Clinical trial NCT04020341
Conditions: Urinary Tract Infections
Keywords: Acute cystitis Efficacy Gepotidacin Nitrofurantoin Urinary Tract Infection Simple cystitis
Sponsor: GlaxoSmithKline
Start date: 2019-10-17; Completion date: 2022-11-30
Enrollment: 1531 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study will be conducted to evaluate the therapeutic response (combined per participant microbiological and clinical response) of oral gepotidacin compared to oral nitrofurantoin for treatment of uncomplicated UTI (acute cystitis) in adolescent and adult female participants.

Detailed description:

Arms: arm 1: Participants will be administered oral doses of 1500 milligrams (mg) gepotidacin plus nitrofurantoin matching placebo twice daily (BID); approximately every 12 hours for 5 days arm 2: Participants will be administered oral doses of 100 mg nitrofurantoin plus gepotidacin matching placebo BID; approximately every 12 hours for 5 days.
Interventions: intervention 1: Gepotidacin intervention 2: Placebo matching nitrofurantoin intervention 3: Nitrofurantoin intervention 4: Placebo matching gepotidacin
Intervention descriptions: intervention 1: Gepotidacin will be available as tablets containing 750 mg gepotidacin. Each dose should be taken with water after consumption of food. intervention 2: Placebo matching nitrofurantoin will be available as over-encapsulated unit-dose capsules. Each dose should be taken with water after consumption of food. intervention 3: Nitrofurantoin will be available as over-encapsulated capsules containing 25 mg nitrofurantoin macrocrystals and 75 mg nitrofurantoin. Each dose should be taken with water after consumption of food. intervention 4: Placebo matching gepotidacin will be available as unit-dose gepotidacin placebo-to-match tablet. Each dose should be taken with water after consumption of food.

Protocol documents:
Prot_000.pdf: 
TMF-13817543 
CONFIDENTIAL 
 
GlaxoSmithKline group of companies 
 
204989 
 
1 
 
TITLE PAGE 
Protocol Title:  A Phase III, Randomized, Multicenter, Parallel-Group, Double-Blind, 
Double-Dummy Study in Adolescent and Adult Female Participants Comparing the 
Efficacy and Safety of Gepotidacin to Nitrofurantoin in the Treatment of Uncomplicated 
Urinary Tract Infection (Acute Cystitis) 
Protocol Number:  204989 / Amendment 2 
Short Title:  Phase III, Double-Blind, Parallel-Group, Comparator-Controlled, Efficacy 
and Safety Study of Gepotidacin in the Treatment of Uncomplicated Urinary Tract 
Infection (Acute Cystitis); Efficacy of Antibacterial Gepotidacin Evaluated (EAGLE-2) 
Compound 
Number: 
GSK2140944 
 
Sponsor Name and Legal Registered Address:  
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
Sponsor Contact Address: 
GlaxoSmithKline 
1250 South Collegeville Road 
PO Box 5089 
Collegeville, PA 19426-0989 
USA 
Medical monitor name and contact information can be found in the Study Reference 
Manual 
Regulatory Agency Identifying Numbers:  
IND 111885 
EudraCT 2018-001801-98 
Protocol Amendment Number:  2 
Approval Date: 03-NOV-2021 
Copyright 2021 the GlaxoSmithKline group of companies. All rights reserved. 
Unauthorized copying or use of this information is prohibited. 


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SPONSOR SIGNATORY: 
Protocol Title:  A Phase III, Randomized, Multicenter, Parallel-Group, Double-Blind, 
Double-Dummy Study in Adolescent and Adult Female Participants Comparing the 
Efficacy and Safety of Gepotidacin to Nitrofurantoin in the Treatment of Uncomplicated 
Urinary Tract Infection (Acute Cystitis) 
Protocol Number:  204989 / Amendment 2 
Compound Number:  GSK2140944  
 
 
 
 
 
Salim Janmohamed, BSc, MBBS (Hons), FRCP, FACE 
Senior Director, Clinical Sciences (Infectious Diseases)  
GlaxoSmithKline  
Pharmaceutical Research and Development 
 
Date 
The signed page is a separate document. 
 
 
 
Medical Monitor Name and Contact Information can be found in the Study Reference 
Manual. 
 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
DNG Number 
Amendment 2 
03-NOV-2021 
TMF-13817543 
Amendment 1 
06-MAY-2021 
2017N318043_01 
Original Protocol 
12-APR-2019 
2017N318043_00 
 
Amendment 2  03-NOV-2021 
This global amendment is considered to be substantial. 
Overall Rationale for the Amendment: This global amendment added details for an 
interim analysis to be conducted and managed by an Independent Data Monitoring 
Committee and sample size impact on the primary analysis population. The primary 
analysis method was updated from Cochran-Mantel-Haenszel to Miettinen and 
Nurminen. Other revisions also included updates to the PK Population definition and the 
exploratory PK/PD objective, and increasing the inclusion window for the onset of acute 
cystitis clinical signs and symptoms from ≤72 hours to <96 hours. In addition, minor 
revisions to 3 exclusion criteria were made, unblinding of PPD PK analysts (who have no 
involvement in study conduct) was described, prescreening activities for consent and 
urine pregnancy testing were clarified, the potential for home healthcare visits was added, 
minor revisions were made to allow more site and participant flexibility at the Baseline 
and On-therapy Visits, and minor updates were made to the Schedule of Events table for 
the interactive response technology. The amendment also includes additional minor 
administrative and wording edits. 


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Section # and Name 
Description of Change 
Brief Rationale 
Synopsis 
5.4 Scientific 
Rationale for Study 
Design 
7.4 Blinding 
10.1 Statistical 
Hypothesis 
10.2 Sample Size 
Determination 
10.4.1 General 
Considerations 
10.4.2 Efficacy 
Analysis 
10.5 Interim Analysis 
10.6 Data Monitoring 
Committee or Other 
Review Board 
12.3 Appendix 3: 
Study Governance 
Consideration 
Throughout 
Added interim analysis and 
Independent Data Monitoring 
Committee details, including 
updates to the number of 
evaluable participants needed and 
sample size determination 
revisions, as well as applicable 
revisions to section numbers and 
content (i.e., additions and 
deletions) in the statistical section 
To allow interim statistical 
evaluation for efficacy and futility  
Synopsis 
4 Objectives and 
Estimands/Endpoints 
Revised the secondary objective 
related to therapeutic response 
Consistency between primary and 
secondary endpoint 
Synopsis 
5.2 Number of 
Participants 
10.2 Sample Size 
Determination 
10.5 Interim Analysis 
Revised description of the number 
of participants in the primary 
analysis population based on 
interim analysis considerations 
and clarified that the number of 
randomized participants may vary 
based on evaluability rate and 
review of qualifying uropathogens  
Updated for clarification related to 
the interim analysis on the primary 
analysis population 
2 Schedule of 
Activities 
Divided the “Interactive response 
technology” row in to 2 separate 
rows specific for the screening 
and randomization modules 
To align with how the interactive 
response is being used at study 
sites and to more closely follow 
the expected order of procedures 


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Section # and Name 
Description of Change 
Brief Rationale 
2 Schedule of 
Activities 
9 Study Assessments 
and Procedures 
Clarified prescreening activities 
that may occur  
Consistency with the Study 
Reference Manual  
2 Schedule of 
Activities 
5.1 Overall Design 
12.5.2 Study 
Procedures During 
the COVID-19 
Pandemic 
Added text to allow potential home 
healthcare visits. Such visits will 
be limited to where applicable 
regulations and infrastructure 
allow. 
To support study feasibility  
3.3.1 Risk 
Assessment 
Minor text clarifications for clinical 
QTc effects and added relevant 
exposures for nonclinical 
embryofetal effects 
Consistency with currently known 
safety data 
4 Objectives and 
Estimands/Endpoints 
Revised the exploratory PK/PD 
endpoint 
Re-defined the PK intercurrent 
event as first dose to On-therapy 
Visit 
Alignment with the planned 
analysis 
6.1 Inclusion Criteria 
#2 
Revised the criterion to allow the 
onset of clinical signs and 
symptoms of acute cystitis within 
<96 hours prior to study entry  
To support study enrollment  
6.2 Exclusion Criteria 
#2 
Edited to include “uncontrolled” 
before high blood pressure 
Text clarification 
6.2 Exclusion Criteria 
#23 
Added details to the exclusion 
note for ECG exclusion 
To support consistency in ECG 
measurements 
6.2 Exclusion Criteria 
#30 
Revised wording to support a “no” 
response, which is in line with this 
being an exclusion criterion 
Text clarification 
7.4 Blinding 
Added text to describe the 
unblinding of PPD PK analysts  
To support ongoing PK model 
development and refinement 
9 Study Assessments 
and Procedures 
Removed the requirement for 
participants to remain at the site 
for approximately 1 to 2 hours 
after dosing at the Baseline Visit; 
however, retained text indicating 
that posttreatment assessments 
still need to be completed 
To support site flexibility for study 
conduct  


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Section # and Name 
Description of Change 
Brief Rationale 
9 Study Assessments 
and Procedures 
Clarified options for the PK 
sample collection with respect to 
dose administration for the 
On-therapy Visit 
To support site and participant 
flexibility  
9.1.2.1 
Microbiological 
Outcome and 
Response  
9.1.3.1 Clinical Signs 
and Symptom Scores, 
Clinical Outcomes, 
and Clinical 
Response 
Removed footnote from tables 
with regard to comparing the date 
and time of other systemic 
antimicrobials received with the 
date and time of On-therapy Visit 
Updated as “time” will not be used 
10.1 Statistical 
Hypothesis 
Clarified null and alternative 
hypotheses for superiority testing 
Clarification of the planned 
analysis 
10.3 Populations for 
Analyses 
Revised the definition of the PK 
Population 
Consistency with the reporting 
and analysis plan 
10.4.2 Efficacy 
Analysis 
Revised the primary analysis to be 
performed using the Miettinen and 
Nurminen method instead of the 
Cochran-Mantel-Haenszel method  
Consistency with the reporting 
and analysis plan 
12.3 Appendix 3 
Study Governance 
Considerations 
Clarified that, in countries where 
certain responsibilities reside with 
the sponsor instead of the 
investigator, GSK or its designee 
will be responsible for those 
activities  
Incorporation of the 26-May-2021 
site clarification letter  
Throughout 
Minor editorial and document 
formatting revisions 
Minor, therefore, have not been 
summarized 
 


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TABLE OF CONTENTS 
PAGE 
TITLE PAGE ................................................................................................................... 1 
SPONSOR SIGNATORY: ............................................................................................... 2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3 
1. 
SYNOPSIS ............................................................................................................. 10 
2. 
SCHEDULE OF ACTIVITIES ................................................................................. 15 
3. 
INTRODUCTION .................................................................................................... 17 
3.1. 
Study Rationale .......................................................................................... 17 
3.2. 
Background ................................................................................................ 18 
3.3. 
Benefit/Risk Assessment ............................................................................ 19 
3.3.1. 
Risk Assessment ......................................................................... 20 
3.3.2. 
Benefit Assessment ..................................................................... 27 
3.3.3. 
Overall Benefit:Risk Conclusion ................................................... 27 
4. 
OBJECTIVES AND ESTIMANDS/ENDPOINTS ..................................................... 28 
5. 
STUDY DESIGN .................................................................................................... 36 
5.1. 
Overall Design ............................................................................................ 36 
5.2. 
Number of Participants ............................................................................... 39 
5.3. 
Participant and Study Completion ............................................................... 39 
5.4. 
Scientific Rationale for Study Design .......................................................... 39 
5.5. 
Dose Justification ........................................................................................ 40 
6. 
STUDY POPULATION ........................................................................................... 42 
6.1. 
Inclusion Criteria ......................................................................................... 43 
6.2. 
Exclusion Criteria ........................................................................................ 43 
6.3. 
Lifestyle Restrictions ................................................................................... 47 
6.3.1. 
Meals and Dietary Restrictions .................................................... 47 
6.4. 
Screen Failures........................................................................................... 47 
7. 
TREATMENTS ....................................................................................................... 47 
7.1. 
Treatments Administered ............................................................................ 47 
7.2. 
Dose Modification ....................................................................................... 48 
7.3. 
Method of Treatment Assignment ............................................................... 49 
7.4. 
Blinding ....................................................................................................... 49 
7.5. 
Preparation/Handling/Storage/Accountability .............................................. 50 
7.6. 
Treatment Compliance ................................................................................ 51 
7.7. 
Concomitant Therapy.................................................................................. 51 
7.7.1. 
Permitted Medications and Nondrug Therapies ........................... 51 
7.7.2. 
Prohibited Medications and Nondrug Therapies........................... 52 
7.8. 
Treatment After the End of the Study .......................................................... 53 
8. 
DISCONTINUATION CRITERIA ............................................................................. 53 
8.1. 
Discontinuation of Study Treatment ............................................................ 53 
8.1.1. 
Liver Chemistry Stopping Criteria ................................................ 53 


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8.1.2. 
QTc Stopping Criteria .................................................................. 55 
8.1.3. 
Rechallenge ................................................................................. 55 
8.1.4. 
Gastrointestinal Evaluation Criteria .............................................. 55 
8.2. 
Withdrawal From the Study ......................................................................... 56 
8.3. 
Lost to Follow-Up ........................................................................................ 56 
9. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 57 
9.1. 
Efficacy Assessments ................................................................................. 60 
9.1.1. 
Therapeutic Response Evaluation ............................................... 60 
9.1.2. 
Bacteriology Samples .................................................................. 60 
9.1.3. 
Clinical Evaluation ....................................................................... 65 
9.2. 
Adverse Events........................................................................................... 69 
9.2.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................... 69 
9.2.2. 
Method of Detecting AEs and SAEs ............................................. 70 
9.2.3. 
Follow-up of AEs and SAEs ......................................................... 70 
9.2.4. 
Regulatory Reporting Requirements for SAEs ............................. 70 
9.2.5. 
Adverse Events of Special Interest .............................................. 70 
9.2.6. 
Cardiovascular and Death Events ................................................ 71 
9.2.7. 
Pregnancy ................................................................................... 71 
9.3. 
Treatment of Overdose ............................................................................... 71 
9.4. 
Safety Assessments ................................................................................... 72 
9.4.1. 
Physical Examinations ................................................................. 72 
9.4.2. 
Vital Signs .................................................................................... 72 
9.4.3. 
Electrocardiograms ...................................................................... 72 
9.4.4. 
Clinical Safety Laboratory Assessments ...................................... 73 
9.5. 
Pharmacokinetics ....................................................................................... 73 
9.6. 
Pharmacodynamics .................................................................................... 73 
9.7. 
Genetics ..................................................................................................... 73 
9.8. 
Biomarkers ................................................................................................. 74 
9.9. 
Health Economics or Medical Resource Utilization and Health 
Economics .................................................................................................. 74 
10. STATISTICAL CONSIDERATIONS ........................................................................ 74 
10.1. 
Statistical Hypothesis .................................................................................. 74 
10.2. 
Sample Size Determination ........................................................................ 75 
10.2.1. 
Justification of Sample Size ......................................................... 75 
10.2.2. 
Sample Size Sensitivity ................................................................ 76 
10.3. 
Populations for Analyses ............................................................................ 77 
10.4. 
Statistical Analyses ..................................................................................... 78 
10.4.1. 
General Considerations ............................................................... 79 
10.4.2. 
Efficacy Analyses ......................................................................... 79 
10.4.3. 
Safety Analyses ........................................................................... 82 
10.4.4. 
PK and PK/PD Analyses .............................................................. 83 
10.5. 
Interim Analysis .......................................................................................... 83 
10.6. 
Data Monitoring Committee or Other Review Board ................................... 84 
11. REFERENCES ....................................................................................................... 85 
12. APPENDICES ........................................................................................................ 88 
12.1. 
Appendix 1: Clostridium Difficile Testing Procedure and Algorithm ............. 88 


T M F -1 3 8 1 7 5 4 3  
C O N FI D E N TI A L  
 
 
 
2 0 4 9 8 9  
 
9  
 
1 2. 2.  A p p e n di x  2: C o ntr a c e pti v e G ui d a n c e a n d C oll e cti o n of Pr e g n a n c y 
I nf or m ati o n .................................................................................................. 8 9  
1 2. 3.  A p p e n di x  3: St u d y G o v er n a n c e C o n si d er ati o n s  .......................................... 9 3  
1 2. 4.  A p p e n di x  4: Al g orit h m f or D et er mi ni n g Q u alif yi n g Ur o p at h o g e n s  ................ 9 8  
1 2. 5.  A p p e n di x  5: C O VI D -1 9 Pr ot o c ol I nf or m ati o n  ............................................... 9 9  
1 2. 5. 1.  
O v er all R ati o n al e f or t hi s A p p e n di x  .............................................. 9 9  
1 2. 5. 2.  
St u d y Pr o c e d ur e s D uri n g t h e C O VI D -1 9 P a n d e mi c  ..................... 9 9  
1 2. 6.  A p p e n di x  6: Cli ni c al Si g n s a n d S y m pt o m s S c or e f or A c ut e C y st iti s .......... 1 0 1  
1 2. 7.  A p p e n di x  7: A d diti o n al G ui d a n c e o n P er mitt e d a n d Pr o hi bit e d 
M e di c ati o n s a n d Cr e di bl e m e d s. or g  ........................................................... 1 0 3  
1 2. 8.  A p p e n di x  8: Li v er S af et y: R e q uir e d A cti o n s a n d F oll o w -u p 
A s s e s s m e nt s  ............................................................................................ 1 0 6  
1 2. 1 0.  A p p e n di x  1 0: A d v er s e E v e nt s: D efi niti o n s a n d Pr o c e d ur e s f or 
R e c or di n g, E v al u ati n g, F oll o w -u p, a n d R e p orti n g  ..................................... 1 1 1  
1 2. 1 1.  A p p e n di x  1 1: Cli ni c al L a b or at or y T e st s  ..................................................... 1 1 6  
1 2. 1 2.  A p p e n di x  1 2: G e n eti c s  .............................................................................. 1 1 8  
1 2. 1 3.  A p p e n di x  1 3: Di vi si o n of Mi cr o bi ol o g y a n d I nf e cti o u s Di s e a s e s A d ult 
T o xi cit y T a bl e s f or A d v er s e E v e nt A s s e s s m e nt ......................................... 1 1 9  
1 2. 1 4.  A p p e n di x  1 4: A b br e vi ati o n s a n d Tr a d e m ar k s  ............................................ 1 2 6  
1 2. 1 5.  A p p e n di x  1 5: Pr ot o c ol A m e n d m e nt Hi st or y  ............................................... 1 2 8  
 
C CI


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1. 
SYNOPSIS 
Protocol Title:  A Phase III, Randomized, Multicenter, Parallel-Group, Double-Blind, 
Double-Dummy Study in Adolescent and Adult Female Participants Comparing the 
Efficacy and Safety of Gepotidacin to Nitrofurantoin in the Treatment of Uncomplicated 
Urinary Tract Infection (Acute Cystitis) 
Short Title:  Phase III, Double-Blind, Parallel-Group, Comparator-Controlled, Efficacy 
and Safety Study of Gepotidacin in the Treatment of Uncomplicated Urinary Tract 
Infection (Acute Cystitis); Efficacy of Antibacterial Gepotidacin Evaluated (EAGLE-2) 
Rationale: 
Urinary tract infections (UTIs; acute cystitis) are very common, with approximately 11% 
of women (greater than 18 years of age) reporting at least 1 episode of acute cystitis per 
year. In addition, one third of all female adolescents and women experience more than 
1 episode of acute cystitis, requiring antimicrobial therapy, by the age of 24 years. The 
predominant uropathogen isolated in community-acquired UTIs is Escherichia coli (75% 
to 90%) followed by Staphylococcus saprophyticus (5% to 15%). Multidrug resistance, 
which is typically associated with nosocomial infections, has now emerged at the 
community level and has made treatment approaches for UTIs more difficult. 
Gepotidacin is a first-in-class, novel triazaacenaphthylene bacterial type II topoisomerase 
inhibitor. The microbiological spectrum of activity of gepotidacin includes E. coli, 
S. saprophyticus, and Enterococcus faecalis. This Phase III study aims to evaluate the 
therapeutic response (combined microbiological and clinical efficacy per participant) of 
oral gepotidacin compared to oral nitrofurantoin for acute cystitis in adolescent and adult 
female participants. 
Objectives and Estimands/Endpoints: 
Objectives 
Endpoints 
Primary 
• 
To assess the combined clinical 
and microbiological efficacy of 
gepotidacin compared to 
nitrofurantoin, at the Test-of-Cure 
(TOC) Visit, in female participants 
with acute cystitis with qualifying 
bacterial uropathogen(s) at 
Baseline that all are susceptible to 
nitrofurantoin 
• 
Therapeutic response (combined per-participant 
microbiological and clinical response) at the TOC 
Visit 


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Objectives 
Endpoints 
Secondary 
• 
To assess the clinical efficacy of 
gepotidacin compared to 
nitrofurantoin, at the TOC and 
Follow-up Visits, in female 
participants with acute cystitis  
• 
Clinical outcome and response at the TOC and 
Follow-up Visits 
• 
To assess the clinical efficacy of 
gepotidacin compared to 
nitrofurantoin, at the TOC and 
Follow-up Visits, in female 
participants with acute cystitis with 
qualifying bacterial uropathogen(s) 
at Baseline that all are susceptible 
to nitrofurantoin 
• 
Clinical outcome and response at the TOC and 
Follow-up Visits 
• 
To assess the microbiological 
efficacy of gepotidacin compared 
to nitrofurantoin, at the TOC and 
Follow-up Visits, in female 
participants with acute cystitis with 
qualifying bacterial uropathogen(s) 
at Baseline that all are susceptible 
to nitrofurantoin 
• 
Microbiological outcome and response at the 
TOC and Follow-up Visits 
• 
To assess the combined clinical 
and microbiological efficacy of 
gepotidacin compared to 
nitrofurantoin, at the Follow-up 
Visit, in female participants with 
acute cystitis with qualifying 
bacterial uropathogen(s) at 
Baseline that all are susceptible to 
nitrofurantoin 
• 
Therapeutic response (combined per-participant 
microbiological and clinical response) at the 
Follow-up Visit 
• 
To determine the plasma and 
urine pharmacokinetic (PK) 
concentrations of gepotidacin in 
female participants with acute 
cystitis 
• 
Gepotidacin plasma and urine concentrations  
• 
To assess the safety and 
tolerability of gepotidacin 
compared to nitrofurantoin in 
female participants with acute 
cystitis 
• 
Treatment-emergent adverse events and serious 
adverse events and change from baseline results 
for clinical laboratory tests and vital sign 
measurements 
Note: Exploratory objectives are described in the main protocol text. 


