Clinical trial NCT03366207
Conditions: UTI - Lower Urinary Tract Infection Antibiotic Resistant Infection
Sponsor: Iterum Therapeutics, International Limited
Start date: 2017-12-15; Completion date: 2018-10-26
Enrollment: 250 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a prospective, Phase 4, open label, multi-center study of the clinical and microbiologic efficacy of ciprofloxacin for the treatment of uncomplicated urinary tract infections in adult women.

Detailed description:

Arms: arm 1: Ciprofloxacin for the treatment of uncomplicated urinary tract infection
Interventions: intervention 1: Ciprofloxacin
Intervention descriptions: intervention 1: Ciprofloxacin 250 mg PO twice daily (BID) x 3 days for women with uUTI.

Protocol documents:
Prot_000.pdf: 
 
 
Iterum Therapeutics US Limited. 
Clinical Trial Protocol: IT-004-401 
 
Amendment 02: 27 March 2018 
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Clinical Trial Protocol: IT-004-401 
Study Title: 
A prospective, Phase 4, open label, multi-center study of the 
clinical and microbiologic efficacy of ciprofloxacin for the 
treatment of uncomplicated urinary tract infections in adult 
women. 
Study Number: 
IT-004-401 
Study Phase: 
Phase 4 
 
Product Name: 
Ciprofloxacin 
Indication: 
Uncomplicated urinary tract infection 
Investigators: 
Multicenter 
Sponsor: 
Iterum Therapeutics US Limited 
Sponsor Contact: 
Steven I. Aronin, M.D.  
Sponsor’s Legal 
Representative: 
Iterum Therapeutics US Limited 
20 Research Parkway, Suite A 
Old Saybrook, CT 06475 
 
Medical Monitor: 
 
Steven I. Aronin, M.D. 
Office: 860-661-4035 
Email: saronin@iterumtx.com 
 
Pharmacovigilance 
Iterum Therapeutics US Limited 
Pharmacovigilance 
Contact 
Steven I. Aronin, M.D. 
Office: 860-661-4035 
Mobile: 860-876-2690 
Email: saronin@iterumtx.com 
 
 
 
 
 
 
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. 
 
 
 
 
Date 
Original FINAL Protocol
September 29, 2017 


 
 
 
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SYNOPSIS 
Sponsor: 
Iterum Therapeutics US Limited 
Name of Finished Product: 
Ciprofloxacin 
Study Title: 
A prospective, Phase 4, open label, multi-center study of the clinical and microbiologic efficacy of ciprofloxacin for the 
treatment of uncomplicated urinary tract infections in adult women.  
Study Number: 
IT-004-401 
Study Phase: Phase 4 
Primary Objective(s):  
To evaluate the clinical and microbiologic response of patients with a uUTI treated with ciprofloxacin.   
Secondary Objective(s):  
To evaluate the validity of specific tests found on the urine dipstick as a screening tool to identify symptomatic patients with a 
positive urine culture, defined as growth of ≥105 CFU/mL of a uropathogen at baseline.  
Study Design:  
This prospective, Phase 4, open label, multi-center study documents the clinical and microbiologic response of adult women 
patients with uUTI treated empirically with ciprofloxacin.  Approximately 250 adult women with uUTI will receive oral 
ciprofloxacin 250 mg twice daily for 3 days.  
The primary outcome measure for efficacy evaluation will be the overall response on Day 12 (+/- 1 day). For the primary 
efficacy evaluation, these percentages will be based on a microbiologic-modified intent to treat population (m-MITT). The m-


 
 
 
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MITT population will be comprised of all patients who received at least one dose of ciprofloxacin and had ≥105 CFU/mL of a 
baseline pathogen isolated from a urine culture specimen taken at baseline, prior to initiation of ciprofloxacin therapy. 
Study Population:  
A total of approximately 250 patients are planned.   
 
 
Inclusion Criteria: 
1. Female patients ≥18 years of age with more than 24 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 collected for the purpose of diagnosing a UTI with:  
a. a dipstick analysis positive for nitrite AND 
b. a dipstick analysis positive for leukocyte esterase  
4. Has given written informed consent to participate in the study prior to Screening/Baseline (D1) 
 
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 prior effective antibacterial drug therapy for uUTI for the presenting illness unless the recovered pathogen 
demonstrates resistance to the initial antibiotic and clinical symptoms persist 


 
 
 
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3. Concurrent use of non-study antibacterial drug therapy that would have a potential effect on outcome evaluations in 
patients with uUTI  
4. Patients with ileal loops or urinary stoma 
5. Patients with an indwelling urinary catheter in the previous 30 days 
6. Patients with paraplegia 
7. Patients who are likely to receive ongoing antibacterial drug prophylaxis after treatment of uUTI (e.g., patients with 
vesico-ureteral reflux) 
8. Any history of trauma to the pelvis or urinary tract 
9. Patient's urine culture results, if available at study entry, identify more than 2 microorganisms regardless of colony 
count or a potential fungal pathogen 
10. Patient’s urine culture results, if available at study entry, identifies causative uropathogen for the presenting illness to 
be resistant to ciprofloxacin 
11. Patient has severe chronic kidney disease, or is receiving hemodialysis, or peritoneal dialysis or had a renal transplant 
12. Patient is known to have severe neutropenia 
13. Patient is known to be pregnant 
14. Patients with uncontrolled diabetes mellitus 
15. Patients with a known history of myasthenia gravis 
16. Patients who require concomitant administration of tizanidine 
17. Patients with a history of allergy to quinolones 
18. Patient is considered unlikely to survive the study period or has a rapidly progressive or terminal illness, including 
septic shock, associated with a high risk of mortality 
 


 
 
 
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Test Product, Dose, and Mode of Administration:  
Patients will receive ciprofloxacin 250 mg, to be taken by mouth twice daily for 3 days. 
 
Formulation and Packaging: 
The site Investigator or designee will provide the patient with either a pharmacy prescription or a supply for a 3 day (250 mg 
BID) course of generic ciprofloxacin for the treatment of their uUTI. The generic ciprofloxacin will be supplied by a local 
pharmacy, in the form of a filled prescription, that includes 6- 250 mg tablets of ciprofloxacin.  
Preparation and Dispensing: 
All generic ciprofloxacin will be prepared and provided to the patient via a prescribing pharmacy prescription, or, provided by 
the Investigator or designee.  
 
Administration: 
The patient will receive one 3-day treatment course of generic ciprofloxacin, with instructions to take one tablet or capsule of 
oral ciprofloxacin 250 mg twice daily beginning day 1 through 3 (+ 1 day).   
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 4 to 
receive the 6 doses of ciprofloxacin, and the EOT visit will occur on day 4 instead of day 3. 
 
 


 
 
 
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Safety Assessments 
Safety will be assessed by means of collection of adverse events.  Adverse events will be collected at every visit, beginning 
from the signing of Informed Consent.  
Efficacy Assessments: 
The assessment of clinical response includes a review of the following symptoms:   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. 
 
Statistical Methods:  
 


 
 
 
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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.  Comparisons will be made 
between response rates for patients with infection due to ciprofloxacin-susceptible and ciprofloxacin-non-susceptible isolates.  
Exploratory analyses may also be performed.  Listings of individual patient’s data will be produced. 
 
Efficacy Analyses:   
The study is designed to determine the clinical and microbiologic response of patients with a uUTI, due to ciprofloxacin-
sensitive and ciprofloxacin-non-susceptible isolates, treated with ciprofloxacin for the outcome measure of overall response 
(combined clinical and microbiologic response) at Day 12 (+/- 1 day).  
A patient will be defined as a responder 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, and analyzed as a non-responder for uUTI 
• The patient has resolution of the symptoms of uUTI present at trial entry and no new uUTI symptoms 
• Urine culture taken on Day 12 (+/- 1 day) demonstrates <103 CFU/mL of the baseline uropathogen  
 
All other patients will be considered non-responders. If data are unavailable to determine if the patient is a responder or 
non-responder, the patient will be considered an indeterminate response. 
 
The number and percentage of responders, non-responders and indeterminates will be determined. 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. In addition to the randomized m-MITT population, 
additional analyses will be performed in the subset of patients with ciprofloxacin-susceptible organisms at baseline and in 


 
 
 
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those with ciprofloxacin-non-susceptible organisms at baseline. 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 
database lock. 
 
The number and percentage of patients with a microbiologic success at the Day 12 (+/-1 day) visit will be determined. The 
validity of the urine dipstick as a screening tool to identify patients with a positive urine culture will be evaluated by 
calculating the percentage of patients with both a positive nitrite test and a positive test for pyuria on dipstick/urinalysis, who 
have ≥105 CFU/ml of a uropathogen isolated from urine culture.  Safety analyses will be conducted in all patients who receive 
any amount of ciprofloxacin.  Safety will be assessed through summaries of AEs.  
Date of Original Approved Protocol:  September 29, 2017 
Date of Most Recent Protocol Amendment (if applicable):  March 27, 2018 
 
 
 
 


 
 
 
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TABLE OF CONTENTS 
SYNOPSIS ......................................................................................................................................................2 
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 
Rationale for Study ...........................................................................................................17 
1.2.2 
Dose Rationale ..................................................................................................................18 
2 
STUDY OBJECTIVES .........................................................................................................................18 
2.1 
Objectives ...................................................................................................................................18 
3 
STUDY DESIGN..................................................................................................................................19 
3.1 
Investigational Study Medications ..............................................................................................19 
3.2 
Adjunctive Systemic Antibiotics ................................................................................................19 
3.3 
Additional, Non-Study Therapy Antibiotics ...............................................................................20 
4 
STUDY POPULATION SELECTION ................................................................................................20 
4.1 
Inclusion Criteria ........................................................................................................................20 
4.2 
Exclusion Criteria .......................................................................................................................21 
4.3 
Enrollment Criteria .....................................................................................................................22 
4.4 
Women of Child-Bearing Potential ............................................................................................22 
5 
STUDY TREATMENTS ......................................................................................................................23 
5.1 
Allocation to Treatment ..............................................................................................................23 
5.2 
Drug Supplies..............................................................................................................................23 
5.2.1 
Formulation and Packaging ..............................................................................................23 


 
 
 
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5.2.2     Preparation and Dispensing .................................................................................................24 
5.2.3 
Compliance .......................................................................................................................24 
5.3 
Drug Storage and Drug Accountability ......................................................................................24 
5.4 
Medication(s), Adjunctive Therapy and Non-drug Therapy ......................................................25 
5.4.1 
Concomitant Medications .................................................................................................25 
5.4.2 
Concomitant Antibacterial Medications ...........................................................................25 
5.4.3 
Non-drug Adjunctive Therapy ..........................................................................................25 
6 
STUDY PROCEDURES ......................................................................................................................26 
6.1 
Screening (Day 1) .......................................................................................................................26 
6.2 
Treatment Period .........................................................................................................................26 
6.2.1 
Baseline (Day 1) ...............................................................................................................26 
6.2.2   
End Of Treatment (EOT) Day 3 or 4 (+1 day) .................................................................27 
6.3 
Follow-up Period ........................................................................................................................27 
6.3.1 
Test of Cure (TOC) Day 12 (+/- 1 day) ............................................................................27 
6.3.2 
Post Test of Cure (TOC) Day 21 (+/- 3 days) ...................................................................28 
6.4 
Patient Withdrawal from Treatment or Study .............................................................................28 
7 
ASSESSMENTS ...................................................................................................................................28 
7.1 
Safety ..........................................................................................................................................28 
7.1.1 
Clinical Laboratory Assays ...............................................................................................28 
7.2 
Efficacy .......................................................................................................................................29 
7.2.1 
Overall Response ..............................................................................................................29 
7.2.2 
Microbiologic ....................................................................................................................29 
7.2.3 
Investigator-Determined Clinical Response .....................................................................30 
7.2.4 
Other Assessments ............................................................................................................31 


 
 
