  
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl Transpeptidase 
GMP 
 
hERG 
Good Manufacturing Practice 
 
Human Ether-a-go-go-Related Gene  
 
HIV 
Human Immunodeficiency Virus  
hs-CRP 
High-sensitivity C-reactive Protein 
ICH 
International Conference on Harmonisation 
ICF 
 
IDSA 
Informed Consent Form 
 
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 
 
LTFU 
Lactate Dehydrogenase 
 
Lost to Follow-Up 
 
ME 
 
MeDRA 
 
MIC 
 
Microbiologically Evaluable 
 
Medical Dictionary of Regulatory Activities 
 
Minimal Inhibitory Concentration 
 


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MITT 
 
Micro-MITT 
 
Modified ITT  
 
Microbiologic-MITT  
NI 
 
NOAEL 
 
PBP 
 
PCS 
 
Non-inferior/Non-inferiority 
 
No Observed Adverse Effect Level  
 
Penicillin-Binding Proteins 
 
Potentially clinically significant 
PK 
Pharmacokinetic 
PK/PD 
 
PO 
 
PSAQ 
 
PV 
 
RBC 
Pharmacokinetic / Pharmacodynamic 
 
Per-oral 
 
Patient symptom assessment questionnaire 
 
Pharmacovigilance 
 
Red Blood Cell 
 
SAE 
Serious Adverse Event 
SAP 
 
SOC 
 
SUSAR 
 
TA 
 
TEAE 
 
TOC 
 
Statistical Analysis Plan 
 
System organ class 
 
Suspected Unexpected Serious Adverse Reaction 
 
Target Achievement 
 
Treatment Emergent Adverse Event 
 
Test of Cure 
 
Tmax 
Time to maximum concentration 
uUTI 
Uncomplicated urinary tract infection 
WBC 
 
2-EBA 
White Blood Cell 
 
2-Ethylbutryic Acid 
 
 


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1 
INTRODUCTION 
1.1 Indication 
Sulopenem is 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 
Enterobacteriaceae has been increasing worldwide and includes both hospital acquired and 
community onset infections. An analysis of data reported from 2011 to 2014 to the National 
Healthcare Safety Network performed by the Centers for Disease Control in March 2016 
revealed that the proportion of E. coli resistant to extended-spectrum cephalosporins causing 
hospital-acquired infection was 13.4% nationally, with rates as high as 24% reported in some 
Northeastern, Southern and Western states.  The same analysis also demonstrated that over a 
third of E. coli isolates in 2014 were resistant to quinolones. 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-sulphamethoxazole. 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-sulphamethoxazole 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]. Even with these limitations, almost two-thirds of patients with a 
uUTI receive therapy with a quinolone antibiotic. Efficacy outcomes for patients treated with 
quinolones for uUTI caused by quinolone non-susceptible pathogens are not known. The 
currently proposed study will compare the safety, tolerability and efficacy of oral sulopenem 
etzadroxil/probenecid versus oral ciprofloxacin for the treatment of uncomplicated urinary tract 
infection 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 Enterobacteriaceae that encode ESBLs or AmpC-
type β-lactamases that confer resistance to third generation cephalosporins. The targeted gram-
negative spectrum of sulopenem is balanced by its potent in vitro activity against anaerobic 
pathogens, which is similar to that of imipenem.  
An in vitro susceptibility study of sulopenem was conducted in April 2016 utilizing 
contemporary clinical bacterial isolates from patients in the United States and Europe. Minimal 
inhibitory concentrations (MICs) of sulopenem and 18 comparators were determined against 
1,122 recent (2013-2015) clinical isolates following Clinical and Laboratory Standards Institute 
(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 
Enterobacteriaceae (CRE) were excluded from the analysis shown below, but the MIC90 of 
Enterobacteriaceae remains at 0.25 µg/mL even if CRE are included, given that their overall 
prevalence is low (data on file). 
Table 1   Sulopenem In-Vitro Susceptibility (2013-2015) 
Organism Class 
N 
MIC50 
MIC90 
Enterobacteriaceae 
636 
0.03 
0.25 
E. coli                       ESBL negative 
169 
0.015 
0.03 
                                 ESBL positive 
20 
0.03 
0.06 
Klebsiella spp.         ESBL negative 
108 
0.03 
0.06 
                                 EBSL positive 
16 
0.03 
0.25 
P. mirabilis 
14 
0.12 
0.25 
E. aerogenes 
57 
0.06 
0.25 
C. koseri 
60 
0.03 
0.03 
S. marcescens 
55 
0.12 
0.5 
Gram-Negative Anaerobes 
121 
0.12 
0.25 
Staphylococcus saprophyticus 
31 
0.25 
0.25 


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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 subjects 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.  Phase 2 studies in patients with urinary tract infection or intra-
abdominal infection have not been conducted in the United States. 
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, 
ciprofloxacin, in an era of significant antibacterial resistance to fluoroquinolones. The activity of 
sulopenem will be compared to ciprofloxacin in patients with organisms susceptible to 
ciprofloxacin, to provide a quantitative estimate of relative activity established by non-inferiority 
testing as well as in patients with organisms that are resistant to fluoroquinolones 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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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 
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). 
 


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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. 
  
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).    
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, 


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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.  Fourteen hundred and seventy-eight 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 are available in the 
respective Investigator’s Brochures. 
1.2.2 
Rationale for Study  
ß-lactam antimicrobials are widely recognized for their efficacy and low toxicity and form 
the cornerstone of therapy for the treatment of infections caused by gram-positive and 
gram-negative bacteria. However, extensive use of ß-lactams during the past 50 years has 
resulted in the development of microbial resistance to these agents among clinically 
important bacteria. This resistance commonly takes the form of ß-lactamase production, 
development of porins or alterations in penicillin-binding proteins (PBPs). Such mechanisms 
have reduced the clinical utility of frequently prescribed ß-lactams such as amoxicillin, 
amoxicillin plus clavulanate (a ß-lactamase inhibitor), and cephalosporins. The issue of 
resistance continues to drive the search for new compounds with increased stability and activity 
against resistant pathogens. Nowhere is the importance of resistance more evident than among 
agents of the ß-lactam family.  
 
For Escherichia coli, ampicillin resistance has risen to ≥50% in high-risk populations, and 
resistance to third generation cephalosporins is now being seen in certain areas. Only through the 


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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-sulphamethoxazole among Escherichia coli is now > 20% in the United States 
(CDC summary data). However, quinolones continue to be the most prescribed category of 
medicines used to treat uUTI in the US.  
 
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.  
 
The current study will compare oral sulopenem etzadroxil/probenecid with oral ciprofloxacin for 
the treatment of patients with uUTI. 
 
Rationale for probenecid 
Probenecid is known to increase plasma levels of weak organic acids such as penicillins, 
cephalosporins, and other beta-lactam antibiotics, including penems, by competitively inhibiting 
their renal tubular secretion.  Probenecid has been used safely with other beta-lactam antibiotics, 
to either reduce dose or dosing frequency of beta-lactams when used to treat infectious diseases 
in human beings.  
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 
etzadrozil 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. 
 


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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.  
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 is encouraged, but not required. 
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.  
 


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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.  
Ciprofloxacin 
The recommended dose of 250 mg oral ciprofloxacin administered twice daily for 3 days for 
treatment of uncomplicated UTI, per the Ciprofloxacin USPI and Ciprofloxacin SmPC, will be 
used in this study.  
For the full prescribing information for probenecid or ciprofloxacin, please refer to respective 
local country product labels (USPI or SmPC). 
2 
STUDY OBJECTIVES 
2.1 
Objectives 
The primary objective of this study is to compare the overall response of oral sulopenem 
etzadroxil/probenecid versus oral ciprofloxacin for the treatment of uncomplicated urinary tract 
infection in adult women at the primary time-point. 
The secondary objectives of this study are: 
a) To compare the overall response (clinical and microbiologic combined response) at other 
relevant time-points 
b) To compare the microbiologic success across treatment groups. 
c) To compare the clinical efficacy outcomes of oral sulopenem etzadroxil/probenecid 
versus oral ciprofloxacin at relevant time points  
d) To compare the safety profile of treatment with oral sulopenem etzadroxil/probenecid 
versus oral ciprofloxacin for treatment of uncomplicated urinary tract infection in adult 
women. 
e) To assess the population PK profile of oral sulopenem etzadroxil/probenecid. 
3 
STUDY DESIGN 
This prospective, Phase 3, randomized, multicenter, double-blind, controlled study compares 
oral sulopenem etzadroxil/probenecid with oral ciprofloxacin for the treatment of patients with 
uUTI.  Approximately 1,128 adult women with uUTI will be randomized in a 1:1 fashion to 
receive either oral sulopenem etzadroxil 500mg/probenecid 500 mg twice daily for 5 days or oral 
ciprofloxacin 250 mg twice daily for 3 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-MITTS and micro-MITTR populations 
on Day 12 (± 1 day). A key secondary efficacy assessment will be the microbiologic response 


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(success [eradication], failure [persistence or persistence with increasing MIC] or indeterminate) 
on Day 12 (± 1 day). See Appendix 1, Schedule of Activities Table. 
 
3.1 
Investigational Study Medications 
Patients will be randomized to receive either sulopenem etzadroxil 500 mg/probenecid 500 mg 
PO twice daily for 5 days or ciprofloxacin 250 mg PO twice daily for 3 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 500 mg/probenecid 500 mg 
and one blister pack with 6 ciprofloxacin placebo capsules. 
 
Comparator treatment group:  The study drug will be supplied as a study kit containing one 
blister pack with 6 over-encapsulated ciprofloxacin 250 mg tablets, and one bottle with 10 
placebo bilayer tablets to match sulopenem etzadroxil/probenecid tablets.  
 
3.2 
Adjunctive Systemic Antibiotics 
None allowed 
 
3.3 
Additional Non-Study Therapy Antibiotics 
For Clostridium difficile infections, IV or oral metronidazole, or oral vancomycin may be used in 
both treatment groups (see Section 5.4.2 for further details).  
Patients with a co-infection with a gram-positive uropathogen resistant to study drugs are 
allowed to receive agents with narrow spectrum gram-positive coverage (i.e., such as oral 
linezolid). 
4 
STUDY POPULATION SELECTION 
Female patients who present with uUTI, defined by symptoms and a dipstick positive for 
leukocyte esterase and nitrite, 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  


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2. Two of the following signs and symptoms of uUTI:  urinary frequency, urinary urgency, 
pain or burning on micturition, suprapubic pain, gross hematuria. 
3. A mid-stream urine specimen with:  
a. a dipstick analysis positive for nitrite  
AND, in the same specimen  
b. evidence of pyuria as defined by either: 
i. a dipstick analysis positive for leukocyte esterase AND/OR 
ii. at least 10 white blood cells per cubic millimeter on microscopic analysis 
of unspun urine AND/OR  
iii. White blood cell count ≥10 cells/HPF in 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 3 days, unless the recovered pathogen demonstrates resistance to the initial 
antibiotic (other than quinolone or penem antibiotics) and clinical symptoms persist 
3. Causative uropathogen for the presenting illness known to be resistant to a carbapenem 
4. 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 
5. Patients with ileal loops or urinary stoma 
6. Patients with an indwelling urinary catheter in the previous 30 days 
7. Patients with paraplegia 
8. Patients who are likely to receive ongoing antibacterial drug prophylaxis after treatment 
of uUTI (e.g., patients with vesico-ureteral reflux) 
9. Any history of trauma to the pelvis or urinary tract 
10. Patient's urine culture results, if available at study entry, identify more than 2 
microorganisms regardless of colony count or patient has a confirmed fungal UTI 
11. Patient is receiving hemodialysis, peritoneal dialysis or had a renal transplant 


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12. Creatinine clearance <50 mL/min as calculated by Cockcroft and Gault equation 
(Appendix 3) 
13. Patient known to be immunocompromised (e.g. absolute neutrophil count [ANC] < 500 
cells/mm3, human immunodeficiency virus (HIV) infected patients with a CD4 cell count 
< 200 cells/mm3, patients with a bone marrow/organ transplant in the 3 months prior to 
study enrollment, patients receiving oral steroids > 20 mg prednisolone per day [or 
equivalent] or receiving immunosuppressant drugs after bone marrow/organ 
transplantation) 
14. Patients known to have a history of liver disease as defined by the following laboratory 
criteria: 
• ALT or AST > 3 X Upper Limit of Normal 
• Total bilirubin > 1.5 X Upper Limit of Normal  
15. Patients who are pregnant 
16. Patients with uncontrolled Diabetes mellitus (defined as the presence of ketoacidosis, 
hyperosmolar hyperglycemia, random or fasting serum glucose ≥ 250 mg/dL at 
screening) 
17. History of seizures 
18. Patients with a history of blood dyscrasias 
19. Patients with a history of uric acid kidney stones 
20. Patients with acute gouty attack 
21. Patients on chronic methotrexate therapy 
22. Patients with a known history of myasthenia gravis 
23. Patients who require concomitant administration of tizanidine or valproic acid 
24. Patients with a history of allergy or hypersensitivity to carbapenems, β-lactams, 
quinolones or probenecid, as formulated with their excipients 
25. Patient is considered 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 
26. The use of any other investigational drug in the 30 days prior to study to the first dose of 
study drug, or prior participation in any sulopenem clinical trial 
 
4.3 
Randomization Criteria 
Patients will be randomized in a 1:1 ratio to sulopenem etzadroxil/probenecid versus 
ciprofloxacin using an IWRS into the study provided they have satisfied all patient selection 
criteria.   


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4.4 
Life Style Guidelines 
For the duration of the study, all female patients of child-bearing potential must agree to be 
strictly abstinent from sexual intercourse with any individual of the opposite sex, or to follow the 
following instructions for contraception. 
4.5 
Women of Child-Bearing Potential 
If the patient is a woman of childbearing potential, she is required to simultaneously use 2 
effective contraceptive methods, from the following list of 5: 
1. A barrier (condoms, diaphragm or cervical cap) with spermicide; 
2. A second, different barrier method (condoms, diaphragm or cervical cap); 
3. Oral or similar contraceptive, which includes, but is not limited to: injectable, implanted, or 
patch hormone therapy, and intrauterine device (IUD); 
4. Documented surgical sterilization at least 4 weeks prior to baseline; 
5. Partner vasectomy at least 6 months prior to baseline. 
 
She 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. 
 
5 
STUDY TREATMENTS 
5.1 
Allocation to Treatment 
This is a randomized double-blind study comparing oral sulopenem etzadroxil/probenecid with 
oral ciprofloxacin in the treatment of uUTI. Approximately 1,128 patients will be randomized to 
receive either oral sulopenem etzadroxil/probenecid twice daily for 5 days or oral ciprofloxacin 
twice daily for 3 days in a 1:1 allocation ratio using an IWRS. 
 
A patient will be eligible for randomization once it has been determined that she meets all 
inclusion criteria and has none of the exclusion criteria. On the day the patient is to receive the 
first dose of study drug, a designated member of the 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 receives the treatment assignment associated 
with the patient entered into the IWRS. 
 


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5.2 
Drug Supplies 
5.2.1 
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 500 mg/probenecid 500 mg 
and one blister pack with 6 ciprofloxacin placebo capsules. 
 
Comparator treatment group:  The study drug will be supplied as a study kit containing one 
blister pack with 6 over-encapsulated ciprofloxacin 250 mg tablets, and one bottle with 10 
placebo bilayer 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 will take one tablet from the kit bottle twice daily (sulopenem etzadroxil/probenecid or 
placebo) for 5 days and they will take one capsule from the blister pack twice daily (over-
encapsulated ciprofloxacin or placebo capsules) for 3 days. The first dose of each medication 
will be administered under the supervision of study site personnel to help ensure compliance 
with dosing directions. In the event a patient’s first dose is taken in the PM on Day 1, the patient 
will be expected to take an AM dose on Day 6 to complete the regimen. 
Study drug administration will be documented in accordance with the Pharmacy Manual.  
Patients are encouraged, but not required, to take their study drug with food. 
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 bottles and blister packs (used and unused) to 
the next scheduled study visit for drug accountability. The total amount of oral dosing completed 
(determined by tablet count from returned bottles and blister packs) will be recorded in the 
IWRS.  
 
To enhance documentation of compliance, this study may employ a Health Insurance Portability 
and Accountability Act (HIPAA) compliant medication adherence monitoring platform 


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(“Platform”) for all subjects in the study.  The Platform uses artificial intelligence on 
smartphones to confirm medication ingestion. In addition, built-in reminders and a 
communication system allow real-time intervention in case of drug interruptions. Complete 
details regarding this Platform will be provided to the sites. 
 
A urine sample will be collected and frozen at the EOT visit if a need to confirm compliance 
with study drug therapy arises for any patient. 
 
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 sulopenem etzadroxil/probenecid and ciprofloxacin.  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 Forms (CRF). 
At each visit, the investigator/site designee will obtain information on any therapeutic 
interventions (e.g., drug and non-drug therapy, surgery, etc.) provided.  The use of any other 
investigational drug is prohibited and patients may not participate in any other studies involving 
marketed products concomitantly while in this study.  
The use of other (non-antibacterial) medications should be limited to those essential for the care 
of the patient.  All medications required by the patient to manage underlying illnesses, 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 the Day 12 (± 1 day) visit. 
The bioavailability of ciprofloxacin is significantly reduced when co-administered with 
magnesium or aluminum containing antacids. As a result, co-administration of these antacids 
with study drug is not permitted.  
Dosing with food does not affect the overall absorption of ciprofloxacin. 