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Primary Estimand 
The primary clinical question of interest is: What is the treatment effect on the 
therapeutic response after 5 days of treatment with gepotidacin 1500 mg twice daily 
compared to 5 days of treatment with nitrofurantoin 100 mg twice daily in participants 
with acute cystitis with qualifying bacterial uropathogen(s) at Baseline that all are 
susceptible to nitrofurantoin, regardless of treatment discontinuation for any reason. 
Receipt of systemic antimicrobials will impact the endpoint definition (see 
Section 9.1.2.1 and Section 9.1.3.1. 
The primary estimand is described by the following attributes: 
• Population: Female participants with acute cystitis with qualifying bacterial 
uropathogen(s) at Baseline that all are susceptible to nitrofurantoin. 
• Treatment condition: Gepotidacin 1500 mg twice daily for 5 days versus 
nitrofurantoin 100 mg twice daily for 5 days, regardless of adherence. 
• Variable: Therapeutic response (combined per-participant microbiological and 
clinical response) at the TOC Visit. Microbiological success is defined as 
eradication (i.e., reduction) of all qualifying bacterial uropathogens recovered at 
baseline to <103 colony-forming units/mL (CFU/mL) as observed on quantitative 
urine culture without the participant receiving other systemic antimicrobials. 
Clinical success is defined as resolution of signs and symptoms of acute cystitis 
present at Baseline (and no new signs and symptoms) without the participant 
receiving other systemic antimicrobials. 
• Summary measure: Absolute difference in the therapeutic success rate in the 
gepotidacin and nitrofurantoin treatment groups.  
• Intercurrent events (ICEs): 
• Study treatment discontinuation (due to any reason) – treatment policy 
strategy (interest is in the treatment effect regardless of study treatment 
discontinuation). 
• Use of systemic antimicrobials – composite strategy. This ICE is captured 
through the definitions of microbiological and clinical response (see 
Section 9.1.2.1 and Section 9.1.3.1) and will be counted as therapeutic 
failures. 
Rationale for Estimand: 
Interest lies in the treatment effect regardless of whether the full course of 5 days of 
treatment was taken or not, which reflects how patients may be treated in clinical 
practice. Hence, a treatment policy strategy is appropriate for treatment withdrawal 
before completing 5 days of treatment. Use of other systemic antimicrobials may 
confound the bacterial culture results; thus, the microbiological response will be 
considered failure. For clinical data, the use of a systemic antimicrobial for acute cystitis 
is a sign of treatment failure and use of a systemic antimicrobial for another infection 
cannot be considered a success as it confounds the assessment of efficacy. Therefore, the 
definition of a successful therapeutic response precludes the use of other systemic 
antimicrobials. 


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2 0 4 9 8 9  
 
1 3  
 
Sec o n dar y Esti ma n ds:  
T he sec o n d ar y cli nical q uesti o ns of i nterest are: W hat is  t he treat me nt effect o n eac h of 
t he sec o n dar y efficac y e n d p oi nts after 5 da ys of tr eat me nt wit h ge p oti daci n 1 5 0 0 m g 
t wice dail y c o m pare d t o 5 da ys of treat me nt wit h nitr of ura nt oi n 1 0 0 m g t wice dail y i n 
partici pa nts wit h ac ute c ystitis (cli nical e n d p oi nts)  a n d i n partici pa nts wit h ac ute c ystitis 
wit h q ualif yi n g bacterial ur o pat h o ge n (s) at B aseli ne t hat all are s us ce pti ble t o 
nitr of ura nt oi n  (t hera pe uti c, cli nical, a n d micr o bi ol o gical e n d p oi nts), re gar dless of 
treat me nt disc o nti n uati o n f or a n y reas o n. Recei pt of s yste mic a nti micr o bials i m pacts t he 
e n d p oi nt defi niti o n (see Secti o n 9. 1. 2. 1  a n d Secti o n  9. 1. 3. 1 ). 
F or eac h of t h e sec o n d ar y e n d p oi nts t he esti ma n d will f oll o w a si milar a p pr oac h t o t he 
esti ma n d f or t he pri mar y e n d p oi nt a n d will use t he sa me strate gies f or t he I C Es. T he 
e x ce pti o n is t he s u m mar y me as ure f or t he o utc o m e e n d p oi nts. T hese e n d p oi nts are 
descri pti vel y s u m mariz e d ; t heref ore, t he su m mar y meas ure w ill be t he perce nta ge i n eac h 
cli nical a n d micr o bi ol o gical o utc o me cate g or y i n t he g e p oti daci n a n d n itr of ura nt oi n ar ms 
se parat el y (as n o direct c o m paris o n bet wee n tr eat me nt gr o u ps will be ma d e)  (see 
Secti o n  9. 1. 2. 1  a n d Secti o n  9. 1. 3. 1  f or e n d p oi nt d efi niti o ns). 
T he safet y e n d p oi nt will use a treat me nt p olic y str ate g y of t he I C E of wit h dra wal fr o m 
treat me nt as t he safet y will be assesse d at all p ost b aseli ne assess me nts irres pecti ve of 
w het her t he p artici pa nt c o m plete d t he treat me nt.  
See Ta ble 2  f or t he c o m p o ne nts of esti ma n d f or t h e sec o n dar y e n d p oi nts.  
O ver all Desi g n:  
•  St u d y 2 0 4 9 8 9 is a P hase III, ra n d o mize d, m ultice nter, parallel -gr o u p, 
d o u ble -bli n d, d o u ble -d u m m y, c o m parat or -c o ntr olle d , n o ni nferi orit y st u d y i n 
a d olesce nt a n d a d ult fe m ale partici pa nts  c o m p ari n g t he efficac y a n d safet y of oral 
ge p oti daci n t o oral nitr of ura nt oi n i n t he treat me nt of u nc o m plicate d U TI (ac ute 
c ystitis).  
•  Partici pa nts will be stratifie d b y a ge cate g or y a n d ac ute c ystitis rec urre n ce a n d 
will be ra n d o ml y assi g n e d i n a 1: 1 rati o t o recei ve eit her oral ge p oti daci n or oral 
nitr of ura nt oi n.  
•  A p pr o priate s afet y , effic ac y, a n d micr o bi ol o gical a ssess me nts will be c o n d ucte d 
at t he Bas eli ne ( Da y 1) Visit a n d re peate d at t he O n -t hera p y ( Da y 2  t o 4 ), T O C 
( Da y 1 0 t o  1 3), a n d F oll o w -u p ( Da y 2 8 ± 3) Visits. P har mac o ki netic sa m ples will 
be c ollecte d at t he O n -t h era p y Visit. 
 
 
 
•  F or t he pri mar y efficac y e n d p oi nt of t hera p e utic res p o nse (c o m bi ne d 
per -partici pa nt micr o bi ol o gical a n d cli nical r es p o nse), t hera p e utic s uccess refers 
t o partici pa nts w h o ha ve bee n dee me d b ot h a micr o bi ol o gical s uc cess (re d u cti o n 
of all q ualif yi n g b acterial ur o pat h o ge n s [e. g., 1 0 5  c ol o n y-f or mi n g u nits/ m L 
(C F U / m L)] rec o v ere d at Baseli ne t o < 1 03 C F U / m L as o bs er ve d o n q u a ntitati ve 
uri ne c ult ure) wit h o ut t he partici pa nt recei vi n g ot her s yste mic a nti micr o bials  a n d 
a cli nical s uccess (res ol uti o n of si g ns a n d s y m pt o ms of ac ute c ystitis prese nt at 
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Baseline [and no new signs and symptoms] without the participant receiving other 
systemic antimicrobials) at the TOC Visit in the Microbiological Intent-to-Treat 
Nitrofurantoin-Susceptible (micro-ITT NTF-S) Population, regardless of 
treatment discontinuation. 
Number of Participants: 
The study is planned to enroll approximately 2500 participants to fulfill the maximum 
target sample size of approximately 884 participants in the primary analysis micro-ITT 
NTF-S Population. The final number of randomized participants may vary based on the 
evaluability rate and review of qualifying uropathogens by an unblinded Statistical Data 
Analysis Center. 
Treatment Groups and Duration: 
• 
Participants will receive 1 of the following treatments: 
• Gepotidacin: 1500 mg administered orally twice daily for 5 days (Note: Each dose 
should be taken after food consumption and with water to assist with tolerability.) 
• Nitrofurantoin: 100 mg administered orally twice daily for 5 days (Note: Each 
dose should be taken after food consumption and with water.) 
• 
The duration of study participation is approximately 28 days with 4 planned study 
visits: 
• 
Baseline (Day 1) Visit 
• 
On-therapy (Day 2 to 4) Visit 
• 
TOC (Day 10 to 13) Visit 
• 
Follow-up (Day 28±3) Visit 
Data Monitoring or Other Committee: Yes; this study will include an Independent 
Data Monitoring Committee for interim analysis purposes, a GlaxoSmithKline Safety 
Review Team will monitor blinded safety data, and a Microbiology Review Team will 
monitor blinded microbiological data instream.  
 


T M F -1 3 8 1 7 5 4 3  
C O N FI D E N TI A L  
 
 
 
2 0 4 9 8 9  
 
1 5  
 
2.  
S C H E D U L E O F A C TI VI TI E S  
T a bl e  1  
S c h e d ul e of A cti viti e s  
Vi sit a 
B a s eli n e  
O n -T h er a p y b 
T O C b 
F oll o w -u p  
E arl y Wit h dra w al  
St u d y D a y  
1  
2  t o 4  
1 0 t o 1 3  
2 8 ± 3  
N A  
Pr o c e d ure  
Pre d o s e  
P o st d o s e  
Writt e n i nf or m e d c o ns e nt/ ass e nt  
X  
 
 
 
 
 
I R T –  Scr e e ni n g m o d ul e  
X  
 
 
 
 
 
I ncl usi o n a n d excl usi o n crit eri a 
X  
 
 
 
 
 
P artici p a nt d e m o gr a p hy  
X  
 
 
 
 
 
P hysic al ex a mi n ati o n (i ncl u di n g h ei g ht a n d w ei g ht at B as eli n e o nly)  
X  
 
 
X c 
 
 
R ec or d ac ut e cystitis si g ns a n d sy m pt o ms d 
X  
 
X  
X  
X  
X  
M e dic al/s ur gic al hist ory  
X  
 
 
 
 
 
Di a g n osis of pr es u m ptiv e ac ut e cystitis f 
X  
 
 
 
 
 
B act eri ol o gy s a m pl es g 
X  
 
X h 
X  
X  
X  
R a n d o miz ati o n  
X  
 
 
 
 
 
1 2 -l e a d el ectr oc ar di o gr a mi 
X  
 
 
 
 
 
Vit al si g n m e as ur e m e nts j 
X  
 
X  
X  
 
 
H e m at ol o gy, c h e mistry, a n d uri n alysis  
X  
 
X  
X  
 
 
S er ol o gy ( h e p atitis B a n d C a n d HI V) k 
X  
 
 
 
 
 
Uri n e pr e g n a ncy t est l 
X l 
 
X l 
X  
 
X  
Dr u g a n d alc o h ol scr e e n  
X  
 
 
 
 
 
I R T –  R a n d o miz ati o n m o d ul e  
X  
 
 
 
 
 
A d mi nist er or al d os e of st u dy tr e at m e nt n 
 
X  
X o 
 
 
 
S eri o us a dv ers e ev e nts p 
X  
X  
X  
X  
X  
X  
A dv ers e ev e nts q 
 
X  
X  
X  
X  
X  
C o nc o mit a nt m e dic ati o n r evi e w  
X  
X  
X  
X  
X  
X  
P K bl o o d s a m pl e  
 
 
X r 
 
 
 
P K uri n e s a m pl e  
 
 
X r 
 
 
 
St u dy tr e at m e nt c o m pli a nc e s 
 
 
X  
X  
 
 
Sc h e d ul e n ext visit  
X t 
 
X u 
X u 
X u 
 
G e n etic s a m pl e v 
X  
 
 
 
 
 
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T M F -1 3 8 1 7 5 4 3  
C O N FI D E N TI A L  
 
 
 
2 0 4 9 8 9  
 
1 6  
 
HI V = h u m a n i m m u n o d efici e ncy virus; H P F = hi g h -p o w er fi el d; I R T =i nt eractiv e res p o ns e t ec h n ol o gy; N A = n ot a p plic a bl e; P K = p h ar m ac oki n etic; T O C = T est -of -Cure; U TI = uri n ary tract i nf ecti o n; W B C = w hit e 
bl o o d c ell.  
Not e:  T o re duc e p artici p a nt o n -sit e visits or if u nf ores e e n iss u es i m p act cli nic visits, a n d p artici p a nts are u n a bl e t o att e n d a sit e visit, h o m e h e alt hc ar e  (h o m e visits a nd t el e me dici n e visits) m ay b e us e d 
t o c o n d uct proce dures as d et ail e d i n t h e St u dy R ef er e nc e M a n u al. Ho m e h e alt hc are will o nly b e utiliz e d wh ere a p plic a bl e c o u ntry a n d l oc al re g ul ati o ns a n d i nfrastruct ur e all o w.   
a.  
F or all st u dy visits, t o mi ni miz e t h e a mo u nt of ti m e t h at p artici p a nts s p e n d at t h e cli nic,  e Co ns e nt m ay b e utiliz e d a n d re mot e c oll ecti o n of st u dy -rel at e d d at a m ay b e o bt ai n e d as d escri b e d i n t h e 
St u dy Ref ere nc e M a n u al. T h us, s o m e visit d at a m ay b e c oll ect e d t hro u g h a c o mbi n ati o n of t el e me dici n e a n d o n -sit e visits. Coll ecti o n of i nf or m ati o n vi a t el e me dici n e will b e p erf or m e d o nly wh ere 
l oc al re gul ati o ns p er mit. Prescr e e ni n g activiti es m ay als o b e c o n d uct e d, i ncl u di n g a prescre e ni n g i nf or m e d c o ns e nt a n d uri n e t est i n g, as d et ail e d i n S ecti o n 9  a n d t h e St u dy Ref ere nc e M a n ual. 
b . 
F or t he O n -t h era py ( D ay 2  t o 4 ) Visit: P artici p a nts will b e i nstruct e d t o ret ur n t o t h e st u dy sit e wit hi n 1  t o 3 d ays p ostra n d o miz ati o n. E ac h tre at m e nt d ay w ill b e ass ess e d ov er 2 4 h ours st arti n g wit h 
t h e first dos e of st u dy tr e at m e nt, as f urt h er d et ail e d i n t h e St u dy R ef ere nc e M a n u al. F or t h e T O C ( D ay 1 0 t o 1 3) Visit: P artici p a nts will b e i nstruct e d t o ret urn t o t h e st u dy sit e 5 t o 8 d ays aft er 
c o mpl eti o n of st u dy tre at m e nt.  
c. 
At t h e T O C Visit, t h e p hysic al ex a mi n ati o n m ay b e sy m pt o m direct e d a n d is o nly re q uir e d if i n dic at e d f or a s p ecific p artici p a nt.  
d.  
I n divi d ual cli nic al si g ns a n d sy m pt o ms sc ores of ac ut e cystitis will b e rec or d e d by a st u dy p hysici a n or ot h er wis e a p pr o pri ately m e dic ally trai n e d st aff b as e d o n p artici p ant i nt ervi e w a n d usi n g t he 
sc ori n g syst e m i n A p p e n dix  6 . T h e s a m e sc orer will b e us e d at all ass ess m e nt ti m e p oi nts f or e ac h p artici p a nt, o n all occ asi o ns, wh en ev er p ossi bl e. 
f. 
B as e d o n c o nfir m ati o n of nitrit e or py uri a ( > 1 5  W B C/ H P F  or t h e pr es e nc e of 3 +/ l arg e l e uk ocyt e est eras e) fro m a pretre at m e nt cle a n -c atc h mi dstre a m uri n e s a m pl e per l oc al l a borat ory proc e dures.  
g . 
P artici p ants will provi d e a cl e a n -c atc h mi dstre a m uri n e s a m pl e at e ac h visit f or Gra m st ai n, q u a ntit ativ e b act eri ol o gy c ult ure, a n d i n vitr o a nti micro bi al s usc e pti bility t esti n g  by a d esi g nat e d 
l a borat ory(i es). R ef er t o t h e l a b orat ory m a n u al.  
h . 
A b act eri ol o gy uri n e s a m pl e will b e c oll ect e d at t h e O n -t h era py Visit, as f urt h er d et ail e d i n t h e St u dy R ef ere nc e M a n u al. 
i. 
S e e S ecti o n 6. 2  f or el ectr oc ar di o gra m excl usi o n crit eri o n f or p artici p a nts a g e d ≥1 2 t o < 1 8 y e ars. F or a d diti o n al d et ails s e e S ecti o n 8. 1. 2  a n d S ecti o n 9. 4. 3 . 
j. 
T ak e m e as ure m e nt of t e m p erat ure, bl o o d press ur e, a n d p uls e rat e.  
k. 
If s erol o gy t esti n g w as p erf or m e d wit hi n 3 m o nt hs pri or t o t h e first d os e of st u dy tre at m e nt a n d t h e res ults were p o siti v e , t esti n g at B as eli n e i s n ot r e q uir e d. If t esti n g was p erf or m e d wit hi n 
3  m o nt hs a n d a ny res ult w as n e g ati v e , t esti n g at B as eli n e i s r e q uir e d.  
l. 
F or wo me n of c hil d b e ari n g p ot e nti al, a n e g ativ e hi g h s e nsitivity uri n e pre g n a ncy t est is s uffici e nt f or eli gi bility. S e e  A p p e n dix  2  f or B as eli n e uri n e t est s e nsitivity re quir e me nts a nd ass oci at e d 
c o ntrac e pti o n re q uir e me nts. Pre g n a ncy t esti n g s h o ul d als o b e p erf or m e d aft er D os e 4 a n d b ef ore D os e 8 as s p ecifi e d i n  A p p e n dix  2 . 
n . 
P artici p ants will rec eiv e oral st u dy tre at m e nt t wic e d aily f or 5  d ays u n d er d o u bl e -bli n d, d o u bl e -d u m my c o n diti o ns. T h e first oral d os e will b e a d mi nist ere d at t h e st u dy sit e d uri n g t h e B as eli n e Visit; 
p artici p ants will s elf -a d mi nist er as o ut p ati e nts t h ere aft er.  E ac h d os e s h o ul d b e t ak e n aft er f o o d c o ns u m pti o n a n d wit h wat er.  
o . 
P artici p ants s h o ul d c o nti n u e t aki n g st u dy tre at m e nt p er t h eir pl a n n e d d osi n g sc h e d ul e. If at all p ossi bl e, t h e a p p oi nt m e nt ti m e of t h e O n-t h era py Visit s h oul d be a pproxi m at ely 1 t o 2 h o urs aft er t h e 
p artici p ant’s m ost rec e nt d os e is ex p ect e d t o b e t ak e n. S e e t h e St u dy Ref ere nc e M a n u al f or a d diti o n al d et ails.  
p . 
Rec ord s eri o us a dv ers e ev e nts fro m t h e ti m e of c o ns e nt/ ass e nt i n ord er t o f ulfill i nt ern ati o n al re g ul at ory r e q uir e m e nts.  
q . 
Rec ord a dv ers e ev e nts fro m t h e ti m e of t h e first d os e of st u dy tre at m e nt.  
r. 
At t h e O n -t h er a py Visit, P K s a mpl es will b e c oll ect e d, as f urt h er d et ail e d i n S ecti o n 9  a n d t h e St u dy Ref ere nc e M a n u al. 
s. 
Det er mi n e st u dy tre at m e nt c o m pli a nc e by p erf or mi n g pill c o u nt.  
t. 
Co nfi r m ret urn d ay/ti m e f or t h e O n-t h era py, T O C, a n d F oll o w-u p Visits.  R ef er t o f o ot n ot e o f or sc h e d uli n g t h e O n -t h era py Visit. 
u . 
Previsit re mi n d er: St u dy s it e st aff will c o nt act t h e p artici p a nt 2 4 ± 4 h o urs b ef ore t h e sc h e d ul e d O n -t h era py, T O C, a n d F oll o w-u p Vi sits. 
v.  
Coll ect s a m pl e o nly if t h e p artici p a nt h as a si g n e d c o ns e nt/ ass e nt s p ecific f or t his p urp os e. T h e B as eli n e Visit is t h e rec o m m e n d e d ti m e t o c oll ect t h e s a m pl e, b ut it c a n b e c oll ect e d at a ny ti m e 
d uri n g t h e st u dy.  
 
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3. 
INTRODUCTION 
Gepotidacin (GSK2140944), a novel triazaacenaphthylene bacterial type II 
topoisomerase inhibitor, is being developed for the treatment of uncomplicated urinary 
tract infections (UTIs; acute cystitis). Gepotidacin has activity versus key pathogens, 
including drug-resistant strains associated with a range of conventional and biothreat 
infections. The microbiological spectrum of activity of gepotidacin includes Escherichia 
coli, the key causative pathogen of acute cystitis, Staphylococcus saprophyticus, and 
Enterococcus faecalis. 
Gepotidacin selectively inhibits bacterial DNA replication by interacting in a unique way 
on the GyrA subunit of bacterial DNA gyrase and the ParC subunit of bacterial 
topoisomerase IV. This interaction appears to be highly specific to bacterial 
topoisomerases as evidenced by weak in vitro inhibition of human topoisomerase II, 
supporting the selective activity of gepotidacin against the bacterial target. The novel 
mode of action of this new class antibacterial affords in vitro activity against most target 
pathogens resistant to established antibacterials, including fluoroquinolones. 
3.1. 
Study Rationale 
This study is being conducted based on the need to identify new and effective oral 
antibiotic treatment options for acute cystitis, as such therapies are becoming limited due 
to the increase of multidrug-resistant (MDR) pathogens and extended-spectrum 
-lactamase (ESBL)-producing Enterobacterales pathogens, which are impacting the 
efficacy of currently available oral antibacterial treatment options (see Section 3.2). 
Two Phase II studies have been conducted and the results demonstrated that gepotidacin 
was efficacious in the treatment of uncomplicated urogenital gonorrhea and acute 
bacterial skin and skin structure infections (ABSSSIs) (see Section 5.3.3 in the 
investigator’s brochure [IB] for details. In addition, a Phase IIa pharmacokinetic (PK) 
study (206899) was recently conducted in 22 participants with acute cystitis that also 
included exploratory clinical and microbiological efficacy objectives. All 22 participants 
were evaluable for PK and clinical efficacy analysis. Of the 22 participants, 
19 participants (86%) and 18 participants (82%) achieved symptom resolution at the 
Test-of-Cure (TOC) and Follow-up Visits, respectively. Eight of 22 participants (36%) 
who received at least 1 dose of gepotidacin had a qualifying baseline uropathogen (5 with 
E. coli isolates, 1 with a S. saprophyticus isolate, 1 with a Klebsiella pneumoniae isolate, 
and 1 with a Citrobacter koseri isolate). Of these 8 participants, 7 participants (88%) and 
6 participants (75%) had a microbiological response of microbiological success 
(<103 CFU/mL) at the TOC and Follow-up Visits, respectively. Furthermore, of these 
8 participants, 6 participants (75%) and 5 participants (63%) had a therapeutic response 
(combined per-participant microbiological and clinical response) of success at the TOC 
and Follow-up Visits, respectively. Refer to the IB for PK, safety, and additional efficacy 
results. 
This study (204989) aims to evaluate the therapeutic response (combined microbiological 
and clinical efficacy per participant) of oral gepotidacin compared to oral nitrofurantoin 
for acute cystitis in adolescent and adult female participants. 