 
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8 
ADVERSE EVENT REPORTING.......................................................................................................31 
8.1 
Adverse Events ...........................................................................................................................31 
8.2 
Reporting Period…………………………………………………………………………...…...31 
8.3 
Definition of an AE .....................................................................................................................32 
8.4 
Abnormal Test Findings .............................................................................................................33 
8.5 
SAEs ...........................................................................................................................................33 
8.6 
Hospitalization ............................................................................................................................34 
8.7 
Severity Assessment ...................................................................................................................35 
8.8 
Causality Assessment..................................................................................................................35 
8.9 
Exposure during Pregnancy ........................................................................................................36 
8.10 
Discontinuation from Ciprofloxacin Due to AEs (See also Patient Withdrawal, Section 6.4) ..37 
8.11 
Eliciting AE Information ............................................................................................................37 
8.12 
Reporting Requirements .............................................................................................................37 
8.12.1 
SAE Reporting Requirements ...........................................................................................38 
8.12.2 
Non-SAE Reporting Requirements...................................................................................38 
8.12.3 
Sponsor Reporting Requirements to Regulatory Authorities ...........................................39 
9 
DATA ANALYSIS/STATISTICAL METHODS ................................................................................39 
9.1 
Sample Size Determination.........................................................................................................39 
9.2 
Definition of Analysis Populations .............................................................................................39 
9.3 
General Statistical Considerations ..............................................................................................41 
9.4 
Patient Characteristics .................................................................................................................41 
9.5 
Efficacy Analysis ........................................................................................................................41 
9.5.1 
Analysis of Primary Outcome Measure ............................................................................41 
9.5.1.1 
Additional Analyses of the Primary Efficacy Outcome .........................................41 


 
 
 
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9.5.2 
Analysis of Secondary Efficacy Outcome Measure .........................................................42 
9.5.3 
Analysis of Additional Efficacy Outcome Measures ........................................................42 
9.6 
Safety Analyses ...........................................................................................................................42 
9.7 
Handling of Missing Data ...........................................................................................................43 
10 QUALITY CONTROL AND QUALITY ASSURANCE ....................................................................43 
11 DATA HANDLING AND RECORD KEEPING ................................................................................44 
11.1 
Case Report Forms / Electronic Data Record .............................................................................44 
11.2 
Record Retention ........................................................................................................................44 
12 ETHICS.................................................................................................................................................45 
12.1 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..................................45 
12.2 
Ethical Conduct of the Study ......................................................................................................45 
12.3 
Patient Information and Consent ................................................................................................45 
13 DEFINITION OF END OF STUDY ....................................................................................................46 
13.1 End of Study in Participating Countries .........................................................................................46 
14 SPONSOR STUDY TERMINATION CRITERIA ..............................................................................46 
15 PUBLICATION OF STUDY RESULTS .............................................................................................47 
15.1 
Communication of Results by Iterum .........................................................................................47 
15.2 
Publications by Investigators ......................................................................................................47 
16 REFERENCE LIST ..............................................................................................................................49 
 
 
 


 
 
 
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LIST OF APPENDICES 
Appendix 1 
Schedule of Activities ...........................................................................................................50 
Appendix 2 
Microbiology.........................................................................................................................52 
Appendix 3 
Patient Symptom Assessment Questionnaire (PSAQ) ..........................................................53 
Appendix 4      Ciprofloxacin Tablets – USPI ...............................................................................................55 
Appendix 5     Summary of Changes ............................................................................................................59 
Appendix 6     Investigator’s Signature ........................................................................................................60 
 
 
 
 
 
 
 


 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
AUC0-24 
Area under the curve from zero to 24 hours 
βhCG 
Beta Human Chorionic Gonadotropin 
BUN 
Blood Urea Nitrogen 
Cmax 
Maximum concentration 
CA 
Community-acquired 
CBC 
Complete Blood Count 
CE 
Clinically Evaluable 
CI 
 
CLSI 
 
Confidence Interval 
 
Clinical and Laboratory Standards Institute 
 
CrCl 
Creatinine Clearance 
CRF 
Case Report Form 
CTA 
Clinical Trial Application 
ECG 
Electrocardiogram 
E.coli 
Escherichia coli 


 
 
 
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EIU 
 
EOT 
 
ESBL 
Exposure in Utero 
 
End of Treatment Visit 
 
Extended Spectrum Beta-lactamase 
 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating Hormone 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl Transpeptidase 
GMP 
Good Manufacturing Practice 
HIV 
 
HPF 
Human Immunodeficiency Virus  
 
High Power Field 
hs-CRP 
High-sensitivity C-reactive Protein 
ICH 
International Conference on Harmonisation 
ICF 
Informed Consent Form 
IRB/IEC 
Institutional Review Board /Independent Ethics Committee  
ITT 
Intent-to-Treat 
IUD 
Intrauterine Device 
IV 
Intravenous 
IWRS 
Interactive Web Randomization System  


 
 
 
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LDH 
 
LTFU 
Lactate Dehydrogenase 
 
Lost to Follow-Up 
 
ME 
 
MIC 
 
MITT 
 
mMITT 
 
Microbiologically Evaluable 
 
Minimal Inhibitory Concentration 
 
Modified ITT (MITT) 
 
Micro-MITT (mMITT) 
NI 
Non-inferior 
PK 
Pharmacokinetic 
PK/PD 
Pharmacokinetic / Pharmacodynamic 
SAE 
Serious Adverse Event 
SAP 
 
TOC 
 
Statistical Analysis Plan 
 
Test of Cure 
 
Tmax 
Time to maximum concentration 
uUTI 
Uncomplicated urinary tract infection 
WBC 
White Blood Cell 
 


 
 
 
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1 
INTRODUCTION 
1.1 
Indication 
Ciprofloxacin is being studied for the treatment of the following indications: 
 
- 
Uncomplicated urinary tract infections 
 
 
1.2 
Background and Rationale 
1.2.1 
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. 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.  Furthermore, the prevalence of infections caused by 
extended-spectrum β-lactamase (ESBL) producing Enterobacteriaceae has been increasing worldwide. 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 fluoroquinolones. Data reported by the European Antimicrobial Resistance 
Surveillance Network (EARS-NET) in Europe demonstrate that the prevalence of fluoroquinolone resistant E. coli and E. coli resistant 
to third-generation cephalosporins is > 25% and E. coli resistant to third generation cephalosporins, aminoglycosides and 
fluoroquinolones has increased to >10% in some southern and eastern European countries. Oral antibiotic treatment options are 
extremely limited for patients with these 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 


 
 
 
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producing organisms include nitrofurantoin, fosfomycin, fluoroquinolones and trimethoprim-sulfamethoxazole. Nitrofurantoin and 
fosfomycin are only approved for the treatment of uncomplicated urinary tract infections in the United States, have rising rates of 
resistance and are associated with inferior efficacy [Munoz-Davila 2014; Schito 2009]. Resistance to trimethoprim-sulfamethoxazole 
is uniformly above 20% in the US. Increasing prevalence of resistance to fluoroquinolones and their propensity to cause collateral 
damage resulted in relegation of fluoroquinolones to second-line therapy by the Infectious Disease Society of America (IDSA) for 
UTI [Gupta 2011].  Even with these limitations, almost two-thirds of patients with a uUTI receive therapy with a fluoroquinolone 
antibiotic.  Furthermore, there is a percentage of uUTI patients treated with a fluoroquinolone who respond to therapy despite 
predicted failure based upon the results of in vitro susceptibility testing. The reason for this is likely multifactorial, including PK/PD 
relationships (i.e., concentration and duration of drug at the site of infection) and host factors.  The proportion of patients with 
infection due to fluoroquinolone resistant pathogens who have clinical or bacteriological response to fluoroquinolone therapy has not 
been well studied, and most studies which have evaluated this issue have done so as part of a secondary analysis of a UTI treatment 
trial. 
 
1.2.2 
Dose Rationale  
Ciprofloxacin 
The recommended dose of ciprofloxacin for the treatment of uncomplicated UTI is 250 mg twice daily by mouth for 3 days, per the 
Ciprofloxacin USPI and Ciprofloxacin SmPC.  
2 
STUDY OBJECTIVES 
2.1 
Objectives 
The primary objective of this study is to evaluate the clinical and microbiologic response of patients with a uUTI treated with 
ciprofloxacin.     
The secondary objective of this study is to evaluate the validity of specific tests found on the urine dipstick as a screening tool to 
identify symptomatic patients with a positive urine culture, defined as growth of ≥105 CFU/mL of a uropathogen at baseline. 


 
 
 
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3 
STUDY DESIGN 
This prospective, Phase 4, open label, multi-center study documents the clinical and microbiologic response of adult women patients 
with uUTI treated empirically with ciprofloxacin.   Since UTIs in males are classified as complicated, males will not be included in 
this study. Approximately 250 adult women with uUTI will receive oral ciprofloxacin 250 mg twice daily for 3 days.  
The primary outcome measure for efficacy evaluation will be the overall response on Day 12 (+/- 1 day).  For the primary efficacy 
evaluation, these percentages will be based on a microbiologic-modified intent to treat population (m-MITT). The m-MITT population 
will be comprised of all patients who received at least one dose of ciprofloxacin and had ≥105 CFU/mL of a baseline pathogen isolated 
from a urine culture specimen taken at baseline, prior to initiation of ciprofloxacin therapy. 
 
See Appendix 1, Schedule of Activities Table. 
 
3.1 
Investigational Study Medications 
Patients who present with uUTI symptoms, have a urine dipstick analysis positive for both leukocyte esterase AND nitrite who meet 
all of the inclusion and none of the exclusion criteria, and who agree to participate in the study, will be treated for their uUTI with 
ciprofloxacin.   
The ciprofloxacin, or a pharmacy prescription for ciprofloxacin, will be provided to the patient by the enrolling study site.  
Patients will be asked to take one 250 mg tablet or capsule twice daily (day 1 to 3 + 1 day) for 3 days.  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 4 to complete the 6 doses of ciprofloxacin, 
and the EOT visit will occur on day 4 instead of day 3.   
3.2 
Adjunctive Systemic Antibiotics 
None allowed 


 
 
 
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3.3 
Additional, Non-Study Therapy Antibiotics 
Concurrent use of non-study antibacterial drug therapy is permitted only if the therapy would not have a potential effect on outcome 
evaluations in patients with uUTI. 
4 
STUDY POPULATION SELECTION 
Female patients who present with uUTI and who have a urine dipstick positive for both 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 more than 24 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 collected for the purpose of diagnosing a UTI with:  
a. a dipstick analysis positive for nitrite AND 
b. a dipstick analysis positive for leukocyte esterase  
 
4. Has given written informed consent to participate in the study prior to Screening/Baseline (D1). 


 
 
 
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4.2 
Exclusion Criteria 
1. Presence of signs and symptoms suggestive of acute pyelonephritis: fever (temperature > 38°Celsius), chills, costovertebral 
angle tenderness, flank pain, nausea and/or vomiting 
2. Receipt of prior effective antibacterial drug therapy for uUTI for the presenting illness unless the recovered pathogen 
demonstrates resistance to initial antibiotic and clinical symptoms persist 
3. Concurrent use of non-study antibacterial drug therapy that would have a potential effect on outcome evaluations in patients 
with uUTI  
4. Patients with ileal loops or urinary stoma 
5. Patients with an indwelling urinary catheter in the previous 30 days 
6. Patients with paraplegia 
7. Patients who are likely to receive ongoing antibacterial drug prophylaxis after treatment of uUTI (e.g., patients with vesico-
ureteral reflux) 
8. Any history of trauma to the pelvis or urinary tract 
9. Patient's urine culture results, if available at study entry, identify more than 2 microorganisms regardless of colony count or 
patient has a potential fungal pathogen 
10. Patient’s urine culture results, if available at study entry, identifies the causative uropathogen for the presenting illness to be 
resistant to ciprofloxacin 
11. Patient has severe chronic kidney disease, or is receiving hemodialysis or peritoneal dialysis or had a renal transplant 
12. Patient is known to have severe neutropenia 


 
 
 
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13. Patient is known to be pregnant 
14. Patients with uncontrolled diabetes mellitus 
15. Patients with a known history of myasthenia gravis 
16. Patients who require concomitant administration of tizanidine 
17. Patients with a history of allergy to quinolones  
18. Patient is considered unlikely to survive the study period or has a rapidly progressive or terminal illness including septic shock 
which is associated with a high risk of mortality 
4.3 
Enrollment Criteria 
Patients will be enrolled into the study to receive ciprofloxacin provided they have satisfied all patient selection criteria.   
4.4 
Women of Child-Bearing Potential 
If the patient is a woman of childbearing potential, she and any male partner are required to simultaneously use 2 effective 
contraceptive methods, from the following list of 5: 
1. A barrier (condoms, diaphragm or cervical cap) with spermicide; 
2. A second, different barrier method (condoms, diaphragm or cervical cap); 
3. Oral or similar contraceptive, which includes, but is not limited to: injectable, implanted, or patch hormone therapy, and 
intrauterine device (IUD) at least 7 days prior to baseline; 
4. Documented surgical sterilization at least 4 weeks prior to baseline; 
5. Partner vasectomy at least 6 months prior to baseline. 
 