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5.4.2 
Concomitant Antibacterial Medications 
Concomitant systemic antibacterials are prohibited during the study, up to the Day 28 (± 2 days) 
visit, with the following exceptions: 
• 
Vancomycin oral 125 mg or 250 mg every 6 hours may be used in both treatment groups for 
the treatment of Clostridium difficile infections and may be continued as required throughout 
the duration of the study.  The Sponsor will not provide oral vancomycin. 
• 
Metronidazole IV or oral 500 mg every 8 hours may be used in both treatment groups for the 
treatment of Clostridium difficile infections and may be continued as required throughout the 
duration of the study.  The Sponsor will not provide metronidazole. 
• 
Patients with a co-infection with a gram-positive uropathogen resistant to study drugs are 
allowed to receive agents with narrow spectrum gram-positive coverage (i.e., such as oral 
linezolid). 
5.4.3 
Adjunctive Antibacterial Therapy 
None allowed 
 
5.4.4 
Non-drug Adjunctive Therapy 
None allowed 
 
6 
STUDY PROCEDURES 
 
6.1 
Screening (Day -1) - Within 24 Hours Prior to First Dose 
The investigator (or an appropriate delegate at the investigator site) will obtain written informed 
consent from each patient prior to the initiation of any study related activities. Sites participating 
in the population PK substudy should offer the PK sampling substudy and obtain written consent 
from willing patients. PK sampling procedures are detailed in Appendix 5. 
The following procedures will be performed prior to randomization and study drug 
administration: 
• Demographics and medical history. 
• Targeted physical examination (including general appearance, examination of heart, 
lungs, abdomen, and extremities) 
• Vital signs (temperature, blood pressure, pulse rate, respiratory rate) and height and 
weight 
• Blood for laboratory testing (including hematology and chemistry studies as well as 
urine or serum (βhCG) pregnancy test (women of child-bearing potential, including 
peri-menopausal women until FSH value is known); serum follicle stimulating 
hormone [FSH] for post-menopausal [amenorrheic for at least 1 year] females <50 


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years of age or those ≥50 years of age who have been post-menopausal [amenorrheic] 
for <2 years.  
• Banked serum and urine for retrospective safety and efficacy assessments 
• Collect urine for urinalysis and urine culture (including gram stain) and sensitivity 
• Review previous drug and non-drug treatments (defined as within the prior 30 days) 
and concomitant drug treatments 
• Adverse events occurring after signing of ICF 
• Administer and collect patient symptom assessment questionnaire from patient 
(Appendix 4) 
 
To prepare for trial participation, subjects will be instructed on the use of Life Style Guidelines 
and Concomitant Medications. 
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. 
• Pharmacokinetic blood specimens: obtain at scheduled time. 
 
 
6.2.1 
Day 1 
• Review concomitant medications 
• Administer the study medication as described in Section 5.2.3 
• Collect blood samples for PK analyses for patients in the PK substudy (Appendix 5) 
• Assess symptoms by spontaneous reporting of adverse events and by asking the 
subjects to respond to a non-leading question such as “How do you feel? 
 
6.2.2 
Day 3 
• Targeted physical examination, if required, based on patient’s symptoms 
• Collect urine for urinalysis and urine culture (including gram stain) and sensitivity  
• Review concomitant medications 
• Check and document compliance with study medication 
• Assess symptoms by spontaneous reporting of adverse events and by asking the 
subjects to respond to a non-leading question such as “How do you feel? 
• Administer and collect patient symptom assessment questionnaire from patient 
(Appendix 4) 
 


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6.2.3 
Day 5 (± 1 day) (End of Treatment/EOT) 
• Targeted physical examination, if required, based on patient’s symptoms 
• Vital signs (temperature, blood pressure, pulse rate, respiratory rate)  
• Collect urine for urinalysis and urine culture (including gram stain) and sensitivity  
• Review concomitant medications 
• Check and document compliance with study medication 
• Assess symptoms by spontaneous reporting of adverse events and by asking the 
subjects to respond to a non-leading question such as “How do you feel? 
• Administer and collect patient symptom assessment questionnaire from patient 
(Appendix 4) 
• 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 
• Vital signs (temperature, blood pressure, pulse rate, respiratory rate)  
• Blood for laboratory testing (including hematology and chemistry studies) 
• Banked serum and urine for retrospective safety and efficacy assessments 
• Collect urine for urinalysis and urine culture (including gram stain) and sensitivity  
• Review concomitant medications 
• Assess symptoms by spontaneous reporting of adverse events and by asking the 
subjects to respond to a non-leading question such as “How do you feel? 
• Administer and collect patient symptom assessment questionnaire from patient 
(Appendix 4) 
• 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 
• Collect urine for urinalysis and urine culture (including gram stain) and sensitivity, 
and pregnancy test 
• Review concomitant medications 
• Assess symptoms by spontaneous reporting of adverse events and by asking the 
subjects to respond to a non-leading question such as “How do you feel? 
• Administer and collect patient symptom assessment questionnaire from patient 
(Appendix 4) 
• Investigator Assessment of Clinical Response (Section 7.2.4) 
 


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6.4 
Premature Discontinuation 
• Targeted physical examination, if required, based on patient’s symptoms 
• Vital signs (temperature, blood pressure, pulse rate, respiratory rate)  
• Blood for laboratory testing (including hematology and chemistry studies as well as 
urine or serum (βhCG) pregnancy test (women of child-bearing potential, including 
peri- menopausal women until FSH value is known); serum follicle stimulating 
hormone [FSH] for post-menopausal [amenorrheic for at least 1 year] 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 (including gram stain) and sensitivity 
• Review concomitant medications 
• Check and document compliance with study medication 
• Assess symptoms by spontaneous reporting of adverse events and by asking the 
subjects to respond to a non-leading question such as “How do you feel? 
• Administer and collect patient symptom assessment questionnaire from patient 
(Appendix 4) 
• Investigators 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 discontinue 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 discontinues 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. 


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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. 
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), 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 will be used to 
measure blood pressure each time.  When the timing of these measurements coincides with a 
blood collection, blood pressure and pulse rate are to be obtained first.  Temperature will be 
measured as an oral, rectal, tympanic (ear) or temporal temperature.  
7.1.3 
Clinical Laboratory Assays 
The following laboratory parameters will be measured:  
• Hematology: Complete blood count (CBC), including white blood cell (WBC) and 
differential counts; at Baseline, Day 12 (± 1 day) 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, 
C-reactive protein (CRP) and LDH at Baseline, Day 12 (± 1 day) or premature 
discontinuation. 
• Urinalysis  and urine culture (including gram stain) at Baseline, Day 3, Day 5 (± 1 day), 
Day 12 (± 1 day) and Day 28 (± 2 days) or premature discontinuation. 
• Pregnancy Test (women of child-bearing potential)/serum FSH (for post-menopausal 
[amenorrheic for at least 1 year] females <50 years of age or those ≥50 years of age who 
have been post-menopausal for <2 years): Urine or serum (βhCG) only at Baseline; urine 
(βhCG) at Day 28 (± 2 days) and premature discontinuation; FSH at Baseline only, as 
needed. Pregnancy test at Baseline should also be performed on peri-menopausal women 
until FSH value is available. 
• Serum and urine samples will be banked for retrospective safety and efficacy analyses as 
needed at Baseline and Day 12 (± 1 day). 
 


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7.1.4 
Clinically Significant Laboratory Tests 
Clinical laboratory tests may be repeated during the study if deemed necessary as part of routine 
practice based on investigator judgment.  All clinically significant abnormal laboratory test 
results occurring during the study will be repeated at appropriate intervals until they return either 
to baseline or to a level deemed acceptable by the investigator and the Iterum appointed medical 
monitor.   
7.2 
Efficacy 
7.2.1 
Overall Response 
Overall Response 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) 
• Urine culture taken on Day 12 (± 1 day) demonstrates <103 CFU/mL of the baseline 
uropathogen (ie, microbiologic response of success [eradication]) 
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. 
 
7.2.2 
Microbiologic 
Microbiologic Response is assessed using the definitions listed below: 
Microbiological 
response 
Definition 
Success  
The urine culture obtained at the Day 3 visit, Day 5 (± 1 day) 
visit, Day 12 (± 1 day) or Day 28 (± 2 days) visit demonstrates 
<103 CFU/mL of the baseline uropathogen; also referred to as 
eradication. 


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Microbiological 
response 
Definition 
Persistence  
A uropathogen present at baseline grew at ≥103 CFU/mL at the 
time-point of analysis, i.e. Day 3, Day 5 (± 1 day), Day 12 (± 1 
day) or Day 28 (± 2 days). 
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-fold 
higher MIC to study drug received at Day 3, Day 5 (± 1 day), 
Day 12 (± 1 day) or Day 28 (± 2 days), respectively. 
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 either the Day 
3, Day 5 (± 1 day), Day 12 (± 1 day) 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 
• 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) 
 
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 at Day 5 (± 1 day), 
Day 12 (± 1 day), 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 


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Clinical response 
Definition 
Clinical failure 
Patients who met any one of the criteria below were considered as failure: 
Death related to uUTI prior to Day 5, Day 12, or Day 28, 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 Day 5, Day 
12 or Day 28 visit 
Death prior to Day 5, Day 12, or Day 28, respectively, 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 (Appendix 4). 
8 
ADVERSE EVENT REPORTING 
8.1 
Adverse Events 
All observed or volunteered AEs regardless of treatment group or suspected causal relationship 
to the investigational product(s) will be reported as described in the following sections.  
For all AEs, the investigator must pursue and obtain adequate information both to determine the 
outcome of the AE and to assess whether it meets the criteria for classification as a serious AE 
(SAE) requiring immediate notification to Iterum Therapeutics designated pharmacovigilance 
provider.  For all AEs, sufficient information should be obtained by the investigator to determine 
the causality of the AE.  The investigator is required to assess causality.  All AEs will be 
followed-up by the investigator until the event or its sequel resolve or stabilize at a level 
acceptable to the investigator, and Iterum concurs with that assessment. 
8.2 
Reporting Period 
Adverse events will be collected from the time that the patient provides informed consent 
through the Day 28 (± 2 days) (Final Visit).  
For SAEs, the reporting period to Iterum Therapeutics begins from the time that the patient 
provides informed consent, which is obtained prior to the patient’s participation in the study, i.e., 
prior to undergoing any study-related procedure and/or receiving investigational product, 
through the Final Visit.  Any SAE occurring any time after the reporting period must be 
promptly reported if a causal relationship to investigational product is suspected.  


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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:   
• 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:  


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• 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; 
• 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; 


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• 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. 
8.7 
Severity Assessment 
The investigator will use the adjectives MILD, MODERATE, or SEVERE to describe the 
maximum intensity of the AE.  For purposes of consistency, these intensity grades are defined as 
follows: 
• MILD:  Does not interfere with the patient's usual function. 
• MODERATE:  Interferes to some extent with the patient's usual function. 
• SEVERE:  Interferes significantly with the patient's usual function.  
 
Note the distinction between the severity and the seriousness of an adverse event.  A severe 
event is not necessarily a serious event.  For example, a headache may be severe (interferes 
significantly with subject's usual function) but would not be classified as serious unless it met 
one of the criteria for serious adverse events, listed above. 
 
8.8 
Causality Assessment 
The investigator’s assessment of causality must be provided for all AEs (serious and non-
serious); the investigator must record the causal relationship in the CRF, as appropriate, and 
report such an assessment in accordance with the serious adverse reporting requirements if 


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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 
 
8.9 
Exposure during Pregnancy 
For investigational products and for marketed products, an exposure during pregnancy (also 
referred to as exposure in-utero [EIU]) occurs if: 
1. A female becomes, or is found to be, pregnant either while receiving or having been directly 
exposed to (e.g., environmental exposure) the investigational product, or the female 
becomes, or is found to be, pregnant after discontinuing and/or being directly exposed to the 
investigational product (maternal exposure); 
2. A male has been exposed, either due to treatment or environmental exposure, to the 
investigational product prior to or around the time of his partner’s conception and/or is 
exposed during his partner’s pregnancy (paternal exposure). 
 
If any study patient or study patient’s partner becomes or is found to be pregnant during the 
study patient’s treatment with the investigational product, no further study drugs should be given 
and the investigator must submit this information to Iterum Therapeutics on a Pregnancy Form.   
 


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This reporting must be done irrespective of whether an AE has occurred and within 24 hours of 
awareness of the pregnancy.  The information submitted should include the anticipated date of 
delivery (see below for information related to induced termination of pregnancy). 
 
Follow-up is conducted to obtain pregnancy outcome information on all Pregnancy reports with 
an unknown outcome.  The investigator will follow the pregnancy until completion or until 
pregnancy termination (i.e., induced abortion) and then notify Iterum of the outcome.  The 
investigator will provide this information as a follow up to the initial Pregnancy Form.  The 
reason(s) for an induced abortion should be specified.  A Pregnancy report is not created when 
an ectopic pregnancy report is received since this pregnancy is not usually viable.  Rather, an 
SAE case is created with the event of ectopic pregnancy. 
If the outcome of the pregnancy meets the criteria for immediate classification as an SAE 
(i.e., spontaneous abortion, stillbirth, neonatal death, or congenital anomaly [including that in an 
aborted fetus, stillbirth or neonatal death]), the investigator should follow the procedures for 
reporting SAEs. 
In the case of a live birth, the “normality” of the newborn can be assessed at the time of birth 
(i.e., no minimum follow-up period of a presumably normal infant is required before a 
Pregnancy Form can be completed).  The “normality” of an aborted fetus can be assessed by 
gross visual inspection, unless pre-abortion test findings are suggestive of a congenital anomaly. 
Additional information about pregnancy outcomes that are classified as SAEs follows:  
• “Spontaneous abortion” includes miscarriage and missed abortion. 
• All neonatal deaths that occur within 1 month of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 1 month that the investigator assesses 
as possibly related to the exposure during pregnancy to the investigational medication should 
be reported. 
 
Additional information regarding the exposure during pregnancy may be requested by the 
investigator.  Further follow-up of birth outcomes will be handled on a case-by-case basis 
(e.g., follow-up on preterm infants to identify developmental delays).  In the case of paternal 
exposure, the investigator must obtain permission from the patient’s partner in order to conduct 
any follow-up or collect any information. 
8.10 Discontinuation from Study Drug Due to AEs (See also Patient 
Withdrawal, Section 6.5) 
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. 


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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 (Iterum’s PV Service 
provider) is to be notified within 24 hours of awareness of the event by the investigator on an 
SAE form or Pregnancy form.  If the SAE is fatal or life-threatening, notification to Iterum must 
be made immediately, irrespective of the extent of available event information.  This timeframe 
also applies to additional new information (follow-up) on previously forwarded SAE reports as 
well as to the initial and follow-up reporting of Pregnancy cases.   
In the rare instance that the investigator does not become aware of the occurrence of an SAE 
immediately (e.g., if an outpatient study patient initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time of 
his/her first awareness of the AE. 
For all SAEs and pregnancies, the investigator is obligated to pursue and provide information to 
Iterum in accordance with the timeframes for reporting specified above.  In addition, an 
investigator may be requested by Iterum Therapeutics to obtain specific additional follow-up 
information in an expedited fashion.  This information may be more detailed than that captured 
on the SAE form.  In general, this information may include hospital discharge summary, 
laboratory test and X-ray results.  Information on other possible causes of the event, such as 
concomitant medications and illnesses must be provided.  In the case of a patient death, a 
summary of available autopsy findings must be submitted as soon as possible to Iterum 
Therapeutics.  The information should be reported on an SAE/Pregnancy form and sent to the 
Iterum PV Service Provider. 
8.12.2 
Non-SAE Reporting Requirements 
All AEs will be reported on the AE page(s) of the CRF.  Please note that while all AEs are 
reported on the AE page of the CRF, there is an additional form used for collection of SAE 
information, as described in Section 8.12.1, which is not the same as the AE CRF.  When the 
same data are collected, the two forms must be completed in a consistent manner.  For example, 
the same AE term should be used on both forms.  Adverse events should be reported using 
concise medical terminology on the CRFs as well as on the form for collection of SAE 
information.  The information on the AE CRF and the SAE form must be the same and will be 
reconciled at defined periods throughout the study to ensure that they do. 


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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 etzadroxil/probenecid is NI to oral 
ciprofloxacin for the outcome measure of overall success (combined clinical and microbiologic 
success) at Day 12 (± 1 day) in the micro-MITTS population and/or whether oral sulopenem 
etzadroxil/probenecid is superior to oral ciprofloxacin for overall success at Day 12 (± 1 day) in 
the micro-MITTR population. The 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 352 patients per arm (total of 704 
patients) based on the method of Farrington and Manning. This assumes a non-inferiority margin 
of 10%, a power of 90%, a one-sided alpha level of 0.025 and a 79% treatment success rate.  
With 99 patients per treatment group in the micro-MITTR population, there is 90% power to 
show superiority given a 75% and 52% overall success rate in the sulopenem 
etzadroxil/probenecid and ciprofloxacin groups, respectively. Assuming that 80% of the 
randomized patients will meet criteria for inclusion into the micro-MITT population (902 
patients), the sample size for the ITT population is 1,128. 
The expected treatment success rate is estimated from 2 large randomized controlled trials of 
quinolones in a similar patient population. In those studies, the estimated success rate for the 
proposed primary efficacy outcome measure of combined clinical and microbiologic success 
around Day 7 in the micro-MITT population was 88%. This was further corroborated by 
findings from a review of the summary basis of approval documents for ciprofloxacin XR and 
levofloxacin for the indication of uUTI, where the estimated number of patients with combined 
clinical and microbiologic cure rates in the microbiologically evaluable populations were noted 
to be between 88.4% and 92%. The overall success rate in uUTI studies that utilized complete 
resolution of uUTI symptoms to define clinical success was 80%. However, these studies 
defined microbiologic eradication as a follow up culture that yielded <104 CFU/mL of the 
baseline pathogen. The overall point estimate could be reduced by about 1% point if the 
definition of microbiologic eradication requires a follow up culture that yields <103 CFU/mL 
of the baseline pathogen, thus bringing the expected overall success rate in the subset of micro-
MITTS population to 79%. 
 
There are no recent studies in patients with uUTI caused by resistant pathogens to provide an 
estimate of the overall clinical success rate in this population.  With 99 patients per treatment 
group in the micro-MITTR population, there is 90% power to show superiority given a 75% 
and 52% overall success rate in the sulopenem etzadroxil/probenecid and ciprofloxacin groups, 


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respectively.  
 