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3.2. 
Background 
Urinary tract infections are very common, with approximately 11% of women >18 years 
of age experiencing at least 1 episode of acute cystitis per year [Foxman, 2000]. Of these, 
half will experience more than 1 recurrent episode over their lifetime [Foxman, 2000]. 
The peak incidence of acute cystitis occurs in young, sexually active women ages 18 to 
29 years [Fihn, 2003]. The predominant uropathogens isolated in community-acquired 
UTIs are E. coli (75% to 90%) followed by S. saprophyticus (5% to 15%) [Stamm, 1993; 
Talan, 2000; Foxman, 2010]. Klebsiella, Enterobacter, Proteus species, and enterococci 
are observed in only 5% to 10% of acute cystitis [Stamm, 1993; Talan, 2000; Foxman, 
2010]. 
Multidrug resistance, which is typically associated with nosocomial infections, has now 
emerged at the community level and has made treatment approaches for UTIs more 
difficult [Hooton, 2012; Flamm, 2014; Sanchez, 2016]. This has led to increasing patient 
morbidity, increasing costs due to reassessment and retreatment, higher rates of 
hospitalization, and increased use of broad-spectrum antibiotics [Foxman, 2002; Gupta, 
2011a; Hooton, 2012]. Furthermore, ESBL-producing Enterobacteriaceae (now 
recognized as Enterobacterales), which includes E. coli, is recognized as a serious threat 
by the Centers for Disease Control and Prevention (CDC) [CDC, 2019] and 
drug-resistant Enterobacteriaceae is a critical priority pathogen for the World Health 
Organization (WHO) [WHO, 2017]. One reason for this serious threat level is the 
growing rise in the MDR E. coli sequence type (ST)-131 clone [Johnson, 2012; Nicolas-
Chanoine, 2014]. Spread of this ST-131 clone has led to UTIs and blood stream 
infections caused by MDR E. coli worldwide [Peirano, 2010]. The availability of oral 
antimicrobials that are effective against ESBLs is limited and, for some outpatient 
infections, no oral options remain. 
An in vitro evaluation of antimicrobial resistance of urinary E. coli isolates 
(n=12,253,679) among US outpatients between 2000 and 2010 was conducted using 
The Surveillance Network and found significant increases in the percentage of E. coli that 
were resistant to ciprofloxacin (3% to 17.1%) and trimethoprim-sulfamethoxazole 
(TMP-SXT) (17.9% to 24.2%), whereas there were minimal changes in the percentage of 
resistance to nitrofurantoin (0.8% to 1.6%) and ceftriaxone (0.2% to 2.3%) over time 
[Sanchez, 2012]. Another surveillance study, which looked at US susceptibility patterns 
and ESBL rates of E. coli from UTIs, showed an increase in ESBL rates from 7.8% to 
18.3% (p<0.0001) from 2010 to 2014 [Lob, 2016]. The expansion of ESBL-producing 
E. coli, which are usually co-resistant to TMP-SXT and fluoroquinolones, is of urgent 
concern globally as well [Oteo, 2010]. Recent global surveillance data of E. coli showed 
high resistance rates to third-generation cephalosporins and fluoroquinolones in all 
6 WHO regions [WHO, 2014]. An evaluation of the prevalence and susceptibility of 
acute cystitis pathogens in 9 European countries and Brazil from 2003 to 2006 showed 
that >10% of E. coli strains were MDR and 1.7% were ESBL producers [Schito, 2009]. A 
separate study in Brazil reported a prevalence of 7.6% ESBL-producing Enterobacterales 
among pathogens from community-acquired UTIs [Abreu, 2013]. In China, the 
prevalence of ESBLs in urinary E. coli in women ranged from 5% to 10.6% depending 
on the age group [Ho, 2007].  


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Based on these resistant pathogen trends, guidelines for acute cystitis now recommend 
first-line antibiotic treatment with nitrofurantoin, TMP-SXT, fosfomycin, or 
pivmecillinam, assuming the drug is available and the patient does not have a concerning 
allergy history or tolerance issues [Gupta, 2011b]. Trimethoprim-sulfamethoxazole 
should not be used as a first-line treatment if the prevalence of resistance exceeds the 
20% threshold or if TMP-SXT was used for treatment of a UTI in the previous 3 months. 
If any of these are concerns for a patient, then fluoroquinolones or β-lactams are 
recommended. 
Gepotidacin is a first-in-class, novel triazaacenaphthylene antibacterial that has 
demonstrated in vitro activity against uropathogens including E. coli (see Section 4.2.1.2 
of the IB for details) and provides high and sustained urine concentrations for the 
treatment of UTIs. With its unique ability to selectively inhibit bacterial DNA replication 
by a means not utilized by any currently approved human therapeutic agent, gepotidacin 
warrants further study as a potential opportunity to address an unmet medical need by 
providing a new and effective oral treatment option for acute cystitis. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of 
gepotidacin is provided in the IB. Details on the active comparator in this study, 
nitrofurantoin, may be found in the locally approved prescribing information. 
3.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events (AEs) of gepotidacin and nitrofurantoin may be 
found in the IB and the locally approved prescribing information, respectively. 
 


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3.3.1. 
Risk Assessment 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
Gepotidacin (GSK2140944) 
Cardiovascular Effects 
Based on nonclinical data, cardiovascular 
effects were reversible increase in heart rate 
and blood pressure (dog and monkey); 
reversible 10 to 21 msec (4% to 9%) increase 
in QTc (monkey); and at the highest dose, a 
reversible 2 to 3 msec (6% to 8%) increase in 
QRS (monkey). 
Based on a thorough QTc clinical study, 
gepotidacin may cause mild, reversible heart 
rate effects and QT prolongation. 
In a thorough QTc study, infusion of gepotidacin 
at doses of 1000 and 1800 mg over 2 hours 
caused a mild increased heart rate effect of 
approximately 6 to 10 bpm and QT prolongation 
measured as ∆∆QTcF of 12 to 22 msec. The QT 
prolongation evolved during the infusion and was 
quickly reversed over 2 hours after the end of the 
infusion (see Section 5.2.6 and Section 6 of the 
IB). 
In Phase I and II studies, 
concentration-dependent QT prolongation has 
been observed during clinical trials with 
gepotidacin; however, this increase has not 
translated into clinically significant QTc values or 
changes from baseline (change from baseline 
>60 msec or QTcF >500 msec) or cardiovascular 
AEs.  
In Phase I and II studies, gepotidacin did not have 
a clinically relevant effect on cardiac conduction 
(PR and QRS intervals).  
See Section 6.2 for excluded cardiac 
conditions. Close monitoring of clinical 
parameters and AEs (Section 2) will be 
conducted, and treatment monitoring and 
evaluation criteria (Section 8.1.2) will be 
utilized to mitigate cardiovascular effects. 
Participants taking medications known to 
increase QT or potent CYP3A4 inhibitors will 
be excluded (see Section 7.7.2). 
See also the Renal and Hepatic sections within 
this table below. 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
Gastrointestinal Effects 
Based on nonclinical data, gastrointestinal 
effects were mild ulceration of the nonglandular 
mucosa and minimal erosion and/or mural 
inflammation of the glandular mucosa in 
stomach (rat, oral study); moderate cecal 
ulceration and minimal colonic erosion (rat, IV 
study); and vomiting (dog). 
Lower gastrointestinal effects (soft stools, 
flatulence, and diarrhea) are among the most 
common AEs reported in gepotidacin clinical 
studies. Nausea and vomiting AEs have also 
been commonly observed in gepotidacin 
clinical studies. 
See also the Acetylcholinesterase Inhibition 
section within this table below. 
Clostridium difficile-associated diarrhea has been 
observed in clinical trials with gepotidacin. 
See Section 6.2 for excluded medical 
conditions. Close monitoring of clinical 
parameters and AEs (Section 2) will be 
conducted to mitigate and assess 
gastrointestinal effects.  
Suspected C. difficile infection will be managed 
according to a prespecified algorithm provided 
in Appendix 1. 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
Acetylcholinesterase Inhibition 
In vitro testing showed gepotidacin to be a 
rapidly reversible inhibitor of 
acetylcholinesterase in the clinical plasma 
concentration range. 
Based on clinical data, caution should be used 
in participants who have a condition requiring 
treatment with anticholinergic medications or 
who have certain medical conditions that may 
be exacerbated by the acetylcholinesterase 
inhibition activity of gepotidacin. 
Increased cholinergic effects can potentially be 
associated with more severe symptoms including 
atrioventricular block, seizure/convulsions, 
bronchospasm, and vasovagal syncope. No 
causal relationship between these events and the 
use of gepotidacin has been established during 
clinical trials to date. 
Adverse events consistent with 
acetylcholinesterase inhibition, including diarrhea, 
nausea, vomiting, gastrointestinal cramping and 
pain, dyspnea, bradycardia, lacrimation, 
salivation, and diaphoresis/sweating have been 
reported during clinical trials with gepotidacin.  
Mild and transient non-gastrointestinal AEs have 
been associated with Cmax levels higher than this 
dosing regimen. 
Participants who have medical conditions or 
require medications that may be impacted by 
inhibition of acetylcholinesterase will be 
excluded from participation in this study. See 
Section 6.2 for excluded medical conditions 
and Section 7.7.2, Prohibited Medications and 
Nondrug Therapies, for prohibited medications. 
Close monitoring of clinical parameters and 
AEs will be conducted to assess effects 
potentially related to acetylcholinesterase 
inhibition (Section 2). 
Hepatic Effects 
In preclinical studies, increases in ALT, GLDH, 
alkaline phosphatase, and total bilirubin were 
observed in some rat studies of varying 
exposure.  
Elevations in ALT have occurred in a few 
participants with pre-existing hepatitis C infection, 
but none were felt related to study treatment. The 
type and pattern of elevation in liver 
transaminases observed has not been suggestive 
of an adverse effect of gepotidacin and none were 
considered related to study treatment. 
A substantial increase in Cmax and AUC and 
decrease in clearance was observed in volunteer 
participants with severe hepatic impairment. 
Participants with severe hepatic impairment are 
excluded from Phase III trials. See Section 6.2 
for excluded medical conditions. Monitoring 
and stopping criteria liver events have been 
implemented. 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
Renal Effects 
In preclinical trials, mild to moderate tubular 
degeneration was noted in the rat and 
proteinuria in the dog. Proteinuria was also 
observed in humans. 
No clinical evidence of renal toxicity has been 
seen in clinical trials to date. 
A substantial increase in Cmax and AUC and 
decrease in clearance was observed in severe 
renal impairment/ESRD participants not on 
hemodialysis and in ESRD participants requiring 
hemodialysis (note: gepotidacin may have been 
administered at any time other than when 
receiving dialysis). 
Participants with severe renal 
impairment/ESRD (including those who may 
require dialysis) are excluded from Phase III 
trials. See Section 6.2 for excluded medical 
conditions. Monitoring criteria have been 
implemented. 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
Reproductive System Effects 
Preclinical studies demonstrated that 
gepotidacin was not genotoxic and no 
drug-related malformations were observed. 
Although positive in vitro findings for 
clastogenicity, consistent with a mechanism 
related to mammalian topoisomerase II 
inhibition were found, in vivo data from rat 
micronucleus and COMET assays suggest that 
gepotidacin does not pose a genotoxic hazard 
to humans. 
Gepotidacin effects on embryofetal 
development were limited to decreased fetal 
weights for male and female fetuses in rats and 
decreased fetal weights and increased fetal 
resorptions (fetal deaths) in mice, both at 
maternally toxic doses. These occurred at 
clinically relevant exposures (65 µg.h/mL in rat 
and 35 µg.h/mL in mouse). 
There are no data on the use of gepotidacin in 
pregnant women. 
Gepotidacin is contraindicated in pregnant or 
nursing mothers and women of childbearing 
potential who are not employing adequate 
contraceptive measures. See Appendix 2 for 
contraceptive measures and for required 
pregnancy testing. 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
Other 
Nitrofurantoin 
The most frequent AEs possibly or probably 
related to oral nitrofurantoin treatment are nausea 
(8%), headache (6%), and flatulence (1.5%). As 
with gepotidacin, there is also a need to monitor 
for C. difficile-associated diarrhea during 
nitrofurantoin treatment.  
Nitrofurantoin is contraindicated for patients with 
anuria, oliguria, or significant impairment of renal 
function; pregnant patients at term (38 to 
42 weeks’ gestation), during labor and delivery, or 
when the onset of labor is imminent; neonates 
under 1 month of age; and patients with a 
previous history of cholestatic jaundice/hepatic 
dysfunction associated with nitrofurantoin. 
Rare adverse reactions that generally occur in 
patients receiving treatment for 6 months or 
longer are acute, subacute, or chronic pulmonary 
reactions, with potential insidious development of 
chronic pulmonary reactions (diffuse interstitial 
pneumonitis or pulmonary fibrosis, or both).  
Peripheral neuropathy has occurred, which may 
be enhanced for patients with anemia, diabetes 
mellitus, electrolyte imbalance, vitamin B 
deficiency, and debilitating disease. 
Nitrofurantoin has induced the occurrence of 
hemolytic anemia of the primaquine-sensitivity 
Close monitoring of clinical parameters and 
AEs (Section 2) will be conducted, and 
treatment monitoring and evaluation criteria 
(Section 8.1.2) will be utilized to mitigate 
hepatic effects. 
Because planned treatment in this study is only 
5 days, the probability for adverse reactions 
associated with long-term use is low. 
The exclusion criteria for this study include 
contraindications to nitrofurantoin use and 
exclude participants at risk for nitrofurantoin 
adverse reactions, including acute porphyria as 
an example of a rare genetic risk (see 
Section 6.2).  
Participants with a history of sensitivity to 
nitrofurantoin, or components thereof, will not 
be allowed to enroll in the study (Section 6.2). 
Participant’s medical history will be carefully 
evaluated for history of hypersensitivity. 
Participants must agree not to use antacid 
preparations containing magnesium trisilicate 
or uricosuric drugs during study treatment (see 
Section 7.7.2). 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
type, which appear to be linked to a 
glucose-6-phosphate dehydrogenase deficiency 
in the red blood cells of the affected patients.  
Hepatic reactions, including hepatitis, cholestatic 
jaundice, chronic active hepatitis, and hepatic 
necrosis, occur rarely. 
Concomitant administration of nitrofurantoin with 
antacids containing magnesium trisilicate reduces 
both the rate and extent of absorption, and 
uricosuric drugs, such as probenecid and 
sulfinpyrazone, can inhibit renal tubular secretion 
of nitrofurantoin.  
Refer to locally approved nitrofurantoin 
prescribing information for specific details relating 
to nitrofurantoin. 
Suspected C. difficile infection will be managed 
according to a prespecified algorithm provided 
in Appendix 1. 
Precautions related to nitrofurantoin are 
summarized in detail in the Study Reference 
Manual. 
bpm=beats per minute; AE=adverse event; ALT=alanine aminotransferase; AUC=area under the drug concentration-time curve; Cmax=maximum concentration; 
CYP3A4=cytochrome P450 enzyme 3A4; ESRD=end-stage renal disease; GLDH=glutamate dehydrogenase; IB=investigator’s brochure; IV=intravenous; 
ΔΔQTcF=placebo-corrected change from baseline in corrected QT interval using the Fridericia formula; QTc=corrected QT interval; QTcF=interval corrected for heart rate according 
to Fridericia’s formula. 
 
 


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3.3.2. 
Benefit Assessment 
Acute cystitis is among the most common indications for which antimicrobials are 
prescribed for otherwise healthy women [Gupta, 2011b]. The increase in antimicrobial 
resistance among pathogens causing community-acquired UTIs over the past 2 decades 
has made treatment approaches for UTIs more difficult. Gepotidacin is active in vitro and 
in vivo against the key causative pathogen in acute cystitis, E. coli, including most 
isolates resistant to other antibacterial treatments. Given gepotidacin’s spectrum of 
activity against E. coli, S. saprophyticus, and E. faecalis, as well as human safety data 
and the PK profile, it is anticipated that gepotidacin will benefit participants with acute 
cystitis. 
The active comparator in this study is nitrofurantoin, a marketed antibiotic for the 
treatment of acute uncomplicated UTIs (acute cystitis) caused by susceptible strains of 
E. coli or S. saprophyticus (refer to locally approved nitrofurantoin prescribing 
information). Participants randomly assigned to this treatment group are also expected to 
experience treatment benefits. It is expected that gepotidacin will have a similar efficacy 
profile to nitrofurantoin.  
Overall, all participants in this study will not only receive routine medical monitoring 
appropriate for acute cystitis, but they will also receive heightened monitoring to ensure 
safety when participating in a clinical study. 
3.3.3. 
Overall Benefit:Risk Conclusion 
Antimicrobial resistance among uropathogens causing acute cystitis has increased in the 
past decades [Gupta, 2011b; Sanchez, 2016]. However, even in the face of increasing 
drug resistance to existing agents, few new antibiotics with novel mechanisms of action 
are being developed. Gepotidacin selectively inhibits bacterial DNA replication by a 
means not utilized by any currently approved human therapeutic agent. Based on the 
known preclinical data for gepotidacin against E. coli, S. saprophyticus, and E. faecalis, 
the Phase II results showing the efficacious treatment of uncomplicated urogenital 
gonorrhea and ABSSSIs, and the cumulative safety results from Phase I and Phase II 
studies with oral gepotidacin treatment, this study will test whether gepotidacin is 
noninferior to the current recommended treatment and thus represents a potential new 
treatment option for acute cystitis. 
None of the potential or identified risks seen to date in participants dosed with 
gepotidacin preclude further clinical development. Mitigation strategies have been 
implemented to promptly identify and appropriately address risks in order to protect 
participant safety and to better characterize the safety profile of the study treatments 
(Section 3.3.1). Furthermore, a GlaxoSmithKline (GSK) Safety Review Team (SRT) will 
monitor blinded safety data instream (see Appendix 3). Careful safety monitoring should 
also identify any emerging safety issues for gepotidacin and contribute to the benefit-risk 
profile of nitrofurantoin.  
The investigator may also, at his or her discretion, discontinue the participant from study 
treatment at any time and initiate appropriate alternative therapy. 


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Taking into account the measures taken to minimize risk to participants participating in 
this study, the potential risks identified in association with gepotidacin and nitrofurantoin 
are justified by the anticipated benefits that may be afforded to participants with acute 
cystitis. 
4. 
OBJECTIVES AND ESTIMANDS/ENDPOINTS 
Objectives 
Endpoints 
Primary 
• 
To assess the combined clinical and 
microbiological efficacy of gepotidacin 
compared to nitrofurantoin, at the 
Test-of-Cure (TOC) Visit, in female 
participants with acute cystitis with 
qualifying bacterial uropathogen(s) at 
Baseline that all are susceptible to 
nitrofurantoin 
• 
Therapeutic response (combined 
per-participant microbiological and clinical 
response) at the TOC Visit 
Secondary 
• 
To assess the clinical efficacy of 
gepotidacin compared to 
nitrofurantoin, at the TOC and 
Follow-up Visits, in female participants 
with acute cystitis  
• 
Clinical outcome and response at the TOC 
and Follow-up Visits 
• 
To assess the clinical efficacy of 
gepotidacin compared to 
nitrofurantoin, at the TOC and Follow-
up Visits, in female participants with 
acute cystitis with qualifying bacterial 
uropathogen(s) at Baseline that all are 
susceptible to nitrofurantoin 
• 
Clinical outcome and response at the TOC 
and Follow-up Visits 
• 
To assess the microbiological efficacy 
of gepotidacin compared to 
nitrofurantoin, at the TOC and 
Follow-up Visits, in female participants 
with acute cystitis with qualifying 
bacterial uropathogen(s) at Baseline 
that all are susceptible to nitrofurantoin 
• 
Microbiological outcome and response at 
the TOC and Follow-up Visits 


T M F -1 3 8 1 7 5 4 3  
C O N FI D E N TI A L  
 
 
 
2 0 4 9 8 9  
 
 
 
 
2 9  
 
O bj e cti ve s  
E n d p oi nt s  
S e c o n d ary  c o nti n u e d  
•  
T o ass ess t h e c o m bi ne d clinic al a nd 
micr o bi ol o gic al effic acy of ge p otid aci n 
c o m p ar e d t o nitr of ur ant oin, at t h e 
F oll o w -u p Visit, i n f e m al e p articip a nts 
wit h ac ute cystitis wit h q ualifyi n g 
b act eri al ur o p at h og en(s) at B as eli n e 
t h at all ar e susc e pti bl e to nitr of ur a ntoi n  
 
•  
T h er a pe utic r esp o nse (c o mbi n e d 
p er -p articip ant micro bi ol ogic al a nd cli nic al 
r es p o nse) at th e Foll o w-u p Visit  
•  
T o d eter mi n e th e pl as m a a nd urin e 
p h ar mac oki netic  ( P K) co nce ntr ati ons 
of ge p oti d aci n in f e m ale p artici p a nts 
wit h ac ute cystitis  
•  
G e p oti d aci n pl as m a a n d urin e 
c o nc entr ati ons 
•  
T o ass ess t h e s afety an d toler a bility of 
g e poti d aci n c o m par e d  to nitr of ur a ntoi n 
i n f e m al e p artici p ants wit h ac ut e 
cystitis 
•  
Tr e at m e nt -e m erg e nt a dverse ev ents a n d 
s erio us a dv ers e ev e nts an d c h a ng e fr o m 
b as eli ne r es ults f or cli nic al la b or atory t ests 
a n d vital si g n me as ur e m ents 
C CI


T M F -1 3 8 1 7 5 4 3  
C O N FI D E N TI A L  
 
 
 
2 0 4 9 8 9  
 
 
 
 
3 0  
 
O bj e cti ve s  
E n d p oi nt s  
 
Pri mar y Esti ma n d  
T he pri mar y cli nic al q uesti o n of i nterest is: W hat is t he treat me nt effect o n t he 
t hera pe utic res p o nse after 5 da ys of treat me nt wit h ge p oti daci n 1 5 0 0 m g t wice dail y 
c o m pare d t o 5 da ys of treat me nt wit h nitr of ura nt oi n 1 0 0 m g t wice d ail y i n p artici pa nts 
wit h ac ute c ystitis wit h q ualif yi n g bacterial ur o pat h o ge n (s) at B as eli ne t hat all are 
s usce pti ble t o nitr of ura nt oi n, re gar dless of treat me nt disc o nti n uati o n f or a n y reas o n. 
Recei pt of s yste mic a nti micr o bials will i m pact t he e n d p oi nt defi niti o n (see 
Secti o n  9. 1. 2. 1  a n d Secti o n  9. 1. 3. 1 ). 
T he pri mar y esti ma n d is descri be d b y t he f oll o wi n g attri b utes:  
•  P o p ulati o n: Fe male parti ci pa nts wit h ac ute c ystitis wit h q ualif yi n g bacterial 
ur o pat h o ge n (s) at B aseli ne t hat all are s us ce pti ble t o nitr of ura nt oi n. 
•  Treat me nt c o n diti o n: Ge p oti daci n 1 5 0 0 m g t wice dail y f or 5 da ys vers us 
n itr of ura nt oi n 1 0 0 m g t wice dail y f or 5 d a ys , re gar dless of a d here nce. 
•  Varia ble: T h era p e utic res p o nse (c o m bi ne d per-partici pa nt micr o bi ol o gical a n d 
cli nical res p o nse) at t he T O C V isit. Micr o bi ol o gical s uccess is defi ne d as 
era dic ati o n (i.e. , re d u cti o n) of all q ualif yi n g bact erial ur o pat h o ge ns rec o vere d at 
baseli ne t o < 1 0 3 c ol o n y-f or mi n g u nits/ mL  ( C F U/ m L) as o bser v e d o n q ua ntitati ve 
uri ne c ult ure wit h o ut t he partici p a nt recei vi n g ot her s yste mic a nti micr o bials. 
Cli nical s uccess is defi ne d as res ol uti o n of si g ns a n d s y m pt o ms of ac ute c ystitis 
C CI


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present at Baseline (and no new signs and symptoms) without the participant 
receiving other systemic antimicrobials. 
• Summary measure: Absolute difference in the therapeutic success rate in the 
gepotidacin and nitrofurantoin treatment groups.  
• Intercurrent events (ICEs): 
• Study treatment discontinuation (due to any reason) – treatment policy 
strategy (interest is in the treatment effect regardless of study treatment 
discontinuation). 
• Use of systemic antimicrobials – composite strategy. This ICE is captured 
through the definitions of microbiological and clinical response (see 
Section 9.1.2.1 and Section 9.1.3.1) and will be counted as therapeutic 
failures. 
Rationale for Estimand: 
Interest lies in the treatment effect regardless of whether the full course of 5 days of 
treatment was taken or not, which reflects how patients may be treated in clinical 
practice. Hence, a treatment policy strategy is appropriate for treatment withdrawal 
before completing 5 days of treatment. Use of other systemic antimicrobials may 
confound the bacterial culture results; thus, the microbiological response will be 
considered failure. For clinical data, the use of a systemic antimicrobial for acute cystitis 
is a sign of treatment failure and use of a systemic antimicrobial for another infection 
cannot be considered a success as it confounds the assessment of efficacy. Therefore, the 
definition of a successful therapeutic response precludes the use of other systemic 
antimicrobials. 
Secondary Estimands: 
The secondary clinical questions of interest are: What is the treatment effect on each of 
the secondary efficacy endpoints after 5 days of treatment with gepotidacin 1500 mg 
twice daily compared to 5 days of treatment with nitrofurantoin 100 mg twice daily in 
participants with acute cystitis (clinical endpoints) and in participants with acute cystitis 
with qualifying bacterial uropathogen(s) at Baseline that all are susceptible to 
nitrofurantoin (therapeutic, clinical, and microbiological endpoints), regardless of 
treatment discontinuation for any reason. Receipt of systemic antimicrobials impacts the 
endpoint definition (see Section 9.1.2.1 and Section 9.1.3.1). 
For each of the secondary endpoints the estimand will follow a similar approach to the 
estimand for the primary endpoint and will use the same strategies for the ICEs. The 
exception is the summary measure for the outcome endpoints. These endpoints are 
descriptively summarized; therefore, the summary measure will be the percentage in each 
clinical and microbiological outcome category in the gepotidacin and nitrofurantoin arms 
separately (as no direct comparison between treatment groups will be made) (see 
Section 9.1.2.1 and Section 9.1.3.1 for endpoint definitions). 
The safety endpoint will use a treatment policy strategy of the ICE of withdrawal from 
treatment as the safety will be assessed at all postbaseline assessments irrespective of 
whether the participant completed the treatment. 