 
 
 
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She and any male partner must agree to continue all of these contraceptive methods until the TOC 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. 
 
Women of childbearing potential include those that meet one of the following criteria: 
• Females who are <45 years of age and have not had a documented hysterectomy, tubal ligation and/or bilateral oophorectomy 
• Females who are >45 years of age and have not been amenorrheic for at least 1 year 
 
5 
STUDY TREATMENTS 
5.1 
Allocation to Treatment 
This is a non-randomized, open label, multi-center study of oral ciprofloxacin in the treatment of uUTI. Approximately 250 female 
patients with uUTI will be administered oral ciprofloxacin twice daily for 3 days. Patients who withdraw prior to initial dose, will be 
replaced to ensure all 250 patients have received at least a single-dose of ciprofloxacin. 
 
A patient will be eligible for the study once it has been determined that she meets all inclusion criteria and has none of the exclusion 
criteria.  
 
5.2 
Drug Supplies 
5.2.1 
Formulation and Packaging 
The site Investigator or designee will provide the patient with a pharmacy prescription or a supply for a 3 day (250 mg BID) course of 
generic ciprofloxacin for the treatment of their uUTI. 


 
 
 
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5.2.2     Preparation and Dispensing 
The patient will receive one 3-day treatment course of generic ciprofloxacin, with instructions to take one tablet or capsule of oral 
ciprofloxacin 250 mg twice daily beginning day 1 through 3 (+ 1 day).   
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 4 to receive the 
6 doses of ciprofloxacin, and the EOT visit will occur on day 4 instead of day 3. 
5.2.3 Compliance 
All patients should be informed that compliance with taking all oral medication 
as instructed is imperative. A site designee will phone the patient or the pharmacy on Day 1 to ensure that the prescription of 
ciprofloxacin was picked up and the first dose was taken.  This phone call should be documented in the patient's source and include 
the date and estimated time the patient took the initial dose. 
Patients will receive a dosing diary on Day 1 and asked to record the dosing administration for the duration of the treatment period.  
The total amount of oral dosing completed during the treatment period will be documented in the CRF.  
5.3 
Drug Storage and Drug Accountability  
Drug should be stored by the patient according to the guidance provided by the site or pharmacy. For drug accountability, the site will 
provide the patient with a diary to collect daily ingestion of ciprofloxacin.  The patient should return the diary to the clinic along with 
the prescription bottle/container after completion of their ciprofloxacin course of treatment. Site staff will keep diary in source and 
record in the CRF.  


 
 
 
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5.4 
Medication(s), Adjunctive Therapy and Non-drug Therapy 
5.4.1 
Concomitant Medications 
Any medication taken by the patient, other than ciprofloxacin, is considered a concomitant medication.  Any concomitant medication 
which is administered from Screening through the TOC Visit must be recorded in the patient's source record.    
Any concomitant medication which is an antibiotic, administered for the treatment of the primary uUTI, should also be recorded in the 
CRF.  No other concomitant medications need to be recorded in the CRF. 
At each visit, the Investigator or site designee will obtain information on any therapeutic interventions (e.g., drug and non-drug 
therapy, surgery, etc.) provided.  The use of any investigational drug is prohibited and patients may not participate in any other studies 
involving other marketed products concomitantly while in this study.  
The use of other (non-antibacterial) medications should be limited to those essential for the care of the patient.  All medications 
required by the patient to manage underlying illnesses, other than the infection under study, and any drugs that may be required for 
emergency treatments must be recorded in the source document.   
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 ciprofloxacin is not permitted.  
Dosing with food does not affect the overall absorption of ciprofloxacin. 
5.4.2 
Concomitant Antibacterial Medications 
Concomitant systemic antibacterials are prohibited during the study, up to the TOC visit, unless it has been determined that the 
antibacterial would not have a potential effect on outcome evaluations in patients with uUTI. 
5.4.3 
Non-drug Adjunctive Therapy 
None allowed 


 
 
 
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6 
STUDY PROCEDURES 
6.1 
Screening (Day 1)  
If a patient is presenting with uUTI symptoms and has a positive dipstick for leukocyte esterase AND nitrite, and all other Inclusion 
and no Exclusion criteria are met then 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.  
The following procedures will be performed prior to ciprofloxacin administration: 
• Demographics and medical history 
• Temperature reading  
• Collect Height and Weight   
• Collect urine for dipstick analysis. If done at an outside institution, then repeat testing. 
• Review previous drug and non-drug treatments (defined as within the past 30 days) and concomitant drug treatments 
• Adverse events occurring after signing of ICF 
• Administer and collect patient assessment questionnaire from patient (Appendix 3) 
 
6.2 
Treatment Period  
 
6.2.1 
Baseline (Day 1)  
The following activities will be completed: 
• Collect urine for urinalysis, and urine culture and sensitivity 


 
 
 
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• Issue prescription of generic ciprofloxacin  
• Check and document compliance with study medication (phone call) 
• Distribute patient dosing diary  
 
6.2.2  
End Of Treatment (EOT) Day 3 or 4 (+1 day)  
• Collect urine for culture and sensitivity  
• Review concomitant medications 
• Check and document compliance with study medication 
• Collect patient dosing diary  
• Assess symptoms by spontaneous reporting of adverse events and by asking the subjects to respond to a non-leading 
question such as “How do you feel? 
• Administer and collect patient assessment questionnaire from patient (Appendix 3) 
• Investigator-Determined Assessment of Clinical Response (Section 7.2.3) 
 
6.3 
Follow-up Period  
6.3.1 
Test of Cure (TOC) Day 12 (+/- 1 day)  
• Collect urine for culture 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 assessment questionnaire from patient (Appendix 3) 
• Investigator-Determined Assessment of Clinical Response (Section 7.2.3) 
 


 
 
 
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6.3.2 
Post Test of Cure (TOC) Day 21 (+/- 3 days)  
Call patient to assess for resolution of uUTI symptoms  
 
6.4 
Patient Withdrawal from Treatment or Study 
Patients may withdraw from the study or ciprofloxacin at any time at their own request, or they may be withdrawn at any time at the 
discretion of the Investigator or Iterum Therapeutics 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 ciprofloxacin 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 TOC. 
If the patient withdraws from the study, and also withdraws consent for disclosure of future information, no further study-specific 
evaluations should be performed, and no additional data should be collected.  Iterum Therapeutics may retain and continue to use any 
data collected before such withdrawal of consent. 
7 
ASSESSMENTS 
7.1 
Safety 
7.1.1 
Clinical Laboratory Assays 
No additional laboratory testing will be performed beyond routine urine testing for uUTI. 
 


 
 
 
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7.2 
Efficacy 
7.2.1 
Overall Response 
Overall Response is assessed on Day 12 (+/- 1 day) TOC using the definitions listed below: 
 
A patient will be defined as a responder if the following criteria are met (programmatically, based on the data on the CRF): 
• 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, and analyzed as a non-responder for uUTI 
• The patient has resolution of the symptoms of uUTI present at trial entry and no new uUTI symptoms 
• Urine culture taken on Day 12 (+/- 1 day) demonstrates <103 CFU/mL of the baseline uropathogen 
All other patients will be considered non-responders. If data are unavailable to determine if the patient is a responder or non-
responder, the patient will be considered as having an indeterminate response. 
 
7.2.2 
Microbiologic 
Microbiologic Response is assessed on Day 3 or 4 (+1 day) EOT and Day 12 (+/- 1 day) TOC using the definitions listed below: 


 
 
 
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Microbiological response 
Definition 
Eradication 
A urine culture taken at baseline and compared with the culture from the EOT 
visit or TOC visit showed that the urine culture obtained at the relevant visit 
demonstrated <103 CFU/mL of the original uropathogen.  
Persistence  
A uropathogen present at baseline grew at ≥103 CFU/mL at the time-point of 
analysis, i.e. EOT or TOC. 
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 EOT or the TOC visit. 
 
7.2.3 
Investigator-Determined Clinical Response 
Investigators will use the definitions below to document clinical response at Day 3 or 4 (+ 1 day) (EOT) and Day 12 (+/- 1 day) 
(TOC): 
Clinical response 
Definition 
Clinical cure 
All pre-therapy signs and symptoms of the index infection had resolved such that no 
additional antibiotics were required 
Clinical failure 
Patients who met any one of the criteria below were considered as failure: 
Death related to uUTI prior to Day 3 or Day 12 respectively 
No apparent response to treatment; persistence or progression of most or all pre-
therapy signs and symptoms or use of additional antibiotics for the current infection 
Patient previously met criteria for failure  


 
 
 
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Clinical response 
Definition 
Indeterminate 
Study data were not available for evaluation of efficacy for any reason, including: 
Patient lost to follow-up or assessment not undertaken such that a determination of 
clinical response could not be made at either the EOT or TOC visit 
Death prior to EOT visit or Day 12, respectively, where uUTI was clearly 
noncontributory 
 
7.2.4 
Other Assessments 
Patients will score their symptoms and record them on a Patient Symptom Assessment Questionnaire (Appendix 3). 
8 
ADVERSE EVENT REPORTING 
8.1 
Adverse Events 
All observed or volunteered AEs, regardless of suspected causal relationship, 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.  For all 
AEs, sufficient information should be obtained by the Investigator to determine the causality of the AE.  The Investigator is required 
to assess causality.  All AEs will be followed-up by the Investigator until the event or its sequelae resolve or stabilize at a level 
acceptable to the Investigator, and Iterum concurs with that assessment. 
8.2 
Reporting Period 
Adverse events will be collected from the time that the patient provides informed consent through TOC.  


 
 
 
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For SAEs, the reporting period to Iterum Therapeutics begins from the time that the patient signed informed consent, which may be 
prior to the patient’s participation in the study, i.e., prior to undergoing any study-related procedure through the TOC.   Any SAE 
occurring any time after the reporting period must be promptly reported if a causal relationship to investigational product is suspected 
All AEs should be recorded on the CRF if they occur from the time the patient provides informed consent through TOC. 
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 include all of the following: 
• Symptoms of uUTI have not resolved from Baseline to such an extent that new antibiotics are not 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:   
• Clinically significant symptoms and signs; 
• Hypersensitivity; 
• Progression/worsening of underlying disease.  
 
Additionally, they may include the signs or symptoms resulting from: 


 
 
 
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• Drug overdose; 
• Drug withdrawal; 
• Drug abuse; 
• Drug misuse;  
• Drug interactions; 
• Drug dependency; 
• Exposure during Pregnancy. 
 
8.4 
Abnormal Test Findings 
No additional laboratory testing will be performed beyond urine testing for uUTI.  
8.5 
SAEs 
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; 
• 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. 


 
 
 
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8.6 
Hospitalization 
Adverse events associated with hospitalization are considered serious.  Admission also includes transfer within the hospital (e.g., from 
the psychiatric wing to a medical floor). 
Hospitalization does not include the following: 
• Rehabilitation facilities; 
• Hospice facilities; 
• Respite care (e.g., caregiver relief); 
• Skilled nursing facilities; 
• Nursing homes; 
• Routine emergency room evaluation; 
• Same day surgeries (as outpatient/same day/ambulatory procedures). 
 
Hospitalization 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. 