The primary populations for this study are: the micro-MITTS population, defined as all 
randomized patients with a positive baseline urine culture defined as ≥105 CFU/mL of a 
uropathogen (and no more than 2 species of microorganisms), with a pathogen susceptible 
(ciprofloxacin MIC ≤1 mg/L) to the comparator study drug, ciprofloxacin; and the micro-
MITTR population defined as all randomized patients with a positive baseline urine culture 
defined as ≥105 CFU/mL of a uropathogen (and no more than 2 species of microorganisms), 
with a pathogen non-susceptible (ciprofloxacin MIC ≥2 mg/L; includes strains with 
intermediate susceptibility and resistance to ciprofloxacin) to the comparator study drug, 
ciprofloxacin.  
 
A review of the literature showed that only approximately 60% of symptomatic uUTI patients 
will have ≥105 CFU/mL of a uropathogen. Thus, in order to optimize the enrollment of patients 
with ≥105 CFU/mL of a uropathogen, the inclusion criteria were designed to require a urine 
dipstick analysis to be positive for nitrite in addition to having evidence of pyuria, as this has 
been shown to increase the sensitivity and specificity of enrolling patients with ≥105 CFU/mL 
of a uropathogen to 84% and 98% respectively [Semeniuk 1999].   
 
Two blinded interim analyses for sample size re-estimation and one unblinded interim analysis 
for sample size re-estimation are 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 
 
3. Safety: randomized patients who received at least a single dose of study medication 
 
4. Micro-MITT: All MITT patients with a positive study entry urine culture defined as 
≥105 CFU/mL of a uropathogen (Enterobacteriaceae 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 to the 
comparator drug, ciprofloxacin, and no baseline pathogen non-susceptible to 
ciprofloxacin. 
 
6. Micro-MITTR: All micro-MITT patients with a baseline uropathogen non-susceptible 
(defined as MIC ≥2 mg/L) to the comparator drug, ciprofloxacin. 
 
7. Clinically Evaluable: Clinically Evaluable (CE) at the Day 5 and Day 12 visits 
population:  
 


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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 an outcome assessment  at the relevant visit and the assessment was within the 
protocol allowed visit window.   
d) Had not received prior antibiotic before the initiation of study therapy for this 
infection unless the recovered pathogen demonstrates resistance to initial antibiotic 
(other than quinolone and carbapenems) and clinical symptoms persist 
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 or Day 12 culture, respectively.  This excludes the protocol defined 
study therapy and patients who were considered clinical failures and required 
additional antibiotic therapy.  Patients with a coinfection with a gram-positive 
uropathogen resistant to study drugs are allowed to receive agents with narrow 
spectrum gram-positive coverage (i.e., such as oral linezolid)  
f) Had a study entry urine culture obtained ≤48 hours before study drug administration  
Clinically Evaluable (CE) at the FV population 
All patients who: 
a) Were included in the CE population at the Day 12 visit 
b) Had an outcome assessment at the FV and the assessment was within the protocol 
allowed visit window 
c) Had no important protocol deviations that would affect the assessment of efficacy (to 
be defined in the SAP). 
d) Did not receive any antibiotic therapy with potential activity against any of the 
baseline uropathogen(s) collected at Baseline through the Day 28 visit, 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. 
 
8. 
Microbiologically evaluable (ME): all patients included in both the micro-MITT and 
CE populations at the Day 3 (ME-Day 3), Day 5 visit (ME-Day 5), Day 12 visit (ME-
Day 12) and at the Day 28 visit (ME-Day28) and have an appropriately collected urine 
culture specimen and interpretable urine culture result at the Day 3, Day 5, Day 12 and 
Day 28 visits, respectively.   
 
 


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9.3 
General Statistical Considerations 
Descriptive statistics, including the numbers and percentages for categorical variables, and the 
numbers, means, standard deviations, medians, minimums, and maximums for continuous 
variables will be provided. All comparisons will be for the sulopenem etzadroxil/probenecid 
treatment group and the ciprofloxacin treatment group. Exploratory analyses may also be 
performed. Listings of individual patient’s data will be produced. A comprehensive SAP will be 
finalized prior to the first interim analysis. 
 
9.4 
Patient Characteristics 
Enrollment, protocol deviations, discontinuations from the study drug and withdrawal from the 
study will be summarized by treatment group.  Demographics (age, race, sex), medical and 
surgical history, baseline assessment of the symptoms of uUTI, microbiological assessment of 
the urine, and study drug administration will also be summarized.  Differences between 
treatment groups will be analyzed using the chi-square or Fisher’s exact test for dichotomous 
variables and the Wilcoxon Rank Sum test for ordinal variables and continuous variables.   
 
9.5 
Efficacy Analysis 
For all efficacy analyses, patient data will be analyzed in the treatment group to which the 
patient was randomized.  Unless otherwise stated, for the ITT analyses, patients who were 
randomized to the wrong geographic region strata will be analyzed in the stratum to which they 
were 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) in the 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-MITTS and micro-MITTR populations.  
The primary comparisons for regulatory approval are in two mutually exclusive populations 
defined by a baseline characteristic: 
1) the 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, ciprofloxacin).  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
, 


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where p1 is the primary efficacy outcome rate in the sulopenem etzadroxil/probenecid group, p2 
is the primary efficacy outcome rate in the ciprofloxacin 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 rate (sulopenem etzadroxil/probenecid group minus ciprofloxacin 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-MITTS 
population is greater than -10%, the null hypothesis will be rejected and the NI of sulopenem 
etzadroxil/probenecid to ciprofloxacin will be concluded. 
 2) the 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, ciprofloxacin). 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% 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 sulopenem 
etzadroxil/probenecid to ciprofloxacin will be concluded. 
 
9.5.1.1 
Additional Hypothesis Testing of the Primary Outcome Measure 
Additional hypothesis testing of the primary efficacy outcome will be conducted following the 
framework detailed below.  
1) 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 continue testing hypotheses of 
the primary efficacy outcome.  If NI or superiority is declared for the primary 
comparisons, the secondary comparisons will be statistically tested in the order presented 
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. NI test of overall 
success, 
∆
−
≤
−
2
1
01 :
p
p
H
 and 
∆
−
>
−
2
1
1 :
p
p
H A
, in the micro-MITT population. The 
number and percentage of subjects in each treatment group with an overall response of 
success, failure, and indeterminate will be provided for the micro-MITT population. 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%, the null hypothesis will be rejected 
and the NI of sulopenem etzadroxil/probenecid to ciprofloxacin in the micro-MITT 
population will be concluded.  


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2)   Superiority test of overall success, 
2
1
02 :
p
p
H
=
 and 
2
1
2 :
p
p
H A
≠
, 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 sulopenem 
etzadroxil/probenecid to ciprofloxacin in the micro-MITT population will be concluded. 
 
9.5.1.2 
Additional Analyses of the Primary Efficacy Outcome 
The primary efficacy outcome will also be assessed within each geographic region stratum by 
treatment group. For each geographic region stratum, a 2-sided 95% CI for the observed 
difference in the overall success rates in the micro-MITTS and the micro-MITTR populations 
will be calculated. 
 
Sensitivity analyses of the primary outcome will also be conducted in the micro-MITTS and 
micro-MITTR populations. An adjusted analysis (95% CI will be adjusted for the geographic 
region using the stratified method of Miettinen and Nurminen) will be provided for the 
difference in the overall success rate between the two treatment groups. Cochran-Mantel-
Haenszel weights will be used for the stratum weights in the calculation of the CI. An analysis 
will consider all patients who have missing data for the primary outcome (ie, 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 also be conducted. 
 
A sub-group analysis of the primary efficacy outcome in those patients with and without 
hypoalbuminemia (serum albumin <2.5 g/dL) at baseline will be conducted. Additional sub-
group analyses, such as the effect of food, may be conducted as exploratory analyses. 
 
9.5.2 
Analysis of Secondary Efficacy Outcome Measure 
The number and percentage of patients with a microbiologic response of success (eradication) or 
failure (persistence or persistence with increasing MIC), at the Day 12 (± 1 day) visit will be 
determined in each treatment group in the ME-Day 12 population. The observed difference in 
percentage of patients with microbiologic success (eradication) (sulopenem 
etzadroxil/probenecid group minus the ciprofloxacin group) will be determined and a 2-sided 
95% CI for the observed difference will be computed using the unstratified method of Miettinen 
and Nurminen. 
 
9.5.3 
Analysis of Additional Efficacy Outcome Measures 
The number and percentage of subjects in each treatment group with an overall response of 
success, failure and indeterminate at Day 3, Day 5, and Day 28 will be presented for the micro-
MITT, micro-MITTS, and micro-MITTR populations. The number and percentage of subjects in 
each treatment group with an overall response of success and failure at Day 3, Day 5, Day 12 
and Day 28 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. 


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The number and percentage of subjects in each treatment group with a clinical response of 
success, failure and indeterminate at Day 3, Day 5, Day 12 and Day 28 will be presented for the 
micro-MITT, micro-MITTS, and micro-MITTR populations. The number and percentage of 
subjects in each treatment group with a clinical response of success and failure at Day 3, Day 5, 
Day 12 and Day 28 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. 
The number and percentage of subjects in each treatment group with a microbiologic response of 
success, failure and indeterminate at Day 3, Day 5, Day 12 and Day 28 will be presented for the 
micro-MITT, micro-MITTS, and micro-MITTR populations. The number and percentage of 
subjects in each treatment group with a microbiologic response of success and failure at Day 3, 
Day 5, Day 12 and Day 28 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. 
Investigator determined clinical response (clinical success, failure and indeterminate) at the Day 
5, Day 12, and Day 28 Visits will be presented by treatment group for the micro-MITT, micro-
MITTS, micro-MITTR, CE-Day12 and ME-Day12 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 3, Day 5, Day 12 and Day 28 will be provided by treatment 
group for the micro-MITTS and micro-MITTR populations. 
 
Overall success and microbiologic success at the Day 5 and Day 12 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 subjects in each treatment group with a microbiologic response of 
complete eradication defined as no growth of baseline pathogen on a follow-up urine culture at 
Day 12 will also be presented 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 


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newly appeared, increased in frequency, or worsened in severity following initiation of study 
drug.  The incidence of TEAEs will be tabulated by system organ class (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 all study visits.  The change from baseline to each post-baseline visit and to the 
overall worst post-baseline value will also be summarized by treatment group.  Laboratory 
values will be classified as potentially clinically significant and the number and percentage of 
patients with a PCS lab value will be summarized by visit and treatment group.  Descriptive 
statistics of the vital signs will be presented by treatment group and study visit, as well as the 
change from baseline at each study visit.   
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 is valid for this study, two interim analyses for 
sample size re-estimation will be performed when response data at Day 12 (± 1 day) are 
available for approximately 33% and 66% of the patients (approximately 372 and 745 patients 
respectively).  The FDA Guidance “Non-inferiority Clinical Trials” [FDA Guidance 2010] 
notes that such a sample size re-estimation if based on the blinded overall response rates is not 
only acceptable but is advisable.  The interim analysis will involve a sample size re-estimation 
to either confirm the initial sample size estimate is adequate or increase the sample size 
(number of randomized patients) to ensure the study has adequate power for determining 
whether oral sulopenem etzadroxil/probenecid is NI to oral ciprofloxacin for the primary 
outcome measure in the micro-MITTS population. 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) or lower than expected 
percentage of subjects with a susceptible pathogen. The sample size re-estimation will be based 
on the blinded overall (not by treatment group) outcome and evaluability rates. 
The blinded interim analyses 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, 
ciprofloxacin) pathogen (micro-MITTS population) and a non-susceptible (to 
ciprofloxacin) pathogen (micro-MITTR population) 
3. Determine the overall success rate 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 


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a. If NO, then increase the sample size in the micro-MITTS population to have 
sufficient power, up to a maximum number of subjects. 
In addition, the micro-MITT rate (i.e. evaluability rate) and proportion of subjects with a 
susceptible pathogen (micro-MITTS evaluability rate) will be used to determine the total 
number of subjects needed. 
In order to determine whether the sample size is sufficient to determine if sulopenem 
etzadroxil/probenecid is superior to ciprofloxacin in the patients whose baseline pathogen is 
non-susceptible to ciprofloxacin, a conditional power analysis for the superiority hypothesis in 
the micro-MITTR population will be conducted when 66% of patients have been enrolled. A 
conditional power analysis using the approach of Lan and Wittes [Lan 1988] will be conducted 
to determine if the sample size needs to be adjusted.  The sample size adjustment would be 
conducted as described by Mehta and Pocock [Mehta 2011].  If the conditional power is <40%, 
the superiority hypothesis in the micro-MITTR population will not be tested at the end of the 
study.  If the conditional power is 40%-<80%, the sample size for micro-MITTR population 
will be calculated based on the observed overall success rates in each treatment group and 
increased to a maximum number.  If the conditional power is ≥80%, no change to the sample 
size will be made.  The final sample size in the ITT population will be adjusted to take into 
account the proportion of subjects in the micro-MITT population and the micro-MITTR 
population.  No adjustment to the overall alpha level is needed if given a conditional power 
<40%, the superiority hypothesis is not conducted at the end of the study. 
The sample size re-estimations will be conducted by an independent, unblinded statistician. A 
Data Monitoring Committee (DMC) will be provided the results of the interim analysis by the 
independent, unblinded statistician and make a recommendation regarding changes to the 
sample size.  A detailed DMC charter will be developed which outlines the analyses to be 
completed, statistical rules, the potential changes to the sample size, and the recommendations 
that can be made to the Sponsor.   
 
9.8 
Handling of Missing Data 
Details of the handling of missing data will be provided in the SAP.  For the primary and 
secondary efficacy analyses, if any data field needed to determine overall response (primary) 
and microbiological response (secondary) is missing at the Day 12 (primary) and Day 28 
(secondary) visit, the patient will be considered an indeterminate response. By definition, 
patients with an indeterminate response are included in the denominator in the m-MITT 
population and thus, are analyzed in the same manner as 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 in indeterminate 
outcomes between treatment regimens. By definition, patients with missing data are excluded 
from the CE and ME populations. 
 


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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 


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call reports).  The records should be retained by the investigator according to ICH, local 
regulations, or as specified in the Clinical Study Agreement, whichever is longer. 
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (e.g., retirement, relocation), Iterum should be prospectively notified.  The study 
records must be transferred to a designee acceptable to Iterum, such as another investigator, 
another institution, or to Iterum.  The investigator must obtain Iterum's written permission before 
disposing of any records, even if retention requirements have been met. 
12 ETHICS 
12.1 Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent forms, and other relevant documents, e.g., recruitment 
advertisements, if applicable, from the IRB/IEC.  All correspondence with the IRB/IEC should 
be retained in the Investigator File.  Copies of IRB/IEC approvals should be forwarded to 
Iterum. 
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In that 
event, the investigator must notify the IRB/IEC and Iterum in writing immediately after the 
implementation. 
12.2 Ethical Conduct of the Study 
The study will be conducted in accordance with the Declaration of Helsinki on Ethical Principles 
for Medical Research Involving Human Patients, adopted by the General Assembly of the World 
Medical Association (2013).  
In addition, the study will be conducted in accordance with the protocol, the International 
Conference on Harmonisation (ICH) guideline on Good Clinical Practice (GCP), and applicable 
local regulatory requirements and laws. 
12.3 Patient Information and Consent 
All parties will ensure protection of patient personal data and will not include patient names on 
any sponsor forms, reports, publications, or in any other disclosures, except where required by 
laws.  In case of data transfer, Iterum will maintain high standards of confidentiality and 
protection of patient personal data. 
The informed consent form must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements. 
The informed consent form used in this study, and any changes made during the course of the 
study, must be prospectively approved by both the IRB/IEC and Iterum before use. 


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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. 
12.4 Reporting of Safety Issues and Serious Breaches of the Protocol or 
ICH GCP 
In the event of any prohibition or restriction imposed (i.e., clinical hold) by an applicable 
Competent Authority in any area of the world, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the investigational 
product, Iterum should be informed immediately.   
In addition, the investigator will inform Iterum immediately of any urgent safety measures taken 
by the investigator to protect the study patients against any immediate hazard, and of any serious 
breaches of this protocol or of ICH GCP that the investigator becomes aware of. 
13 DEFINITION OF END OF STUDY 
13.1 
End of Study in 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 discussed in the Clinical Study Agreement. 
15.1 Communication of Results by Iterum 
Iterum fulfills its commitment to publicly disclose the results of studies through registration and 
posting of the results of this study on clinicaltrials.gov and EudraCT.   
If posting of study results to clinicaltrials.gov jeopardizes a planned publication of the study 
results, a Pending Full Publication notice is substituted for the synopsis until the study results 
publication has been issued or 2 years have elapsed, whichever occurs first.  


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15.2 Publications by Investigators 
Iterum has no objection to publication by the Investigator of any information collected or 
generated by the Investigator, whether or not the results are favorable to the Investigational 
Drug.  However, to ensure against inadvertent disclosure of Confidential Information or 
unprotected Inventions, the Investigator will provide Iterum an opportunity to review any 
proposed publication or other type of disclosure before it is submitted or otherwise disclosed. 
The Investigator will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc.) to Iterum at 
least 30 days before they are submitted for publication or otherwise disclosed.  If any patent 
action is required to protect intellectual property rights, the Investigator agrees to delay the 
disclosure for a period not to exceed an additional 60 days. 
The Investigator will, on request, remove any previously undisclosed Confidential Information 
(other than the study results themselves) before disclosure. 
If the study is part of a multi-center study, the Investigator agrees that the first publication is to 
be a joint publication covering all centers.  However, if a joint manuscript has not been 
submitted for publication within 12 months of completion or termination of the study at all 
participating sites, the Investigator is free to publish separately, subject to the other requirements 
of this section. 
For all publications relating to the study, the Institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical Considerations 
in the Conduct and Reporting of Research” of the Uniform Requirements for Manuscripts 
Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, established by 
the International Committee of Medical Journal Editors. 
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 
Foulds G, Knirsch A, Lazar J, et al. Pharmacokinetics of the penem CP 65,207 and its separate 
stereoisomers in humans. Antimicrob Agents Chemother 1991;35:665 71. 
 