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Components of estimand for all secondary endpoints are listed in Table 2.  


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Table 2 
Estimand for the Secondary Endpoints 
Secondary 
Endpoint 
Population 
Treatment Condition 
Variable 
Summary Measure 
Intercurrent Event 
Clinical response at 
the TOC and 
Follow-up Visits 
Female participants 
with acute cystitis 
Gepotidacin 1500 mg 
BID for 5 days versus 
nitrofurantoin 100 mg 
BID for 5 days, 
regardless of 
adherence 
See Table 11 and 
Table 12 
Absolute difference in the 
clinical success rate in the 
gepotidacin and 
nitrofurantoin treatment 
groups 
Study treatment discontinuation 
(due to any reason) – treatment 
policy 
Use of systemic antimicrobials – 
composite strategy 
Clinical outcome at 
the TOC and 
Follow-up Visits 
Female participants 
with acute cystitis 
Gepotidacin 1500 mg 
BID for 5 days versus 
nitrofurantoin 100 mg 
BID for 5 days, 
regardless of 
adherence 
See Table 11 and 
Table 12 
Percentage of participants in 
each outcome category in 
the gepotidacin and 
nitrofurantoin arms 
separately 
Study treatment discontinuation 
(due to any reason) – treatment 
policy 
Use of systemic antimicrobials – 
composite strategy 
Clinical response at 
the TOC and 
Follow-up Visits 
Female participants 
with acute cystitis with 
qualifying bacterial 
uropathogen(s) at 
Baseline that all are 
susceptible to 
nitrofurantoin 
Gepotidacin 1500 mg 
BID for 5 days versus 
nitrofurantoin 100 mg 
BID for 5 days, 
regardless of 
adherence 
See Table 6 
Absolute difference in the 
clinical success rate in the 
gepotidacin and 
nitrofurantoin treatment 
groups 
Study treatment discontinuation 
(due to any reason) – treatment 
policy 
Use of systemic antimicrobials – 
composite strategy 
Clinical outcome at 
the TOC and 
Follow-up Visits 
Female participants 
with acute cystitis with 
qualifying bacterial 
uropathogen(s) at 
baseline that all are 
susceptible to 
nitrofurantoin 
Gepotidacin 1500 mg 
BID for 5 days versus 
nitrofurantoin 100 mg 
BID for 5 days, 
regardless of 
adherence 
See Table 6 
Percentage of participants in 
each outcome category in 
the gepotidacin and 
nitrofurantoin arms 
separately 
Study treatment discontinuation 
(due to any reason) – treatment 
policy 
Use of systemic antimicrobials – 
composite strategy 


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Secondary 
Endpoint 
Population 
Treatment Condition 
Variable 
Summary Measure 
Intercurrent Event 
Microbiological 
response at the 
TOC and Follow-up 
Visits 
Female participants 
with acute cystitis with 
qualifying bacterial 
uropathogen(s) at 
Baseline that all are 
susceptible to 
nitrofurantoin 
Gepotidacin 1500 mg 
BID for 5 days versus 
nitrofurantoin 100 mg 
BID for 5 days, 
regardless of 
adherence 
See Table 6 
Absolute difference in the 
microbiological success rate 
in the gepotidacin and 
nitrofurantoin treatment 
groups 
Study treatment discontinuation 
(due to any reason) – treatment 
policy 
Use of systemic antimicrobials – 
composite strategy 
Microbiological 
outcome at the 
Follow-up Visit 
Female participants 
with acute cystitis with 
qualifying bacterial 
uropathogen(s) at 
Baseline that all are 
susceptible to 
nitrofurantoin 
Gepotidacin 1500 mg 
BID for 5 days versus 
nitrofurantoin 100 mg 
BID for 5 days, 
regardless of 
adherence 
See Table 6 
Percentage of participants in 
each outcome category in 
the gepotidacin and 
nitrofurantoin arms 
separately 
Study treatment discontinuation 
(due to any reason) – treatment 
policy 
Use of systemic antimicrobials – 
composite strategy 
Therapeutic 
response at the 
Follow-up Visit 
Female participants 
with acute cystitis with 
qualifying bacterial 
uropathogen(s) at 
Baseline that all are 
susceptible to 
nitrofurantoin 
Gepotidacin 1500 mg 
BID for 5 days versus 
nitrofurantoin 100 mg 
BID for 5 days, 
regardless of 
adherence 
See Table 6 and 
Table 12 
Absolute difference in the 
therapeutic success rate in 
the gepotidacin and 
nitrofurantoin treatment 
groups 
Study treatment discontinuation 
(due to any reason) – treatment 
policy 
Use of systemic antimicrobials – 
composite strategy 
Pharmacokinetic 
Female participants 
with acute cystitis  
Gepotidacin 1500 mg 
BID for 5 days 
Refer to the 
reporting and 
analysis plan 
Summary statistics 
(appropriate for each type of 
endpoint) in the gepotidacin 
arm 
Study treatment discontinuation 
(due to any reason) – while on 
treatment strategy (treatment phase 
defined as from first dose to 
On-therapy Visit) 


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Secondary 
Endpoint 
Population 
Treatment Condition 
Variable 
Summary Measure 
Intercurrent Event 
Safety  
Female participants 
with acute cystitis  
Gepotidacin 1500 mg 
BID for 5 days versus 
nitrofurantoin 100 mg 
BID for 5 days, 
regardless of 
adherence 
TEAEs, SAEs, as 
well as change 
from baseline 
results for clinical 
laboratory tests 
and vital sign 
measurements 
Summary statistics 
(appropriate for each type of 
endpoint) in the gepotidacin 
and nitrofurantoin arms 
separately 
Study treatment discontinuation 
(due to any reason) – treatment 
policy 
BID=twice daily; SAE=serious adverse event; TEAE=treatment-emergent adverse event; TOC=Test-of-Cure. 
 


T M F -1 3 8 1 7 5 4 3  
C O N FI D E N TI A L  
 
 
 
2 0 4 9 8 9  
 
3 6  
 
5.  
S T U D Y D E SI G N  
5. 1.  
O v er all D e si g n  
•  St u d y 2 0 4 9 8 9 is a P hase III, ra n d o mize d, m ultice nter, parallel -gr o u p, d o u bl e -bli n d, 
d o u ble -d u m m y, c o m p arat or -c o ntr olle d , n o ni nferi orit y st u d y i n a d olesce nt a n d a d ult 
fe male partici pa nt s c o m p ari n g t h e efficac y a n d safet y of oral ge p oti daci n t o oral 
nitr of ura nt oi n i n t he treat me nt of u nc o m plicate d U TI  (ac ut e c ystitis). 
•  Partici pa nts will be stratifie d b y a ge cate g or y ( < 1 8 years, ≥1 8 t o 5 0 years, or 
> 5 0  years) a n d ac ute c ystitis rec urre n ce ( n o nrec urre nt i nfecti o n or rec urre nt i nfecti o n, 
defi ne d as a c o nfir m e d i nfecti o n [ n ot i ncl u di n g t he c urre nt i nfecti o n i n t he 
calc ulati o n] wit h at least 1  pri or e pis o de wit hi n t he past 3  m o nt hs, at least 2  pri or 
e pis o des wit hi n t he past 6  m o nt hs,  or at least 3  pri or e pis o des wit hi n t he past 
1 2  m o nt hs bef ore st u d y e ntr y) a n d will be ra n d o ml y assi g ne d i n a 1: 1 rati o t o recei v e 
1 of t he f oll o wi n g st u d y treat me nts: 
•  Ge p oti daci n: 1 5 0 0 m g a d mi nistere d orall y t wi ce d ail y (BI D ) f or 5 d a ys ( N ote: 
Eac h d ose s h o ul d be ta ke n after f o o d c o ns u m pti o n a n d wit h water t o assist 
wit h t olera bilit y.)  
•  Nitr of ura nt oi n: 1 0 0 m g a d mi nistere d orall y BI D f or 5 da ys  ( N ote: E ac h d ose 
s h o ul d be ta ke n aft er f o o d c o ns u m pti o n a n d wit h water.) 
•  A p pr o priate s afet y, effic ac y, a n d micr o bi ol o gical assess me nts will be c o n d ucte d at 
t he Bas eli ne ( Da y 1) Visit a n d re peate d at t he O n-t hera p y ( Da y 2 t o 4), T O C ( Da y 1 0 
t o 1 3), a n d F oll o w -u p ( Da y 2 8 ± 3) Visits. P har mac o ki netic sa m ples will be c ollecte d 
at t he O n-t hera p y Visit. 
 
 
 Eac h treat me nt da y will be assesse d o ver 2 4  h o urs starti n g wit h 
t he first d ose of st u d y treat me nt, as f urt her detaile d i n t he St u d y Refere nce Ma n ual 
( S R M). 
•  
F or t he pri mar y efficac y e n d p oi nt of t hera p e utic res p o nse (c o m bi ne d p er -p artici pa nt 
micr o bi ol o gical a n d cli nical res p o nse), t hera pe utic s uccess r efers t o partici p a nt s w h o 
ha ve bee n dee m e d b ot h a micr o bi ol o gical  s u ccess (re d ucti o n of all q ualif yi n g 
bacterial ur o pat h o ge n s [e. g., 1 0 5  c ol o n y-f or mi n g u nits/ m L (C F U/ m L ); defi ne d i n 
A p pe n di x  4 ] rec o vere d at Baseli ne t o < 1 0 3 C F U / m L as o bs er ve d o n q u a ntitati ve 
uri ne c ult ure ) wit h o ut t he partici pa nt recei vi n g ot her s yste mic a nti micr o bials  a n d a 
cli nical s uccess (res ol uti o n of si g ns a n d s y m pt o ms of ac ute c ystitis pres e nt at 
Baseli ne [a n d n o ne w si g ns a n d s y m pt o ms] wit h o ut t he partici pa nt recei vi n g ot her 
s yste mic a nti micr o bials) at t he T O C Visit  i n t he Micr o bi ol o gical I nte nt -t o-Treat 
N itr of ura nt oi n-S usce pti ble ( micr o -I T T N T F-S) P o p ulati o n . T he T O C Visit is 1 0 t o 
1 3 da ys after ra n d o mizati o n , w hic h is als o 5 t o 8  da ys after c o m pleti o n of st u d y 
treat me nt. 
•  
Partici pa nts ma y ret ur n t o t he st u d y site at a n y ti me d ue t o A Es or if t he y are 
e x perie nci n g n e w or c o nti n ui n g si g ns a n d s y m pt o ms of ac ute c ystitis. Partici pa nts 
will be assesse d a n d tr eat e d per t he i n vesti gat or’s j u d ge m e nt . If a p artici pa nt is 
s witc he d t o a differe nt a nti bi otic bef ore or d uri n g t he T O C Visit, all T O C pr oce d ures 
s h o ul d be c o m plete d bef ore t he ot her a nti bi otic is starte d.  
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• 
Participants with a concomitant fungal infection can only be treated with topical 
antifungals per local standard of care. 
• 
Participants will return to the study site on Day 28 (±3) for a Follow-up Visit. 
Participants experiencing signs and symptoms suggestive of infection recurrence or 
relapse will be assessed and treated per the investigator’s judgement.  
• 
The duration of study participation is approximately 28 days with 4 planned study 
visits (see Section 9 for study visit details): 
• 
Baseline (Day 1) Visit 
• 
On-therapy (Day 2 to 4) Visit 
• 
TOC (Day 10 to 13) Visit 
• 
Follow-up (Day 28±3) Visit 
A study design schematic is depicted in Figure 1. 
Refer to Appendix 5 for details regarding allowed revisions to study conduct and/or 
monitoring due to coronavirus disease (COVID-19). For all study visits, to minimize the 
amount of time that participants spend at the clinic, eConsent may be utilized and remote 
collection of study-related data may be obtained as described in the SRM. Thus, some 
visit data may be collected through a combination of telemedicine and on-site visits. 
Collection of information via telemedicine will be performed only where local 
regulations permit. 
Of note, to reduce participant on-site visits or if unforeseen issues impact clinic visits, 
and participants are unable to attend a site visit, home healthcare (home visits and 
telemedicine visits) may be used to conduct procedures as detailed in the Study 
Reference Manual. Home healthcare will only be utilized where applicable country and 
local regulations and infrastructure allow. 
 


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Figure 1 
Study Design Schematic 
 
BID=twice daily; HPF=high-power field; TOC=Test-of-Cure; WBC=white blood cell. 
a. 
There will be central randomization with stratification by age category (<18 years, ≥18 to 50 years, or >50 years) and acute cystitis recurrence (nonrecurrent infection or recurrent 
infection, defined as a confirmed infection [not including the current infection in the calculation] with at least 1 prior episode within the past 3 months, at least 2 prior episodes 
within the past 6 months, or at least 3 prior episodes within the past 12 months before study entry).  
b. 
Study treatment will be administered under double-blind, double-dummy conditions. Each dose should be taken after food consumption and with water. 
 


T M F -1 3 8 1 7 5 4 3  
C O N FI D E N TI A L  
 
 
 
2 0 4 9 8 9  
 
3 9  
 
5. 2.  
N u m b er of P arti ci p a nt s  
T he st u d y is pla n ne d t o e nr oll a p pr o x i matel y 2 5 0 0 partici pa nts  t o f ulfill t he ma xi m u m 
tar get sa m ple siz e of a p pr o xi matel y 8 8 4 p artici pa nts i n t he pri mar y a nal ysis micr o -I T T 
N T F -S P o p ulati o n. T he fi nal n u m ber of ra n d o mize d partici pa nts ma y v ar y base d o n t he 
e val ua bilit y rate a n d re vi e w of q ualif yi n g ur o pat h o ge ns b y a n u n bli n de d St atistical Data 
A nal ysis Ce nter ( S D A C) . 
5. 3.  
P arti ci p a nt a n d St u d y C o m pl e ti o n 
A partici pa nt  is c o nsi dere d t o ha ve c o m plet e d st u d y treat me nt if s he has t a ke n all d oses 
of t he ra n d o ml y assi g ne d st u d y treat me nt a n d c o m plete d t he T O C Visit. A partici pa nt  is 
c o nsi dere d t o ha v e c o m plete d t he st u d y if s h e has c o m plete d all st u d y visit s i ncl u di n g t he 
F oll o w -u p Visit . 
T he e n d of t he st u d y is d efi ne d as t he d ate of t he l ast visit of t he last partici pa nt  i n t he 
st u d y. 
5. 4.  
S ci e ntifi c R ati o n al e f or St u d y D e si g n  
T he st u d y d esi g n is bas e d o n t he F o o d a n d Dr u g A d mi nistrati o n ( F D A) g ui da nce f or 
i n d ustr y f or d e vel o pi n g dr u g tr eat me nts f or u n c o m plicate d a n d c o m plicat e d U TIs 
[D H H S , 2 0 1 9 ; D H H S , 2 0 18 ], t he E ur o pea n Me di ci nes A ge nc y ( E M A) a d de n d u m t o t he 
g ui deli ne o n t he e val uati o n of me dici nal pr o d ucts i n dicate d f or treat me nt of bacterial 
i nfecti o ns [E M A , 2 0 1 3], a n d fee d b ac k fr o m t he F D A a n d E M A. T h e pri mar y efficac y 
e n d p oi nt will be t he t hera pe utic res p o nse (c o m bi ne d per -partici pa nt micr o bi ol o gical a n d 
cli nical res p o nse) at t he T O C Visit ( i.e., 10 t o 1 3  da ys after ra n d o mizati o n, w hic h is als o 
5 t o 8  da ys after c o m pleti o n of st u d y tr eat me nt) i n partici pa nts w h o ha v e a q ualif yi n g 
bacterial ur o pat h o ge n at Baseli ne. Alt h o u g h t he g ui da nces differ i n t heir criteria f or 
defi ni n g q u alif yi n g ur o pat h o ge ns , t his st u d y h as b ee n desi g ne d wit h t he q ualif yi n g 
ur o pat h o ge n criteria defi ne d i n A p pe n di x  4  a n d micr o bi ol o gical s uccess defi ne d as 
re d ucti o n of all q ualif yi n g bacterial ur o pat h o ge n s rec o vere d at Bas eli ne t o <1 0 3 C F U/ m L  
as o bser ve d o n q u a ntitati ve uri ne c ult ure  wit h o ut t he partici pa nt recei vi n g ot her s yste mic 
a nti micr o bial s. Cli nical s uccess at t he T O C Visit is defi ne d as t he res ol uti o n of si g ns a n d 
s y m pt o ms of ac ute c ystitis prese nt at Baseli ne (a n d n o ne w si g ns a n d s y m pt o ms) wit h o ut 
t he partici pa nt recei vi n g ot her s yst e mic a nti micr o bials. T hera pe utic s u ccess refers t o 
partic i pa nts w h o ha v e bee n dee me d b ot h a micr o bi ol o gical s uc cess a n d a cli nical s uccess 
(i.e., res p o n ders). 
 
 
Nitr of ura nt oi n has bee n s electe d as t he acti ve c o m parat or i n t his st u d y. Nitr of ura nt oi n is 
a n a p pr o ve d treat me nt t h at is i n dicate d f or t he tr eat me nt of ac ute u nc o m plicate d U T I 
(ac ute c ystitis) ca use d b y s usce pti ble strai ns of E. c oli  or S. s a pr o p hytic us  (refer t o l ocall y 
a p pr o ve d prescri bi n g i nf or mati o n ). It is gl o ball y a vaila ble i n m ost re gi o ns a n d is a 
rec o m me n de d oral first-li ne treat me nt f or ac ut e c ystitis per c urre nt U S, U K, a n d 
E ur o pea n  Ass o ciati o n of Ur ol o g y  g ui d eli nes [ G u pta , 2 0 1 1b ; NI C E , 2 0 19 ; E A U , 2 0 1 7]. 
B ot h ge p oti daci n a n d nitr of ura nt oi n will be a d mi nistere d BI D  f or a tr eat me nt d urati o n of 
5  da ys.  As descri b e d i n Secti o n  5. 5 , t he d ose of eac h st u d y tr eat me nt a n d t h e 5-da y 
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duration were selected to provide efficacious treatment for acute cystitis and is in 
alignment with current clinical practice. Having the same dose regimen will also support 
double-blind dose administration. A noninferiority margin of 10% has been selected for 
this study [DHHS, 2019].  
Both adult and adolescent (≥12 to <18 years of age) eligible female participants will be 
enrolled in this double-blinded study. The study is restricted to female participants per 
FDA guidance [DHHS, 2019]. Adolescent participants will only be enrolled at study sites 
where investigators have experience in this population and if allowed per the study site’s 
institutional ethics committees and local country/national regulatory guidelines and 
enrollment will be contingent upon such approvals. Adolescent assent forms and adult 
consent forms will be developed with oversight from local governing institutional review 
boards (IRBs)/independent ethics committees (IECs) (see Appendix 3). There is no upper 
age limit for study participants; however, participants are excluded if they reside in a 
nursing home or dependent care type-facility, or if they have any comorbidities 
associated with complicated UTI. Thus, any participants >75 years of age will only be 
eligible for the study if they are residing independently. 
A separate Phase IIa study (206899) to evaluate the pharmacokinetics in participants with 
acute cystitis was conducted. This additional study allowed serial PK collections and 
evaluation of systemic and urinary exposures in this population; thus, only sparse plasma 
and urine sample collection for PK analysis has been included in this Phase III protocol. 
In order to maximize the efficiency of this study while minimizing discomfort and 
inconvenience to participants consenting to this protocol, a GSK SRT will monitor 
blinded safety data instream, while a Microbiology Review Team will monitor blinded 
uropathogen identification and susceptibility data instream, including the enrollment rate 
of participants with a qualifying bacterial uropathogen at Baseline and the resistance 
profile of uropathogens. In addition, an Independent Data Monitoring Committee 
(IDMC) will manage the interim analysis (IA) as described in Section 10.5. 
5.5. 
Dose Justification 
The oral gepotidacin dose in this study is 1500 mg BID (total daily dose of 3000 mg) for 
5 days. A 5-day dosing duration is in alignment with current treatment guidelines for 
efficacious antibacterial treatment of uncomplicated acute cystitis in women, which 
typically ranges from 3 to 7 days [Gupta, 2011b; NICE, 2019; EAU, 2017]. The safety 
and tolerability at this oral dose and duration have been evaluated in Phase I studies and 
in Phase II studies (BTZ116704 and 206899) (see Section 5 of the IB for details). 
Furthermore, high urine concentrations of gepotidacin are expected in this study based on 
a healthy volunteer Phase I study (BTZ117351) and a Phase IIa study in participants with 
acute cystitis (206899). In BTZ117351, approximately 287 mg of unchanged gepotidacin 
was excreted in urine after a single oral 1500-mg (2 × 750-mg tablets) dose of 
gepotidacin (minimum urine area under drug concentration-time curve over 12 hours 
[AUC12h]=807 µg.h/mL). In the Phase IIa study, 206899, in participants with 
uncomplicated UTIs, approximately 460 mg of unchanged gepotidacin was excreted in 
urine over the steady-state dosing interval of 12 hours after repeat BID oral dosing of 