 
 
 
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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 applicable.  An Investigator’s causality assessment is the determination of whether there exists a reasonable possibility 
that the ciprofloxacin caused or contributed to an AE.  If the Investigator does not know whether or not ciprofloxacin caused the event, 
then the event will be handled as “related to ciprofloxacin” for reporting purposes, as defined by Iterum Therapeutics (see Section 8.12 
on Reporting Requirements).  If the Investigator's causality assessment is "unknown but not related to ciprofloxacin", 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 ciprofloxacin. 


 
 
 
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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 ciprofloxacin based on the following defined criteria:  
• UNRELATED: No relationship between the event and medicinal product 
• UNLIKELY: Event with a time to drug intake that makes a relationship improbable (but not impossible); Disease or other drugs 
provide plausible explanations 
• POSSIBLY: Event 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 with reasonable time relationship to drug intake; Unlikely to be attributed to disease or other drugs; Response 
to withdrawal clinically reasonable; Re-challenge not required 
 
8.9 
Exposure during Pregnancy 
Ciprofloxacin is Pregnancy Category C, indicating that there are no adequate and well-controlled studies of ciprofloxacin in pregnant 
women. Ciprofloxacin should not be used during pregnancy unless the potential benefit justifies the potential risk to both fetus and 
mother. An expert review of published data on experiences with ciprofloxacin use during pregnancy by TERIS–the Teratogen 
Information System–concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk, but the data 
are insufficient to state that there is no risk.   
 
If any study patient becomes or is found to be pregnant during the study, patient’s treatment with ciprofloxacin, the investigator must 
complete a Med Watch Form FDA 3500 and submit it by email to Iterum Therapeutics.   The decision to continue ciprofloxacin, stop 
ciprofloxacin, or switch to an alternative agent will be left to the discretion of the Investigator.  
 


 
 
 
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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.   
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]), Iterum Therapeutics will 
submit the Med Watch Form FDA 3500 to the FDA and to the manufacturer of ciprofloxacin.  
 
8.10 Discontinuation from Ciprofloxacin Due to AEs (See also Patient Withdrawal, Section 6.4) 
Discontinuation from ciprofloxacin 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 ciprofloxacin due to an SAE, the SAE must be reported in accordance with the reporting requirements 
defined below. 
8.11 Eliciting AE Information 
The Investigator is to report all directly observed AEs and all AEs spontaneously reported by the study patient from informed consent 
through the TOC.  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 
Iterum Therapeutics to be at least possibly related to ciprofloxacin, the Investigator must complete a Med Watch Form FDA 3500 and 
submit it by email to Iterum Therapeutics who will then submit the Med Watch Form FDA 3500 to the FDA and to the manufacturer 
of ciprofloxacin.  
 


 
 
 
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8.12.1 SAE Reporting Requirements 
If an SAE or exposure during pregnancy occurs, Iterum Therapeutics is to be notified within 24 hours of awareness of the event by the 
Investigator on a Med Watch Form FDA 3500.  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 Therapeutics 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 
Med Watch Form FDA 3500.  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 by email to Iterum Therapeutics.  The 
information should be reported on a Med Watch Form FDA 3500 and sent to Iterum Therapeutics.  
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.  Serious 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 serious unexpected adverse reactions, will be carried out in accordance with 
applicable local regulations.  Death and life-threatening Suspected Unexpected Serious Adverse Reactions (SUSARs) are subject to 
expedited reporting within a 7 calendar day (life-threatening and fatal) or 15 calendar day (all other SUSARs) timeframe.  
  
9 
DATA ANALYSIS/STATISTICAL METHODS 
9.1 
Sample Size Determination 
The study is designed to determine the clinical and microbiologic efficacy of ciprofloxacin for adult female patients with uUTI, due to 
either a ciprofloxacin susceptible or non-susceptible organism. Two-hundred fifty (250) symptomatic patients will be enrolled with the 
expectation that there will be no screen failures.  Of the 250 enrolled patients, we expect 50 will not have a positive urine culture for 
≥105 CFU/mL of a uropathogen at baseline.   Of the 250 enrolled patients, we expect 40 will have a uUTI due to a ciprofloxacin non-
susceptible organism.  
 
Patients who withdraw prior to initial dose, will be replaced to ensure all 250 patients have received at least a single-dose of 
ciprofloxacin.   
 
 
 
9.2 
Definition of Analysis Populations 
1. Intent-to-Treat (ITT): all randomized patients regardless of whether or not the patient received ciprofloxacin 
2. Modified ITT (MITT): randomized patients who received at least a single-dose of ciprofloxacin 
3. Safety: randomized patients who received any amount of ciprofloxacin 


 
 
 
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4. Micro-MITT (mMITT): All MITT patients with a positive study entry urine culture defined as ≥105 CFU/mL of a 
uropathogen and no more than 2 species of microorganisms identified in the study entry urine culture, regardless of colony 
count.  
5. Clinically evaluable: 
1)  Clinically evaluable (CE) at the EOT and TOC visits population:  
a) Received a minimum number of days of ciprofloxacin (to be defined in the Statistical Analysis Plan [SAP]) 
b) Had no important protocol deviations that would affect the assessment of efficacy (to be defined in the SAP) 
c) Had an  outcome assessment of clinical cure or failure (and not indeterminate) at the EOT, or TOC visits (i.e., within the 
protocol allowed visit window), respectively.   
d) Had not received prior antibiotic before the initiation of study therapy for this infection unless the recovered pathogen 
demonstrates resistance to initial antibiotic and clinical symptoms persist 
e) Did not receive any antibiotic therapy with potential activity against any of the baseline uropathogens collected at 
screening between the time of the baseline culture and the EOT or TOC 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 ciprofloxacin are allowed to receive agents with 
narrow spectrum gram-positive coverage (i.e., such as linezolid or vancomycin) 
f) Had a study entry urine culture obtained before ciprofloxacin administration  
 
2) Microbiologically evaluable (ME): all patients included in both the micro-mITT and CE populations at the (ME-EOT), 
and at the TOC visit (ME-TOC) and have an appropriately collected urine culture specimen and interpretable urine culture 
result at the EOT, and TOC 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.  Comparisons will be made between response rates for 
patients with infection due to ciprofloxacin-susceptible and ciprofloxacin-non-susceptible isolates.  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 final database lock. 
 
9.4 
Patient Characteristics 
Enrollment, protocol deviations, discontinuations from the ciprofloxacin and withdrawal from the study will be summarized.  
Demographics (age, race, sex), medical and surgical history, baseline assessment of the symptoms of uUTI, microbiological 
assessment of the urine, and ciprofloxacin administration will also be summarized.     
 
9.5 
Efficacy Analysis 
9.5.1 
Analysis of Primary Outcome Measure 
The primary outcome is overall response (clinical plus microbiologic) at the Day 12 (+/- 1 day) visit in the m-MITT population. The 
number and percentage of responders, non-responders and indeterminates will be determined.   
 
9.5.1.1 
Additional Analyses of the Primary Efficacy Outcome 
In addition to the overall response rate, response rates for patients infected by ciprofloxacin susceptible and non-susceptible organism 
will be evaluated.   
 


 
 
 
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9.5.2 
Analysis of Secondary Efficacy Outcome Measure 
All symptomatic subjects enrolled in the study will have a positive urine dipstick for both leukocyte esterase and nitrite.  The number 
and percentage of subjects who go on to have a positive baseline urine culture for >100,000 CFU/mL of a uropathogen will be 
evaluated.  
 
9.5.3 
Analysis of Additional Efficacy Outcome Measures 
The number and percentage of subjects treated with ciprofloxacin with an overall response of responder, non-responder, and 
indeterminate (by definition subjects with an indeterminate response are excluded the ME population) at the TOC visit will be 
presented for the m-MITT and ME-TOC populations.   
Investigator determined clinical response (clinical cure, failure and indeterminate) at the Day 3 or 4 (+ 1 day) (EOT) and TOC Visits 
will be presented for the m-MITT, CE, and ME populations.  The number and percentage of subjects with a microbiologic response 
of eradication, persistence, persistence with increasing MIC, and indeterminate (by definition subjects with an indeterminate response 
are excluded from the ME populations) will be presented for the following time points and analysis populations: 
• Day 3 or 4 (+ 1 day) (EOT) in the m-MITT and ME-EOT populations 
• Day 12 in the m-MITT and ME-Day12 populations 
Overall response and microbiologic eradication at the EOT and TOC visits by baseline pathogen (key pathogens) will be summarized 
in the m-MITT and ME populations.  
9.6 
Safety Analyses 
Safety will be assessed through summaries of AEs.  All safety analyses will be based on the Safety population.   
Summary tables of treatment-emergent AEs (TEAEs) will be provided.  A TEAE is any AE that newly appeared, increased in 
frequency, or worsened in severity following initiation of ciprofloxacin.  The incidence of TEAEs will be tabulated by system organ 


 
 
 
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class and preferred term, and by severity and relationship to treatment.  Tables of TEAEs leading to ciprofloxacin discontinuation, 
withdrawal from the study or an SAE will be provided.  AEs occurring prior to the first dose of ciprofloxacin (AEs are recorded from 
the time of informed consent) will be provided in a listing. 
9.7 
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) 
visit, the patient will be considered an indeterminate response. By definition, patients with an indeterminate response are included 
in the denominator in the m-MITT population and thus, are analyzed in the same manner as non-responders and persistence.   
Additional sensitivity analyses for handling missing data will be detailed in the SAP.  By definition, patients with missing data are 
excluded from the CE populations. 
 
10 QUALITY CONTROL AND QUALITY ASSURANCE 
During study conduct, Iterum or its agent will conduct periodic monitoring visits to ensure that the protocol and GCPs are being 
followed.  The monitors may review source documents to confirm that the data recorded on CRFs are accurate.  The Investigator and 
institution will allow Iterum monitors or its agents and appropriate regulatory authorities direct access to source documents to perform 
this verification. 
The study site may be subject to review by the institutional review board (IRB)/independent ethics committee (IEC), and/or to quality 
assurance audits performed by Iterum, or companies working with or on behalf of Iterum, and/or to inspection by appropriate 
regulatory authorities. 
It is important that the Investigator(s) and their relevant personnel are available during the monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process. 


 
 
 
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11 DATA HANDLING AND RECORD KEEPING 
11.1 Case Report Forms / Electronic Data Record 
As used in this protocol, the term CRF should be understood to refer to either a paper form or an electronic data record or both, 
depending on the data collection method used in this study. 
A CRF is required and should be completed for each included patient.  The completed original CRFs are the sole property of Iterum 
and should not be made available in any form to third parties, except for authorized representatives of Iterum or appropriate regulatory 
authorities, without written permission from Iterum. 
The Investigator has ultimate responsibility for the accuracy, authenticity, and timely collection and reporting of all clinical, safety, 
laboratory data entered on the CRFs and any other data collection forms.  The CRFs must be signed by the Investigator or by an 
authorized staff member to attest that the data contained on the CRFs are true.  Any corrections to entries made in the CRFs and 
source documents must be dated, initialed and explained (if necessary) and should not obscure the original entry.  
In most cases, the source documents are the hospital's or the physician's patient chart.  In these cases, data collected on the CRFs must 
match the data in those charts.  
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these cases, a document should be available at 
the Investigator’s site as well as at Iterum and clearly identify those data that will be recorded in the CRF, and for which the CRF will 
stand as the source document. 
11.2 Record Retention 
To enable evaluations and/or audits from regulatory authorities or Iterum, the Investigator agrees to keep records, including the 
identity of all participating patients (sufficient information to link records, e.g., CRFs and hospital records), all original signed 
informed consent forms, copies of all CRFs, SAE forms, source documents, and detailed records of treatment disposition, and 
adequate documentation of relevant correspondence (e.g., letters, meeting minutes, telephone call reports).  The records should be 
retained by the Investigator according to ICH, local regulations, or as specified in the Clinical Study Agreement, whichever is longer. 