Gupta K, Hooton TM, Naber KG, et al. 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;52:e103-e120. 
 
Lan KKG, and Wittes, J. The B-value: A tool for monitoring data. Biometrics 1988; 44: 579-585. 
 
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. 
 
Schito GC, Naber KG, Botto H et al. The ARESC study: an international survey on the antimicrobial 
resistance of pathogens involved in uncomplicated urinary tract infections. International Journal of 
Antimicrobial Agents 34 (2009) 407–413. 
 
Semeniuk H & Church D. Evaluation of the leukocyte esterase and nitrite urine dipstick screening tests 
for detection of bacteriuria in women with suspected uncomplicated urinary tract infections. Journal of 
Clinical Microbiology, September 1999; 3051-3052. 
 


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Appendix 1 
Schedule of Activities 
 
SCREENING 
TREATMENT PERIOD 
FOLLOW-UP PERIOD 
 
Protocol Activity 
D-1 to D1  
 
Baseline 
D1 
 D3 
D5 
(± 1 day)  
EOT 
D12 
(± 1 day) 
TOC 
D28 
(± 2 days) 
FV 
Premature 
Discontinuation 
Informed Consent 
X 
 
 
 
 
 
 
Medical History and 
Demographics 
X 
 
 
 
 
 
 
Targeted Physical 
Examination 
X 
 
X1 
X1 
X1 
X1 
X1 
Vital Signs 
X 
 
 
X 
X 
 
X 
Hematology 
X 
 
 
 
X 
 
X 
Serum Chemistry 
X 
 
 
 
X 
 
X 
Pregnancy testing/FSH2 
X 
 
 
 
 
X 
X 
Banked serum sample 
X 
 
 
 
X 
 
 
Banked urine sample 
X 
 
 
 
X 
 
 
Urinalysis  
X 
X 
X 
X 
X 
X 
Urine Culture and gram 
stain 
X 
 
X 
X 
X 
X 
X 
Plasma PK sampling for 
CP-70,4293 
 
X 
 
 
 
 
 
Previous Drug and Non-
drug Treatments 
X 
 
 
 
 
 
 
Concomitant Medications 
 
X 
X 
X 
X 
X 
X 
Treatment  
 
          X     (BID for 5 days) 
 
 
 
Treatment Compliance 
Check 
 
 
X 
X 
 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
Patient Symptom 
Assessment Questionnaire 
X 
 
X 
X 
X 
X 
X 
Investigator Assessment of 
Clinical Response  
 
 
 
X 
X 
X 
X 
 
Schedule of Activities Footnotes: 
1 If needed, based on symptoms 
2     Baseline: Pregnancy test (women of childbearing potential) or serum FSH (to confirm post-menopausal status for 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; Day 28 or 
Premature Discontinuation: urine pregnancy test for women of childbearing potential only. 
3    In subset of patients enrolled in the PK substudy, collect plasma for PK analysis 2 hours, 4 hours, and 6 hours post-dose after first oral dose. 
      
 
 
 


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Appendix 2 
Microbiology 
Method of Collection of Urine Specimens: 
To obtain a clean catch sample of urine from a female patient, a thorough cleansing of the 
periurethral area is essential before specimen collection. Wash the area with a disinfectant and 
make all efforts to avoid any contact until urination is complete. 
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 will be tested locally for antimicrobial susceptibility, as 
appropriate.  
 
The local laboratory should retain all isolates until the end of the study, if possible, or until 
confirmation of a viable organism is received from the central laboratory. Back-up cultures will 
be requested when the central laboratory does not receive a viable culture or recovers an 
organism different from the one recorded by the local laboratory.  
 
Gram-staining of urine  
One slide for Gram-stain is to be prepared from each unspun specimen obtained from the urine. 
The slide is to be stained and read by the local laboratory and then sent to the central laboratory 
for rereading and confirmation.  
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: 
 
• Enterobacteriaceae 
• Enterococci  
• Pseudomonas aeruginosa  
• S. saprophyticus 
 
The micro-MITT population for this study will only include patients with UTIs caused by 
Enterobacteriaceae and/or S. saprophyticus. 
 
• Even if the organism was isolated from an acceptable urine culture specimen, the 
following are never a pathogen: 


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• Corynebacterium spp. 
• S. epidermidis 
• S. aureus 
• Bacillus spp. 
• Diphtheroids 
• Micrococcus spp. 
• Lactobacillus spp. 
• Viridans Streptococci 
• Group B Streptococci 
• Gardnerella vaginalis 
• Neisseria gonorrhoeae 
• Yeasts 
 
All isolates not defined above will be assessed on a case-by-case basis via manual review by the 
Sponsor. If needed, patient clinical and microbiological information (e.g., Gram stain) will be 
used to assist in determining if the isolate is a pathogen.  
 
Based on the results of in vitro testing, animal studies, PK/PD modeling, surveillance programs 
and clinical trial data, a provisional breakpoint for susceptibility of sulopenem to 
Enterobacteriaceae, Streptococci and methicillin-susceptible Staphylococcus aureus is ≤ 0.5 
µg/mL. 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 3 
Method for Determination of Creatinine Clearance 
Creatinine clearance should be determined by the method of Cockroft-Gault based on serum 
creatinine concentrations obtained at Baseline, using ideal body weight instead of actual weight. 
For females: 
GFR = [(140-age) * (Ideal body wt in kg) * 0.85] / (72 * Cr), for serum Cr reported as 
mg/dl 
GFR = [(140-age) * (Ideal body wt in kg) * 1.0455] / (Cr), for serum Cr reported as 
micromol/L 
 
Ideal body weight is calculated as: 
For females:  
If H > 152.5 cm 
Ideal body weight (kg) = 45.4 + [(H-152.4) * 0.89] 
If H < 152.5 cm 
Ideal body weight  (kg) = 45.4 – [(152.4 – H)* 0.89] 
 
Reference: Gault MH, Longerich LL, Harnett JD, Wesolowski C (1992). "Predicting glomerular function from 
adjusted serum creatinine". Nephron. 62 (3): 249–56 
 
 
 


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Appendix 4 
Patient Symptom Assessment Questionnaire (PSAQ) 
UTI symptoms  
Symptom assessment 
Gross hematuria (blood in urine) 
No symptom 
 
Mild 
 
Moderate 
 
Severe 
Pain or uncomfortable pressure in the lower abdomen/pelvic area 
No symptom 
 
Mild  
 
Moderate 
 
Severe 
Pain or burning when passing urine 
No symptom 
 
Mild 
 
Moderate 
 
Severe 
Frequency of urination or going to the toilet very often 
No symptom  
 
Mild 
 
Moderate 
 
Severe 
Urgency of urination or a strong and uncontrollable urge to pass 
urine 
No symptom 
 
Mild 
 
Moderate 
 
Severe 
Source: Adapted from Wagenlehner et al, Ceftazidime-avibactam versus doripenem for the treatment of complicated urinary tract 
infections including acute pyelonephritis: RECAPTURE, a phase 3 randomized trial program. CID 2016:63; 754-762. 
 
 


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Appendix 5 
Population PK Substudy 
 
1 INTRODUCTION 
This study will be conducted within the context of an ongoing Phase 3 sulopenem clinical trial in 
order to generate confirmatory data for the population PK profile of oral sulopenem etzadroxil. 
 
1.1 Overall Study Design and Plan 
This protocol appendix describes the plan for collection, processing and analysis of population 
PK samples collected within Study IT001-301. 
 
At selected IT001-301 study sites, randomized patients will also be asked to provide plasma 
samples for population PK, according to the schedule noted below. Samples will be collected 
from subjects in both treatment arms. The study will remain blinded, regardless of whether or 
not any individual patient chooses to participate in the population PK sampling. 
 
See Schedule of Events Table in Section 6. 
 
1.2 Rationale for Study Design and Control Group 
Population PK analysis requires sampling from an adequate number of patients and must 
necessarily be done in the setting of a therapeutic clinical trial. The number of subjects and 
samples, and the sampling schedule has been determined using accepted population PK 
principles. A subset of the treatment population is needed for the study to meet its objectives, 
thus this study will be conducted at a subset of sites selected for their ability and willingness to 
collect and process the additional plasma samples. 
 
2 STUDY PROCEDURES 
2.1 Study Population 
Patients at selected investigational sites who meet the inclusion criteria and none of the 
exclusion criteria for study IT001-301 will be eligible for participation in this study. 
 
This study can fulfill its objectives only if appropriate patients are enrolled. All relevant medical 
and non-medical conditions should be taken into consideration when deciding whether a 
particular patient is suitable for enrollment in this sub-study. 
 
2.2 Inclusion Criteria 
Each patient must meet the following criteria to be enrolled in this study. 
• Patient is randomized into study IT001-301 
• Patient has given informed consent to participate in the population PK sampling 
 
2.3 Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from the study. 
• Patients who are not participating in clinical study IT001-301 
• Patients in study IT001-301 who have not received study treatment 
 


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2.4 Pharmacokinetic Assessments 
A blood sample will be collected at the following time points: 
• Two hours (± 1 hour) after first oral dose of study medication is administered 
• Four hours (± 2 hours) after first oral dose of study medication is administered 
• Six hours (± 2 hours) after first oral dose of study medication is administered 
 
4 mL of blood will be collected at each time point in Gray top Sodium Fluoride (2.5 
mg/mL)/Potassium Oxalate (2 mg/mL) tubes (BD part#368587).  
 
The labels for all biological sample collection and storage containers will contain, at a minimum, 
the subject’s number, study number, collection date, and collection time. Additional details are 
provided in the Study Laboratory Manual. 
 
Table 1: Sulopenem Pharmacokinetic Blood Sample Collection Schedule 
 
Relative Time on Day 1, post first oral dose 
Volume (mL) 
2 hr (±1 hr) 
4.0  
4 hr (±2 hr) 
4.0  
6 hr (±2hr) 
4.0  
 
 
Total Blood Collected 
12.0 mL 
 
 
3. PLANNED STATISTICAL METHODS 
 
3.1 General Considerations 
The statistical methods for analysis of clinical data are described in detail in the protocol for the 
primary study. Relevant clinical data, including baseline and demographic data and data on 
clinical outcomes will be excerpted from the primary database for use in the PK/PD analyses. 
 
3.2 Sample Size Considerations 
For this class of drugs, the pharmacokinetic-pharmacodynamic (PK-PD) index which best 
describes efficacy is the time of free concentration of sulopenem above MIC (Tfree>MIC). 
Therefore, the sparse pharmacokinetic (PK) sampling strategy chosen for this study are the times 
which are most informative of the Tfree>MIC. The optimal times at which the three samples 
should be drawn, in hours after the administration of the first dose of oral medication, are as 
follows: 2 (1-3), 4 (2-6), and 6 (4-8). 
 
 
 


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The intention is to gather quality PK-PD data in several studies and to pool the concentration 
and effect data to achieve reasonable precision. Approximately 125 sulopenem-treated 
patients from this study are targeted to provide a significant contribution to these PKPD 
analyses. 
 
4 PLASMA SAMPLE HANDLING AND ANALYSIS 
 
Detailed instructions for the collection, processing, storage and shipment of samples will be 
provided in the study Laboratory Manual. 
 
4.1 Sample Collection and Processing 
• Blood samples for PK analysis of sulopenem levels will be collected via direct 
venipuncture using 4 mL Gray top Sodium Fluoride (2.5 mg/mL)/Potassium Oxalate 
(2 mg/mL) tubes (BD part#368587). 
• Immediately after the sample is drawn, the tube must be mixed gently by inversion 8 
to 10 times and placed on ice. 
• The samples will be centrifuged at 2500 g for 10 minutes at 4ºC within 60 minutes of 
collection to achieve a clear plasma layer over the red cells.  
• The plasma will be immediately separated into two 0.5 ml aliquots, transferred into 1.8 
mL NUNC Cryovials and stored at approximately -70ºC within 60 minutes of 
collection. 
• The time of the sampling as well as the time when the dose was administered prior to 
the sampling will be noted in the CRF. 
 
 
4.2 Transport of Samples 
The clinical staff will inventory the samples which are to be shipped to the central lab for 
accessioning and storage. The central lab will ship samples to the bioanalytic lab for 
measurement of sulopenem plasma concentrations. Each shipment will contain a complete 
set of samples. 
 
For sample shipment, the samples will be packed in ample dry ice within a Styrofoam 
container to ensure the samples will remain frozen for at least 72 hours and shipped via 
express delivery to the central lab. Written notification of sample shipment will be 
communicated to the bioanalytical facility and Sponsor. The samples will be tracked to 
assure arrival in a safe and timely manner. 
 
The shipment will be accompanied by logs showing the name of the study drug product, the 
protocol number, and the subjects and samples included in the shipment. Documentation 
noting the conditions of the samples upon arrival at the central lab and the bioanalytical 
laboratory will be forwarded to the Sponsor/and or Representative. 
 
4.3 Bioanalytical Sample Analyses 
The sulopenem plasma concentrations will be measured in plasma samples collected from 
patients in the sulopenem treatment group using a validated bioanalytical method and 


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according to the Bioanalytical Laboratory’s Standard Operating Procedures and FDA 
Guidances. 
 
4.4 Bioanalytical Methodology 
A full validation of a sensitive assay for the appropriate analytes in each biological matrix, 
including precision, accuracy, reproducibility, limit of quantitation, recovery, and selectivity 
will be completed and approved prior to sample analysis. The bioanalytical summary report 
will include the stability of the frozen samples, and a summary of the standard curves and 
quality control samples. 
 
4.5 Patient Withdrawal 
Patients may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety, behavioral, 
or administrative reasons. 
 
4.6 Handling Dropout and Withdrawn Subjects 
Samples from subjects will be analyzed by the bioanalytical laboratory and concentration 
data will be included in the pharmacokinetic and statistical analyses if the subject completes 
the study. 
 
Samples from subjects who choose to discontinue their participation in the study without 
submitting a written request to withdraw consent or are dropped by the Investigator(s), or the 
Sponsor, may be analyzed and included in the pharmacokinetic and statistical analyses, if 
pharmacokinetic parameters can be estimated using the remaining data points, or if requested 
by the Sponsor.  Unanalyzed samples from subjects who submit a written request to 
withdraw consent authorization from the study will not be analyzed. 
 
4.7 Final Integrated Report 
A final report will be issued by the Sponsor after it has been reviewed and released by a 
quality assurance specialist, and this report may be appended to the clinical study report for 
the primary study. Where applicable, it will contain a narrative description of the clinical, 
bioanalytical, pharmacokinetic, and statistical procedures used during the conduct of the 
study.  Appropriate tables and graphs will be created to summarize the data. 
 
The regulatory agency for submission will include the U.S. Food and Drug Administration 
and other Health Agencies, as deemed appropriate for the purpose of study conduct or 
product registration. 
 
5 PHARMACOKINETIC AND STATISTICAL DATA ANALYSES 
Pharmacokinetic and statistical analyses will be performed for sulopenem plasma data. 
 
Data from subjects with missing concentration values (missed blood draws, lost samples, 
samples unable to be quantitated) may be used if pharmacokinetic parameters can be 
estimated using the remaining data points. 
 
5.1 Pharmacokinetic Data Analyses 


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PK-PD analyses will include all patients who are clinically and/or microbiologically 
evaluable and for whom sulopenem concentration-time data are available. An estimate of 
sulopenem PK parameters will be derived for every patient who undergoes PK sampling. 
This will be accomplished by fitting the population PK model developed for sulopenem 
using the data from patients from multiple Phase 1 studies to the sulopenem concentration-
time data. The PK PD index (Tfree>MIC) will be calculated. The PK-PD index data as well as 
patient demographics and outcome information may also be pooled with other Phase 3 
studies of sulopenem for the conduct of the PK-PD analysis. The results of the PK-PD 
analysis may be reported separate from the clinical study report. 
 
6 SCHEDULE OF EVENTS 
 
Evaluation 
Baseline 
Day 1 
Within 24 
hours prior to 
first dose 
Dose Day 1a 
Sample 1 
2 hrs ± 1 hr  
Sample 2 
4 hrs ± 2 hrs  
Sample 3 
6 hrs ± 2 hrs  
Informed Consent 
X 
 
 
 
 
Study drug dose 
 
X 
 
 
 
PK sample collection 
 
 
X 
X 
X 
a 
Study "Day" is calendar day beginning with Day 1, the calendar day the first dose of study medication 
is started. 
 
 
 
 


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Appendix 6 
Criteria for Safety Values of Potential Clinical Concern 
Hematology 
 
Hemoglobin 
<0.8 x baseline 
Hematocrit 
<0.8 x baseline 
Leukocytes 
<1.5 or >20 x 103/mm3 
Platelets 
<75 or >700 x 103/mm3 
Chemistry 
 
Total bilirubin 
>2 times the upper limit of the reference range 
Direct bilirubin 
>2 times the upper limit of the reference range 
AST 
>3 times upper limit of the reference range 
ALT 
>3 times upper limit of the reference range 
GGT 
>3 times upper limit of the reference range 
Alk Phosphatase 
>3 times upper limit of the reference range 
Creatinine 
>1.5 times upper limit of the reference range 
BUN/Urea 
>1.3 times upper limit of the reference range 
Sodium 
<0.95 or >1.05 times the limits of the reference range 
Potassium 
<0.9 or >1.1 times the limits of the reference range 
Calcium 
<0.9 or >1.1 times the limits of the reference range 
Albumin 
<0.8 times the lower limit of the reference range 
Total protein 
<0.8 times the lower limit of the reference range 
Creatine Kinase 
>3.0 times upper limit of the reference range 
Urinalysis 
 
Urine WBC 
≥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 7    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 ciprofloxacin for treatment of 
uncomplicated urinary tract infections in adult women. 
Study Number: 
IT001-301 
Final Date: 
06 March 2018 
 
 
I have read the protocol described above.  I agree to comply with all applicable regulations 
and to conduct the study as described in the protocol.  I understand the study protocol and 
will conduct the study according to the procedures therein and according to the principles of 
good clinical practice. 
 