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1500 mg (2 × 750-mg tablets) gepotidacin (minimum steady-state urine 
AUC12h=2256 µg.h/mL). 
The gepotidacin dose and duration for this study were selected based on in vitro and 
in vivo studies including experimental animal pyelonephritis studies that simulated 
human PK exposures of gepotidacin to determine the efficacy of gepotidacin against 
isolates of E. coli, including MDR strains (see Section 4.2 of the IB for further details).  
Additionally, an in vitro study to determine the PK/PD characteristics of gepotidacin 
against E. coli (dose-fractionation and dose-ranging studies) indicate that AUC/MIC is 
the primary PK/PD index predictive of gepotidacin efficacy against E. coli. The 
magnitude of the ratio of free-drug AUC to MIC over 24 hours (fAUC/MIC) required to 
achieve net bacterial stasis as well as 1- and 2-log reductions in bacterial burden from 
Baseline across multiple E. coli isolates with gepotidacin MIC values ranging from 1 to 
4 µg/mL, were 34.5, 41.3, and 49.7, respectively.  
A set of duplicate 10-day hollow fiber infection model studies was also completed using 
E. coli isolate NCTC 13441 to determine the fAUC/MIC exposure of gepotidacin 
required to prevent the amplification of a resistant subpopulation. An inverted-U shaped 
function described the relationship between drug resistance amplification and fAUC, with 
fAUC values ≥549 preventing resistance amplification to gepotidacin for E. coli in the 
hollow fiber infection model for 10 days. This equates to an fAUC/MIC value ≥275 when 
applying the gepotidacin broth microdilution MIC of 2 µg/mL for E. coli 13441, as 
determined in this study.  
When taking the fAUC/MIC target of 275 for resistance suppression into consideration 
with the concentrations of gepotidacin in human urine measured in BTZ117351 
(minimum urine AUC12h=807 µg.h/mL; thus, minimum urine AUC over 24 hours 
[AUC24h]=1614 µg.h/mL) and applying an MIC value of 4 µg/mL, the minimum human 
urine AUC/MIC achieved for the 1500 mg oral BID dose exceeds the fAUC/MIC 
resistance suppression target of 275 by approximately 1.5-fold and 100% target 
attainment for a urine AUC/MIC target of 275 would be expected for participants with 
E. coli isolates with gepotidacin MICs ≤4 µg/mL following 1500 mg BID oral dosing.  
When applying the higher concentrations of gepotidacin in human urine measured in the 
Phase IIa study (206899; minimum urine AUC12h=2256 µg.h/mL; thus, 
AUC24h=4512 µg.h/mL) and applying a MIC value of 4 µg/mL, the minimum human 
urine AUC/MIC achieved for the 1500 mg oral BID dose further exceeds the fAUC/MIC 
resistance suppression target of 275 by approximately 4-fold and 100% target attainment 
for a urine AUC/MIC target of 275 would also be expected for participants with E. coli 
isolates with gepotidacin MICs ≤4 µg/mL following 1500 mg BID oral dosing. 
Additionally, in the Phase IIa study (206899), for 4 participants with available urine 
steady-state PK and qualifying Enterobacterales uropathogens who were microbiological 
successes at TOC, plasma fAUC24h/MIC values ranged from 7 to 90.5 and urine 
AUC24h/MICs ranged from 1292 to 121,698. The participant with the lowest plasma 
fAUC24h/MIC (7.0) and urine AUC/MIC (1292) had a K. pneumoniae uropathogen with 
a gepotidacin MIC of 4 µg/mL. No participants had an outcome of microbiological 
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In conclusion, minimum urine levels of gepotidacin are anticipated to be in excess of the 
fAUC/MIC target necessary for both efficacy and resistance suppression for E. coli as 
determined from the in vitro PK/PD models. Given that the bladder is the primary site of 
infection in cystitis, the use of gepotidacin urine PK data, coupled with the robust in vivo 
efficacy demonstrated in the Phase IIa uncomplicated UTI study and human simulated 
PK pyelonephritis model, is appropriate for selecting the gepotidacin 1500 mg BID oral 
dose for 5 days for study in the treatment of participants with acute cystitis.  
In addition, a PK evaluation (Study 209611) in healthy adult and adolescent participants 
has been completed (see Section 5 of the IB for further details). Overall, plasma Cmax 
values were 27% higher in adolescents; however, the range of Cmax values were similar, 
and AUC(0-∞) values were similar for adults and adolescents following a 1500-mg single 
gepotidacin dose. Following the first of two 3000 mg gepotidacin doses 6 hours apart, 
Cmax values were 29% higher in adolescents; however, the ranges of Cmax values were 
similar, and following the second dose for adults and adolescents Cmax values were 
similar. The AUC(0-τ) was approximately 35% higher in adolescents following both 
doses compared to adults. The total amount of gepotidacin excreted in urine was similar 
in adult and adolescent participants following a 1500-mg single gepotidacin dose. 
Following two 3000 mg gepotidacin doses given 6 hours apart, the total amount excreted 
was approximately 35% higher in adolescents compared to adults. The maximum dose of 
gepotidacin evaluated in adolescents was 3000 mg given as 2 doses 6 hours apart. Across 
the age groups, the safety-risk profile was similar. 
The oral nitrofurantoin dose in this study is 100 mg BID (total daily dose of 200 mg) for 
5 days. This oral dose and duration of nitrofurantoin is within the prescribed labeling 
recommendations, which is 100 mg BID for up to 7 days for adults and pediatric patients 
over 12 years of age (refer to locally approved prescribing information). The labeled 
7-day dosing duration of nitrofurantoin was based on clinical registration studies from 
several decades ago. More recently, a 5-day dosing duration of nitrofurantoin was shown 
to be efficacious for the treatment of uncomplicated acute cystitis in women 
[Gupta, 2007] and a treatment duration of <7 days for nitrofurantoin is in alignment with 
current treatment guidelines [Gupta, 2011b; NICE, 2019; EAU, 2017]. 
6. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 


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6.1. 
Inclusion Criteria 
Otherwise healthy participants are eligible to be included in the study only if all of the 
following criteria apply: 
Age and Weight 
1. The participant is ≥12 years of age at the time of signing the informed consent/assent 
and has a body weight ≥40 kg. 
Note:  Although participants as young as 12 years may enroll in the study, study sites 
must follow their institutional ethics committee and local country/national regulatory 
guidelines and enrollment will be contingent upon such approvals regarding the 
allowed lower age limit for clinical study participants.  
Type of Participant and Disease Characteristics 
2. The participant has 2 or more of the following clinical signs and symptoms of acute 
cystitis with onset <96 hours prior to study entry: dysuria, frequency, urgency, or 
lower abdominal pain (see Appendix 6). 
3. The participant has nitrite or pyuria (>15 WBC/HPF or the presence of 3+/large 
leukocyte esterase) from a pretreatment clean-catch midstream urine sample based on 
local laboratory procedures. 
Sex 
4. The participant is female. A female participant is eligible to participate if she is a 
woman of childbearing potential (WOCBP) who is not pregnant as confirmed by a 
high sensitivity urine pregnancy test at Baseline (Day 1) regardless of current or prior 
contraception use or abstinence, is not breastfeeding, or is not a WOCBP.  
Note:  Pregnancy testing requirements, contraceptive guidance, and WOCBP 
definitions are provided in Appendix 2. 
Informed Consent 
5. The participant is capable of giving signed informed consent/assent as described in 
Appendix 3, which includes compliance with the requirements and restrictions listed 
in the informed consent form (ICF)/assent form and in this protocol. 
6.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions and History 
1. The participant resides in a nursing home or dependent care type-facility. 
2. The participant has a body mass index ≥40.0 kg/m2 or a body mass index ≥35.0 kg/m2 
and is experiencing obesity-related health conditions such as uncontrolled high blood 
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3. The participant has a history of sensitivity to the study treatments, or components 
thereof, or a history of a drug or other allergy that, in the opinion of the investigator 
or medical monitor, contraindicates her participation. 
4. The participant is immunocompromised or has altered immune defenses that may 
predispose the participant to a higher risk of treatment failure and/or complications 
(e.g., uncontrolled diabetes, renal transplant recipients, participants with clinically 
significant persistent granulocytopenia [absolute neutrophil count <1000/µL], and 
participants receiving immunosuppressive therapy, including corticosteroid therapy 
[>40 mg/day prednisolone or equivalent for >1 week, ≥20 mg/day prednisolone or 
equivalent for >2 weeks, or prednisolone or equivalent ≥10 mg/day for >6 weeks]). 
Participants with a known CD4 count of <200 cells/mm3 should not be enrolled. 
5. The participant has any of the following: 
• 
Medical condition that requires medication that may be impacted by inhibition 
of acetylcholinesterase, such as: 
• Poorly controlled asthma or chronic obstructive pulmonary disease at Baseline 
and, in the opinion of the investigator, not stable on current therapy 
• Acute severe pain, uncontrolled with conventional medical management 
• Active peptic ulcer disease 
• Parkinson disease 
• Myasthenia gravis 
• A history of seizure disorder requiring medications for control (this does not 
include a history of childhood febrile seizures) 
OR 
• Known acute porphyria 
• Any surgical or medical condition (active or chronic) that may interfere with 
drug absorption, distribution, metabolism, or excretion of the study treatment 
(e.g., ileostomy or malabsorption syndrome). 
6. The participant has a known glucose-6-phosphate dehydrogenase deficiency. 
7. The participant, in the judgment of the investigator, would not be able or willing to 
comply with the protocol or complete study follow-up. 
8. The participant has a serious underlying disease that could be imminently 
life-threatening, or the participant is unlikely to survive for the duration of the study 
period. 
Urinary Tract Infection/Renal/Urogenital Exclusions 
9. The participant has acute cystitis that is known or suspected to be due to fungal, 
parasitic, or viral pathogens; or known or suspected to be due to Pseudomonas 
aeruginosa or Enterobacterales (other than E. coli) as the contributing pathogen. 
10. The participant has symptoms known or suspected to be caused by another disease 
process, such as asymptomatic bacteriuria, overactive bladder, chronic incontinence, 


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or chronic interstitial cystitis, that may interfere with the clinical efficacy 
assessments or preclude complete resolution of acute cystitis symptoms.  
11. The participant has an anatomical or physiological anomaly that predisposes the 
participant to UTIs or may be a source of persistent bacterial colonization, including 
calculi, obstruction or stricture of the urinary tract, primary renal disease (e.g., 
polycystic renal disease), or neurogenic bladder, or the participant has a history of 
anatomical or functional abnormalities of the urinary tract (e.g., chronic 
vesico-ureteral reflux, detrusor insufficiency). 
12. The participant has an indwelling catheter, nephrostomy, ureter stent, or other 
foreign material in the urinary tract. 
13. The participant who, in the opinion of the investigator, has an otherwise complicated 
UTI, an active upper UTI (e.g., pyelonephritis, urosepsis), signs and symptom onset 
≥96 hours before study entry, or a temperature ≥101.4°F (≥38°C), flank pain, chills, 
or any other manifestations suggestive of upper UTI. 
14. The participant has known anuria, oliguria, or significant impairment of renal 
function (creatinine clearance <60 mL/min or clinically significant elevated serum 
creatinine as determined by the investigator). 
15. The participant presents with vaginal discharge at Baseline (e.g., suspected sexually 
transmitted disease). 
Cardiac Exclusions 
16. The participant has congenital long QT syndrome or known prolongation of the 
corrected QT (QTc) interval. 
17. The participant has uncompensated heart failure. 
18. The participant has severe left ventricular hypertrophy. 
19. The participant has a family history of QT prolongation or sudden death. 
20. The participant has a recent history of vasovagal syncope or episodes of 
symptomatic bradycardia or brady arrhythmia within the last 12 months. 
21. The participant is taking QT-prolonging drugs or drugs known to increase the risk of 
torsades de pointes (TdP) per the www.crediblemeds.org. “Known Risk of TdP” 
category at the time of her Baseline Visit, which cannot be safely discontinued from 
the Baseline Visit to the TOC Visit; or the participant is taking a strong 
cytochrome P450 enzyme 3A4 (CYP3A4) inhibitor. 
Cardiac ECG Exclusions 
22. For any participant ≥12 to <18 years of age, the participant has an abnormal 
electrocardiogram (ECG) reading. 


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23. The participant has a QTc >450 msec or a QTc >480 msec for participants with 
bundle-branch block.  
Note:   
• 
The QTc is the QT interval corrected for heart rate according to either 
Bazett’s formula (QTcB), or Fridericia’s (QTcF) formula, and/or another 
method. It is either machine read or manually overread.  
• 
The specific formula used to determine eligibility and discontinuation for an 
individual participant should be determined prior to initiation of the study. In 
other words, several different formulas cannot be used to calculate the QTc 
for an individual participant and then the lowest QTc value used to include or 
discontinue the participant from the trial. 
24. The participant has a documented or recent history of uncorrected hypokalemia 
within the past 3 months 
Hepatic Exclusions 
25. The participant has a known alanine aminotransferase (ALT) value >2 × upper limit 
of normal (ULN). 
26. The participant has a known bilirubin value >1.5 × ULN (isolated bilirubin >1.5 × 
ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). 
27. The participant has a current or chronic history of liver disease, or known hepatic or 
biliary abnormalities (with the exception of Gilbert’s syndrome or asymptomatic 
gallstones), including symptomatic viral hepatitis or moderate-to-severe liver 
insufficiency (Child Pugh class B or C).  
Note:  Participants with asymptomatic viral hepatitis are eligible for study 
participation. 
28. The participant has a previous history of cholestatic jaundice/hepatic dysfunction 
associated with nitrofurantoin. 
Prior Antibiotic/Antifungal Use Exclusion 
29. The participant has received treatment with other systemic antimicrobials or 
systemic antifungals within 1 week before study entry. 
Concomitant Medication Use Exclusion 
30. The participant plans to use any of the prohibited medications or nondrug therapies 
from the Baseline Visit through the TOC Visit as detailed in Section 7.7.2. 
Prior/Concurrent Clinical Study Experience 
31. The participant has been previously enrolled in this study or has previously been 
treated with gepotidacin. 
32. The participant has participated in a clinical trial and has received an investigational 
product within 30 days or 5 half-lives, whichever is longer. 


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6.3. 
Lifestyle Restrictions 
Participants will be requested to abstain from sexual activity from the Baseline Visit 
through the TOC Visit to prevent possible re-infection. 
6.3.1. 
Meals and Dietary Restrictions 
Study treatment should be taken with food (a meal or a snack) (see Section 7.1). 
6.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized. Participants who are screen failures are allowed to 
be rescreened for the same infection episode or a subsequent infection episode and 
participate in the study if they meet all of the inclusion and exclusion criteria. A minimal 
set of screen failure information is required to ensure transparent reporting of screen 
failure participants to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any 
serious adverse events (SAEs). 
7. 
TREATMENTS 
Study treatment is defined as any investigational treatments, marketed products, or 
placebo intended to be administered to a study participant according to the study 
protocol. 
7.1. 
Treatments Administered 
All doses of study treatment should always be taken after food consumption and with 
water. Participants will receive oral study treatment (gepotidacin [2 tablets] + 
nitrofurantoin matching placebo [1 capsule] or nitrofurantoin [1 capsule] + gepotidacin 
matching placebo [2 tablets]) BID (approximately every 12 hours) for 5 days. The first 
oral dose will be administered at the study site during the Baseline Visit; participants will 
self-administer subsequent doses as outpatients thereafter.  
 


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Study 
Treatment 
Name: 
Gepotidacin 
Placebo 
(Matched to 
Nitrofurantoin) 
Nitrofurantoin 
Placebo 
(Matched to 
Gepotidacin) 
Dosage 
Formulation: 
Tablets containing 
gepotidacin and 
inactive formulation 
excipients 
Over-encapsulated 
unit-dose 
nitrofurantoin 
placebo-to-match 
capsule 
Over-encapsulated 
capsules containing 
nitrofurantoin (25 mg 
nitrofurantoin 
macrocrystals and 
75 mg nitrofurantoin 
monohydrate) and 
inactive formulation 
excipients 
Unit-dose 
gepotidacin 
placebo-to-match 
tablet 
Unit Dose 
Strengths/ 
Dosage Levels: 
2 x 750-mg tablets 
Not applicable 
1 x 100-mg capsule 
Not applicable 
Route of 
Administration:  
Oral 
Oral 
Oral 
Oral 
Dosing 
Instructions: 
Administer twice daily 
for 5 days: 
1500 mg – 2 tablets  
(3000 mg total daily 
dose) 
Each dose should be 
taken after food 
consumption and 
with water. 
Administer twice daily 
for 5 days: 
1 capsule  
 
 
Each dose should be 
taken after food 
consumption and 
with water. 
Administer twice daily 
for 5 days: 
100 mg – 1 capsule  
(200 mg total daily 
dose) 
Each dose should be 
taken after food 
consumption and 
with water. 
Administer twice daily 
for 5 days: 
2 tablets  
 
 
Each dose should be 
taken after food 
consumption and 
with water. 
Packaging and 
Labeling:  
Gepotidacin tablets 
will be provided in 
bottles. Each bottle 
will be labeled as 
required per country 
requirement. 
Placebo-to-match 
nitrofurantoin 
capsules will be 
over-encapsulated 
and provided in 
bottles. Each bottle 
will be labeled as 
required per country 
requirement. 
Nitrofurantoin 
capsules will be 
over-encapsulated 
and provided in 
bottles. Each bottle 
will be labeled as 
required per country 
requirement. 
Placebo-to-match 
gepotidacin tablets 
will be provided in 
bottles. Each bottle 
will be labeled as 
required per country 
requirement. 
Manufacturer: 
Patheon Canada  
(part of Thermo 
Fisher Scientific) 
Almac, LTD 
(Over-encapsulation 
by Almac, LTD) 
Alvogen 
(Over-encapsulation 
by Almac, LTD) 
Patheon Canada  
(part of Thermo 
Fisher Scientific) 
 
 
7.2. 
Dose Modification 
The study design does not allow for dose modifications. 


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7.3. 
Method of Treatment Assignment 
Participants will be stratified by age category (<18 years, ≥18 to 50 years, or >50 years) 
and acute cystitis recurrence (nonrecurrent infection or recurrent infection, defined as a 
confirmed infection [not including the current infection in the calculation] with at least 
1 prior episode within the past 3 months, at least 2 prior episodes within the past 
6 months, or at least 3 prior episodes within the past 12 months before study entry). 
Participants will be centrally randomized in a 1:1 ratio to either gepotidacin + matching 
nitrofurantoin placebo or nitrofurantoin + matching gepotidacin placebo. All participants 
will be centrally randomized using interactive response technology (IRT). Before the 
study is initiated, information and directions for the IRT will be provided to each study 
site. 
Study treatment will be dispensed at the study visits summarized in Table 1. 
Returned study treatment should not be re-dispensed to other participants. 
7.4. 
Blinding 
This is a double-blind, double-dummy study. The study treatment taken during the study 
will be double-blind. Neither the participant nor study personnel (i.e., investigators, GSK, 
PPD [full service partner]) will know which study treatment a participant is receiving, 
with the exception of a few select PPD PK analysts to support PK model development 
and refinement. In order to maintain treatment blinding, participants will receive, in 
addition to their randomized active treatment (gepotidacin or nitrofurantoin), a matching 
placebo form of the active treatment to which they were not assigned. The matching 
placebos will look identical to the active form. 
Individual participant-level, de-identified, unblinded, and scrambled (i.e., random 
reassignment of participant identification numbers) drug concentration information will 
be analyzed prior to unblinding the study. In that case, independent PPD clinical PK 
analysts (who have no involvement in study conduct) will have access to an unblinded 
scrambled population PK-specific dataset (e.g., drug concentrations, actual dosing 
information, demographics, and laboratory details, but no AE or efficacy data) at 1 or 
more time points (e.g., prior to the interim and/or final analysis) throughout the study for 
population PK model development and refinement. 
The IRT will be programmed with blind-breaking instructions. In case of an emergency, 
the investigator has the sole responsibility for determining if unblinding of a participant’s 
treatment assignment is warranted. Participant safety must always be the first 
consideration in making such a determination. If the investigator decides that unblinding 
is warranted, the investigator should make every effort to contact GSK/PPD prior to 
unblinding a participant’s treatment assignment unless this could delay emergency 
treatment of the participant. If a participant’s treatment assignment is unblinded 
GSK/PPD must be notified within 24 hours after breaking the blind. The date and reason 
that the blind was broken must be recorded in the source documentation and electronic 
case report form (eCRF), as applicable. 


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A participant may continue in the study if that participant’s treatment assignment is 
unblinded provided that there are no safety concerns for the participant per the 
investigator’s judgement. 
The GSK SRT, which will monitor safety data instream, will remain blinded to 
participant treatment assignment throughout the study (see Appendix 3). A Microbiology 
Review Team will monitor blinded pathogen identification and susceptibility data 
instream as well as the number of participants eligible for the micro-ITT Population. 
Blinded monitoring of pathogens will be conducted, to determine whether end-of-study 
targets are likely to be achieved. Provision will be made for a limited degree of 
unblinding of a minority of participant sample data should this be viewed as appropriate 
for planning closure of trial enrollment. Procedures will be described in a separate 
microbiology sample monitoring plan, and no impact on trial integrity is expected. 
The IDMC and SDAC will be unblinded for the IA (Section 10.5). The IDMC details will 
be described in a separate charter and analysis plan. The GSK and PPD study teams that 
are operating the study and conducting the final analysis will remain blinded. 
GSK’s Global Clinical Safety and Pharmacovigilance staff may unblind the treatment 
assignment for any participant with an SAE. If the SAE requires that an expedited 
regulatory report be sent to one or more regulatory agencies, a copy of the report, 
identifying the participant’s treatment assignment, may be sent to investigators in 
accordance with local regulations and/or GSK policy. 
7.5. 
Preparation/Handling/Storage/Accountability 
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment. 
2. Only participants enrolled in the study may receive study treatment and only 
authorized study site staff may supply or administer study treatment. All study 
treatments must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the investigator and authorized study site staff. 
3. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of unused study treatment 
are provided in the SRM.  
Under normal conditions of handling and administration, study treatment is not expected 
to pose significant safety risks to the study site staff.  
A Material Safety Data Sheet or equivalent document describing occupational hazards 
and recommended handling precautions either will be provided to the investigator, where 
this is required by local laws, or is available upon request from GSK. 