 
 
 
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If the Investigator becomes unable for any reason to continue to retain study records for the required period (e.g., retirement, 
relocation), Iterum should be prospectively notified.  The study records must be transferred to a designee acceptable to Iterum, such as 
another Investigator, another institution, or to Iterum.  The Investigator must obtain Iterum's written permission before disposing of 
any records, even if retention requirements have been met. 
12 ETHICS 
12.1 Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
It is the responsibility of the Investigator to have prospective approval of the study protocol, protocol amendments, informed consent 
forms, and other relevant documents, e.g., recruitment advertisements, if applicable, from the IRB/IEC.  All correspondence with the 
IRB/IEC should be retained in the Investigator File.  Copies of IRB/IEC approvals should be forwarded to Iterum or its agent 
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. 


 
 
 
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The informed consent form must be in compliance with ICH GCP, local regulatory requirements, and legal requirements. 
The informed consent form used in this study, and any changes made during the course of the study, must be prospectively approved 
by both the IRB/IEC and Iterum before use. 
The Investigator must ensure that each study patient, or his/her legally acceptable representative, is fully informed about the nature 
and objectives of the study and possible risks associated with participation.  The Investigator, or a person designated by the 
Investigator, will obtain written informed consent from each patient or the patient's legally acceptable representative before any study-
specific activity is performed.  The Investigator will retain the original of each patient's signed consent form. 
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 Participating Countries 
End of Study in all participating countries is defined as the TOC 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.   


 
 
 
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If a study is prematurely terminated, Iterum will promptly notify the Investigator and the Investigator must also inform the IRB/IEC.  
After notification, the Investigator must contact all participating patients and the hospital pharmacy (if applicable) within 90 days.  
Investigator must also inform the IRB/IEC.  As directed by Iterum, all study materials must be collected and all CRFs completed to 
the greatest extent possible. 
15 PUBLICATION OF STUDY RESULTS 
Publication of study results is discussed in the Clinical Study Agreement. 
15.1 Communication of Results by Iterum 
Iterum fulfills its commitment to publicly disclose the results of studies through registration and posting of the results of this study on 
clinicaltrials.gov.   
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.  
15.2 Publications by Investigators 
Iterum has no objection to publication by the Investigator of any information collected or generated by the Investigator, 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. 


 
 
 
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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 
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. 
 
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. 
 
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. 
 
Friedman J, Polifka J. Teratogenic effects of drugs: a resource for clinicians (TERIS). Baltimore, Maryland: Johns Hopkins University 
Press, 2000:149-195.  
 


 
 
 
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Appendix 1 
Schedule of Activities 
 
SCREENING 
PERIOD 
TREATMENT PERIOD 
FOLLOW-UP PERIOD 
Protocol Activity 
Screening 
(D1) 
Baseline 
(D1) 
EOT1 
(D3 or D4) 
(+ 1 day) 
TOC 
(D12) 
(+/- 1 day) 
Post TOC  
(D21) 
(+/- 3 days) 
Informed Consent 
X 
 
 
 
 
Medical History and 
Demographics 
X 
 
 
 
 
Temperature 
X 
 
 
 
 
Height and Weight 
X 
 
 
 
 
Urine dipstick  
X 
 
 
 
 
Urinalysis 
 
X 
 
 
 
Urine Culture and Sensitivity 
 
X 
X 
X 
 
Previous Drug and Non-Drug 
Treatments 
X 
 
 
 
 
Concomitant Medications 
X 
 
X 
X 
 
Treatment1  
 
               X         (for 3 days) 
 
 
Treatment Compliance Check2 
 
X2 
X 
 
 
Patient Dosing Diary 
 
Distribute 
Collect 
 
 
Adverse Events 
X 
 
X 
X 
 


 
 
 
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1In the event that the first dose of ciprofloxacin is taken in the morning on Day 1, the EOT visit will be on day 3 (+1 day). In the event that the first dose of ciprofloxacin is taken in 
the evening on Day 1, the EOT visit will be on day 4 (+1 day). 
2Site personnel will call the patient and/or dispensing pharmacy on Day 1 (+1 day) to confirm patient is in receipt of medication. 
 
 
 
 
 
 
Patient Symptom Assessment 
Questionnaire 
X 
 
X 
X 
 
Investigator-Determined 
Clinical Response Evaluation 
 
 
X 
X 
 
Post TOC Telephone Contact 
 
 
 
 
X 


 
 
 
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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.  
Culture and Susceptibility testing  
 
All gram-negative pathogens will be tested locally for antimicrobial susceptibility, as appropriate.  
 
.  
 
 
 


 
 
 
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Appendix 3 
Patient Symptom Assessment Questionnaire (PSAQ) 
 


 
 
 
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Appendix 4 
Ciprofloxacin Tablets – USPI 
HIGHLIGHTS OF PRESCRIBING INFORMATION  
These highlights do not include all the information needed to use CIPRO safely and effectively. See full prescribing information for CIPRO.  
CIPRO®  (ciprofloxacin hydrochloride) tablet, for oral use  
CIPRO®  (ciprofloxacin hydrochloride), for oral suspension  
Initial U.S. Approval: 1987  
WARNING: SERIOUS ADVERSE REACTIONS INCLUDING    
TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY,    
CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION   
OF MYASTHENIA GRAVIS     
See full prescribing information for complete boxed warning.  
• 
   
Fluoroquinolones, including CIPRO®, have been associated with 
disabling and potentially irreversible serious adverse reactions that 
have occurred together (5.1), including:   
o Tendinitis and tendon rupture (5.2) o  Peripheral 
neuropathy (5.3)  
o Central nervous system effects (5.4)  
Discontinue CIPRO immediately and avoid the use of  
fluoroquinolones, including CIPRO, in patients who experience any of 
these serious adverse reactions (5.1)   
• 
Fluoroquinolones, including CIPRO, may exacerbate muscle 
weakness in patients with myasthenia gravis. Avoid CIPRO in 
patients with known history of myasthenia gravis. (5.5)  
• 
Because fluoroquinolones, including CIPRO, have been associated 
with serious adverse reactions (5.1-5.15), reserve CIPRO for use in 
patients who have no alternative treatment options for the 
following indications: o  Acute exacerbation of chronic bronchitis 
(1.10) o  Acute uncomplicated cystitis (1.11) o  Acute sinusitis 
(1.12)  
 --------------------------  RECENT MAJOR CHANGES -------------------------­  
Boxed Warning     M/2016 Indications and Usage (1.10, 1.11, 1.12)   M/2016 Dosage and Administration, Dosage in Adults (2.1)  M/2016  
Warnings and Precautions (5.1)   
  
  
M/2016  
 ---------------------------  INDICATIONS AND USAGE  -------------------------­ 


 
 
 
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CIPRO is a fluoroquinolone antibacterial indicated in adults (≥18 years of age) with the following infections caused by designated, susceptible bacteria and in pediatric patients where indicated: •   
 
Skin and Skin Structure Infections (1.1)  
• 
Bone and Joint Infections (1.2)  
• 
Complicated Intra-Abdominal Infections (1.3)  
• 
Infectious Diarrhea (1.4)  
• 
Typhoid Fever (Enteric Fever) (1.5)  
• 
Uncomplicated Cervical and Urethral Gonorrhea (1.6)  
• 
Inhalational Anthrax post-exposure in adult and pediatric patients (1.7)  
• 
Plague in adult and pediatric patients (1.8)  
• 
Chronic Bacterial Prostatitis (1.9)  
• 
Lower Respiratory Tract Infections (1.10) o  Acute Exacerbation of Chronic Bronchitis   
• 
Urinary Tract Infections (1.11)  o  Urinary Tract Infections (UTI) o  Acute Uncomplicated Cystitis   
o  Complicated UTI and Pyelonephritis in Pediatric Patients •   Acute Sinusitis (1.12)  
Usage  
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO and other antibacterial drugs, CIPRO should be used only to treat or prevent infections that are proven or 
strongly suspected to be caused by bacteria. (1.13)  
 ----------------------  DOSAGE AND ADMINISTRATION ---------------------­  
Adult Dosage Guidelines  
Infection  
Dose  
Frequency  
Duration  
  
  
  
  
Skin and Skin Structure  
500 -750 mg every 12 hours  
7 to 14 
days  
Adult Dosage Guidelines  
Infection  
Dose  
Frequency  
Duration  
Bone and Joint  
500-750 mg  every 12 hours  
4 to 8 weeks  
Complicated IntraAbdominal  
500 mg  
every 12 hours  
7 to 14 days  
Infectious Diarrhea  
500 mg  
every 12 hours  
5 to 7 days  
Typhoid Fever  
500 mg  
every 12 hours  
10 days  
Uncomplicated Gonorrhea   
250 mg  
single dose  
single dose  
Inhalational anthrax 
(postexposure)  
500 mg  
every 12 hours  
60 days  


 
 
 
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Plague   
500–750 mg  every 12 hours  
14 days  
Chronic Bacterial Prostatitis  
500 mg  
every 12 hours  
28 days  
Lower Respiratory Tract  
500 -750 mg  every 12 hours  
7 to 14 days  
Urinary Tract  
250-500 mg  every 12 hours  
7 to 14 days  
Acute Uncomplicated 
Cystitis  
250 mg  
every 12 hours  
3 days  
Acute Sinusitis  
500 mg  
every 12 hours  
10 days  
• 
Adults with creatinine clearance 30–50 mL/min 250–500 mg q 12 h (2.3)  
• 
Adults with creatinine clearance 5–29 mL/min 250–500 mg q 18 h (2.3)  
• 
Patients on hemodialysis or peritoneal dialysis 250–500 mg q 24 h (after dialysis) (2.3)  
  
Pediatric Oral Dosage Guidelines  
 
Infection  
Dose  
Frequency  
Duration  
Complicated UTI and 
Pyelonephritis  
(1 to 17 years of age)  
10–20 mg/kg   
(maximum 750 mg  
per dose)  
Every 12 
hours  
10–21 days  
Inhalational Anthrax 
(Post-Exposure)    
15 mg/kg  
(maximum   
500 mg per dose)  
Every 12 
hours  
60 days  
Plague  
15mg/kg  
(maximum 500 mg  
per dose)  
Every 8 to 
12 hours  
10–21 days  
 ---------------------  DOSAGE FORMS AND STRENGTHS  -------------------­ 
• 
Tablets: 250 mg, 500 mg (3)  
• 
Oral Suspension: 5% (250 mg/5 mL), 10% (500 mg/5 mL) (3)  
 ------------------------------ CONTRAINDICATIONS ----------------------------­  
• 
Known hypersensitivity to CIPRO or other quinolones (4.1, 5.6, 5.7)  
• 
Concomitant administration with tizanidine (4.2)  
 -----------------------  WARNINGS AND PRECAUTIONS  ---------------------­ 
• 
Hypersensitivity and other serious reactions: Serious and sometimes fatal reactions (for example, anaphylactic reactions) may occur after the first or subsequent doses of CIPRO. Discontinue 
CIPRO at the first sign of skin rash, jaundice or any sign of hypersensitivity. (4.1, 5.6, 5.7)   
• 
Hepatotoxicity: Discontinue immediately if signs and symptoms of hepatitis occur. (5.8)  
• 
Clostridium difficile-associated diarrhea: Evaluate if colitis occurs.  
(5.10)  


 
 
 
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• 
QT Prolongation: Prolongation of the QT interval and isolated cases of torsade de pointes have been reported. Avoid use in patients with known prolongation, those with hypokalemia, and with 
other drugs that prolong the QT interval. (5.11, 7, 8.5)  
 ------------------------------  ADVERSE REACTIONS ----------------------------­  
 
To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1-800FDA-1088 or www.fda.gov/medwatch.  
 ------------------------------  DRUG INTERACTIONS  ----------------------------­ 
Interacting Drug  
Interaction  
Theophylline  
Serious and fatal reactions. Avoid concomitant 
use. Monitor serum level (7)  
Warfarin  
Anticoagulant 
effect 
enhanced. 
Monitor 
prothrombin time, INR, and bleeding (7)  
Antidiabetic agents  
Hypoglycemia including fatal outcomes have 
been reported. Monitor blood glucose (7)  
Phenytoin  
Monitor phenytoin level (7)  
Methotrexate   
Monitor for methotrexate toxicity (7)  
Cyclosporine  
May increase serum creatinine. Monitor serum 
creatinine (7)  
Multivalent 
cationcontaining 
products including 
antacids, metal cations 
or didanosine  
Decreased CIPRO absorption. Take 2 hours 
before or 6 hours after CIPRO (7)  
 ----------------------- USE IN SPECIFIC POPULATIONS ---------------------­  
See full prescribing information for use in pediatric and geriatric patients (8.4, 8.5)   
See 17 for PATIENT COUNSELING INFORMATION and Medication    
Guide    
Revised: 7/2016   
 
 
 
 
 
 


 
 
 
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Appendix 5 Summary of Changes 
 
This summary of changes provides an overview of substantive changes and additions made for protocol IT-004-401 amendments. In addition, 
minor editorial revisions have been made for consistency. 
 