 
Name: 
 
 
 
 
 
 
 
 
 
 
 
Signature: 
 
Date: 
 

SAP_001.pdf: 
Statistical Analysis Plan: IT001-301 
 
 
 
Study Title: 
A prospective, Phase 3, randomized, multi-center, double-blind study of 
the efficacy, tolerability and safety of PF-03709270 with probenecid 
versus oral ciprofloxacin for treatment of uncomplicated urinary tract 
infections in adult women. 
Study Number: 
IT001-301 
Study Phase: 
Phase 3 
Product Name: 
sulopenem etzadroxil/probenecid  
(PF-03709270/probenecid)  
 
Indication: 
Uncomplicated urinary tract infection 
 
 
Study Statistician: 
 
 
Michael Zelasky 
Study Clinician: 
 
Steven I. Aronin, M.D. 
 
Sponsor: 
Iterum Therapeutics International Limited 
20 Research Parkway, Suite A 
Old Saybrook, CT 06475 
 
 
Final SAP Date: 
September 30, 2019 
Revised SAP Date: 
March 11, 2020 
 
 
Protocol Version 
January 6, 2020 (amendment 2) 
 
 
 
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 




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TABLE OF CONTENTS 
 
TABLE OF CONTENTS ............................................................................................................ 3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................................. 5 
1 
INTRODUCTION............................................................................................................. 7 
2 
STUDY DESIGN ............................................................................................................... 7 
3 
STUDY OBJECTIVES ..................................................................................................... 7 
3.1 
Primary Objective ................................................................................................. 7 
3.2 
Secondary Objectives ........................................................................................... 7 
4 
DEFINITION OF ANALYSIS POPULATIONS ........................................................... 8 
4.1 
Intent-to-Treat (ITT) ............................................................................................ 8 
4.2 
Modified Intent-to-Treat (MITT) ....................................................................... 8 
4.3 
Microbiological Modified Intent-to-Treat (micro-MITT or m-MITT) ......... 8 
4.3.1 Susceptible (micro-MITTS or m-MITTS) ............................................................. 8 
4.3.2 Resistant (micro-MITTR or m-MITTR) ............................................................... 8 
4.4 
Clinical Evaluable (CE) ......................................................................................... 8 
4.5 
Microbiological Evaluable (ME) ....................................................................... 10 
4.5.1 Susceptible (ME-S) ................................................................................................ 10 
4.5.2 Resistant (ME-R).................................................................................................. 11 
4.6 
Safety ..................................................................................................................... 11 
4.7 
Determination of Inclusion in Analysis Populations ................................... 11 
5 
DEFINITION OF ENDPOINTS ................................................................................... 11 
5.1 
Overall Response ................................................................................................... 11 
5.2 
Microbiologic Response ........................................................................................ 12 
5.2.1 Baseline Pathogens ................................................................................................ 12 
5.2.2 Post-Baseline Pathogens ....................................................................................... 13 
5.3 
Patient-Determined Clinical Response (Clinical Response) ............................. 14 
5.4 
Investigator-Determined Clinical Response: ...................................................... 14 
5.5 
Patient Symptom Assessment Questionnaire (PSAQ) ................................. 15 
5.6 
Safety Endpoint Measures ................................................................................. 15 
6 
STATISTICAL METHODS .......................................................................................... 16 
6.1 
Sample Size ........................................................................................................... 16 
6.2 
Randomization ...................................................................................................... 17 
6.3 
Visit Windows........................................................................................................ 17 
6.4 
Microbiology Data ................................................................................................ 17 


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6.5 
Handling of Missing Data ..................................................................................... 18 
6.6 
Comments on Statistical Analysis........................................................................ 20 
7 
STATISTICAL ANALYSES ......................................................................................... 20 
7.1 
Patient Disposition ................................................................................................ 20 
7.2 
Demographics and Baseline Characteristics ...................................................... 21 
7.2.1 
Baseline Microbiology .................................................................................. 21 
7.3 
Prior and Concomitant Medications ................................................................... 22 
7.4 
Study Drug Exposure ........................................................................................... 22 
7.5 
Efficacy Analyses .................................................................................................. 22 
7.5.1 
Primary Efficacy Analysis .................................................................................... 23 
7.5.2 
Additional Hypothesis Testing of the Primary Efficacy Endpoint ................... 24 
7.5.3 
Additional Analyses of the Primary Efficacy Endpoint .................................... 25 
7.5.4 
Secondary Efficacy Analysis ................................................................................ 27 
7.5.5 
Additional Efficacy Analyses ............................................................................... 27 
7.6 
Interim Analysis .................................................................................................... 32 
7.7 
Safety Analyses ...................................................................................................... 33 
7.7.1 
Adverse Events ...................................................................................................... 33 
7.7.1.1 Diarrhea Episodes ................................................................................................. 34 
7.7.2 
Laboratory Values ................................................................................................ 35 
7.7.3 
Physical Examinations .......................................................................................... 36 
7.7.4 
Vital Signs .............................................................................................................. 36 
7.8 
Protocol Deviations ............................................................................................... 37 
8 
DIFFERENCES WITH ANALYSES SPECIFIED IN THE PROTOCOL............... 37 
9 
REFERENCES ................................................................................................................ 38 
Appendix A: Schedule of Activities ............................................................................. 39 
Appendix B: Criteria for Safety Values of Potential Clinical Concern ........................ 40 
Appendix C: Method for Determination of Creatinine Clearance ................................ 41 
Appendix D: Microbiology Rules ................................................................................. 42 
Appendix E: Inclusion of OpGen (PCR) Data for Exploratory Analysis ..................... 43 
 


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


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


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1 
INTRODUCTION 
This document presents the Statistical Analysis Plan (SAP) for the protocol IT001-301, “A 
prospective, Phase 3, randomized, multi-center, double-blind study of the efficacy, tolerability 
and safety of PF-03709270 with probenecid versus oral ciprofloxacin for treatment of 
uncomplicated urinary tract infections in adult women.”  The statistical plan described is an a 
priori plan, and the analyses outlined here have not been conducted on the final and unblinded 
data prior to the preparation of this plan. This SAP summarizes the design and objectives of 
protocol IT001-301 and provides details of the definitions of analysis populations, derived 
variables, the outcome measures and statistical methodology that will be used to analyze the 
data from the study. 
Any deviation from the planned analysis after unblinding will be documented in the clinical 
study report (CSR). This SAP is based on the most recent version of the study protocol as noted 
on page 1.  
 
2 
STUDY DESIGN 
This prospective Phase 3, randomized, multicenter, double-blind, double dummy, controlled 
study compares oral sulopenem etzadroxil/probenecid to oral ciprofloxacin for the treatment 
of patients with uncomplicated urinary tract infection (uUTI).  Approximately 1,364 adult 
women with uUTI will be randomized in a 1:1 fashion to receive either a bilayer tablet with 
sulopenem etzadroxil 500 mg/probenecid 500 mg twice daily for 5 days or oral ciprofloxacin 
250 mg twice daily for 3 days.  
Visits occur on Day 1, Day 3, Day 5 (± 1 day), Day 12 (± 1 day), and Day 28 (± 2 days).  The 
Day 5 visit is the End of Therapy (EOT) visit, Day 12 is the Test of Cure (TOC) visit and Day 
28 is the Final Visit (FV). 
 
3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
To compare the overall response (clinical and microbiologic combined response) of oral 
sulopenem etzadroxil/probenecid versus oral ciprofloxacin for the treatment of 
uncomplicated urinary tract infection in adult women at the primary time-point, TOC. 
3.2 Secondary Objectives 
• To compare the overall response at other relevant time-points. 
• To compare the microbiologic efficacy across treatment groups.  
• To compare the clinical efficacy outcomes across treatment groups.  
• To compare the safety profile of treatment with oral sulopenem etzadroxil/probenecid 
versus oral ciprofloxacin for treatment of uncomplicated urinary tract infection in adult 
women.  
• 
To assess the population PK profile of oral sulopenem etzadroxil/probenecid in selected 
patients. 
 
 


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4 
DEFINITION OF ANALYSIS POPULATIONS 
 
4.1 Intent-to-Treat (ITT)  
The ITT population is comprised of all randomized patients regardless of whether the 
patient received study drug. 
4.2 Modified Intent-to-Treat (MITT)  
The MITT population will include all patients in ITT population who received at least 
a single dose of study medication and had the disease under study defined as having 
two of the four baseline uUTI symptoms and pyuria in the baseline UA. 
4.3 Microbiological Modified Intent-to-Treat (micro-MITT or m-MITT)  
All MITT patients with a positive study entry urine culture within 48 hours prior to first 
dose defined as ≥105 colony forming units (CFU)/mL of a uropathogen 
(Enterobacteriaceae or Staphylococcus saprophyticus only) and no more than 2 species 
of microorganisms with ≥105 (CFU)/ml (Wilson ML and Gaido L. Laboratory diagnosis 
of urinary tract infections in adult patients. Clin Infect Dis 2004;38:1150-8).  See 
section 6.4 for further details on the use of lab results for determining eligibility. 
 
4.3.1 Susceptible (micro-MITTS or m-MITTS)  
All micro-MITT patients with a baseline uropathogen susceptible to the 
comparator drug, ciprofloxacin (ciprofloxacin MIC ≤ 1 mg/L), and no baseline 
pathogen non-susceptible to ciprofloxacin. 
4.3.2 Resistant (micro-MITTR or m-MITTR) 
All micro-MITT patients with a baseline uropathogen non-susceptible (defined 
as MIC ≥2 mg/L) to the comparator drug, ciprofloxacin. 
4.4 Clinical Evaluable (CE) 
Four CE populations will be defined based on the timing of the outcome assessment, 
CE-Day 3, 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 all 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 (must 
take all the doses by day 6 for sulopenem patients and day 4 for ciprofloxacin 
patients).   
For patients who appear to not have taken drug, based on the artificial intelligence 
data (see section 7.4), their banked urine samples at day 3 will be analyzed for 
study drug.  If there is no active drug in the samples then these patients will be 
excluded from the CE.  


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b) Met the following inclusion criteria:  
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; 
 
and didn’t 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.  Patients with ileal loops or urinary stoma 
Exclusion Criterion 5.  Patients with an indwelling urinary catheter in the previous 
30 days 
Exclusion Criterion 6.  Patients with paraplegia 
Exclusion Criterion 7.  Patients who are likely to receive ongoing antibacterial 
drug prophylaxis after treatment of uUTI (e.g., patients with vesico-ureteral 
reflux) 
Exclusion Criterion 9.  Patient's urine culture results, if available at study entry, 
identify more than 2 microorganisms regardless of colony count or patient has a 
confirmed fungal UTI 
Exclusion Criterion 15.  Patients with uncontrolled Diabetes mellitus (defined as 
the presence of ketoacidosis, hyperosmolar hyperglycemia, or glucosuria with a 
random or fasting fingerstick or serum glucose ≥ 250 mg/dL at screening) 
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 7.8) 
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), respectively.     
e) Had not received antibacterial drug therapy potentially effective as treatment of 
uUTI within the prior 7 days to the initiation of study therapy. 


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f) For CE-Day 3, CE-EOT and CE-TOC, did not receive any systemic antibiotic 
therapy with potential activity against any of the uropathogens collected at baseline 
(excluding linezolid, daptomycin, vancomycin, azithromycin, metronidazole, 
josamycin, macrolide, nifuratel, tergynan, fluconazole, cystone, butoconazole 
nitrate, clindamycin hydrochloride, clotrimazole, tinidazole and clarithromycin, as 
well as ‘antibiotics and chemotherapeutics for dermatological use’ and 
‘ophthalmologicals' since they have no activity against the pathogens in the study) 
between the time of the baseline culture and the Day 3, EOT or TOC visits, 
respectively. This excludes the protocol defined study therapy and patients who 
were considered clinical failures and required additional antibiotic therapy. Patients 
with a coinfection with a gram-positive uropathogen resistant to study drugs are 
allowed to receive agents with narrow spectrum gram-positive coverage (i.e., such 
as 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. 
g) 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 (excluding S. saprophyticus) at 
baseline and has symptoms at the post-baseline visit  
h) Site personnel involved in the assessment of efficacy parameters remained blinded 
to study treatment up to the time of the efficacy assessment.  
i) Patients who receive study drug therapy beyond the protocol treatment period 
(Study Day 5) as a result of the investigator's assessment that additional drug 
therapy is needed for treatment of the underlying urinary tract infection will be 
defined as failures for patient determined clinical response at TOC. Thus, these 
patients will be included in the CE populations, if all other criteria are met. 
4.5 Microbiological Evaluable (ME) 
All patients included in both the micro-MITT and CE populations at the Day 3 (ME-
Day 3), Day 5 visit (ME-EOT), Day 12 visit (ME-TOC) and at the Day 28 visit (ME-
FV) and interpretable urine culture result at the Day 3, Day 5, Day 12 and Day 28 visits 
(i.e., within the SAP defined allowed visit window), respectively. 
4.5.1 Susceptible (ME-S) 
All ME patients with a baseline uropathogen susceptible to the comparator drug, 
ciprofloxacin (ciprofloxacin MIC ≤ 1 mg/L), and no baseline pathogen non-


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susceptible to ciprofloxacin. 
4.5.2 Resistant (ME-R) 
All ME patients with a baseline uropathogen non-susceptible (defined as MIC 
≥2 mg/L) to the comparator drug, ciprofloxacin.  
4.6 
Safety  
The safety population is comprised of all patients in ITT population who received at 
least a single 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 eCRF data and as needed by manual review.   
Inclusion into the CE populations will be determined programmatically from the eCRF 
data and through a manual review conducted by the Sponsor. The Sponsor will review 
clinical data for determination of criteria used to assess inclusion in the CE populations. 
The Sponsor will be blinded to treatment assignment and will review the data 
concurrent with the conduct of the study.  
Inclusion into the Micro-MITT, 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 for the study is the outcome of Overall Response at TOC. 
A patient will be defined as a success at a given timepoint (Day 3, EOT, TOC and FV) if 
the following criteria are met: 
• The patient is alive 
• The patient has received no non-study antibacterial therapy for uUTI (excluding 
linezolid, daptomycin, vancomycin, azithromycin, metronidazole, josamycin, 
macrolide, nifuratel, tergynan, fluconazole, cystone, butoconazole nitrate, 
clindamycin hydrochloride, clotrimazole, tinidazole and clarithromycin, as well as 
‘antibiotics and chemotherapeutics for dermatological use’ and ‘ophthalmologicals' 
since they have no activity against the pathogens in the study)  
- If an antibiotic active against the urinary tract pathogen is given for non-uUTI 
reasons, then the patient will be considered indeterminate 
• The patient has resolution of the symptoms of uUTI present at trial entry and no new 
UTI symptoms (based on the Patient Symptom Assessment Questionnaire).  Missing 
answers to PSAQ questions are treated as missing thus the outcome will be 


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indeterminate. 
• Urine culture collected at the follow-up visit demonstrates <103 CFU/mL of the 
baseline uropathogen 
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 (excluding linezolid, 
daptomycin, vancomycin, azithromycin, metronidazole, josamycin, macrolide, 
nifuratel, tergynan, fluconazole, cystone, butoconazole nitrate, clindamycin 
hydrochloride, clotrimazole, tinidazole and clarithromycin, as well as ‘antibiotics 
and chemotherapeutics for dermatological use’ and ‘ophthalmologicals' since they 
have no activity against the pathogens in the study) 
• Patient has no resolution or worsening of symptoms of uUTI present at trial entry 
and/or has new uUTI symptoms.  Missing answers to PSAQ questions are treated as 
missing thus the outcome will be indeterminate. 
• Urine culture at the follow-up visit demonstrates ≥103 CFU/mL of the baseline 
uropathogen. 
Patients will also be defined to have an indeterminate outcome if any data needed to 
determine whether the outcome is success or failure are missing. For example, if the 
assessment of the UTI symptoms was not completed at TOC, the patient will be considered 
an indeterminate response for overall response at TOC (unless the urine 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. 
5.2 
Microbiologic Response 
Per pathogen microbiologic response is assessed using the definitions listed below.  It will 
be analyzed at each timepoint (Day 3, EOT, TOC and FV).  It is assessed for each pathogen 
that a patient has at baseline. 
Per patient microbiologic response is a patient level response determined by the outcome 
of any culture results at that visit.   
Note, if a patient did not have a positive culture at baseline, they are not included in the 
micro-MITT or ME populations even if a pathogen is isolated post-baseline.  
 
5.2.1 Baseline Pathogens 
 
Microbiological response  
Definition  
Eradication  
The urine culture obtained at the timepoint 
of analysis demonstrates <103 CFU/mL of 
the baseline uropathogen. 
Persistence  
A uropathogen present at baseline 
regardless of susceptibility grew at ≥103 
CFU/mL at the timepoint of analysis.*  


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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-fold 
higher MIC to study drug received at the 
timepoint of analysis. 
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*) at the 
timepoint of analysis (contaminated results 
are considered a negative culture and 
therefore an eradication7).  
* The genus/species and susceptibility profiles need to match. Additional molecular testing by pulsed field 
gel electrophoresis (PFGE), PCR or whole genome sequencing (WGS) may be performed for confirmation; 
in the case of missing culture data PCR may be used to confirm the presence or absence of the baseline 
pathogen. 
 
A per pathogen microbiologic success is defined as Eradication.  A pathogen failure is 
Persistence or Persistence with Increasing MIC.   
A per patient microbiologic success is defined as all pathogen responses for a patient are 
Eradication.  A per patient microbiologic failure is one or more pathogens for a patient are 
Persistence or Persistence with increasing MIC.  Otherwise, the patient will be 
Indeterminate. 
5.2.2 Post-Baseline Pathogens 
For patients with a baseline pathogen meeting the micro-MITT criteria, the following post-
baseline pathogen definitions will be used. 
 