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7.6. 
Treatment Compliance 
• 
When participants are dosed at the study site during the Baseline Visit, they will take 
their study treatment when directed by the investigator or designee, under medical 
supervision. The date and time of any dose administered at the study site will be 
recorded in the source documents. The dose of study treatment and study participant 
identification will be confirmed at the time of dosing by a member of the study site 
staff other than the person administering the study treatment.  
• 
When participants self-administer study treatments as outpatients, compliance with 
gepotidacin, nitrofurantoin placebo, nitrofurantoin, and gepotidacin placebo will be 
assessed through querying the participant during the study site visits and documented 
in the source documents and eCRF. A record of the number of gepotidacin and 
gepotidacin placebo tablets and nitrofurantoin and nitrofurantoin placebo capsules 
dispensed to and returned by each participant must be maintained and reconciled 
with study treatment and compliance records. Treatment start and stop dates, 
including dates for treatment delays, will also be recorded in the eCRF. 
7.7. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving within 30 days prior 
to the Baseline Visit or receives during the study must be recorded in the eCRF. In 
addition, any antibiotic use within 6 months prior to the Baseline Visit or during the study 
must be recorded in the eCRF. The concomitant therapy name must be recorded in the 
eCRF along with the following: 
• 
Reason for use 
• 
Dates of administration including start and end dates 
• 
Dosage information including dose and frequency 
The medical monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
7.7.1. 
Permitted Medications and Nondrug Therapies 
The use of H1 antihistaminics not associated with QT prolongation is allowed (e.g., 
loratadine, cetirizine, ebastine, and fexofenadine). The use of topical, nonsystemic 
antibacterials (e.g., topical clindamycin, neomycin, or polymyxin) and topical, 
nonsystemic antifungals (e.g., topical clotrimazole, tolnaftate, or ketoconazole) is allowed 
throughout the study. Please also refer to Appendix 7. 
Acetaminophen or paracetamol use is permitted throughout the study as it does not mask 
symptoms of the disease under study. A list of permitted medications commonly used for 
nausea, vomiting, pain, and diarrhea per investigator discretion is provided in 
Appendix 7. As described in Appendix 7, low-dose acetylsalicylic acid (≤100 mg/day) is 
permitted for the prevention of cardiovascular (CV) disease events. 
A further detailed list of medications will be provided in the SRM. 


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7.7.2. 
Prohibited Medications and Nondrug Therapies 
At the time of enrollment and/or during the study from the Baseline Visit through the 
TOC Visit, the participant is prohibited from use of the following medications and 
nondrug therapies: 
• 
An investigational product within 30 days or 5 half-lives, whichever is longer, of the 
Baseline Visit. 
• 
Treatment with other systemic antimicrobials (e.g., oral ciprofloxacin, 
amoxicillin/clavulanate, cephalexin, or doxycycline) or systemic antifungals (e.g., 
oral fluconazole, itraconazole, or terbinafine) within 1 week before study entry. 
Treatment with systemic fluconazole or other systemic antifungals per local standard 
of care is only allowed after all TOC Visit procedures have been completed. 
• 
Immunosuppressive therapy, including corticosteroid therapy (>40 mg/day 
prednisolone or equivalent for >1 week, ≥20 mg/day prednisolone or equivalent for 
>2 weeks, or prednisolone or equivalent ≥10 mg/day for >6 weeks). 
• 
QT-prolonging drugs or drugs with known TdP risk, per the www.crediblemeds.org 
“Known Risk of TdP” category, at the time of their Baseline Visit, which cannot be 
safely discontinued from the Baseline Visit to the TOC Visit. Details regarding 
website access are provided in the SRM; additional guidance is provided in 
Appendix 7. Of note, ondansetron is not allowed from the Baseline Visit to the TOC 
Visit due to its known TdP risk. Alternative antiemetics that are permitted per 
investigator discretion are listed in Appendix 7.  
Note:  Crediblemeds.org categorizes drugs into 4 categories. The only category for 
exclusion in this study is the “Known Risk of TdP” category; participants taking 
drugs that meet criteria of other categories are NOT excluded from participation. 
• 
Strong CYP3A4 inhibitors (a list of strong CYP3A4 inhibitors is provided in the 
SRM). 
• 
St John’s wort or other strong CYP3A4 inducers are not permitted from 14 days 
before study entry through the TOC Visit (a list is provided in the SRM). 
• 
Prescription, nonprescription, or supplements that may impact UTI clinical or 
microbiological efficacy outcomes including, but not limited to, Uva ursi, 
D-mannose, cranberry tablets, phenazopyridine, nonsteroidal anti-inflammatory 
drugs including ibuprofen and cyclooxygenase-2 inhibitors, and uricosuric drugs 
(e.g., probenecid and sulfinpyrazone). As described in Appendix 7, acetylsalicylic 
acid (doses >100 mg/day) is not permitted. 
In addition, antacid preparations containing magnesium trisilicate are prohibited from the 
start of study treatment at the Baseline Visit throughout the completion of the dosing 
period (i.e., until all 10 doses of study treatment have been received). 
Due to the gepotidacin’s property of acetylcholinesterase inhibition, the concomitant use 
of succinylcholine or other nondepolarizing paralytic agents is also prohibited. Caution 
should be used in participants who have a condition requiring medication that may 
exacerbate the inhibition of acetylcholinesterase, or neuromuscular blocking agents. 


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7.8. 
Treatment After the End of the Study 
Participants will not receive any additional treatment from GSK after they discontinue or 
complete the study (i.e., after the Follow-up Visit). Participants experiencing signs and 
symptoms suggestive of infection recurrence or relapse at the Follow-up Visit will be 
assessed and treated per the investigator’s judgement. 
8. 
DISCONTINUATION CRITERIA 
8.1. 
Discontinuation of Study Treatment 
Participants may voluntarily discontinue study treatment at any time. The investigator 
may also, at his or her discretion, discontinue the participant from study treatment at any 
time and initiate appropriate alternative therapy. 
Reasons for study treatment discontinuation may include the following: 
• 
Adverse event 
• 
Protocol deviation 
• 
Termination of the study by GSK 
• 
Investigator discretion 
• 
Lack of efficacy 
Note:  Pathogen identification or in vitro resistance of recovered uropathogens is not 
a reason for study treatment discontinuation. 
The reason for study treatment discontinuation will be recorded in the eCRF. Participants 
who discontinue study treatment for the reasons above will not be considered withdrawn 
from the study and should attend all subsequent study visits (see Table 1). 
8.1.1. 
Liver Chemistry Stopping Criteria 
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology. 
Discontinuation of study treatment for abnormal liver tests is required when: 
• 
a participant meets one of the conditions outlined in Figure 2 and Figure 3  
OR 
• 
when in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes study treatment discontinuation is in the best 
interest of the participant.  
Liver safety required actions and follow-up assessments section can be found in 
Appendix 8. 


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Figure 2 
Phase III Liver Chemistry Stopping and Increased Monitoring 
Algorithm 
 
Figure 3 
Phase III Liver Chemistry Increased Monitoring Algorithm with 
Continued Therapy for ALT 3 x ULN but <8 x ULN 
 


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8.1.2. 
QTc Stopping Criteria 
This protocol only requires an ECG evaluation at the Baseline Visit. Should further ECG 
monitoring or evaluation be needed for an individual participant, per investigator 
discretion, the following should be considered: 
A participant who meets the following bulleted criteria based on triplicate ECG readings 
will be withdrawn from study treatment: 
• 
QTc >500 msec OR uncorrected QT >600 msec 
• 
Change from baseline of QTc >60 msec 
For participants with underlying bundle-branch block, follow the discontinuation criteria 
listed below: 
Baseline QTc with Bundle-Branch Block 
Discontinuation QTc with Bundle-Branch 
Block 
<450 msec 
>500 msec 
450 to 480 msec 
≥530 msec 
 
• 
The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study. This formula may not be 
changed or substituted once the participant has been enrolled. (Note: Ideally, all 
ECGs for a participant should be performed with the same ECG machine.)  
• 
For example, if a participant is eligible for the protocol based on QTcB, then 
QTcB must be used for discontinuation of this individual participant as well. 
• 
Once the QT correction formula has been chosen for a participant’s eligibility, 
the same formula must continue to be used for that participant for all QTc data 
being collected for data analysis. Safety ECGs and other nonprotocol-specified 
ECGs are an exception. 
• 
The QTc should be based on averaged QTc values of triplicate ECGs obtained over a 
brief (e.g., 5- to 10-minute) recording period.  
8.1.3. 
Rechallenge 
8.1.3.1. 
Study Treatment Restart or Rechallenge 
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed. 
8.1.4. 
Gastrointestinal Evaluation Criteria 
If a participant meets the criteria in Appendix 1, Clostridium difficile toxin testing should 
be conducted and the specific eCRF page completed. C. difficile infection or colitis is 
considered an AE of special interest (Section 9.2.5). 


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8.2. 
Withdrawal From the Study 
• 
A participant may withdraw from the study at any time at his/her own request, or 
may be withdrawn at any time at the discretion of the investigator for safety, 
behavioral, compliance, or administrative reasons. 
• 
Reasons for study withdrawal include: 
• 
Participant lost to follow-up 
• 
Participant withdrew consent 
• 
Termination of the study by GSK 
• 
Investigator discretion 
• 
If the participant withdraws consent for disclosure of future information, the sponsor 
may retain and continue to use any data collected before such a withdrawal of 
consent. 
• 
If a participant withdraws from the study, he or she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records. 
The reason for participant withdrawal will be recorded in the eCRF. Participants who are 
withdrawn from the study should return to the study site and have the microbiological 
and clinical outcomes assessed at the time of withdrawal (see the Schedule of Activities 
[SoA] in Section 2), if data permit, and return all unused study treatment. Data from these 
participants will be considered evaluable up to the point at which they are withdrawn, 
using the same criteria for evaluability as for participants who complete the study. 
8.3. 
Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the study site for a 
required study visit: 
• 
The study site must attempt to contact the participant and reschedule the missed 
visit as soon as possible and counsel the participant on the importance of 
maintaining the assigned visit schedule and ascertain whether or not the 
participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 
3 telephone calls and, if necessary, a certified letter to the participant’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the participant’s medical record. 
• 
Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up.  


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9. 
STUDY ASSESSMENTS AND PROCEDURES 
• 
Study procedures and their timing are summarized in Table 1.  
• 
Protocol waivers or exemptions are not allowed. 
• 
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment. 
• 
Adherence to the study design requirements, including those specified in Table 1, is 
essential and required for study conduct. 
• 
All baseline screening evaluations must be completed and reviewed to confirm that 
potential participants meet all eligibility criteria. The investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility 
or record reasons for screening failure, as applicable.  
• 
Procedures conducted as part of the participant’s routine clinical management (e.g., 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in Table 1. 
• 
Prescreening activities may be conducted, including a prescreening informed consent 
and urine testing, as further detailed in the SRM. The required baseline urine 
specimen may be collected as part of an optional prescreening process, if not already 
part of standard of care, and is further detailed in the SRM. This specimen can be 
used for the required baseline procedures of the diagnosis of presumptive acute 
cystitis and pregnancy testing. 
• 
The maximum amount of blood collected from each participant over the duration of 
the study, including any extra assessments that may be required, will not exceed 
200 mL. 
• 
Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples. 
• 
Participants may return to the study site at any time due to AEs or if they are 
experiencing new or continuing signs and symptoms of acute cystitis. Participants 
will be assessed and treated per the investigator’s judgement. If a participant is 
switched to a different antibiotic before or during the TOC Visit, all TOC procedures 
should be completed before the other antibiotic is started. 
• 
Each treatment day will be assessed over 24 hours starting with the first dose of 
study treatment, as further detailed in the SRM. 
The study will comprise the following 4 planned study visits: 
Note: For all study visits, to minimize the amount of time that participants spend at 
the clinic, eConsent may be utilized and remote collection of study-related data may 
be obtained as described in the SRM. Thus, some visit data may be collected through 
a combination of telemedicine and on-site visits. Collection of information via 
telemedicine will be performed only where local regulations permit. 


T M F -1 3 8 1 7 5 4 3  
C O N FI D E N TI A L  
 
 
 
2 0 4 9 8 9  
 
5 8  
 
•  
B aseli ne ( D a y 1) Visit : T he Baseli ne Visit will be perf or me d bef ore d osi n g o n 
Da y  1. Assess me nts will be perf or me d as s h o w n i n Ta ble  1 , i ncl u di n g t h e f oll o wi n g: 
•  
Pretreat me nt b as eli ne s peci me ns f or micr o bi ol o gical testi n g will be c ollecte d , as 
descri be d i n Secti o n  9. 1 . Cli nical si g ns a n d s y m pt o ms of ac ute c ystitis will be 
rec or de d, as des cri be d i n Secti o n  9. 1. 3. 1  a n d A p pe n di x  6 . 
 
 
•  
F oll o wi n g c o m pleti o n of  all pretreat me nt assess me nts, eli gi ble partici pa nt s will 
be ra n d o ml y assi g ne d t o treat me nt , as des cri be d i n Secti o n 7. 3 . 
•  
T he first d ose of ra n d o ml y assi g ne d oral st u d y treat me nt will be a d mi nistere d at 
t he st u d y site. After d ose a d mi nistrati o n, Da y 1 p osttreat me nt assess me nts will 
be perf or me d , as s h o w n i n Ta ble  1 . A n y A Es or cli nicall y si g nifica nt c ha n ges 
s h o ul d be f oll o we d acc or di n gl y. S u bse q ue nt t o a d mi nistrati o n of t he first d ose at 
t he st u d y site, partici p a nt s will self-a d mi nister d oses as o ut patie nts  t hereaft er. 
( N ote: Eac h d os e s h o ul d be ta ke n after f o o d c o ns u m pti o n a n d wit h water.) 
•  
T he O n -t hera p y, T O C , a n d F oll o w-u p Visits s h o ul d be sc he d ule d bef ore t h e 
partici pa nt  lea v es t he st u d y site o n Da y 1 (as p er t he Sc he d ule of Acti vities 
Ta ble i n Secti o n  2  [Ta ble  1 ]); t he pla n ne d ret ur n d a y/ti me s h o ul d be at t he 
c o n ve nie nce of t he p artici pa nt  a n d als o t he a vaila bilit y of t h e  st u d y site staff. If 
at all p ossi ble, t he a p p oi nt me nt ti me of t he O n -t hera p y Visit s h o ul d be 
a p pr o xi matel y 1 t o 2 h o urs after t h e partici pa nt’s m ost rece nt  d ose is e x pecte d t o 
be ta ke n. See t h e S R M f or a d diti o nal details.  
•  
O n -t her a p y ( D a y 2  t o 4 ) Visit : Partici pa nt s will be i nstr ucte d t o ret ur n t o t he st u d y 
site 1  t o 3  da ys f oll o wi n g  st u d y treat me nt a d mi nistrati o n at Baseli ne i n or der t o 
c o m plete t he O n -t hera p y Visit. Assess me nts will be perf or me d as s h o w n i n Ta ble  1 , 
i ncl u di n g t he f oll o wi n g:  
•  
T he O n -t hera p y Visit will be prece de d b y a d o c u me nte d re mi n der c o ntact fr o m 
t he st u d y site t o t he parti ci pa nt  2 4  ±  4 h o urs bef ore t he sc he d ule d a p p oi nt me nt 
ti me per t he met h o d (e. g., te xt messa ge, tele p h o n e call, e-mail) c o nfir me d wit h 
t he st u d y site staff pri or t o de parti n g t he st u d y site o n Da y 1. 
•  
At t he O n -t hera p y Visit, w he ne ver it is p ossi ble, t he partici pa nt will ha ve t he 
pre g na nc y t est perf or me d at t he st u d y s ite. If t he visit c oi nci des wit h t he 8t h 
d ose, t he partici pa nt will ta ke t heir ne xt d ose of st u d y treat me nt at t he st u d y site 
after ne gati ve pre g na nc y test res ults are c o nfir me d.  
•  
Bef ore t he O n -t hera p y Visit, if t he re q uire me nt f or t he si n gle pre g na n c y test t o 
be d o ne bet w ee n d ose 4 a n d d ose 8 ca n n ot be d o ne at t he st u d y site d u e t o 
a vaila bilit y of o pe n cli nic h o urs a n d t he i n vesti gat or c o nsi ders t he p artici pa nt 
relia ble t o acc urat el y p erf or m t he st u d y-pr o vi de d pre g na nc y t est at h o me will be 
i nstr ucte d t o d o s o. If t he pre g na nc y t est is ne gati ve, t h ose partici pa nts will be 
i nstr ucte d t o ta ke t heir ne xt d ose of st u d y tr eat me nt at h o me via te xt or b y st u d y 
site staff bef ore g oi n g t o t he st u d y site f or t h eir O n-t hera p y Visit. 
N ote:   I n W O C B P, t he hi g h se nsiti vit y pre g na n c y test m ust be perf or me d a n d 
s h o w ne gati ve res ults at t he latest bef ore  D ose 8 of st u d y tr eat me nt is ta ke n.  
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C O N FI D E N TI A L  
 
 
 
2 0 4 9 8 9  
 
5 9  
 
•  T he O n -t hera p y Visit s h o ul d be sc he d ule d t o s u p p ort c o m pleti o n of t he p ost d ose 
P K c ollecti o n, if at all p ossi ble, 1 t o 2 h o urs after t he m ost rece nt d ose is ta ke n. 
H o we ver, t he f oll o wi n g o pti o ns  are acce pta ble a n d s h o ul d be prearra n ge d wit h 
eac h p artici pa nt base d o n pers o nal prefere nce:  
•  Partici pa nts ma y t a ke t he m or ni n g d ose as us ual, t he n g o t o t he st u d y 
cli nic f or P K sa m ple c oll ecti o n at a p pr o xi matel y 1 t o 2 h o urs p ost d ose.  
•  Partici pa nts ma y g o t o t h e st u d y cli nic , ta ke t he m or ni n g d ose at t he 
cli nic, a n d t he n wait at t h e cli nic f or a p pr o xi matel y 1 t o 2 h o urs p ost d ose 
f or t he P K sa m ple c ollecti o n t o be perf or me d. 
•  Partici pa nts ma y g o t o t h e st u d y cli nic b ef ore  ta ki n g t he m or ni n g d ose, 
ha ve t he P K sa m ple c ollecti o n perf or me d, a n d t he n ta ke t he m or ni n g 
d ose, w hile ai mi n g t o kee p t h e ti me of d osi n g as cl ose as p ossi ble t o 
1 2  h o urs after t h e pre vi o us e ve ni n g d ose was t a ke n.  
•  
S peci me ns f or micr o bi ol o gical testi n g, as d escri b e d i n Secti o n  9. 1 , a n d bl o o d 
a n d uri ne sa m ples f or P K a nal ysis, as descri be d i n Secti o n 9. 5 , will be c ollecte d. 
Cli ni cal si g ns a n d s y m pt o ms of ac ute c ystitis will be rec or de d , as descri b e d i n 
Secti o n 9. 1. 3. 1  a n d A p pe n di x  6 . 
 
  
•  
Pre g n a nc y testi n g as re q uire d after D ose 4 a n d bef ore D os e 8 . Refer t o 
A p pe n di x  2  f or details.  
•  
T O C ( D a y 1 0  t o 1 3 ) Visit : Partici pa nt s will be i nstr ucte d t o ret ur n t o t he st u d y site 
5  t o 8  da ys after c o m pleti o n of st u d y tr eat me nt i n or der t o c o m plete t h e T O C Visit. 
Assess me nts  will be perf or me d as s h o w n i n Ta ble  1 , i ncl u di n g t he f oll o wi n g: 
•  
T he T O C Visit will be prece d e d b y a d oc u m e nte d re mi n der c o nt act fr o m t h e 
st u d y site t o t he partici pa nt  2 4  ±  4 h o urs bef ore t h e sc he d ule d a p p oi nt me nt ti me 
per t he met h o d (e. g., te xt messa ge, tele p h o n e call, e -mail) c o nfir me d wit h t he 
st u d y site staff pri or t o de parti n g t he st u d y site o n Da y 1. 
•  
S peci me ns f or micr o bi ol o gical testi n g will be c oll ecte d, as d esc ri be d i n 
Secti o n  9. 1 . Cli nical si g ns a n d s y m pt o ms of ac ute c ystitis will be rec or de d , as 
descri be d i n Secti o n  9. 1. 3. 1  a n d A p pe n di x  6 . 
 
 
  
•  
F oll o w -u p ( D a y 2 8 ± 3 ) Visit. Partici pa nt s will be i nstr ucte d t o ret ur n t o t h e st u d y site 
2 8  ( ±3 ) da ys p ostra n d o miz ati o n i n or der t o c o m plete t he F oll o w-u p Visit. 
Assess me nts  will be perf or me d as s h o w n i n Ta ble  1 , i ncl u di n g t he f oll o wi n g: 
•  
T he F oll o w -u p Visit will be pre ce de d b y a d oc u me nte d re mi n der c o ntact fr o m 
t he st u d y site t o t he parti ci pa nt  2 4  ± 4 h o urs bef ore t he sc he d ule d a p p oi nt me nt 
ti me per t he met h o d (e. g., te xt messa ge, tele p h o n e call, e-mail) c o nfir me d wit h 
t he st u d y site staff pri or t o de parti n g t he st u d y site o n Da y 1.  
•  
S peci me ns f or micr o bi ol o gical testi n g will be c oll ecte d, as d escri be d i n 
Secti o n  9. 1 . Cli nical si g ns a n d s y m pt o ms of ac ute c ystitis will be rec or de d, as 
descri be d i n Secti o n  9. 1. 3. 1  a n d A p pe n di x  6 . 
 