General  
• 
All Pages: Header  
From:   Amendment 01:08 November 2017 
To:       Amendment 02:27 March 2018  
 
Study Procedures  
• 
Section 4, 4.1-3, 4.1-4: clarification of; study population requirement of positive for both leukocyte esterase and nitrite dipstick, mid-
stream specimen for diagnosis, informed consent process  
• 
Section 5.2-1, 5.2-3: removal of additional language that does not apply to this study, clarification of site to collect at least the day and 
time of patients first dose taken during treatment follow up.  
• 
Section 6.1: updated language to align with revisions to Section 4.  
• 
Section 6.3.2: added requirement for Post Test of Cure (TOC) Day 21 (+/- 3 days) follow up call  
• 
Section 9.2-5: clarified outcome assessment language 
• 
Appendix 1 Schedule of Activities: Post Test of Cure (TOC) Day 21 (+/- 3 days) follow up call added 
• 
Appendix 2 Microbiology: removed reference to requirement of long term storage of specimen at local lab  
• 
Appendix 3: Revised Patient Assessment Symptom Questionnaire  
 
 
 
 


 
 
 
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Appendix 6 Investigator’s Signature 
Study Title: 
A prospective, Phase 4, open label, multi-center study of the clinical and microbiologic efficacy 
of ciprofloxacin for the treatment of uncomplicated urinary tract infections in adult women. 
Study Number: 
IT-004-401 
Final Date: 
March 27, 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: 
Ciprofloxacin 
 
Iterum Therapeutics 
Statistical Analysis Plan: IT004-401 
 
Version: 30 July 2019 
 
Confidential 
 
 
 
Statistical Analysis Plan: IT-004-401 
 
 
 
 
Study Title: 
A prospective, Phase 4, open label, multi-center study of the 
clinical and microbiologic efficacy of ciprofloxacin for the 
treatment of uncomplicated urinary tract infections in adult women. 
Study Number: 
IT-004-401 
Study Phase: 
Phase 4 
Product Name: 
Ciprofloxacin 
Indication: 
Uncomplicated urinary tract infections 
 
 
Sponsor: 
Iterum Therapeutics US Limited 
 
 
Study Statistician: 
Karthik Akinapelli 
Study Clinician: 
Steven I. Aronin, M.D. 
 
 
Final SAP Date: 
07/30/2019 
Revised SAP Date: 
{date} 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This document is strictly confidential. It was developed by Iterum Therapeutics US Limited should 
not be disclosed to a third party, with the exception of regulatory agencies and study audit personnel. 
Reproduction, modification or adaptation, in part or in total, is strictly forbidden without prior 
written approval by Iterum Therapeutics US Limited 
 
Throughout this document, symbols indicating proprietary names (®, ™) are not displayed.  The appearance of 
product names without these symbols does not imply that these names are not protected. 


Ciprofloxacin 
 
Iterum Therapeutics 
Statistical Analysis Plan: IT004-401 
 
Version: 30 July 2019 
 
Confidential 
 
 
 
Date: 
SIGNATURE PAGE 
 
 
Study Title: 
A prospective, Phase 4, open label, multi-center study of the 
clinical and microbiologic efficacy of ciprofloxacin for the 
treatment of uncomplicated urinary tract infections in adult women. 
Study Number: 
IT-004-401 
 
 
I have read this report and confirm that to the best of my knowledge it accurately describes the 
statistical analysis plan for the study. 
 
 
 
Prepared by:   
 
  
 
Karthik Akinapelli 
Lead Statistical Programmer 
Iterum Therapeutics 
 
 
Approved by: _________________________________ 
Date: ___________________ 
 
Michael Zelasky 
Head of Biotatistics & Statistical Programming 
Iterum Therapeutics 
 
 
Approved by:   
              Date: 
 
Steven I. Aronin 
Senior Director, Clinical Development 
Iterum Therapeutics 


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Version: 30 July 2019 
 
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TABLE OF CONTENTS 
Contents 
TABLE OF CONTENTS ......................................................................................................... 2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................................. 4 
1 
INTRODUCTION............................................................................................................. 5 
2 
STUDY DESIGN ............................................................................................................... 5 
3 
STUDY OBJECTIVES ..................................................................................................... 5 
3.1 
Primary Objective ................................................................................................. 5 
3.2 
Secondary Objective ............................................................................................. 5 
4 
DEFINITION OF ANALYSIS POPULATION ............................................................. 5 
4.1 
Intent-to-Treat (ITT) Population ....................................................................... 6 
4.2 
Modified Intent-to-Treat (MITT) Population .................................................. 6 
4.3 
Safety Population .................................................................................................. 6 
4.4 
Micro-MITT (m-MITT) .......................................................................................... 6 
4.5 
Clinically Evaluable (CE) ...................................................................................... 6 
4.6 
Microbiologically Evaluable (ME) ...................................................................... 6 
4.7 
Determination of Inclusion in Analysis Populations ..................................... 7 
5 
DEFINITION OF OUTCOME MEASURES ................................................................ 7 
5.1 
Primary Efficacy Outcome Measure .................................................................. 7 
5.1.1 Additional Analysis of the Primary Efficacy Outcome Measure .................. 8 
5.2 
Secondary Efficacy Outcome Measure .............................................................. 8 
5.3 
Additional Efficacy Outcomes Measures .......................................................... 9 
5.4 
Safety Outcome Measures ................................................................................. 11 
6 
STATISTICAL METHODS .......................................................................................... 11 
6.1 
Sample Size ........................................................................................................... 11 
6.2 
Randomization .................................................................................................... 12 
6.3 
Visit Windows for Efficacy Analysis ................................................................ 12 
6.4 
Handling of Culture Data from Central and Local Laboratory ................... 12 
6.5 
Handling of Missing Data ................................................................................... 12 
6.6 
Comments on Statistical Analysis .................................................................... 13 
7 
STATISTICAL ANALYSES ......................................................................................... 14 
7.1 
Patient Disposition ............................................................................................. 14 
7.2 
Demographics and Baseline Characteristics ................................................. 14 
7.3 
Baseline Microbiology ........................................................................................ 14 
7.4 
Prior and Concomitant Medications ............................................................... 15 
7.5 
Study Drug Exposure and Compliance ............................................................ 15 


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7.6 
Efficacy Analyses ................................................................................................. 15 
7.7 
Interim Analysis .................................................................................................. 15 
7.8 
Safety Analyses .................................................................................................... 16 
7.9 
Protocol Deviations ............................................................................................ 16 
8 
DIFFERENCES WITH ANALYSES SPECIFIED IN THE PROTOCOL............... 17 
9 
REFERENCES ................................................................................................................ 18 
Appendix 1 - Schedule of Activities ....................................................................................... 19 
Appendix 2 - Patient Symptom Assessment Questionnaire (PSAQ) .................................. 20 
Appendix 3 - Organisms considered as Uropathogens ........................................................ 22 
 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
AE 
Adverse event 
CE 
Clinically evaluable 
CFU 
Colony forming unit 
CRF 
Case report form 
CSR 
Clinical study report 
EOT 
End of treatment 
ESBL 
Extended-spectrum bets-lactamase 
ITT 
Intent-to-treat 
ME 
Microbiologically evaluable 
MedDRA 
Medical Dictionary for Regulatory Activities 
MG 
Milligram 
MIC 
Minimal inhibitory concentration 
MITT 
Modified intent-to-treat 
m-MITT 
Micro-modified intent-to-treat 
mL 
Milliliter  
SAE 
serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SE 
Standard error  
TOC 
Test of cure 
US 
United States 
uUTI 
Uncomplicated urinary tract infection 
 
 
 
 
 
 


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1 
INTRODUCTION 
This document presents the Statistical Analysis Plan (SAP) for the IT-004-401, “A 
prospective, Phase 4 open label, multi-center study of the clinical and microbiologic efficacy 
of ciprofloxacin for the treatment of uncomplicated urinary tract infections in adult women.” 
This plan contains definitions of analysis populations, derived variables and statistical 
methods for the analysis of clinical and microbiologic efficacy. The statistical plan described 
is an “a priori” plan, and the analyses outlined here have not been conducted prior to the 
preparation of this plan.  
This SAP summarizes the design and objectives of protocol IT-004-401 and provides details 
of the definitions of the outcome measures and statistical methodology that will be used to 
analyze the data from the study. Any deviation from the planned analysis will be documented 
in clinical study report (CSR). 
 
2 
STUDY DESIGN 
This prospective Phase 4 open label, multi-center study documents the clinical and 
microbiologic response of adult women patients with uUTI treated empirically with 
ciprofloxacin. Approximately 250 adult women with uUTI will receive oral ciprofloxacin 250 
mg twice daily for 3 days.  
The primary outcome measure for efficacy evaluation will be the overall response on Day 12 
(+/- 1 day). For the primary efficacy evaluation, these percentages will be based on a 
microbiologic-modified intent to treat population (m-MITT). The m-MITT population will be 
comprised of all patients who received at least one dose of ciprofloxacin and had ≥105 
CFU/mL of a baseline pathogen isolated from a urine culture specimen taken at baseline, prior 
to initiation of ciprofloxacin therapy. 
 
3 
STUDY OBJECTIVES 
3.1 Primary Objective 
To evaluate the clinical and microbiologic response of patients with a uUTI treated with 
ciprofloxacin. 
3.2 Secondary Objective 
To evaluate the validity of specific tests found on the urine dipstick as a screening tool to 
identify symptomatic patients with a positive urine culture, defined as growth of ≥105 
CFU/mL of a uropathogen at baseline. 
 
4 
DEFINITION OF ANALYSIS POPULATION 
The definition of analysis populations included in this study are below. 


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4.1 Intent-to-Treat (ITT) Population 
All enrolled patients regardless of whether or not they received ciprofloxacin. 
4.2 Modified Intent-to-Treat (MITT) Population 
All patients in ITT population who received at least a single dose of ciprofloxacin. 
4.3 Safety Population 
All patients in ITT population who received at least a single dose of ciprofloxacin. 
4.4 Micro-MITT (m-MITT) 
All MITT patients with a positive study entry urine culture defined as ≥105 CFU/mL of a 
uropathogen and no more than 2 species of microorganisms identified in the study entry urine 
culture, regardless of colony count. 
4.5 Clinically Evaluable (CE) 
Clinically evaluable is defined both at the end of treatment (EOT) and test of cure (TOC) 
visits. 
- 
All patients who were included in the MITT population and meet the following criteria 
are clinically evaluable. 
a) Received a minimum of four doses of ciprofloxacin. 
b) Had no important protocol deviations that would affect the assessment of efficacy as 
indicated in the protocol deviation log (see section 7.9). These will be pointed out by 
clinical team and marked in the CE spreadsheet. 
c) Had a Clinical response assessment of clinical cure or clinical failure (and not 
indeterminate) at the EOT or TOC visits (within Protocol visit window), respectively.  
Note: Since the PSAQ does not contain a date completed, the date if lab culture will 
be used.  
d) Did not receive any antibiotic therapy with potential activity against any of the 
baseline uropathogens collected at screening between the time of the baseline culture 
and the EOT or TOC 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 ciprofloxacin are allowed to receive agents with narrow spectrum gram-
positive coverage (i.e., such as linezolid or vancomycin).  
Note: This rule will be applied through the manual review of CE spreadsheet by the 
sponsor. 
4.6 Microbiologically Evaluable (ME) 
All patients included in both the m-mITT and CE populations at the EOT visit (ME-EOT), 
and at the TOC visit (ME-TOC) and meet the following criteria are microbiologically  


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evaluable: 
a) Have an appropriately collected urine culture specimen and interpretable urine culture 
result at the EOT and TOC visits, respectively. 
b) Had a microbiologic assessment of eradication or persistence (and not indeterminate) 
at the EOT or TOC visits, respectively. 
  