Microbiologic response  
Definition  
Superinfection 
A 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 
microbiological success at EOT, isolation of 


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a baseline 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 micro-organism 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). 
* excluding linezolid, daptomycin, vancomycin, azithromycin, metronidazole, josamycin, 
macrolide, nifuratel, tergynan, fluconazole, cystone, butoconazole nitrate, clindamycin 
hydrochloride, clotrimazole, tinidazole and clarithromycin, as well as ‘antibiotics and 
chemotherapeutics for dermatological use’ and ‘ophthalmologicals' since they have no 
activity against the pathogens in the study 
 
 
5.3 Patient-Determined Clinical Response (Clinical Response) 
A patient will be defined as a clinical success at a given timepoint (Day 3, 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 (excluding 
linezolid, daptomycin, vancomycin, azithromycin, metronidazole, josamycin, 
macrolide, nifuratel, tergynan, fluconazole, cystone, butoconazole nitrate, 
clindamycin hydrochloride, clotrimazole, tinidazole and clarithromycin, as well as 
‘antibiotics and chemotherapeutics for dermatological use’ and ‘ophthalmologicals' 
since they have no activity against the pathogens in the study) prior to the visit 
- If an antibiotic active against the urinary tract pathogen is given for non-UTI 
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).   
- 
Missing answers to PSAQ questions are treated as missing thus the outcome will be 
indeterminate.  
- 
Baseline symptoms associated with anatomic abnormalities that predispose to 
symptoms of a uUTI (e.g., frequency and urgency associated with 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 
indeterminate outcome. 
5.4 Investigator-Determined Clinical Response: 


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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 cure  
All pre-therapy signs and symptoms of the 
index infection had resolved such that no 
additional antibiotics were required 
Clinical failure  
Patients who met any one of the criteria 
below are considered a failure:  
• 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 
noncontributory  
 
5.5 Patient Symptom Assessment Questionnaire (PSAQ) 
Patients will report their UTI symptoms as no symptom, mild, moderate or severe and this 
will be recorded on the Patient Symptom Assessment Questionnaire (PSAQ).  The symptoms 
are: 
• Pain (uncomfortable pressure) in the lower abdomen/pelvic area 
• Burning (dysuria) when passing urine 
• 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. 
5.6 Safety Endpoint Measures 
The safety parameters include AEs, clinical laboratory evaluations and vital signs. Adverse 


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Events will be coded using the Medical Dictionary of Regulatory Activities (MedDRA) 
Version 21.0 or higher to the System Organ Class and Preferred Term levels. 
 
6 
STATISTICAL METHODS 
6.1 Sample Size 
The study is designed to determine whether oral sulopenem etzadroxil/probenecid is NI to oral 
ciprofloxacin for the outcome measure of overall success (combined clinical and 
microbiologic success) at TOC in the micro-MITTS population and/or whether oral sulopenem 
etzadroxil/probenecid is superior to oral ciprofloxacin for overall success at TOC in the micro-
MITTR population. The primary endpoint 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]). 
There are two primary populations for this study. One is the micro-MITTS population, defined 
as all randomized patients with a baseline urine culture demonstrating no more than 2 species 
of a uropathogen at ≥105 CFU/mL susceptible (ciprofloxacin MIC ≤1 mg/L) to the comparator 
study drug, ciprofloxacin. The other is the micro-MITTR population, defined as all 
randomized patients with a baseline urine culture demonstrating among no more than 2 species 
of a uropathogen at least one pathogen at ≥105 CFU/mL non-susceptible (ciprofloxacin MIC 
≥2 mg/L) to the comparator study drug, ciprofloxacin.  
A review of the literature showed that only approximately 60% of symptomatic uUTI patients 
will have ≥105 CFU/mL of a uropathogen. Thus, in order to optimize the enrollment of patients 
with ≥105 CFU/mL of a uropathogen, the inclusion criteria were designed to require a urine 
dipstick analysis to be positive for nitrite in addition to having evidence of pyuria, as this has 
been shown to increase the sensitivity and specificity of enrolling patients with ≥105 CFU/mL 
of a uropathogen to 84% and 98% respectively [Semeniuk 1999].  However, patients who were 
randomized and subsequently not found to have evidence of both pyuria and nitrites on their 
baseline urinalysis are still to be included in the micro-MITT populations if the baseline urine 
culture was positive as described above. 
The proposed sample size in the micro-MITTS population is 441 patients per arm (total of 882 
patients) based on the method of Farrington and Manning. This assumes a non-inferiority 
margin of 10%, a power of 90%, a one-sided alpha level of 0.025 and a 70% treatment success 
rate.  With 105 patients per treatment group in the micro-MITTR population, there is 90% 
power to show superiority given a 66% and 43% overall success rate in the sulopenem 
etzadroxil/probenecid and ciprofloxacin groups, respectively. Assuming that 22% of the 
patients will have non-susceptible pathogens and 83% of the randomized patients will meet 
criteria for inclusion into the micro-MITT population (1,132 patients), the sample size for the 
ITT population is 1,364. 
Historically, the treatment success rate in a similar patient population with susceptible 
pathogens was noted to be between 88.4% and 92%. However, preliminary results from an 
ongoing uUTI study (IT004-401) indicate that the point estimate for overall success in uUTI 


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patients with susceptible pathogens is closer to 70%, using the outcome measures defined in 
this study. 
There are no recent studies in patients with uUTI caused by ciprofloxacin resistant pathogens 
but treated with another antibiotic to which the organism is susceptible to provide an estimate 
of the overall clinical success rate in this population.  It is assumed the response rate in this 
group of patients will be slightly lower. 
Two blinded interim analyses for sample size re-estimation and one unblinded interim analysis 
for sample size re-estimation are planned (See Section 7.6). 
6.2 Randomization 
 
Patients will be randomized in a 1:1 ratio to sulopenem etzadroxil/probenecid versus 
ciprofloxacin 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. 
6.3 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.   
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. 
For laboratory and vital signs by-visit analyses, the value closest to the target date for the 
visit will be used in the analyses if more than one assessment was within the visit window 
(i.e., unscheduled assessments were obtained).  If two values are equidistant from the 
planned visit date, then the first value will be used. 
 
Visit 
Window 
Day 3 
No window 
Day 5 - End of Treatment (EOT) 
± 1 day 
Day 12 - Test of Cure (TOC) 
± 1 day 
Day 28 - Final Visit (FV) 
± 2 days 
 
6.4 Microbiology Data 
The following organisms will be considered a uropathogen for this study: 
• Monomicrobial or polymicrobial infections caused by: 
o Enterobacteriaceae 
o Enterococci 


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o Pseudomonas aeruginosa 
o S. saprophyticus 
• The micro-MITT population will only include patients with uUTIs caused by the 
following (study pathogens):  Enterobacteriaceae and/or S. saprophyticus.   
The following normal flora are never a pathogen: 
 
• Corynebacterium spp. 
• S. epidermidis 
• S. aureus 
• 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 of a spreadsheet by the 
Sponsor.  This could include isolates not listed above.  If needed, patient clinical and 
microbiological information (e.g., Gram stain, PFGE or other appropriate tests) will be used 
to assist in determining if the isolate is a pathogen.  
The microbiology rules for identification of pathogens are in appendix D. 
6.5 Handling of Missing Data 
Missing data will be handled as outlined below: 
• All missing and partial dates for events and assessments occurring after randomization 
or for medications received after randomization will be queried for a value. If no value 
can be obtained, the dates or partial dates will remain missing, but the following 
actions will take place: 
- 
Adverse Events 
• If an adverse event is missing a start date, the adverse event will be 
treated as treatment-emergent.   
• 
If the start date only contains the year, then if the year is prior to the year 
of first dose then the adverse event will not be treatment 
emergent.  Otherwise, it will be treatment emergent unless it is possible 
to conclude that the stop date is prior to first dose (based on the available 
parts of stop date if it is partial). 
• 
If the start date only contains the year and month, then if the year/month 
combination is prior to the year/month combination of first dose then the 
adverse event will not be treatment emergent.  Otherwise, it will be 


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treatment emergent unless it is possible to conclude that the stop date is 
prior to first dose (based on the available parts of stop date if it is partial). 
• 
If the start date only contains the month and day, then if the month/day 
combination is prior to the month/day combination of first dose then the 
adverse event will not be treatment emergent.  Otherwise, it will be 
treatment emergent unless it is possible to conclude that the stop date is 
prior to first dose (based on the available parts of stop date if it is partial). 
• 
Other partial start dates will be treated as treatment-emergent unless it is 
possible to conclude that the stop date is prior to first dose (based on the 
available parts of stop date if it is partial). 
- 
Prior/Concomitant Medications and Prior/Concomitant Antibiotic Therapy 
• 
If a concomitant drug is missing a start date and stop date, then the 
concomitant drug should be reported both as a prior and concomitant 
drug. 
• 
If the start date only contains the year and month, then if the year/month 
combination is after the year/month combination of first dose then the 
drug should be reported as concomitant only.  Otherwise, it should be 
reported as both prior and concomitant unless it is possible to conclude 
that the stop date is prior to first dose (based on the available parts of stop 
date if it is partial).  In this case it should be reported as prior only. 
• 
If the start date only contains the month and day, then if the month/day 
combination is after the month/day combination of first dose then the 
drug should be reported as concomitant only.  Otherwise, it should be 
reported as both prior and concomitant unless it is possible to conclude 
that the stop date is prior to first dose (based on the available parts of stop 
date if it is partial).  In this case it should be reported as prior only. 
• 
Other partial start dates will be treated as both prior and concomitant 
unless it is possible to conclude that the stop date is prior to first dose 
(based on 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. 
• Except as specifically noted for preplanned imputation analyses, missing values 
for other individual data points (not described above) will remain as missing. 
Missing values will not be imputed and only observed values will be used in data 
analyses and presentations. 
• Where individual data points are missing, categorical data will be summarized 
based on reduced denominators (i.e., only patients with available data will be 
included in the denominators). 
 


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6.6 
Comments on Statistical Analysis 
The following general comments apply to all statistical analyses and data presentations: 
• Summaries will include frequency and percentages for categorical data; frequency 
and median for ordinal data; and number, mean, standard deviation, and median, 
minimum, maximum and quartiles for quantitative data. 
• Duration variables will be calculated using the general formula (end date - start date) 
+1. 
• If the reported value of a clinical laboratory parameter cannot be used in a statistical 
summary table (e.g., a character string is reported for a parameter of the numerical 
type), a coded value must be appropriately determined and used in the statistical 
analyses. In general, a value or lower and upper limit of normal range such as ‘<10’ 
or ‘≤ 5’ will be 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. 
 
7 
STATISTICAL ANALYSES 
All tables except safety tables will be presented for three groups of patients, once each for 
patients whose pathogens are susceptible to ciprofloxacin, non-susceptible to ciprofloxacin 
and all patients regardless of susceptibility.  Safety tables will be presented only once for 
the safety population regardless of susceptibility. 
7.1 Patient Disposition 
The number of patients included in each of the study populations (i.e., ITT, Safety, MITT, 
Micro-MITT, Micro-MITTS, Micro-MITT R, CE-Day 3, CE-EOT, CE-TOC, CE-FV, ME-
Day 3, ME-EOT and ME-TOC, ME-FV) will be summarized by treatment group. A table 
and listing will be provided that details the reasons the patient is excluded from the 
population. 
A listing will be provided of randomized patients who did not meet all inclusion/exclusion 
criteria.  
The frequency and percentage of patients completing the study, prematurely discontinuing 
from study drug, and prematurely discontinuing from the study will be presented for each 
treatment group and overall for each study population. Comparisons between treatment 
groups will be made using Fisher‘s exact test. 
Reasons for premature discontinuation of study drug and/or withdrawal from the study as 
recorded on the eCRF will be summarized (frequency and percentage) by treatment group.  


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A listing of all patients who prematurely discontinued from study drug or withdrew from 
the study will be presented, and the primary reason for premature discontinuation of study 
drug or withdrawal from the study will be provided. 
 
A listing of deaths will be presented separately. 
7.2 Demographics and Baseline Characteristics 
Demographic data and baseline characteristics will be presented by treatment group in all 
study populations. A table will present the patient demographics (e.g., gender, age, 
ethnicity, race, geographic region) and baseline characteristics (e.g., height, weight, BMI, 
diabetes status, creatinine clearance). Differences between treatment groups will be 
analyzed using Fisher‘s exact test for dichotomous variables (gender, ethnicity, race, 
geographic region, diabetes status, creatinine clearance as a categorical variable: <30, 30-
<60, ≥60) and the Wilcoxon Rank Sum test for continuous variables (age, BMI, creatinine 
clearance). 
Medical history will be summarized based on body site/system category and treatment 
group.   
Signs and symptoms at baseline as captured on the PSAQ will be summarized by treatment 
group and compared using the Wilcoxon Rank Sum test for ordinal data. 
7.2.1 Baseline Microbiology 
The microbiological assessment of the baseline urine sample will be summarized by 
treatment group for all populations. A frequency distribution of the result of the central 
lab’s Gram stain, including organism characteristics will be presented. The number and 
percentage of patients with no growth, contaminant and positive for a pathogen 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 presented. 
A table will be provided of the distribution of pathogens by culture concentration at baseline. 
The number and percentage of patients with a gram-positive pathogen and with a gram-
negative pathogen will be presented by genus and species. 
A listing will be provided that includes all baseline and post-baseline isolates obtained from 
the urine specimens and whether or not the isolate is considered the pathogenic organism. 
Several tables providing the frequency distribution of the minimum inhibitory concentrations 
(MIC) by treatment group and treatment groups combined will be provided for the micro-
MITT and the ME populations. These include the following. 
• The distribution of MIC to sulopenem, ciprofloxacin and other drugs for the baseline 
pathogens 


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• MIC summary statistics (i.e., range, MIC50 and MIC90 for pathogens that have 10 or 
more occurrences) for the study pathogens:  Enterobacteriaceae and S. saprophyticus 
7.3 Prior and Concomitant Medications 
All medications taken within 30 days prior to the first dose of the study drug and through the 
FV visit will be recorded on the eCRF.  Medications will be summarized by WHODRUG 
(March 1, 2018 version or higher) ATC level 3 and generic medication name for all 
populations.  Patients will be counted only once for an ATC class and generic medication 
name. 
Medications are considered prior if taken prior to the first dose of study drug or if their start 
date is unknown.  Medications are considered concomitant if taken on or after the first dose 
of study drug, or if their stop date is unknown or marked as continuing. 
Tables will be provided for prior medications, all concomitant medications and concomitant 
antibacterial medications.  Concomitant medications and concomitant antibacterial 
medications will be present in several tables of medications taken from study start to each 
visit (e.g., concomitant medications taken from study start through EOT visit).  If a 
medication was taken during this interval, regardless if it was started in that interval, it will 
be counted. 
A listing will be provided of all prior and concomitant medications. 
 
7.4 Study Drug Exposure  
To enhance documentation of compliance, this study employs a platform that uses artificial 
intelligence on smartphones to confirm medication ingestion for U.S. sites.  In addition, built-
in reminders and a communication system allow real-time intervention in case of drug 
interruptions. For non-U.S. sites, a paper diary will be used to capture compliance. 
A listing of patients not in compliance, based on the artificial intelligence data, will be 
provided.  For patients who appear to not have taken drug, based on the artificial intelligence 
data, their banked urine samples at day 3 will be analyzed for study drug.  If there is no active 
drug in the samples then these patients will be excluded from the CE. 
A dosing summary by treatment group will be presented for all study populations. The 
distribution of patients by the number of active doses of study drug therapy in the 3-day 
regimen and 5-day regimen will be presented.  Each tablet or capsule taken is considered a 
half day of therapy. 
7.5 Efficacy Analyses 
For all the efficacy analyses, patients will be analyzed in the treatment group based on the 
treatment to which they were randomized.  Patients who receive the study drug regimen other 
than the study drug regimen to which they were randomized are not included in the CE and 
ME populations by definition.  
By definition, patients with an indeterminate response are included in the denominator for 
analyses in the ITT, MITT and micro-MITT populations, and are counted as failures. 
For the ITT, MITT and micro-MITT populations, the proportion of successes is defined 


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using the following formula: 
Number of successes 
Number of successes + Number of failures + Number of indeterminates 
 
By definition, patients in the CE and ME populations must have sufficient information for 
determination of overall response. Thus, for the CE and ME populations, the proportion of 
successes is defined using the following formula: 
Number of successes 
Number of successes + Number of failures  
7.5.1 Primary Efficacy Analysis 
The primary efficacy endpoint is based on the outcome of overall success (combined clinical 
and microbiologic success) at TOC in the micro-MITTS and, separately, in the 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-MITTS and micro-MITTR populations.  
The primary objective of this study is to compare the outcomes in patients with quinolone 
susceptible organisms as well as, in parallel, in patients with quinolone non-susceptible 
pathogens. The primary comparisons for regulatory approval are in these two mutually 
exclusive populations as defined by a baseline characteristic.  If either of the two analyses are 
positive (i.e., reject null hypothesis), the efficacy of sulopenem will have been established 
consistent with the primary objective of the trial.  These two populations are defined as 
follows: 
1) The micro-MITTS population  
This population is a subset of the micro-MITT population in which the baseline pathogen is 
determined to be susceptible to the comparator study drug, ciprofloxacin.  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 endpoint rate in the sulopenem etzadroxil/probenecid group, 
p2 is the primary efficacy endpoint rate in the ciprofloxacin 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 rate (sulopenem etzadroxil/probenecid group minus ciprofloxacin 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-


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Manning test.  If the lower limit of the 95% CI for difference in success rates in the micro-
MITTS population is greater than -10%, the null hypothesis will be rejected and the NI of 
sulopenem etzadroxil/probenecid to ciprofloxacin will be concluded. 
2) The micro-MITTR population  
This population is a subset of the micro-MITT population in which the baseline pathogen is 
determined to be non-susceptible to the comparator study drug, ciprofloxacin. 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 sulopenem 
etzadroxil/probenecid to ciprofloxacin will be concluded. 
7.5.2 Additional Hypothesis Testing of the Primary Efficacy Endpoint 
Additional analyses will be performed to provide guidance to the practicing physician in the 
setting where culture results are not available. To do this, all randomized patients who received 
drug will be analyzed, this population being more consistent with what the practicing physician 
is faced with every day.  
The table below presents a family of analyses to be conducted in the micro-MITTS and micro-
MITTR populations in the sequence in which they will be conducted. The regulatory outcomes 
are focused on the primary analyses, as stated in Section 7.5.1. The secondary analyses, which 
sequentially progress towards an assessment in the randomized population prior to the benefit 
of culture data, may provide guidance to physicians who need to choose an empiric treatment 
regimen without the support of a urine culture. 
 