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T M F -1 3 8 1 7 5 4 3  
C O N FI D E N TI A L  
 
 
 
2 0 4 9 8 9  
 
6 0  
 
 
 
•  
Partici pa nt s e x perie nci n g si g ns a n d s y m pt o ms s u g gesti ve of i nfecti o n rec urre nce 
or rela pse will be assesse d a n d treate d p er t he i n v esti gat or’s j u d ge m e nt. 
9. 1.  
Eff i c a c y A s s e s s m e nt s 
9. 1. 1.  
T h er a p e uti c R e s p o n s e E v al u ati o n  
T hera p e utic res p o nse (c o m bi ne d per-partici pa nt micr o bi ol o gical a n d cli nical res p o nse) 
(s uccess/fail ure) is a m eas ure of t he o v erall efficac y res p o nse. A t hera pe utic s uccess 
refers t o partici pa nts w h o ha ve bee n dee m e d b ot h a “ micr o bi ol o gical s uc cess” (see 
Secti o n 9. 1. 2. 1 ) a n d a “cli nical s uccess” (see Secti o n 9. 1. 3. 1 ). All ot her c o m bi nati o ns 
( ot her t ha n cli nical s u ccess + micr o bi ol o gical s uccess) will be dee me d fail ures f or 
t hera pe utic res p o nse. 
T hera p e utic res p o nse will be deter mi ne d b y statistical pr o gra m mi n g f or t h e T O C a n d 
F oll o w -u p Visits.  
T hera p e utic res p o nse at T O C is t he pri mar y effi cac y e n d p oi nt.  
9. 1. 2.  
B a ct eri ol o g y S a m pl e s  
At t he Bas eli ne  Visit , a pretreat me nt, clea n -cat c h mi dstrea m uri ne sa m ple m ust  be 
o btai ne d fr o m all ra n d o miz e d partici pa nt s f or Gra m stai n, q ua ntitati ve bacteri ol o gical 
c ult ure, a n d i n vitr o a nti micr o bial s usce pti bilit y testi n g at a d esi g nate d la b orat or y(ies). 
F or i ncl usi o n i n t he micr o -I T T P o p ulati o n, a baseli ne q ualif yi n g b acterial ur o pat h o ge n is 
re q uire d as defi ne d i n A p pe n di x  4 ; f or i ncl usi o n i n t he micr o-I T T N T F -S P o p ulati o n, t he 
baseli ne q ualif yi n g ur o pat h o ge n m ust als o be s usce pti ble t o nitr of ura nt oi n . At t he 
O n -t hera p y, T O C, a n d F oll o w-u p Visits, a clea n -catc h mi d strea m uri n e sa m ple will be 
o btai ne d a n d se nt t o a desi g nate d la b orat or y(i es) f or Gra m stai n, q ua ntitati ve 
bacteri ol o gical c ult ure , a n d i n vitr o a nti micr o bial s usce pti bilit y t esti n g. I d e ntificati o n a n d 
s usce pti bilit y t esti n g of is olates rec o v ere d fr o m uri ne s peci me ns at all visits will als o be 
c o n d ucte d at a desi g nate d  la b orat or y(ies). A d diti o nal tests, as nee de d, t o f urt her 
c haracteriz e rec o vere d is olates will als o be perf or me d b y a desi g nate d  la b orat or y(ies). 
I nstr u cti o ns f or sa m ple c ollecti o n, pr ocessi n g, a n d s hi p me nt are pr o vi de d i n t he S R M a n d 
t he la b orat or y ma n u al. T he st u d y site s h o ul d f oll o w t he Micr o bi ol o g y Pr oce d ures secti o n 
of t he la b orat or y m a n ual t o mi ni mize p ote ntial c o nta mi nati o n of t he s peci me ns. 
9. 1. 2. 1.  
Mi cr o bi ol o gi c al O ut c o m e a n d R e s p o n s e  
O nl y t h ose p artici pa nts w h o ha ve a q u alif yi n g b acterial ur o pat h o ge n ( defi ne d i n 
A p pe n di x  4 ) i de ntifie d at Baseli ne will be e val uat e d f or micr o bi ol o gical o utc o me a n d 
res p o nse b y  bas eli ne q ualif yi n g ur o pat h o ge n  f or t he pri mar y efficac y e n d p oi nt. T he 
micr o bi ol o gical o utc o m e a n d res p o nse t o st u d y treat me nt will be deter mi ne d 
pr o gra matic all y  f or eac h partici pa nt /ur o pat h o ge n  pri or t o brea ki n g of t h e st u d y bli n d.  
T he micr o bi ol o gi cal o u tc o me b y b aseli ne q ualif yi n g ur o pat h o ge n is deter mi ne d b y 
c o m pari n g t he bas eli ne c ult ure res ults t o t he c ult ure res ults at eac h s u bse q ue nt visit (see 
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Table 3, Table 4, and Table 5 for baseline qualifying uropathogen outcomes). The 
corresponding microbiological response (success or failure) “by uropathogen” is then 
assigned, as shown in Table 4 and Table 5. Participant-level microbiological response is a 
measure of the combined “by uropathogen” response(s). Participant-level microbiological 
success refers to participants who have been deemed a “microbiological success” for all 
of their “by uropathogen” microbiological responses. All other combinations (other than 
all “microbiological successes”) are deemed failures for participant-level microbiological 
response. The participant-level microbiological outcome and response definitions are 
provided in Table 6. 
Microbiological outcome criteria for new qualifying uropathogens (i.e., uropathogens not 
identified at Baseline) are defined by visit in Table 7, Table 8, and Table 9. 
Table 3 
Microbiological Outcome by Baseline Qualifying Uropathogen at the 
On-Therapy Visit 
Defining Criteria 
Outcome 
A quantitative urine culture taken at the 
On-therapy Visit shows that the qualifying 
bacterial uropathogen recovered at Baseline is 
reduced to <103 CFU/mL, without the 
participant receiving other systemic 
antimicrobials before the On-therapy Visit 
Microbiological eradication 
A quantitative urine culture taken at the 
On-therapy Visit shows that the qualifying 
bacterial uropathogen recovered at Baseline 
grows 103 CFU/mL, without the participant 
receiving other systemic antimicrobials before 
the On-therapy Visit 
Microbiological persistence 
1) The On-therapy urine culture result is 
missing, or  
2) The participant received other systemic 
antimicrobials before the On-therapy Visit 
Unable to determine 
CFU=colony-forming units. 
 


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Table 4 
Microbiological Outcome and Response by Baseline Qualifying 
Uropathogen at the Test-of-Cure Visit 
Defining Criteria 
Outcome 
Response 
Participants considered microbiological failures at the TOC Visit will also be considered 
microbiological failures at the Follow-up Visit. 
A quantitative urine culture taken at the TOC 
Visit shows reduction of the qualifying 
bacterial uropathogen recovered at Baseline 
to <103 CFU/mL, without the participant 
receiving other systemic antimicrobials 
before the TOC Visit 
Microbiological 
eradication 
Microbiological 
success 
A quantitative urine culture taken at the TOC 
Visit shows that the qualifying bacterial 
uropathogen recovered at Baseline, and 
which was also shown to persist or unable to 
determine at the On-therapy Visit, grows 
≥103 CFU/mL, without the participant 
receiving other systemic antimicrobials 
before the TOC Visit  
Microbiological 
persistence 
Microbiological failure 
A quantitative urine culture taken at the TOC 
Visit shows that the qualifying bacterial 
uropathogen recovered at Baseline, and 
which was also shown to be eradicated at 
the On-therapy Visit, grows ≥103 CFU/mL, 
without the participant receiving other 
systemic antimicrobials before the TOC Visit 
Microbiological 
recurrence 
Microbiological failure 
1) The TOC urine culture result is missing, 
or 
2) The participant received other systemic 
antimicrobials before the TOC Visit 
Unable to determine 
Microbiological failure 
CFU=colony-forming units; TOC=Test-of-Cure. 
 


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Table 5 
Microbiological Outcome and Response by Baseline Qualifying 
Uropathogen at the Follow-Up Visit 
Defining Criteria 
Outcome 
Response 
Participants considered microbiological failures at the TOC Visit will also be considered 
microbiological failures at the Follow-up Visit. 
A quantitative urine culture taken at the 
Follow-up Visit shows reduction of the qualifying 
bacterial uropathogen recovered at Baseline to 
<103 CFU/mL, following microbiological 
eradication at the TOC Visit, without the 
participant receiving other systemic 
antimicrobials before the Follow-up Visit 
Sustained 
microbiological 
eradication 
Microbiological 
success 
A quantitative urine culture taken at the 
Follow-up Visit shows that the qualifying 
bacterial uropathogen recovered at Baseline 
grows 103 CFU/mL, following microbiological 
eradication at the TOC Visit, without the 
participant receiving other systemic 
antimicrobials before the Follow-up Visit 
Microbiological 
recurrence 
Microbiological 
failure 
A quantitative urine culture taken at the 
Follow-up Visit shows that the qualifying 
bacterial uropathogen recovered at Baseline 
grows 103 CFU/mL, and also did not achieve 
an outcome of microbiological eradication at the 
TOC Visit, without the participant receiving other 
systemic antimicrobials before the Follow-up 
Visit 
Microbiological 
persistence 
Microbiological 
failure 
A quantitative urine culture taken at the 
Follow-up Visit shows reduction of the qualifying 
bacterial uropathogen recovered at Baseline to 
<103 CFU/mL, and also did not achieve an 
outcome of microbiological eradication at the 
TOC Visit, without the participant receiving other 
systemic antimicrobials before the Follow-up 
Visit 
Delayed  
microbiological  
eradication 
Microbiological 
failure 
1) The Follow-up urine culture result is 
missing, or 
2) The participant received other systemic 
antimicrobials before the Follow-up Visit 
Unable to determine 
Microbiological 
failure 
CFU=colony-forming units; TOC=Test-of-Cure. 
 


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Table 6 
Participant-Level Microbiological Outcome and Response 
Definitions per Study Visit 
Defining Criteria at the On-Therapy Visit 
Outcome 
Response 
All qualifying baseline uropathogens have a microbiological 
outcome of eradication at On-therapy 
Microbiological 
eradication 
NA 
At least one qualifying baseline uropathogen has an 
outcome of persistence at On-therapy 
Microbiological 
persistence 
NA 
All qualifying baseline uropathogen outcomes are unable to 
determine at On-therapy  
Unable to determine 
NA 
 
Defining Criteria at the TOC Visit 
Outcome 
Response 
All qualifying baseline uropathogens have a microbiological 
outcome of eradication at TOC 
Microbiological 
eradication 
Microbiological 
success 
At least one qualifying baseline uropathogen has an 
outcome of persistence at TOC 
Microbiological 
persistence 
Microbiological 
failure 
At least one qualifying baseline uropathogen has an 
outcome of recurrence and none have an outcome of 
persistence at TOC 
Microbiological 
recurrence 
Microbiological 
failure 
All qualifying baseline uropathogen outcomes are unable to 
determine at TOC 
Unable to determine 
Microbiological 
failure 
 
Defining Criteria at the Follow-up Visit 
Outcome 
Response 
All qualifying baseline uropathogens have a microbiological 
outcome of sustained eradication at Follow-up 
Sustained 
microbiological 
eradication 
Microbiological 
success 
At least one qualifying baseline uropathogen has an 
outcome of recurrence and none have an outcome of 
persistence at Follow-up 
Microbiological 
recurrence 
Microbiological 
failure 
At least one qualifying baseline uropathogen has an 
outcome of persistence at Follow-up 
Microbiological 
persistence 
Microbiological 
failure 
At least one qualifying baseline uropathogen has an 
outcome of delayed eradication and none have an outcome 
of persistence or recurrence at Follow-up 
Delayed 
microbiological 
eradication 
Microbiological 
failure 
All qualifying baseline uropathogen outcomes are unable to 
determine at Follow-up 
Unable to determine 
Microbiological 
failure 
NA=Not applicable; TOC=Test-of-Cure. 
 
Table 7 
Microbiological Outcome by New Qualifying Uropathogen at the 
On-Therapy Visit 
Defining Criteria 
Outcome 
A new qualifying bacterial uropathogen, not 
identified at Baseline, is documented by 
quantitative urine culture at the On-therapy 
Visit 
New uropathogen 
 


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Table 8 
Microbiological Outcome by New Qualifying Uropathogen at the 
Test-of-Cure Visit 
Defining Criteria 
Outcome 
A new qualifying bacterial uropathogen, not 
identified at Baseline, is documented by 
quantitative urine culture at the Test-of-Cure 
Visit in a participant who did not achieve a 
clinical outcome of clinical resolution at the 
Test-of-Cure Visit 
New infection 
A new qualifying bacterial uropathogen, not 
identified at Baseline, is documented by 
quantitative urine culture at the Test-of-Cure 
Visit in a participant who did achieve a clinical 
outcome of clinical resolution at the 
Test-of-Cure Visit 
Colonization 
 
Table 9 
Microbiological Outcome by New Qualifying Uropathogen at the 
Follow-up Visit 
Defining Criteria 
Outcome 
A new qualifying bacterial uropathogen, not 
identified at Baseline, is documented by 
quantitative urine culture at the Follow-up Visit 
in a participant who did not achieve a clinical 
resolution at the Follow-up Visit 
New infection 
A new qualifying bacterial uropathogen, not 
identified at Baseline, is documented by 
quantitative urine culture at the Follow-up Visit 
in a participant who did achieve a clinical 
resolution at the Follow-up Visit 
Colonization 
 
9.1.3. 
Clinical Evaluation 
9.1.3.1. 
Clinical Signs and Symptom Scores, Clinical Outcomes, and Clinical 
Response  
Clinical signs and symptoms of acute cystitis will be recorded based on participant 
interview per the SoA (Section 2) using the scoring system and instructions in 
Appendix 6. At Baseline, the participant must present with at least 2 signs and symptoms 
and have a total cumulative symptom score ≥2. At TOC, success is defined as normal 
presentation of signs and symptoms with a total cumulative symptom score of zero and 
no new signs and symptoms of the infection under study. 
A study physician or otherwise appropriately medically trained staff will determine the 
individual clinical signs and symptoms scores for acute cystitis (Appendix 6) at the 
On-therapy, TOC, and Follow-up Visits. The same scorer will be used at all assessment 
time points for each participant, on all occasions, whenever possible. The score will be 


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used to programmatically determine the clinical outcome at the On-therapy Visit 
(Table 10) and the clinical outcome and response (success or failure) at the TOC Visit 
(Table 11) and the Follow-up Visit (Table 12).  
Table 10 
Clinical Outcome at the On-Therapy Visit 
Defining Criteria 
Outcomea 
Resolution of signs and symptoms of acute 
cystitis present at Baseline (and no new signs 
and symptoms), without the participant 
receiving other systemic antimicrobials before 
the On-therapy Visit 
Clinical resolution 
Improvement in total symptom scores from 
Baseline, but not complete resolution, without 
the participant receiving other systemic 
antimicrobials before the On-therapy Visit 
Clinical improvement 
Worsening or no change in total symptom 
scores from Baseline or the participant 
received other systemic antimicrobials for the 
current infection prior to or on the date of the 
On-therapy Visit 
Clinical worsening 
1) The Baseline score is missing, or 
2) The On-therapy assessment is missing, or 
3) The participant received other systemic 
antimicrobials not for the current infection 
prior to the assessment (unless clinical 
worsening outcome criteria were met) 
Unable to determine 
a. 
A study physician or otherwise appropriately medically trained staff will determine the individual clinical signs 
and symptoms scores for acute cystitis (Appendix 6), which will then be used to programmatically determine 
the clinical outcome. The same scorer will be used at all assessment time points for each participant, on all 
occasions, whenever possible.  
 


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Table 11 
Clinical Outcome and Response at the Test-of-Cure Visit 
Defining Criteria 
Outcomea 
Response 
Resolution of signs and symptoms of 
acute cystitis present at Baseline (and no 
new signs or symptoms), without the 
participant receiving other systemic 
antimicrobials before the TOC Visit 
Clinical resolution 
Clinical success 
Improvement in total symptom scores 
from Baseline, but not complete 
resolution, without the participant 
receiving other systemic antimicrobials 
before the TOC Visit 
Clinical improvement  
Clinical failure 
Worsening or no change in total symptom 
scores from Baseline or the participant 
received other systemic antimicrobials for 
the current infection before or on the date 
of the TOC Visit 
Clinical worsening 
Clinical failure 
1) The Baseline score is missing, or 
2) The TOC assessment is missing, or 
3) The participant received other 
systemic antimicrobials not for the 
current infection prior to the 
assessment (unless clinical 
worsening criteria were met) 
Unable to determine 
Clinical failure 
TOC = Test-of-Cure 
a. 
A study physician or otherwise appropriately medically trained staff will determine the individual clinical signs 
and symptoms scores for acute cystitis (Appendix 6), which will then be used to programmatically determine 
the clinical outcome. The same scorer will be used at all assessment time points for each participant, on all 
occasions, whenever possible.  
 


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Table 12 
Clinical Outcome and Response at the Follow-up Visit 
Defining Criteria 
Outcomea 
Response 
Resolution of signs and symptoms of 
acute cystitis demonstrated at the TOC 
Visit persist at the Follow-up Visit (and no 
new signs and symptoms), without the 
participant receiving other systemic 
antimicrobials before the Follow-up Visit 
Sustained clinical resolution 
Clinical success 
Resolution of signs and symptoms of 
acute cystitis present at Baseline (and no 
new signs or symptoms), after clinical 
failure at TOC, without the participant 
receiving other systemic antimicrobials 
before the Follow-up Visit 
Delayed clinical resolution 
Clinical failure 
Improvement in total symptom scores 
from Baseline, but not complete 
resolution, without the participant 
receiving other systemic antimicrobials 
before the Follow-up Visit 
Clinical improvement 
Clinical failure 
Worsening or no change in total symptom 
scores at Follow-up compared to Baseline 
after clinical failure at TOC, or the 
participant received other systemic 
antimicrobials for the current infection 
before or on the date of the Follow-up 
Visit 
Clinical worsening 
Clinical failure 
Signs and symptoms of acute cystitis 
reoccur at the Follow-up Visit after clinical 
success at TOC 
Clinical recurrence 
Clinical failure 
1) The Baseline score is missing, or 
2) The Follow-up assessment is missing, 
or 
3) The participant received other 
systemic antimicrobials not for the 
current infection prior to the 
assessment (unless the clinical 
worsening or recurrence outcome 
criteria were met) 
Unable to determine 
Clinical failure 
TOC = Test-of-Cure 
a. 
A study physician or otherwise appropriately medically trained staff will determine the individual clinical signs 
and symptoms scores for acute cystitis (Appendix 6), which will then be used to programmatically determine 
the clinical outcome. The same scorer will be used at all assessment time points for each participant, on all 
occasions, whenever possible.  
 


T M F -1 3 8 1 7 5 4 3  
C O N FI D E N TI A L  
 
 
 
2 0 4 9 8 9  
 
6 9  
 
9. 2.  
A d v er s e E v e nt s  
T he defi niti o ns of a n A E or S A E ca n be f o u n d i n A p pe n di x  1 0 . 
T he i n vesti gat or a n d a n y desi g nees are res p o nsi ble f or detecti n g, d o c u me nti n g, a n d 
re p orti n g e ve nts t hat meet t he defi niti o n of a n A E or S A E a n d re m ai n res p o nsi ble f or 
f oll o wi n g u p A Es t hat are seri o us, c o nsi dere d relate d t o t he st u d y treat me nt or t he st u d y, 
or t hat ca use d t h e partici pa nt t o disc o nti n ue t he st u d y tre at me nt or fr o m t he st u d y (see 
Secti o n  8 ).  
9. 2. 1.  
Ti m e P eri o d a n d Fr e q u e n c y f or C oll e cti n g A E a n d S A E 
I nf or m ati o n 
•  
All S A E s will be c ollecte d fr o m t he si g ni n g of t h e I C F u ntil t he F oll o w -u p Vi sit 
at t he ti me p oi nts s pecifie d i n t he Ta ble  1  ( Secti o n 2 ).  
•  
All A E s will be c ollecte d fr o m t he start of treat me nt u ntil t he F oll o w -u p Visit at 
t he ti me p oi nts s pecifie d i n t he Ta ble  1  ( Secti o n 2 ). 
•  
Me dical occ urre n ces t hat be gi n b ef ore t he start of st u d y treat me nt b ut after 
o btai ni n g i nf or me d c o nse nt will be rec or de d o n t he m e dical h ist or y/curre nt 
m e dical co n diti o ns secti o n of t he  eC R F  a n d n ot t h e A E secti o n.  
•  
All S A E s will be rec or de d a n d re p ort e d t o  t he s p o ns or or desi g nee i m me di atel y 
a n d u n der n o circ u msta n ces s h o ul d t his e x cee d 2 4  h o urs, as i n dicate d i n 
A p pe n di x  1 0 . T he i n vesti gat or will s u b mit a n y u p date d S A E data t o t he s p o ns or 
wit hi n 2 4  h o urs of it bei n g a v aila ble.  
•  
I n v esti gat ors are n ot o bli gat e d t o acti vel y see k A Es or S A Es  i n f or mer st u d y 
partici pa nts. H o we v er, if t he i n vesti gat or l ear ns of a n y S A E, i n cl u di n g a d eat h, 
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at any time after a participant has been discharged from the study, and he or she 
considers the event to be reasonably related to the study treatment or study 
participation, the investigator must promptly notify the sponsor. 
• 
The method of recording, evaluating, and assessing causality of AEs and SAEs 
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 10. 
9.2.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and nonleading verbal questioning of the participant is the preferred method to inquire 
about AE occurrence. 
9.2.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs and nonserious AEs of special interest 
(as defined in Section 9.2.5), will be followed until the event is resolved, stabilized, 
otherwise explained, or the participant is lost to follow-up (as defined in Section 8.3). 
Further information on follow-up procedures is given in Appendix 10. 
9.2.4. 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the investigator to the sponsor of an SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are 
met.  
• 
The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study treatment 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
IRB/IEC, and investigators. 
• 
Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions according to local regulatory requirements and sponsor policy 
and forwarded to investigators as necessary. 
• 
An investigator who receives an investigator safety report describing an SAE or 
other specific safety information (e.g., summary or listing of SAEs) from the 
sponsor will review and then file it along with the IB and will notify the 
IRB/IEC, if appropriate according to local requirements. 
9.2.5. 
Adverse Events of Special Interest 
Predefined AEs of special interest for this study are CV events, gastrointestinal events, C. 
difficile infection or colitis events, and AEs related to acetylcholinesterase inhibition (see 
Section 3.3.1), which will be identified by a prespecified list of coded terms or 
determined by algorithm, as described in the reporting and analysis plan (RAP). 
Additional details are provided in Appendix 10. 


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9.2.6. 
Cardiovascular and Death Events 
For any CV events detailed in Appendix 10 and all deaths, whether or not they are 
considered SAEs, specific CV and death sections of the eCRF will be required to be 
completed. These sections include questions regarding CV (including sudden cardiac 
death) and non-CV death.  
The CV eCRFs are presented as queries in response to reporting of certain CV Medical 
Dictionary for Regulatory Activities (MedDRA) terms. The CV information should be 
recorded in the specific CV section of the eCRF within 1 week of receipt of a CV event 
data query prompting its completion. 
The death eCRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within 1 week 
of when the death is reported. 
9.2.7. 
Pregnancy 
• 
Details of all pregnancies in female participants will be collected after the start of 
study treatment and through the Follow-up Visit. 
• 
If a pregnancy is reported, the investigator should inform GSK/PPD within 24 hours 
of learning of the pregnancy and should follow the procedures outlined in 
Appendix 2. 
• 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
9.3. 
Treatment of Overdose 
There is no specific antidote for overdose with a bacterial topoisomerase inhibitor. In the 
event of a suspected overdose, it is recommended that the appropriate supportive clinical 
care should be instituted, as dictated by the participant’s clinical status. 
Occasional incidents of acute overdosage of nitrofurantoin have not resulted in any 
specific symptoms other than vomiting (refer to locally approved prescribing 
information). Induction of emesis is recommended. There is no specific antidote, but a 
high fluid intake should be maintained to promote urinary excretion of the drug.  
In the event of an overdose, the investigator should 
1. Contact the medical monitor immediately. 
2. Closely monitor the participant for AEs/SAEs and laboratory abnormalities until 
study treatment can no longer be detected systemically (at least 72 hours). 
3. Obtain a plasma sample for PK analysis within 24 hours from the date of the last 
dose of study treatment if requested by the medical monitor (determined on a 
case-by-case basis). 
4. Document the quantity of the excess dose as well as the duration of the overdosing in 
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Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the medical monitor based on the clinical evaluation of the 
participant. 
9.4. 
Safety Assessments 
Planned time points for all safety assessments are provided in Table 1. 
9.4.1. 
Physical Examinations 
• 
A physical examination will be performed at the time points indicated in the 
SoA (Section 2).  
• 
At Baseline, the examination will include assessments of the respiratory, CV, 
abdominal, gastrointestinal, neurological, and urogenital systems. Height and 
weight will only be measured and recorded at the Baseline Visit (before 
dosing). 
• 
At the TOC Visit, the physical examination may be symptom directed and is 
only required if indicated for a specific participant.  
• 
Investigators should pay special attention to clinical signs related to previous 
serious illnesses. 
• 
Clinically significant changes from baseline or clinically significant new clinical 
signs will be reported as AEs. 
9.4.2. 
Vital Signs 
• 
Vital signs will be measured at the time points indicated in Table 1. 
• 
Vital signs will be measured in a semi-supine position after 5 minutes rest and 
will include temperature, systolic and diastolic blood pressure, and pulse rate. 
• 
Vital sign measurements should be obtained before any blood draws scheduled 
on the same assessment day. 
• 
Clinically significant changes from baseline will be reported as AEs. 
9.4.3. 
Electrocardiograms 
• 
Triplicate 12-lead ECGs (over an approximate 5- to 10-minute period) will be 
performed at the Baseline Visit using an ECG machine that automatically 
calculates the heart rate and measures PR, QRS, QT, and QTc intervals. Refer to 
Section 8.1.2 for QTc withdrawal criteria and additional QTc readings that may 
be necessary. 
• 
This protocol only requires an ECG evaluation at the Baseline Visit. Ideally, 
ECGs will be obtained before any vital sign measurements or blood draws 
scheduled on the same assessment day; however, sites may perform procedures 
in an order per their standard of care, as long as participants return to a resting 
state prior to the start of the ECG collections. Subsequent ECGs only need to be 
triplicate if the initial one is prolonged. 