4.7 Determination of Inclusion in Analysis Populations 
Inclusion into the ITT, MITT, m-MITT and Safety populations will be determined 
programmatically from the electronic case report form (e-CRF) data.  Inclusion into the CE 
populations will be determined programmatically from the e-CRF data and through a manual 
review conducted by the sponsor. The sponsor will review both clinical and microbiological 
data for determination of criteria used to assess inclusion in the CE populations and for 
determination of baseline and post-baseline pathogens. The sponsor will review the data 
concurrent with the conduct of the study.  Inclusion into the ME populations will be 
determined programmatically. 
 
5 
DEFINITION OF OUTCOME MEASURES 
5.1 Primary Efficacy Outcome Measure 
The primary efficacy outcome is overall response assessed on Day 12 (+/- 1 day) in the m-
MITT using the definitions listed below. 
A patient will be programmatically defined as a responder based on the following: 
• 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, and analyzed as a non-responder); 
• The patient has resolution of the symptoms of uUTI present at trial entry and no new 
uUTI symptoms, on Day 12 (+/- 1 day); 
• Urine culture taken on Day 12 (+/- 1 day) demonstrates <103 CFU/mL of the baseline 
uropathogen; 
 
A patient will be defined as a non-responder if at least one of the following criteria is met: 
• The patient has died; 
• The patient has received 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, and analyzed as a non-responder for 
uUTI); 
• The patient has no resolution or worsening of the symptoms of uUTI present at trial 
entry and/or with new uUTI symptoms; 
• Urine culture taken demonstrates ≥ 103 CFU/mL of the baseline uropathogen; 


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All other patients will be considered indeterminate, including those with missing data needed 
to determine if the patient is a responder or non-responder. For example, if either urine culture 
or uUTI symptoms are not completed, the patient will be considered an indeterminate. 
For the ITT and m-MITT populations, the proportion of ITT or m-MITT patients with a 
responder is defined using the following formula: 
Number of responders 
Number of responders + Number of non-responders + Number of indeterminates 
 
By definition, patients in the CE and ME populations must have sufficient information for 
determination of efficacy response. Thus, the proportion of CE and ME patients is defined 
using the following formula: 
Number of responders 
Number of responders + Number of non-responders 
 
5.1.1 Additional Analysis of the Primary Efficacy Outcome Measure 
In addition to the primary efficacy outcome measure, following sensitivity analyses will be 
performed on Day 12 (+/- 1 day) in the m-MITT population, 
• Sensitivity Analysis 1: Will follow the same definition of primary outcome measure 
defined in section 5.1 except, urgency is excluded and considering all other symptoms 
(in Appendix 2) are resolved and no new uUTI symptoms. 
• Sensitivity Analysis 2: Will follow the same definition of primary outcome measure 
defined in section 5.1 except, frequency is excluded and considering all other symptoms 
(in Appendix 2) are resolved and no new uUTI symptoms. 
• Sensitivity Analysis 3: Will follow the same definition of primary outcome measure 
defined in section 5.1 except, improvement of symptoms (instead of resolution, in 
Appendix 2) from baseline and no worse than mild from baseline and no new uUTI 
symptoms are considered. 
• Sensitivity Analysis 4: Will follow the same definition of primary outcome measure 
defined in section 5.1 except, improvement of symptoms (instead of resolution, in 
Appendix 2) from baseline and no new uUTI symptoms are considered. 
• Sensitivity Analysis 5: Will follow the same definition of primary outcome measure 
defined in section 5.1 except, urgency and frequency are improved and no worse than 
mild from baseline and all other symptoms (in Appendix 2) are resolved and no new 
uUTI symptoms are considered. 
• Sensitivity Analysis 6: Will follow the same definition of primary outcome measure 
defined in section 5.1 except, investigator response will be used instead of symptoms 
filled in by patient (from patient dairy).  
5.2 Secondary Efficacy Outcome Measure 
All symptomatic subjects enrolled in the study will have a positive urine dipstick for both 
leukocyte esterase and nitrite.  The number and percentage of subjects who go on to have a 
positive baseline urine culture for ≥105 CFU/mL of a uropathogen will be evaluated.  


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5.3 Additional Efficacy Outcomes Measures 
• Microbiologic response 
Microbiologic response is assessed on Day 3 or 4 (+1 day) EOT and Day 12 (+/- 1 day) TOC in 
the ITT, m-MITT, CE-EOT, CE-TOC, ME-EOT and ME-TOC populations. 
 
Microbiological 
response 
Definition 
Eradication 
A urine culture taken at baseline and compared with the culture 
from the Day 3 (+1 day) (EOT) visit or Day 12 (+/- 1 day) 
(TOC) visit showed that the urine culture obtained at the 
relevant visit demonstrated <103 CFU/mL of the original 
uropathogen.  
Persistence  
Uropathogen present at baseline grew at ≥103 CFU/mL at the 
time-point of analysis, i.e. EOT or TOC. 
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 
EOT or the TOC visit. 
 
• Clinical response: 
Clinical response (done programmatically) will use the definitions below to document response 
at Day 3 or Day 4 (+ 1 day) (EOT), Day 12 (+/- 1 day) (TOC) and Day 21 in the ITT, m-MITT, 
CE-EOT, CE-TOC, ME-EOT and ME-TOC populations. 
 
Clinical response 
Definition 
Clinical cure 
All pre-therapy signs and symptoms of the index infection had resolved such 
that no additional antibiotics were required 
Clinical failure 
Patients who met any one of the criteria below were considered as failure: 
Death related to uUTI prior to Day 3 or Day 12 or Day 21 respectively 
No apparent response to treatment; persistence or progression of most or all 
pre-therapy signs and symptoms or use of additional antibiotics for the current 
infection 
Patient previously met criteria for failure and received rescue antibiotics 
Indeterminate 
Study data were not available for evaluation of efficacy for any reason, 
including: 
Patient lost to follow-up or assessment not undertaken such that a 
determination of clinical response could not be made at either the EOT or 
TOC visit 
Death prior to Day 3 or Day 12 or Day 21, respectively, where uUTI was 
clearly noncontributory 
 


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In addition to the clinical response above, following sensitivity analyses will be performed on 
Day 12 (+/- 1 day) in the m-MITT population, 
• Sensitivity Analysis 1: Will follow the same definition of clinical response defined 
in section 5.3 except, urgency is excluded and considering all other symptoms are 
resolved and no new uUTI symptoms. 
• Sensitivity Analysis 2: Will follow the same definition of clinical response defined 
in section 5.3 except, frequency is excluded and considering all other symptoms are 
resolved and no new uUTI symptoms. 
• Sensitivity Analysis 3: Will follow the same definition of clinical response defined 
in section 5.3 except, improvement of symptoms (instead of resolution) from 
baseline and no worse than mild from baseline and no new uUTI symptoms are 
considered. 
• Sensitivity Analysis 4: Will follow the same definition of clinical response defined 
in section 5.3 except, improvement of symptoms (instead of resolution) from 
baseline and no new uUTI symptoms are considered. 
• Sensitivity Analysis 5: Will follow the same definition of clinical response defined 
in section 5.3 except, urgency and frequency are improved and no worse than mild 
from baseline and all other symptoms are resolved and no new uUTI symptoms are 
considered. 
 
• Investigator response: 
Investigator-determined response will use the definitions below to document response at Day 3 
or Day 4 (+ 1 day) (EOT) and Day 12 (+/- 1 day) (TOC) in the ITT, m-MITT, CE-EOT, CE-
TOC, ME-EOT and ME-TOC populations. 
 
Clinical response 
Definition 
Clinical cure 
All pre-therapy signs and symptoms of the index infection had resolved such 
that no additional antibiotics were required 
Clinical failure 
Patients who met any one of the criteria below were considered as failure: 
Death related to uUTI prior to Day 3 or Day 12, respectively 
No apparent response to treatment; persistence or progression of most or all 
pre-therapy signs and symptoms or use of additional antibiotics for the current 
infection 
Patient previously met criteria for failure  


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Clinical response 
Definition 
Indeterminate 
Study data were not available for evaluation of efficacy for any reason, 
including: 
Patient lost to follow-up or assessment not undertaken such that a 
determination of clinical response could not be made at either the EOT or 
TOC visit 
Death prior to Day 3 or Day 12, respectively, where uUTI was clearly 
noncontributory 
 
• Patient Symptom Assessment Questionnaire (filled out by patient) at Day 3 or Day 4 (+ 
1 day) (EOT) and Day 12 (+/- 1 day) (TOC) in the ITT, m-MITT, CE-EOT, CE-TOC, 
ME-EOT and ME-TOC populations 
• Overall response at Day 3 or Day 4 (+ 1 day) (EOT) in the ITT, m-MITT, CE-EOT and 
ME-EOT populations 
• Overall response at Day 12 (+/- 1 day) (TOC) in the ITT, CE-TOC and ME-TOC 
population (m-MITT is used with the primary endpoint) 
• Overall response, microbiologic response, clinical response and investigator response at 
the EOT and TOC visits by baseline pathogen (key pathogens) in the m-MITT and ME 
populations 
• Overall response, microbiologic response and clinical response at the EOT and TOC 
visits by baseline ESBL in the m-MITT and ME populations 
• Distribution of pathogens by culture concentration at EOT and TOC in the m-MITT, 
ME-EOT and ME-TOC populations 
 
5.4 Safety Outcome Measures 
The safety parameters include adverse events (AEs). No additional laboratory testing will be 
performed beyond routine urine testing for uUTI. AEs will be coded using the Medical 
Dictionary of Regulatory Activities (MedDRA) Version 21.0 to the System Organ Class and 
Preferred Term levels. 
 
6 
STATISTICAL METHODS 
6.1 Sample Size 
The study is designed to determine the clinical and microbiologic efficacy of ciprofloxacin for 
adult female patients with uUTI, due to either a ciprofloxacin susceptible or non-susceptible 
organism. Two-hundred fifty (250) symptomatic patients will be enrolled with the expectation 
that there will be no screen failures.  Of the 250 enrolled patients, we expect 50 will not have 
a positive urine culture for ≥105 CFU/mL of a uropathogen at baseline.   Of the 250 enrolled 
patients, we expect 40 will have a uUTI due to a ciprofloxacin non-susceptible organism. 
Patients who withdraw prior to initial dose, will be replaced to ensure a total of 250 patients 


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will receive at least a single-dose of ciprofloxacin. 
6.2 Randomization 
No randomization performed. Approximately 250 female patients with uUTI will be 
administered oral ciprofloxacin twice daily for 3 days. 
A patient will be eligible for the study once it has been determined that she meets all inclusion 
criteria and has none of the exclusion criteria. 
6.3 Visit Windows for Efficacy Analysis 
No analysis will be performed for any unscheduled visits. 
 
 
Visit  
Window  
Baseline 
Day -1 or 1, defined as period prior to the 
administration of the first dose of study drug 
Day 3 or Day 4 (EOT)  
+1 day 
Day 12 (TOC)  
± 1 days 
Day 21 
± 3 days 
 
6.4 Handling of Culture Data from Central and Local Laboratory 
Culture data from both central lab (IHMA) and local lab at Baseline (no post-baseline for 
central lab) will be handled as outlined below: 
• All the culture results from central and local labs are merged by subject id. 
• Final pathogen, susceptibility (to Ciprofloxacin) and extended-spectrum beta-lactamases 
(ESBL) status  at baseline will be determined in the following order as follows, 
1. For all uropathogen (Appendix 3) central records with concentration of ≥ 105 
CFU/mL then central lab pathogen, susceptibility and ESBL (ceftriaxone > 1 as 
positive) status is considered as final results. 
2. For all other central lab records with concentration < 105 CFU/mL or 
contaminated sample or ‘no growth’, if their local lab records have a 
uropathogen with concentration of ≥ 105 CFU/mL then local pathogen, 
susceptibility and ESBL status is considered as final results. 
3. If both statement 1 and statement 2 do not apply, then central results are 
considered as final results. 
 