Analysis 
Populations 
Primary 
1. micro-MITTS 
    (if non-inferior then test #2) 
1. micro-MITTR 
    (if superior then test #2) 
Secondary 
2. NI in micro-MITT 
    (if non-inferior then test #3) 
2. NI in micro-MITT 
    (if non-inferior then test #3) 
3. Superiority in micro-MITT 
    (if superior then test #4) 
3. Superiority in micro-MITT 
    (if superior then test #4) 
4. NI in MITT*  
(if NI then test#5) 
4. NI in MITT*  
(if NI then test#5) 
5. Superiority in MITT* 
5. Superiority in MITT* 
* Based on clinical response 
To control for inflation of the overall type I error rate in assessment of the secondary analyses, 


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the hierarchical testing procedure of Westfall and Krishen (Westfall 2001) will be used to 
continue testing hypotheses of the primary efficacy endpoint.  If NI or superiority is declared 
for the primary comparisons, the secondary comparisons will be statistically tested in the order 
presented 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 test of overall success, 
∆
−
≤
−
2
1
01 :
p
p
H
  and 
∆
−
>
−
2
1
1 :
p
p
H A
 , in the micro-
MITT population. The number and percentage of patients in each treatment group with 
an overall response of success, failure, and indeterminate will be provided for the 
micro-MITT population. 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%, the null hypothesis will be rejected and the NI of sulopenem 
etzadroxil/probenecid to ciprofloxacin in the micro-MITT population will be 
concluded.  
2)   Superiority test of overall success, 
2
1
02 :
p
p
H
=
  and 
2
1
2 :
p
p
H A
≠
 , 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 
sulopenem etzadroxil/probenecid to ciprofloxacin in the micro-MITT population will 
be concluded. 
7.5.3 Additional Analyses of the Primary Efficacy Endpoint 
 
 
Subgroup Analyses 
Geographic Region (U.S. vs. non-U.S.) 
Fed / Fasted State 
Sensitivity Analyses 
Missing Data / Indeterminates Equal Success 
Multiple Imputation for Missing Data 
An analysis of the primary endpoint where microbiologic eradication contributing 
to the overall response requires complete eradication defined as no growth 
(<100 CFU/mL) of the baseline pathogen on a follow-up urine culture at TOC 
Overall response defined by improvement of symptoms (instead of resolution) 
from baseline and no worse than mild and no new uUTI symptoms 
Overall response defined by ‘urgency and frequency are improved and no worse 
than mild and all other symptoms are resolved and no new uUTI symptoms’ 
Optional Analysis - Patients with Enterobacteriaceae >105 CFU/mL as identified 
by either urine culture or a rapid PCR diagnostic test with an equivalent number 
of copies/ml  will be included in the adjusted micro-MITT population 
Optional Covariate Analysis 
All primary analyses are done at TOC in the micro-MITT populations 
 
The primary efficacy endpoint at TOC will also be assessed within each geographic region 
(U.S. vs. non-U.S.) by treatment group. For each geographic region, a 2-sided 95% CI for 
the observed difference in the overall success rates in the micro-MITTS and the micro-
MITTR populations will be calculated. 


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A sub-group analysis of the primary efficacy endpoint by fed / fasted state will be conducted.  
A patient will be considered fed if they took 100% of their doses in a fed state.    Different 
proportions of doses taken in a fed state may be explored if the analysis suggests that the fed 
state makes a difference. 
Sensitivity analyses of the primary endpoint at TOC will also be conducted in the micro-
MITTS and micro-MITTR populations. The below sensitivity analyses will be summarized 
and a 2-sided 95% unstratified CI will be computed for the difference in the success rates 
between the treatment groups. 
• 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 also 
be conducted.  The multiple imputation analysis assuming a monotone missing data 
pattern will be used to define the missing data (indeterminate response).  One hundred 
datasets will be created using a logistic regression model with treatment, clinical 
response and microbiological response at EOT, baseline pathogen and possibly other 
variables included as predictive variables. 
• An analysis of the primary endpoint where microbiologic eradication contributing to 
the overall response requires complete eradication defined as no growth (<100 
CFU/mL) of the baseline pathogen on a follow-up urine culture at TOC. 
• 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 other symptoms 
are resolved and no new uUTI symptoms.   
• An optional  analysis of the primary efficacy endpoint measure will be conducted in 
an adjusted micro-MITT population utilizing results from rapid PCR-based 
diagnostic testing.  The rapid diagnostic testing will be done on patients who did not 
meet the micro-MITT criterion of having a pathogen at baseline that was ≥105 
CFU/mL with susceptibility testing performed.  If the rapid diagnostic testing shows 
≥105 copies/mL then that pathogen will be counted as a baseline pathogen and the 
patient will be included in a new adjusted micro-MITT population.  See Appendix E 
for further details. 
• 
An optional covariate exploratory analysis using logistic regression will be performed using 
baseline variables such as study drug, bacteremia at baseline, age, gender, race, E. coli at 
baseline, creatinine clearance, albumin, comorbidities, percentage of doses taken in fed state, 
diabetes and other variables if imbalances exist at baseline.   For the latter, baseline tables 
will be reviewed by Iterum prior to the covariate analysis. 
 
Once the covariates are determined, a univariate logistic regression will be run for each 
covariate.  Covariates with a p-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. 


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7.5.4 Secondary Efficacy Analysis 
The number and percentage of patients with a per patient microbiologic response of success 
(eradication) or failure (persistence or persistence with increasing MIC), at the TOC visit will 
be determined in each treatment group in the ME-TOCS and ME-TOCR populations. The 
observed difference in percentage of patients with microbiologic success (eradication) 
(sulopenem etzadroxil/probenecid group minus the ciprofloxacin group) will be determined 
and a 2-sided 95% CI for the observed difference will be computed using the unstratified 
method of Miettinen and Nurminen. 
7.5.5 Additional Efficacy Analyses  
 
 
Analysis 
 
Day 3 
EOT 
(Day 5) 
TOC 
(Day 12) 
FV 
(Day 28) 
Overall Response 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
ME 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
ME 
Micro-MITT 
Micro-
MITTS# 
Micro-
MITTR# 
ME 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
ME 
Overall Response by Baseline 
Pathogens 
 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
ME 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
ME 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
ME 
Overall Response by MIC 
 
 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
ME 
 
Overall Response by Combination 
of Antibiotic Resistance Classes 
 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
ME 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
ME 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
ME 
Overall Response by Assessment 
Day* 
 
 
 
 
 
 
 
 
 
Overall Response with 
Requirement that Failure is Both 
Symptoms and a Pathogen ≥ 1000 
CFU/mL 
Micro-MITT 
ME 
Micro-MITT 
ME 
Micro-MITT 
ME 
 
Microbiologic Response 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
ME 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
ME 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
ME 
Per Pathogen Microbiologic 
Response 
 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
ME 
MITT 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
ME 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
ME 
Microbiologic Response by ESBL 
Positive and ESBL Negative 
 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
ME 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
ME 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
ME 
Per Pathogen Microbiologic 
Response by MIC 
 
 
Micro-MITT 
Micro-MITTS 
 


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Micro-MITTR 
ME 
Microbiologic Response for 
Complete Eradication 
 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
ME 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
ME 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
ME 
Microbiologic Response for 
Complete Eradication by Baseline 
Pathogens 
 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
ME 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
ME 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
ME 
Microbiologic Response for Post-
Baseline Pathogens 
 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
ME 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
ME 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
ME 
Patient Determined Clinical 
Response 
ITT 
MITT 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
CE 
ME 
ITT 
MITT 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
CE 
ME 
ITT 
MITT 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
CE 
ME 
ITT 
MITT 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
CE 
ME 
Patient Determined Clinical 
Response by Baseline Pathogen 
 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
ME 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
ME 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
ME 
Patient Determined Clinical 
Response by ESBL Positive and 
ESBL Negative 
 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
ME 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
ME 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
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 
Micro-MITTS 
Micro-MITTR 
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 
Micro-MITTS 
Micro-MITTR 
CE 
ME 
 
Patient Determined Clinical 
Response Failure by Symptoms 
and Bothersome Questions 
 
ITT 
MITT 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
CE 
ME 
ITT 
MITT 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
CE 
ME 
ITT 
MITT 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
CE 
ME 
Investigator-Determined Clinical 
Response 
 
ITT 
MITT 
Micro-MITT 
ITT 
MITT 
Micro-MITT 
ITT 
MITT 
Micro-MITT 


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Micro-MITTS 
Micro-MITTR 
CE 
ME 
Micro-MITTS 
Micro-MITTR 
CE 
ME 
Micro-MITTS 
Micro-MITTR 
CE 
ME 
Patient Symptom Assessment 
Questionnaire  
 
ITT 
MITT 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
CE 
ME 
ITT 
MITT 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
CE 
ME 
ITT 
MITT 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
CE 
ME 
Patient Symptom Assessment 
Questionnaire – Shift Table of 
Severity 
 
ITT 
MITT 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
CE 
ME 
ITT 
MITT 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
CE 
ME 
ITT 
MITT 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
CE 
ME 
Patient Symptom Assessment 
Questionnaire – Kaplan-Meier 
Plot for Time to Resolution of All 
Symptoms* 
 
 
 
 
Patient Symptom Assessment 
Questionnaire – Severity by 
Bothersome Questions 
 
ITT 
MITT 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
CE 
ME 
ITT 
MITT 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
CE 
ME 
ITT 
MITT 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
CE 
ME 
Patient Symptom Assessment 
Questionnaire – Sensitivity 
Analysis using bothersome 
questions 
 
ITT 
MITT 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
CE 
ME 
ITT 
MITT 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
CE 
ME 
ITT 
MITT 
Micro-MITT 
Micro-MITTS 
Micro-MITTR 
CE 
ME 
# Primary Endpoint 
*   Overall response by assessment day (not grouped by visit) and Kaplan-Meier Plot of time 
to resolution of all PSAQ symptoms are not done at individual visits and will be done in the 
micro-MITT, micro-MITTS and micro-MITTR populations. 
 
Overall Response 
The number and percentage of patients in each treatment group with an overall response of 
success, failure and indeterminate at Day 3, EOT, and FV will be presented for the micro-
MITT, micro-MITTS and micro-MITTR populations (note, overall response at TOC in the 
micro-MITTS and micro-MITTR populations are the primary endpoints). The number and 
percentage of patients in each treatment group with an overall response of success and failure 
at Day 3, EOT, TOC and FV will be presented for the ME population.  Two-sided 95% 
unstratified CIs will be constructed for the observed difference in the overall success rates 
between the treatment groups for descriptive purposes; no conclusion of NI will be made.  
Note, overall response is not analyzed in the ITT, MITT and CE populations because these 
populations do not require a baseline pathogen.  For the day 3 analysis, overall response will 


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also be presented where clinical success contributing to the overall response requires at least 
one symptom improved from BL with no symptoms worsening and no new symptoms. 
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, micro-MITTS, micro-MITTR and ME populations.  Confidence 
intervals at the genus level will be provided. 
Overall response by ciprofloxacin MIC and sulopenem MIC for baseline pathogens will be 
provided for TOC visit in the micro-MITT, micro-MITTS, micro-MITTR and ME 
populations. 
Overall Response by combination of antibiotic resistance classes will be provided.  The 
classes will be ESBL status, quinolone non-susceptible (QNS), TMP-SMX resistant, 
nitrofurantoin (NTF), non-susceptible to at least 3 classes of antibacterials (MDR – 
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 ampicillin will serve as the reference drug for the 
beta-lactam class. Resistance to a class means resistance to the reference drug in that class. 
A second table will be provided for resistance to oral drugs (ciprofloxacin, TMP-SMX, 
nitrofurantoin, ampicillin, amoxicillin-clavulanate, 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 comparing the treatment groups by day the overall 
assessment was made.  For example, if patient’s EOT assessment was conducted on day 4 
then they would be analyzed in the day 4 table.  A figure of overall response by day of 
assessment will be provided too.  
Overall response with failure defined as the patient has both symptoms and a pathogen ≥ 
1000 CFU/mL will be presented for micro-MITT and ME. 
Microbiologic Response 
The number and percentage of patients in each treatment group with a per patient 
microbiologic response of success, failure (persistence and persistence with increasing MIC) 
and indeterminate at Day 3, EOT, TOC and FV 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 per patient microbiologic response of success and failure at Day 3, 
EOT and FV will be presented for the ME population (note, microbiologic response at TOC 
in the ME-S and ME-R populations are the secondary endpoints).  Two-sided 95% 
unstratified CIs will be constructed for the observed difference in the overall success rates 
between the treatment groups for descriptive purposes; no conclusion of NI will be made. 
Per pathogen microbiologic response at EOT, TOC and FV by baseline pathogen will be 
summarized by treatment group in the micro-MITT, micro-MITTS, micro-MITTR and ME 
populations.  Confidence intervals at the genus level will be provided. 
Per pathogen microbiologic response by ciprofloxacin MIC and sulopenem MIC for 


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individual pathogens will be provided for TOC visit 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 (<100 CFU/mL) of baseline pathogen on a 
follow-up urine culture at TOC will also be presented for the micro-MITT, micro-MITTS, 
micro-MITTR and ME populations and by baseline pathogen.  The EMA endpoint requires 
<102 CFU/mL at TOC for micro-MITT.  Additionally, rows for microbiologic response <103, 
<104 and <105 will be displayed. 
Microbiological categories for pathogens identified after baseline assessment are 
superinfection, colonization, new infection and relapse/recurrence. The number and 
percentage of patients with a superinfection, colonization, new infection and recurrence will 
be presented by treatment group. A listing will be provided that presents the patients with a 
superinfection, colonization, new infection and recurrence including the pathogen. 
Patient Determined Clinical Response 
The number and percentage of patients in each treatment group with a patient-determined 
clinical response of success, failure and indeterminate at Day 3, EOT, TOC and FV will be 
presented for the micro-MITT, micro-MITTS, micro-MITTR, MITT and ITT populations. 
The number and percentage of patients in each treatment group with a patient-determined 
clinical response of success and failure at Day 3, EOT, TOC 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. For the day 3 analysis, patient determined 
clinical response will also be presented where the definition of success is at least one 
symptom improved from BL with no symptoms worsening and no new symptoms. 
Patient determined clinical response will also be presented by baseline pathogen and by 
ESBL positive/negative for EOT, TOC and FV in each treatment group for all populations.  
Confidence intervals at the genus level will be provided. 
Patient determined clinical response defined by improvement of symptoms (instead of 
resolution) from baseline and no worse than mild and no new uUTI symptoms will also be 
presented for EOT, TOC and FV 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 also 
be presented for EOT, TOC and FV in each treatment group for all populations. 
Patient determined clinical response failure by symptoms and bothersome questions will be 
presented for EOT, TOC and FV in each treatment group for all populations.  For patients 
with clinical failure, the worst severity of symptoms will be tabulated and if two symptoms 
have the same worse severity (e.g., the worst severity is moderate and two symptoms are 
moderate) then the worst bothersome category will be used for the two symptoms. 
Investigator-Determined Clinical Response 
Investigator-determined clinical response (clinical success, failure and indeterminate) at the 


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EOT, TOC and FV visits will be presented by treatment group for the micro-MITT, micro-
MITTS, micro-MITTR, CE and ME populations.  Two-sided 95% unstratified CIs will be 
constructed for the observed difference in the clinical cure rates between the treatment groups 
for descriptive purposes. 
Patient Symptom Assessment Questionnaire 
A table of the severity of each uUTI symptom based on the Patient Symptom Assessment 
Questionnaire 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 Patient Symptom 
Assessment Questionnaire 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, micro-MITTS and micro-MITTR populations.  Patients will be censored at 
time of taking non-study antibacterial therapy for uUTI. 
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. 
 