6.5 Handling of Missing Data 
Missing data will be handled as outlined below: 


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• All missing and partial dates for events and assessments occurring after start of enrollment 
or for medications received after start of enrollment will be queried for a value. If no value 
can be obtained, substitutions will be made as follows: 
- 
For start dates, missing months and days will be defined by “01”, as long as this 
occurs on or after the first dose of study drug.  If the algorithm produces a date prior 
to the first dose of study drug, the date of the first dose of study drug will be used 
for the partial date. For stop dates, missing months will be defined as “12” and days 
will be defined by the last day of the respective month. These substitutions will be 
used in calculations; however, the actual value recorded on the e-CRF will be used 
for all listings. 
• The intensity and causality assessment for an AE cannot be missing. Missing data will be 
queried for a value.  If no value can be obtained, worst possible scenario will be considered. 
For example, missing intensity will be considered as ‘severe’ and missing causality will 
be considered as ‘treatment related’. 
 
For efficacy response, missing data will be handled as follows: 
• For any outcome measure, 
- 
Patients will be defined as an indeterminate at any outcome measure (overall or 
clinical or microbiological) if any data needed to determine the outcome of a patient 
is missing. For example, if the assessment of the symptoms was not completed at 
EOT, for any reason, the patient will be considered an indeterminate response. By 
definition, patients with an indeterminate response are included in the denominator 
for analyses in the ITT and m-mITT populations, and are considered failures. 
• For the Investigator‘s assessment of clinical response at EOT and TOC 
- 
Patients will be considered an indeterminate response if data are not available for the 
evaluation of efficacy at EOT and TOC for any reason. 
• Except as specifically noted for preplanned imputation analyses, missing values for other 
individual data points (not described above) will remain as missing. Missing values will 
not be imputed and only observed values will be used in data analyses and presentations. 
• Where individual data points are missing, categorical data will be summarized based on 
reduced denominators (i.e., only patients with available data will be included in the 
denominators). 
6.6 Comments on Statistical Analysis 
The following general comments apply to all statistical analyses and data presentations: 
• Summaries will include frequency and percentages for categorical data; frequency and 
median for ordinal data; and number, mean, standard deviation, and median, minimum 
and maximum for continuous data. 
• Duration variables will be calculated using the general formula: (end date - start date) +1 
for end dates after first dose and (end date - start date) for end dates before first dose. 
• If the reported value of a clinical laboratory parameter cannot be used in a statistical 
summary table (e.g., a character string is reported for a parameter of the numerical type), 


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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 of SAS® statistical software package will be used to provide all summaries, 
listings, graphs, and statistical analyses. 
 
7 
STATISTICAL ANALYSES 
7.1 Patient Disposition 
The number of patients included in each of the study populations (i.e.: ITT, Safety, MITT, m-
MITT, CE-EOT, CE-TOC, ME-EOT and ME-TOC) will be summarized by ciprofloxacin-
susceptible, ciprofloxacin-non-susceptible, other (Includes patients with no pathogen or 
contaminated urine sample at baseline) and total (includes all patients). A listing will be 
provided that details each patient’s inclusion in and exclusion from each analysis population 
and the reasons the patient is excluded from the population(s). 
• The frequency and percentage of patients completing the study, prematurely 
discontinuing from the study will be presented for the ITT, MITT, m-MITT, CE-EOT, 
CE-TOC, ME-EOT and ME-TOC populations. 
• Reasons for premature withdrawal from the study as recorded on the e-CRF will be 
summarized (frequency and percentage).  
• A listing of all patients who prematurely withdrew from the study will be presented, and 
the primary reason for premature withdrawal from the study will be provided. 
• A listing of death will be presented separately. 
7.2 Demographics and Baseline Characteristics 
Demographic data and baseline characteristics will be presented for the ITT, Safety, m-
MITT, CE and ME populations. A table as well as a listing will present the patient 
demographics [e.g., age, height, weight, BMI and race] and baseline characteristics (height, 
weight, as a continuous variable). Age will be calculated from the date of birth to the date 
demographics were collected.  
The UTI symptoms (gross hematuria, pain or uncomfortable pressure in the lower 
abdomen/pelvic area, pain or burning when passing urine, frequency of urination or going 
to the toilet very often, urgency of urination or a strong and uncomfortable urge to pass 
urine) will be summarized. 
Pathogens at baseline will be summarized as well as a categorization by ESBL result.  
Patients with monomicrobial and polymicrobial will be summarized. 
7.3 Baseline Microbiology 


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The bacterial pathogens identified from the baseline urine culture will be presented. In 
addition, the number and percentage of patients with mono-microbial and poly-microbial 
infections will be provided and also distribution of baseline pathogens by ESBL 
(positive/negative) and culture concentration will also be provided. 
A listing will be provided that includes all baseline and post-baseline isolates obtained 
from specimens and whether or not the isolate is considered the pathogenic organism. 
7.4 Prior and Concomitant Medications 
All medications taken prior to the first dose of the study drug and through the TOC visit 
will be recorded on the source document. Concomitant antimicrobial medications will be 
summarized by WHODRUG (Version September 2014 or higher) ATC level 3 and generic 
medication name. Patients will be counted only once for an ATC class and generic 
medication name. 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. 
The proportion of patients who receive, any antibiotic therapy with potential activity 
against any of the baseline uropathogens collected at screening between the time of the 
baseline culture and the EOT or TOC culture, will be summarized. 
A listing will be provided of all antibacterial medications taken within 30 days prior to the 
first dose of study drug. 
7.5 Study Drug Exposure and Compliance 
All patients should be informed that compliance with taking all oral medication as 
instructed is imperative. A site designee will phone the patient or the pharmacy on Day 1 to 
ensure that the prescription of ciprofloxacin was picked up and the first dose was taken.  
This phone call should be documented in the patient's source. 
Patients will receive a dosing diary on Day 1 and be asked to record the dosing 
administration for the duration of the treatment period. The total amount of oral dosing 
completed during the treatment period will be documented in the eCRF. 
A dosing summary will be presented for the ITT, m-MITT, CE and ME populations. The 
distribution of patients by the number of active doses of study drug therapy will be 
presented. 
7.6 Efficacy Analyses 
There is only one treatment group, so hypothesis testing is not needed.  Only descriptive 
statistics will be presented for each endpoint, which will mainly consist of frequency and 
percentage for each category of the endpoint. 
The reasons for non-responder and indeterminate will be summarized for most endpoints. 
7.7 Interim Analysis 
N/A 


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7.8 Safety Analyses 
Safety analysis will be conducted in the safety population. Safety parameters include 
adverse events. 
Verbatim descriptions of AEs will be coded using Version 21.0 or higher of MedDRA. 
Summary tables will be provided for all treatment-emergent AEs (TEAEs). An AE is 
defined as any untoward medical occurrence in a clinical investigation patient administered 
a product or medical device, unless the event is captured in the study endpoint, as defined 
below; the event need not necessarily have a causal relationship with the treatment or 
usage. ATEAE is any AE that newly appeared, increased in frequency, or worsened in 
severity following initiation of ciprofloxacin. In addition, all AEs (including non-TEAEs), 
serious TEAEs, and TEAEs leading to study drug discontinuation will be provided in 
listings containing patient number, verbatim term, MedDRA system organ class and 
preferred terms, 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, and 
any SAE leading to premature study drug discontinuation. 
The number and percentage of patients reporting a TEAE will be tabulated by system 
organ class and preferred term for all TEAEs and TEAEs through TOC. TEAEs through 
TOC 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 or related to study drug). A table will provide all SAEs (through 
TOC) 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. 
Analysis of the distribution of the duration of each adverse event as well as an overall 
mean adverse event duration will be presented. 
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. 
7.9 Protocol Deviations 
A listing of all protocol deviations will be provided. Deviations will also be reviewed by 
the Sponsor and categorized into general categories such as: inclusion/exclusion criteria, 
study drug administration, informed consent, visit schedule, test and procedures and other. 
Protocol deviations will be classified as major, minor or not a deviation. Also, protocol 
deviations that impact the analyses will be marked by the clinical team and will be 
excluded from the clinically evaluable population. 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. 


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8 
DIFFERENCES WITH ANALYSES SPECIFIED IN THE PROTOCOL 
• The clinical evaluability rules in the protocol have been modified in the SAP (section 
4.5). The prior antibiotic rule was dropped because it is an exclusion criterion in the 
protocol and applicable to all patients.  The requirement that a study entry urine culture 
obtained before ciprofloxacin administration was dropped since the clinical evaluability 
rules should only be related to clinical data, not microbiological data. 
• The primary efficacy outcome measure in the SAP (section 5.1) was further clarified by 
adding the rules for non-responder. 
• Analyses were added to the SAP (section 5.3) for day 21 even though they weren’t listed 
in the protocol. 
• The rule, ‘patient previously met criteria for failure’, in the protocol for clinical response 
was modified in the SAP (section 5.3) to ‘patient previously met criteria for failure and 
received rescue antibiotics’ to specify the rule more precisely. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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9 
REFERENCES 
 
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.  
 
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.  
 
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.  
Friedman J, Polifka J. Teratogenic effects of drugs: a resource for clinicians (TERIS). 
Baltimore, Maryland: Johns Hopkins University Press, 2000:149-195. 
 
 
 


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Appendix 1 - Schedule of Activities 
 
1In the event that the first dose of ciprofloxacin is taken in the morning on Day 1, the EOT visit will be on day 3 (+1 day).  In the event that the 
first dose of ciprofloxacin is taken in the evening on Day 1, the EOT visit will be on day 4 (+1 day). 
2Site personnel will call the patient and/or dispensing pharmacy on Day 1 (+1 day) to confirm patient is in receipt of medication. 
 
 
 
 
 
 
SCREENING 
PERIOD 
TREATMENT PERIOD 
FOLLOW-UP PERIOD 
Protocol Activity 
Screening 
(D1) 
Baseline 
(D1) 
EOT1 
(D3 or D4) 
(+ 1 day) 
TOC 
(D12) 
(+/- 1 day) 
Post TOC  
(D21) 
(+/- 3 days) 
Informed Consent 
X 
 
 
 
 
Medical History and 
Demographics 
X 
 
 
 
 
Temperature 
X 
 
 
 
 
Height and Weight 
X 
 
 
 
 
Urine dipstick  
X 
 
 
 
 
Urinalysis 
 
X 
 
 
 
Urine Culture and 
Sensitivity 
 
X 
X 
X 
 
Previous Drug and Non-
Drug Treatments 
X 
 
 
 
 
Concomitant Medications 
X 
 
X 
X 
 
Treatment1  
 
               X         (for 3 days) 
 
 
Treatment Compliance 
Check2 
 
X2 
X 
 
 
Patient Dosing Diary 
 
Distribute 
Collect 
 
 
Adverse Events 
X 
 
X 
X 
 
Patient Symptom 
Assessment Questionnaire 
X 
 
X 
X 
 
Investigator-Determined 
Clinical Response 
Evaluation 
 
 
X 
X 
 
Post TOC Telephone 
Contact 
 
 
 
 
X 


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 Appendix 2 - Patient Symptom Assessment Questionnaire (PSAQ) 
 
UTI symptoms  
Symptom assessment 
Gross hematuria 
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 
 
 
 
 
 
 
 
 


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New Patient Symptom Assessment Questionnaire (PSAQ) 
 
 
 
 
 
 


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Appendix 3 - Organisms considered as Uropathogens 
 
For the purpose of this study, the following organisms will always be considered a uropathogen 
when isolated from an acceptable urine culture specimen: 
 
• Monomicrobial or polymicrobial infections caused by: 
 
• Enterobacteriaceae 
• Enterococci  
• Pseudomonas aeruginosa  
• Staphylococcus. saprophyticus 
 
The m-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: 
• 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.