7.6 Interim Analysis 
To ensure that the point estimate of overall success (combined clinical and microbiologic 
success) used in the estimation of sample size is valid for this study, two interim analyses 
for sample size re-estimation will be performed when response data at TOC are available 
for approximately 33% and 66% of the patients (approximately 450 and 900 patients, 
respectively).  The FDA Guidance “Non-inferiority Clinical Trials” [FDA Guidance 2010] 
notes that such a sample size re-estimation if based on the blinded overall response rates 
is not only acceptable but is advisable.  The interim analysis will involve a sample size re-
estimation to either confirm the initial sample size estimate is adequate or increase the 
sample size (number of randomized patients) to ensure the study has adequate power for 
determining whether oral sulopenem etzadroxil/probenecid is NI to oral ciprofloxacin for 
the primary outcome measure in the micro-MITTS population. 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) 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) 
outcome and evaluability rates. 
The blinded interim analyses will proceed as follows: 
1. Determine the percentage of patients with a baseline pathogen (micro-MITT 


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population) 
2. Determine the percentage of patients with a susceptible (to comparator study drug, 
ciprofloxacin) pathogen (micro-MITTS population) and a non-susceptible (to 
ciprofloxacin) pathogen (micro-MITTR population) 
3. Determine the overall success rate 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. 
In addition, the micro-MITT rate (i.e. evaluability rate) and proportion of patients with a 
susceptible pathogen (micro-MITTS evaluability rate) will be used to determine the total 
number of patients needed. 
In order to determine whether the sample size is sufficient to determine if sulopenem 
etzadroxil/probenecid is superior to ciprofloxacin in the patients whose baseline pathogen 
is non-susceptible to ciprofloxacin, a conditional power analysis for the superiority 
hypothesis in the micro-MITTR population will be conducted when 66% of patients have 
been enrolled (unblinded interim analysis). A conditional power analysis using the 
approach of Lan and Wittes [Lan 1988] will be conducted to determine if the sample size 
needs to be adjusted.  The sample size adjustment would be conducted as described by 
Mehta and Pocock [Mehta 2011].  If the conditional power is <40%, no change to the 
sample size will be made.  If the conditional power is 40%-<80%, the sample size for 
micro-MITTR population will be calculated based on the observed overall success rates 
in each treatment group and increased to a maximum number.  If the conditional power is 
≥80%, no change to the sample size will be made.  The final sample size in the ITT 
population will be adjusted to take into account the proportion of patients in the micro-
MITT population and the micro-MITTR population.  No adjustment to the overall alpha 
level is needed. 
The sample size re-estimations will be conducted by an independent, unblinded 
statistician. A Data Monitoring Committee (DMC) will be provided the results of the 
interim analysis by the independent, unblinded statistician and make a recommendation 
regarding changes to the sample size.  A detailed DMC charter will be developed which 
outlines the analyses to be completed, statistical rules, the potential changes to the sample 
size, and the recommendations that can be made to the Sponsor. 
7.7 
Safety Analyses 
All safety analyses will be conducted in the Safety population. Patients who receive the 
wrong study drug for their entire course of treatment will be analyzed in the group based on 
the drug received. Safety parameters include AEs, clinical laboratory parameters and vital 
signs. For each safety parameter, the last assessment made before the first dose of study drug 
will be used as the baseline for all analyses. 
7.7.1 Adverse Events 


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Verbatim descriptions of AEs will be coded using Version 21.0 or higher of MedDRA. 
Summary tables will be provided for all treatment-emergent AEs (TEAEs). An AE is defined 
as any untoward medical occurrence in a clinical investigation patient administered a product 
or medical device, unless the event is captured in the study outcome, as defined below; the 
event need not necessarily have a causal relationship with the treatment or usage. A TEAE is 
any AE that newly appeared, increased in frequency, or worsened in severity following 
initiation of study drug (on or after start date and time of first dose).   All AEs (including 
non-TEAEs), serious TEAEs, and TEAEs leading to study drug discontinuation will be 
provided in listings by treatment group, site, patient, verbatim term, MedDRA system organ 
class and preferred terms, onset and resolution date, seriousness flag, intensity, relationship 
to study drug, action taken and outcome. 
An overall summary of AEs will include number of patients who experienced at least one 
AE of the following categories: any AE, any TEAE, any drug-related TEAE defined as 
possibly or probably related to study drug, any serious TEAE, any drug-related SAE, any 
SAE leading to death, any TEAE leading to premature discontinuation of study drug or study, 
and any SAE leading to premature study drug discontinuation. 
The number and percentage of patients reporting a TEAE in each treatment group will be 
tabulated by system organ class and preferred term for all TEAEs. TEAEs will also be 
summarized separately by system organ class, preferred term, and intensity (mild, moderate, 
and severe); and by system organ class, preferred term, and 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 group. A table will provide all SAEs (through FV) by system organ class and 
preferred term. For all analyses of TEAEs, if the same AE (based on preferred term) is 
reported for the same patient more than once, the AE is counted only once for that preferred 
term and at the highest intensity and strongest relationship to study drug. 
The incidence of treatment emergent adverse events by system organ class, preferred term 
will also be presented by gender, race and age. 
Analysis of the distribution of the duration of each adverse event as well as an overall mean 
adverse event duration in days for each treatment regimen will be presented.  If the AE is still 
ongoing at the last visit, it will be censored at the last visit. 
If an AE starts on the same day that dosing is initiated, and the start time of the AE is missing 
then the AE is considered TEAE. 
7.7.1.1 Diarrhea Episodes 
Diarrhea episodes will be collected on the adverse event page and will include verbatim terms 
of diarrhea and loose or watery stools.  An AE event will be captured each day there is an 
episode.  If there are multiple episodes on a day, the number of episodes will be captured in 
the verbatim term with an ‘X’ followed by the number of episodes (e.g., X3). 
Clinically significant diarrhea is defined as having three or more episodes of diarrhea 
(preferred term which will included loose or watery stools verbatim terms) in one day or 
having two or more episodes of diarrhea per day for two consecutive days. 
The number and percentage of treatment emergent episodes of clinically significant diarrhea 


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and number and percentage of subjects with treatment emergent clinically significant 
episodes of diarrhea will be summarized by severity level and drug relatedness. If severity 
level differs or drug relatedness differs across days, then the worst severity or the worst drug-
relatedness will be used. The duration of treatment emergent clinically significant episodes 
(i.e., the number of days that diarrhea lasts) will also be summarized. The number of 
treatment emergent clinically significant episodes and the number of subjects with clinically 
significant episodes of diarrhea will be analyzed by fed / fasted state.   
The following bar charts will be provided for diarrhea episodes: 
• Duration of Diarrhea 
• Number of Episodes of Diarrhea by Study Day 
• Percent of Subjects with Diarrhea by Study Day 
• Duration of Clinically Significant Diarrhea  
• Number of Episodes of Clinically Significant Diarrhea by Study Day 
• Percent of Subjects with Clinically Significant Diarrhea by Study Day 
 
7.7.2 Laboratory Values 
Several analyses of the laboratory data will be presented. Both local and central labs were 
performed.  Only the central lab data will be summarized.  However, if a central lab value is 
missing the local lab value will be used for the summary table.  A listing will contain all lab 
data from both local and central labs. 
For descriptive statistics of actual values and the change from baseline, values obtained from 
local laboratories will be normalized against the central laboratory normal ranges according 
to the following formula (Karvanen): 
 
 
 
where s = the individual local laboratory value normalized against the central laboratory 
normal range; x = the original individual laboratory value; Ux is the upper limit of the normal 
range for an individual laboratory parameter; Us is the upper limit of the laboratory normal 
range for that laboratory parameter from the common source. 
Descriptive statistics for chemistry and hematology values and the change from baseline will 
be summarized for all study visits. The change from baseline to each post-baseline visit will 
also be summarized by treatment group and it will be calculated for each patient at the 
specified visit as the value at the specified visit minus the baseline value.  
Laboratory values will also be classified as of potential clinical concern. The number and 
percentage of patients with a laboratory value of potential clinical concern will be 
summarized by visit and treatment group and broken out by patients with normal and 
abnormal at baseline.  Worst overall value for each test will be used for this table.  For a few 
tests, worst value can have both a low and a high value.  When calculating the worst overall 


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


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7.8 
Protocol Deviations 
A listing of all protocol deviations will be provided. Deviations will also be reviewed by the 
Sponsor concurrent with the conduct of the study and categorized into general categories 
such as: inclusion/exclusion criteria, study drug administration, informed consent, visit 
schedule, test and procedures, randomization error, and other. The deviations will be 
adjudicated as major or minor per 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). 
 
8 
DIFFERENCES WITH ANALYSES SPECIFIED IN THE PROTOCOL 
The following is the list of differences between the protocol and the SAP: 
• The additional requirement of having the disease under study has been added to the 
definition of the MITT population. 
• 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 pathogens at baseline and symptoms. 
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. 
o For CE-FV, the protocol states that a patient must be in the CE-TOC 
population.  This rule has been eliminated to include patients with assessment 
outside of the TOC window. 
• Only one micro-evaluable population is defined in the protocol.  The SAP defines 
two:  ME-S for micro-evaluable ciprofloxacin susceptible patients and ME-R for 
micro-evaluable ciprofloxacin resistant patients. 
• For microbiologic response, post baseline responses of superinfection, new infection, 
colonization and recurrence were added. 
• The analysis of diarrhea has been added. 


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• In the Additional Hypothesis Testing of the Primary Efficacy Endpoint section, the 
analysis within the MITT population has been 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 other symptoms are resolved and no new uUTI 
symptoms 
o Patients with positive cultures identified by rapid diagnostic testing will be 
included in the micro-MITT population 
o Covariate Analysis 
o Hypoalbuminemia 
 
9 
REFERENCES 
1. Farrington CP, Manning G. Test statistics and sample size formulae for comparative 
binomial trials with null hypothesis of non-zero risk difference or non-unity relative risk. 
Stat Med. 1990 Dec;9(12):1447–54. 
 
2. Miettinen O, Nurminen M. Comparative analysis of two rates. Statistics in Medicine. 
1985;4(2):213-26. 
 
3. Guidance for Industry: Non-Inferiority Clinical Trials. Draft. March 2010. 
 
4. Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation. 
July 2009. 
 
5. Guidance for Industry: Adaptive Design and Clinical Trials for Drugs and Biologics. 
Draft. March 2010. 
 
6. Karvanen J. The Statistical Basis of Laboratory Data Normalization. Drug Information 
Journal, Vol. 37, pp. 101–107, 2003. 
 
7. Ferry SA, SE Holm, H Stenlund, R Lundholm, and TJ Monsen, 2007, Clinical and 
Bacteriological Outcome of Different Doses and Duration of Pivmecillinam Compared 
With Placebo Therapy of Uncomplicated Lower Urinary Tract Infection in Women: The 
LUTIW Project, Scand J Prim Health Care, 25(1):49–57.


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Appendix A: Schedule of Activities 
 
 
SCREENING 
TREATMENT PERIOD 
FOLLOW-UP PERIOD 
 
Protocol Activity 
D-1 to D1  
 
Baseline 
D1 
 D3 
D5 
(± 1 day) 
EOT 
D12 
(± 1 day) 
TOC 
D28 
(± 2 days) 
FV 
Premature 
Discontinuation 
Informed Consent 
X 
 
 
 
 
 
 
Medical History and 
Demographics 
X 
 
 
 
 
 
 
Targeted Physical 
Examination 
X 
 
X1 
X1 
X1 
X1 
X1 
Vital Signs 
X 
 
 
X 
X 
 
X 
Hematology 
X 
 
 
 
X 
 
X 
Serum Chemistry 
X 
 
 
 
X 
 
X 
Pregnancy testing/FSH2 
X 
 
 
 
 
X 
X 
Banked serum sample 
X 
 
 
 
X 
 
 
Banked urine sample 
X 
 
X 
 
X 
 
 
Urinalysis 
X 
X 
X 
X 
X 
X 
Urine Gram stain 
X 
 
 
 
 
 
Urine Culture and  
sensitivity 
X 
 
X 
X 
X 
X 
X 
Plasma & Urine PK 
sampling for CP-
70,4293 
 
X 
 
 
 
 
 
Previous Drug and Non-
drug Treatments 
X 
 
 
 
 
 
 
Concomitant 
Medications 
 
X 
X 
X 
X 
X 
X 
Treatment  
 
          X     (BID for 5 days) 
 
 
 
Treatment Compliance 
Check 
 
 
X 
X 
 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
Patient Symptom 
Assessment 
Questionnaire 
X 
 
X 
X 
X 
X 
X 
Investigator Assessment 
of Clinical Response  
 
 
 
X 
X 
X 
X 
 
Schedule of Activities Footnotes: 
1 If needed, based on symptoms 
2     Baseline: Pregnancy test (women of childbearing potential) or serum FSH (to confirm post-menopausal status for 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; Day 28 or Premature Discontinuation: 
urine pregnancy test for women of childbearing potential only. 
3    In subset of patients enrolled in the PK sub-study, collect plasma for PK analysis 2 hours, 4 hours, and 6 hours post-dose after first oral dose, and collect 
urine for PK analysis at the following time intervals: 0-2 hours, 2-4 hours and 4-6 hours 
 
 


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Appendix B: Criteria for Safety Values of Potential Clinical Concern 
 
Hematology 
 
Hemoglobin 
<0.8 x baseline 
Hematocrit 
<0.8 x baseline 
Leukocytes 
<1.5 or >20 x 103/mm3 
Platelets 
<75 or >700 x 103/mm3 
 
Chemistry 
 
Total bilirubin 
>2 times the upper limit of the reference range 
Direct bilirubin 
>2 times the upper limit of the reference range 
AST 
>3 times upper limit of the reference range 
ALT 
>3 times upper limit of the reference range 
GGT 
>3 times upper limit of the reference range 
Alk Phosphatase 
>3 times upper limit of the reference range 
Creatinine 
>1.5 times upper limit of the reference range 
BUN/Urea 
>1.3 times upper limit of the reference range 
Sodium 
<0.95 or >1.05 times the limits of the reference range 
Potassium 
<0.9 or >1.1 times the limits of the reference range 
Calcium 
<0.9 or >1.1 times the limits of the reference range 
Albumin 
<0.8 times the lower limit of the reference range 
Total protein 
<0.8 times the lower limit of the reference range 
Creatine Kinase 
>3.0 times upper limit of the reference range 
 
Urinalysis 
 
Urine WBC 
≥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. 
For females: 
GFR = [(140-age) * (Ideal body wt in kg) * 0.85] / (72 * Cr), for serum Cr reported as 
mg/dl 
GFR = [(140-age) * (Ideal body wt in kg) * 1.0455] / (Cr), for serum Cr reported as 
micromol/L 
 
Ideal body weight is calculated as: 
For females:  
If H > 152.5 cm 
Ideal body weight (kg) = 45.4 + [(H-152.4) * 0.89] 
If H < 152.5 cm 
Ideal body weight  (kg) = 45.4 – [(152.4 – H)* 0.89] 
 
Reference: Gault MH, Longerich LL, Harnett JD, Wesolowski C (1992). "Predicting glomerular function from 
adjusted serum creatinine". Nephron. 62 (3): 249–56 
 
 
 


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Appendix D: Microbiology Rules for Determination of Final Pathogen 
 
Baseline 
 
1. Baseline urine sample is submitted for culture to: 
a. Local/Regional Lab (non-U.S.), local lab (a few U.S. sites) or Covance (all U.S. sites) 
b. IHMA (U.S. only) 
2. All baseline pathogens identified at the Local/Regional lab (non-U.S.), local lab (U.S.), Covance and 
IHMA (U.S. only) will be considered as part of the baseline urine culture result. 
a. Uropathogens as defined in section 6.4 will be sent from the Local/Regional Lab (non-U.S.) or 
Covance (U.S.) to IHMA for confirmation of genus/species and IHMA confirmation will be final   
b. Non-uropathogens not sent to IHMA or isolates not available for confirmation at IHMA will remain 
as identified by the Local/Regional Lab (non-U.S.), local lab (U.S.) or Covance. 
3. If Local/Regional Lab’s (non-U.S.), local lab (U.S.) or Covance’s urine culture yields >2 micro-
organisms in a quantity of >105 CFU/mL, this will be considered as “contaminated.” 
4. When the susceptibility status (susceptible, non-susceptible) is inconsistent between the Local/Regional 
lab (non-U.S.), local lab (U.S.), Covance, IHMA (confirmation) and IHMA (baseline urine culture, 
U.S. only) for a pathogen, PCR testing will be used to determine if the pathogen is gyrase positive or 
negative.  If it is gyrase positive then there will be two final baseline pathogens, one susceptible and 
one non-susceptible.  If it is gyrase negative, then there is one final baseline pathogen which is 
susceptible. 
 
Post-Baseline Visits 
 
1. Post-baseline urine sample is submitted for culture to Local/Regional Lab (non-U.S.) or Covance (U.S.) 
2. All pathogens identified at the local/regional lab and Covance will be considered as part of the post-
baseline urine culture result (in the case of missing culture data PCR may be used to confirm the 
presence or absence of the baseline pathogen) 
a. Uropathogens as defined in section 6.4 will be sent from the Local/Regional Lab (non-U.S.) or 
Covance (U.S.) to IHMA for confirmation and IHMA confirmation will be final   
b. Non-uropathogens not sent to IHMA or isolates not available for confirmation at IHMA will remain 
as identified by the Local/Regional Lab or Covance. 
3. If Local/Regional Lab’s or Covance’s urine culture yields >2 micro-organisms in a quantity of >105 
CFU/mL, this will be considered as “contaminated.” 
4. When the susceptibility status (susceptible, non-susceptible) is inconsistent between the Local/Regional 
lab, Covance and IHMA confirmation for a pathogen, PCR testing will be used to determine if the 
pathogen is gyrase positive or negative.  If it is gyrase positive then there will be two final post-baseline 
pathogens, one susceptible and one non-susceptible.  If it is gyrase negative, then there is one final post-
baseline pathogen which is susceptible. 
 
 
 
 
 
 
 


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Appendix E: Inclusion of OpGen (PCR) Data for Exploratory Analysis 
 
Patients that do not qualify for the micro-MITT population will have their baseline urine sample analyzed 
by PCR technology.  The results of the PCR analysis may be used in an optional analysis to determine if 
these patients will be included in the adjusted micro-MITT population. 
 
The PCR analysis detects the following pathogens:  Escherichia coli, Klebsiella pneumoniae, 
Enterococcus faecalis, Pseudomonas aeruginosa and Proteus mirabilis. The test also reports on the 
presence/absence of a variety of antibiotic resistance gene mutations, including the DNA Gyrase gene 
mutation associated with quinolone resistance for E. coli, K. pneumoniae, and P. aeruginosa.  
 
If the PCR analysis detects a E. coli, K. pneumoniae, or P. mirabilis in a quantity ≥ 100,000 CFU/ml, then 
the patient will qualify for the adjusted micro-MITT population.  When available, the results of standard 
antimicrobial susceptibility testing from the baseline urine culture will be used to define the quinolone-
susceptibility group.  When this information is not available, the presence/absence of DNA Gyrase gene 
mutation by OpGen will be used.  If the E. coli and/or K. pneumoniae DNA Gyrase gene mutation is 
detected, then the corresponding organism(s) is considered non-susceptible to ciprofloxacin.  If the DNA 
Gyrase gene mutation is not detected, then the corresponding organism(s) is considered susceptible to 
ciprofloxacin.   
 
If the OpGen test identifies 3 or more organisms in a quantity ≥ 100,000 CFU/ml in the sample, then the 
sample is considered contaminated.