T M F -1 3 8 1 7 5 4 3  
C O N FI D E N TI A L  
 
 
 
2 0 4 9 8 9  
 
7 3  
 
•  
If cli nicall y si g nifica nt c ha n ges occ ur d uri n g t he st u d y , t he y will be re p orte d as 
A Es.  
9. 4. 4.  
Cli ni c al S af et y L a b or at or y A s s e s s m e nt s  
•  
Refer t o A p pe n di x  1 1  f or t he list of cli nical la b orat or y tests t o be perf or m e d a n d 
t o Ta ble  1  f or t he ti mi n g a n d fre q u e nc y.  
•  
T he i n vesti gat or m ust re vie w t he la b orat or y re p ort, d oc u me nt t his re vie w, a n d 
rec or d a n y cli nicall y rele va nt c ha n ges o cc urri n g d uri n g t he st u d y i n t he A E 
secti o n of t he eC R F. T h e la b orat or y re p orts m ust be file d wit h t he s o urce 
d oc u me nts. Cli nicall y si g nif ica nt a b n or mal la b orat or y fi n di n gs are t h ose w hic h 
are n ot ass oci ate d wit h t he u n derl yi n g disease, u nl ess j u d ge d b y t h e i n vesti gat or 
t o be m ore se vere t ha n e x pecte d f or t he partici p a nt’s c o n diti o n. 
•  
All la b orat or y tests wit h val ues c o nsi dere d cli nicall y si g nifi ca ntl y a b n or mal 
d uri n g partici pati o n i n t he st u d y s h o ul d be re peate d u ntil t he val ues ret ur n t o 
n or mal or baseli ne or are n o l o n ger c o nsi dere d si g nifica ntl y a b n or mal b y t h e 
i n vesti gat or or m e dical m o nit or.  
•  
If s uc h val ues d o n ot ret ur n t o n or mal/ baseline wit hi n a peri o d of ti me j u d ge d 
reas o na bl e b y t he i n vesti gat or, t h e eti ol o g y s h o ul d be i de ntifie d a n d t he s p o ns or 
n otifie d.  
•  
All pr ot oc ol -re q uir e d la b orat or y assess me nts, as defi ne d i n A p pe n di x  1 1 , m ust 
be c o n d ucte d i n acc or da n ce wit h t he la b orat or y ma n ual a n d Ta ble  1 .  
9. 5.  
P h ar m a c o ki n eti c s  
•  
Bl o o d a n d uri ne s a m ples f or P K a nal ysis of ge p oti daci n will be c ollecte d at t he 
ti me p oi nt i n dicate d i n Ta ble  1 , wit h c ollecti o n o pti o ns descri be d i n Secti o n 9 . 
T he act ual d ate a n d ti me of  t he sa m ple c ollecti o n will be rec or de d. T he v ol u me 
of bl o o d re q uire d f or t he P K sa m pl e is a p pr o xi matel y 3  m L.  
•  
At t he  O n -t hera p y Visit, as t he uri ne P K c ollecti o n c oi nci des wit h t he uri n e 
bacteri ol o g y sa m ple c ollecti o n, a si n gl e uri ne sa m ple of a de q u ate v ol u me ma y 
be c ollecte d a n d s plit i nt o se parat e sa m ples f or P K a n d micr o bi ol o g i cal 
p ur p oses.  N ote :  T h e dat e a n d ti me of t he last d os e ta ke n bef ore t h e P K 
c ollecti o n will be rec or de d.  
•  
Pr ocessi n g, st or a ge, a n d s hi p pi n g pr oce d ures f or bl o o d a n d uri ne sa m ples are 
pr o vi de d i n t he S R M  a n d/ or la b orat or y ma n ual.  
9. 7.  
G e n eti c s  
A 6 -m L bl o o d s a m ple f or D N A is olati o n will be c ollecte d fr o m partici pa nts w h o ha ve 
c o nse nte d t o partici p ate i n t he ge netics a n al ysis c o m p o ne nt of t he st u d y. Partici pati o n is 
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C O N FI D E N TI A L  
 
 
 
2 0 4 9 8 9  
 
7 4  
 
o pti o nal. Partici pa nts w h o d o n ot wis h t o partici pate i n t he ge netic researc h ma y stil l 
partici pate i n t he st u d y.  
I n t he e ve nt of D N A e xtr acti o n fail ure, a re pl ace m e nt ge netic bl o o d sa m ple ma y b e 
re q ueste d fr o m t he partici pa nt. Si g ne d i nf or me d c o nse nt will be re q uire d t o o btai n a 
re place me nt sa m ple u nless it was i ncl u de d i n t he ori gi nal c o ns e nt. 
Details o n pr ocess es f or c ollecti o n a n d s hi p me nt a n d destr ucti o n of t hes e sa m ples ca n be 
f o u n d i n A p pe n di x  1 2 . 
9. 8.  
Bi o m ar k er s  
Bi o mar kers are n ot e val u ate d i n t his st u d y.  
9. 9.  
H e alt h E c o n o mi c s or  M e di c al R e s o ur c e Utili z ati o n a n d 
H e alt h E c o n o mi c s  
 
 
 
 
1 0.  
S T A TI S TI C A L C O N SI D E R A TI O N S  
F ull details  of all data ha n dli n g c o n ve nti o ns a n d statistical a nal ys es c o n d ucte d f or t his 
st u d y will be pr o vi de d i n t he R A P. 
1 0. 1.  
St ati sti c al H y p ot h e si s  
T he st u d y is desi g ne d t o de m o nstrate t hat ge p oti d aci n a d mi nistere d orall y is n o ni nferi or 
c o m pare d t o nitr of ura nt oi n a d ministere d orall y  o n t he pri mar y efficac y e n d p oi nt of 
t hera pe utic res p o nse (c o m bi ne d per-partici pa nt micr o bi ol o gical a n d cli nical res p o nse) at 
t he T O C Visit i n partici pa nt s wit h a q ualif yi n g b acterial ur o pat h o ge n at Baseli ne  t hat is 
s usce pti ble t o nitr of ura nt oi n. Micr o bi ol o gical s uccess is defi ne d as era dicati o n (i.e., 
re d ucti o n of all q ualif yi n g bacterial ur o pat h o ge n s rec o vere d at Bas eli ne t o < 1 0 3 C F U/ m L 
as o bser ve d o n q u a ntitati ve uri ne c ult ure ) wit h o ut t he partici pa nt rece i vi n g ot her s yst e mic 
a nti micr o bials . Cli nical s uccess is defi n e d as res ol uti o n of si g ns a n d s y m pt o ms of ac ute 
c ystitis prese nt at Bas eli ne (a n d n o ne w si g ns a n d s y m pt o ms) wit h o ut t he partici pa nt 
recei vi n g ot her s yst e mic a nti micr o bials. 
T he f oll o wi n g are n u ll a n d alter nati ve h y p ot hes es f or t he pri mar y a nal ysis of t he 
t hera pe utic s u ccess r ates at t he pres pecifie d n o ni nf eri orit y m ar gi n of -1 0. 0 %:  
H 0: t hera pe utic s uccess r ate of ge p oti daci n 1 5 0 0 m g BI D –  t hera pe utic s u ccess r ate 
of nitr of ura nt oi n  1 0 0 m g BI D  ≤ -1 0. 0 %  
H 1: t hera pe utic s uccess r ate of ge p oti daci n  1 5 0 0 m g BI D  –  t hera pe utic s u ccess r ate 
of nitr of ura nt oi n  1 0 0 m g BI D  > -1 0. 0 %  
 
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The use of a -10% noninferiority margin in the primary efficacy estimand is in 
accordance with current FDA guidance [DHHS, 2019; EMA, 2013]. 
If noninferiority is declared between gepotidacin and nitrofurantoin, superiority will be 
tested with the following null and alternative hypotheses: 
H0: therapeutic success rate of gepotidacin 1500 mg BID – therapeutic success rate 
of nitrofurantoin 100 mg BID ≤0% 
H1: therapeutic success rate of gepotidacin 1500 mg BID – therapeutic success rate 
of nitrofurantoin 100 mg BID >0% 
An IA is planned as described in Section 10.5. The study will utilize a group sequential 
design with 1 IA using Lan-DeMets spending function [Lan, 1983]. The timing of the IA 
is planned to occur when approximately 60% of the maximum planned participants in the 
micro-ITT NTF-S Population (N≈884) have achieved the TOC Visit. The stopping 
boundary for assessing efficacy will use the Pocock stopping rule for efficacy and the 
O’Brien-Flemming stopping rule for futility. At the time of the IA, the IDMC will 
perform an unblinded review to confirm that there are sufficient microbiological data for 
regulatory submission before proceeding to the IA for efficacy and futility. If in any case 
the microbiological data are not sufficient, the IDMC will instead conduct a futility-only 
IA. If futility is not declared, the sample size needed for the final analysis will be 
approximately 768 participants in the micro-ITT NTF-S Population. This will be based 
on the O’Brien-Flemming stopping boundary for futility. Details on the timing and 
design selection process are described in Section 10.5. 
10.2. 
Sample Size Determination 
10.2.1. 
Justification of Sample Size 
Participants will be randomized to gepotidacin and nitrofurantoin in a 1:1 ratio. 
Assuming a 76% therapeutic success rate for both nitrofurantoin and gepotidacin, a 
sample size of approximately 884 participants in the micro-ITT NTF-S Population is 
required, for a design with 1 IA allowing for stopping the study based on efficacy or 
futility, to provide approximately 90% power to demonstrate noninferiority in the 
therapeutic response rate of gepotidacin to nitrofurantoin with a 0.025 one-sided alpha 
level and a -10.0% noninferiority margin. The minimal response rate difference that 
would meet the statistical criterion for noninferiority is provided in Table 13. 
Table 13 
Minimal Response Rate Difference for Efficacy and Futility Interim 
Analysis 
Design 
Information 
Fraction 
Micro-ITT NTF-S 
Sample Size 
Minimal Response Rate 
Difference for Noninferiority 
Interim Analysis for Efficacy and Futility 
60% 
530 
-2.2% 
100% 
884 
-3.6% 
Micro-ITT NTF-S=Microbiological Intent-to-Treat Nitrofurantoin-Susceptible. 
In case a futility-only IA is conducted, under the same assumption for response rate, 
significance level, and noninferiority margin, a sample size of 768 participants in the 


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micro-ITT NTF-S Population will provide approximately 88% power to demonstrate 
noninferiority. The minimal response rate difference that would meet the statistical 
criterion for noninferiority is -4.0% for the final analysis. 
The study is planned to enroll approximately 2500 participants to ensure a sufficient 
number of participants in the primary analysis population (i.e., micro-ITT NTF-S 
Population). If the study proceeds to an efficacy and futility IA, the maximum target 
sample size (assuming there is a decision to continue the study at the IA) for the primary 
analysis population will be around 884 participants. If the study proceeds to the 
futility-only IA, the maximum target sample size (assuming a decision to continue the 
study at the IA) for the primary analysis population will be approximately 
768 participants. The final number of randomized participants may vary based on the 
evaluability rate and review of qualifying uropathogens by an unblinded SDAC.  
Note: “Enrolled” means that a participant’s or their legally acceptable representative’s 
agreement to participate in the clinical study following completion of the informed 
consent process. Potential participants who are screened for the purpose of determining 
eligibility for the study, but do not participate in the study, are not considered enrolled, 
unless otherwise specified in the protocol.  
10.2.2. 
Sample Size Sensitivity 
Sensitivity of the sample size has been explored considering various therapeutic success 
rates. Table 14 and Table 15 show the minimum power under various assumptions of 
“true” therapeutic success rates of gepotidacin and nitrofurantoin under 2 different IA 
designs, when the IA is conducted at approximately 60% information fraction of the 
design allowing for efficacy and futility stop at the IA. For all of these cases, the 1-sided 
type I error is 2.5%, the noninferiority margin is -10%. 
Table 14 
Power of the Study Under Various Assumptions of the True 
Therapeutic Success Rates for Efficacy and Futility Group 
Sequential Design 
Therapeutic 
Success Rate of 
Nitrofurantoin 
Therapeutic 
Success Rate 
of Gepotidacin 
Total Number of 
Participants in 
the Primary 
Analysis 
Number of 
Participants in the 
Primary Analysis in 
the Interim Analysis 
Power 
76% 
76% 
884 
530 
90% 
72% 
72% 
884 
530 
87% 
68% 
68% 
884 
530 
84% 
64% 
64% 
884 
530 
81% 
60% 
60% 
884 
530 
79% 
 


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Table 15 
Power of the Study Under Various Assumptions of the True 
Therapeutic Success Rates for Futility Only Group Sequential 
Design 
Therapeutic 
Success Rate of 
Nitrofurantoin 
Therapeutic 
Success Rate of 
Gepotidacin 
Total Number of 
Participants in 
the Primary 
Analysis 
Number of 
Participants in the 
Primary Analysis in 
the Interim Analysis 
Power 
76% 
76% 
768 
530 
88% 
72% 
72% 
768 
530 
85% 
68% 
68% 
768 
530 
81% 
64% 
64% 
768 
530 
79% 
60% 
60% 
768 
530 
77% 
 
10.3. 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Intent-to-Treat (ITT) 
Population 
All participants randomly assigned to study treatment. Participants 
will be analyzed according to their randomized study treatment. 
Microbiological ITT 
(micro-ITT) Population 
All participants randomly assigned to study treatment who receive 
at least 1 dose of study treatment and have a qualifying baseline 
uropathogen (defined in Appendix 4), from a quantitative 
bacteriological culture of a pretreatment clean-catch midstream 
urine specimen. Participants will be analyzed according to their 
randomized study treatment. 
Micro-ITT NTF-S 
Population 
All participants in the micro-ITT Population whose baseline 
qualifying bacterial uropathogens all are susceptible to 
nitrofurantoin (NTF-S). Participants with missing MIC susceptibility 
results for any qualifying uropathogens will not be included in the 
NTF-S subpopulation. Participants will be analyzed according to 
their randomized study treatment. 
This is the primary analysis population. 


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Population 
Description 
Micro-ITT NTF-NS 
Population 
All participants in the micro-ITT Population who have any 
qualifying baseline bacterial uropathogens that are not susceptible 
to nitrofurantoin (NTF-NS), defined as resistant to nitrofurantoin, 
intermediate to nitrofurantoin, or have no interpretation to 
nitrofurantoin. Participants with missing MIC susceptibility results 
for all qualifying uropathogens will not be included in the NTF-NS 
subpopulation. Participants will be analyzed according to their 
randomized study treatment. 
Microbiologically Evaluable 
(ME) Population 
Participants who meet the definition of the micro-ITT Population, 
follow important components of the study (as specified in the 
RAP) and have an interpretable quantitative urine culture at the 
specified visit. Note: Visit-specific ME populations will be defined 
in the RAP. 
ME NTF-S Population 
All participants in the ME visit-specific population whose baseline 
qualifying bacterial uropathogens all are susceptible to 
nitrofurantoin (NTF-S). Note: Visit-specific ME NTF-S populations 
will be defined in the RAP. 
ME NTF-NS Population 
All participants in the ME visit-specific population who have any 
baseline qualifying bacterial uropathogens that are not susceptible 
to nitrofurantoin (NTF-NS). Note: Visit-specific ME NTF-NS 
populations will be defined in the RAP. 
Clinically Evaluable (CE) 
Population 
All participants in the ITT Population who follow important 
components of the study as specified in the RAP. Note: 
Visit-specific CE populations will be defined in the RAP. 
Pharmacokinetic (PK) 
Population 
All randomized participants who receive at least 1 dose of study 
treatment and have at least 1 nonmissing plasma or urine PK 
concentration.  
Safety Population 
All randomized participants who receive at least 1 dose of study 
treatment. Participants will be analyzed according to their actual 
treatment received. 
 
10.4. 
Statistical Analyses 
The RAP will be finalized prior to unblinding and will include a more technical and 
detailed description of the statistical analyses described in this section. This section is a 
summary of the planned statistical analyses of the most important endpoints including 
primary, secondary, and exploratory endpoints. 


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10.4.1. 
General Considerations 
Treatment effect to be estimated for primary and secondary estimands are clinical 
outcome/response, microbiological outcome/response, and therapeutic response at the 
designated visits in female participants with acute cystitis (clinical outcome/response) 
and female participants with acute cystitis with qualifying bacterial uropathogen(s) at 
Baseline that all are susceptible to nitrofurantoin (clinical outcome/response, 
microbiological outcome/response, and therapeutic response). Intercurrent events include 
receiving other systemic antimicrobials and treatment discontinuation; a combination of 
composite strategy and treatment policy strategy will be implemented to account for the 
2 ICEs, respectively. The ICE event strategies determine that (1) treatment effects will be 
estimated regardless of study treatment discontinuation when the analysis population is 
the ITT Population or its derivatives; and (2) the definition of a successful response or a 
positive outcome (clinical resolution and microbiological eradication) precludes the use 
of other systemic antimicrobials. 
Any supplemental analyses will be detailed in the RAP. Any additional analyses or 
outputs needed as a result of COVID-19 on the study will be detailed in the RAP. 
10.4.2. 
Efficacy Analyses 
Endpoint 
Statistical Analysis Methods 
Primary 
The primary analysis of the primary efficacy endpoint will be performed using the 
micro-ITT NTF-S Population.  
• The primary treatment effect to be estimated (estimand) is therapeutic 
response (combined per-participant microbiological and clinical response) at 
the TOC Visit in female participants with acute cystitis with a qualifying 
bacterial uropathogen(s) at Baseline that all are susceptible to nitrofurantoin. 
Microbiological success at the TOC Visit is defined as reduction of all 
qualifying bacterial uropathogens recovered at Baseline to <103 CFU/mL as 
observed on quantitative urine culture without the participant receiving other 
systemic antimicrobials; clinical success is defined as resolution of signs and 
symptoms of acute cystitis present at Baseline (and no new signs and 
symptoms) without the participant receiving other systemic antimicrobials. 
Therapeutic success refers to participants who have been deemed both a 
microbiological success and a clinical success (i.e., responders). The primary 
treatment effect will be estimated regardless of treatment discontinuation, as 
per the treatment policy strategy. The ICE of use of other systemic 
antimicrobial therapy is captured through the definitions of microbiological 
and clinical response and will be counted as failures (composite strategy). If a 
participant experiences both ICEs of study treatment discontinuation and use 
of systemic antimicrobials, then a composite strategy (assigning therapeutic 
response as a failure) will be used from the point that the relevant systemic 
antimicrobial was taken. Further details on the primary estimand are provided 
in Section 4. 


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Endpoint 
Statistical Analysis Methods 
• The population-level effect will be estimated by the difference in percentage 
response and its 95% CI. For this analysis, participants who do not return for 
the TOC Visit or have missing data at the TOC Visit will be treated as failures. 
• The number and percentage of participants with therapeutic success will be 
summarized, along with the 95% CI, at the TOC Visit by treatment group. 
• The testing procedure at the IA and the final analysis involves comparing the 
noninferiority test statistics with the stopping boundary. Test statistics of the 
therapeutic success rate difference between the 2 treatment groups for 
noninferiority (-10% margin) will be calculated using the Miettinen and 
Nurminen method stratified by age category (<18 years, ≥18 to 50 years, or 
>50 years) and acute cystitis recurrence (nonrecurrent infection or recurrent 
infection) [Miettinen, 1985] and compared to the stopping boundaries. If 
noninferiority is established, test statistics of the success rate difference 
between the 2 treatment groups for superiority will be calculated using the 
same method to compare with the stopping boundary for superiority. Details 
on the testing procedure and stopping boundaries are provided in the IDMC 
analysis plan.  
• In the event that a participant is mis-stratified at randomization, the actual 
stratum will be used instead of the randomized stratum in the primary 
analysis. 
• Sensitivity analysis on the primary endpoint will be done with details provided 
in the RAP. In addition, a tipping point analysis may be performed for the 
primary estimand, if warranted by the degree of missing data. 
• Subgroup analysis and supplemental analysis on additional populations for 
the primary endpoint may be performed with details provided in the RAP. 
• Handling of protocol deviations will be described in the RAP. 


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Endpoint 
Statistical Analysis Methods 
Secondary 
Secondary efficacy endpoints for clinical outcome and response will be 
summarized using the ITT Population and micro-ITT NTF-S Population. 
Secondary efficacy endpoints for microbiological outcome and response, as well 
as therapeutic response (combined per-participant microbiological and clinical 
response), will be summarized using the micro-ITT NTF-S Population. 
• There will be no multiplicity adjustment for the testing of the secondary 
endpoints. No formal hypothesis testing will be performed. 
• The clinical outcome and response (number and percentage of participants 
with resolution of signs and symptoms) will be summarized by treatment 
group at the TOC and Follow-up Visits. The ICE of use of other systemic 
antimicrobials is captured through the defining criteria of clinical outcome and 
response (Section 9.1.3.1). 
• The microbiological outcome and response (number and percentage of 
participants with microbiological success) will be summarized by treatment 
group at the TOC and Follow-up Visits. The ICE of use of other systemic 
antimicrobials is captured through the defining criteria of microbiological 
outcome and response (Section 4). 
• Therapeutic response (combined per-participant microbiological and clinical 
response) will be summarized by treatment group at the Follow-up Visit. 
• Sensitivity analysis on the secondary endpoints, if warranted, will be 
described in the RAP. 
• Subgroup analysis by qualifying baseline uropathogen will be done for 
microbiological outcome and response at relevant visits. Additional subgroup 
analyses and supplemental analysis on additional populations may be carried 
out. Details of these analyses will be provided in the RAP. 


T M F -1 3 8 1 7 5 4 3  
C O N FI D E N TI A L  
 
 
 
2 0 4 9 8 9  
 
8 2  
 
E n d p oi nt  
St ati st i c al A n al ysi s M et h o d s 
 
1 0. 4. 3.  
S af et y A n al y s e s  
All safet y a nal yses will be perf or me d o n t he Safet y P o p ulati o n. T he se v erit y of A Es a n d 
S A Es will be deter mi ne d b y t he i n vesti gat or acc or di n g t o t he U S Nati o nal I nstit ute of 
Aller g y a n d I nfecti o us Diseas es Di visi o n of Micr o bi ol o g y a n d I nfecti o us Diseases 
( D MI D) criteria f or a d ult t o xicit y assess me nt [ D MI D , 2 0 0 7a], wit h t he e x ce pti o n of 
ser u m creati ni ne a d oles ce nt la b orat or y d ata, w hic h will be assesse d usi n g pe diatric 
t o xicit y criteri a [D MI D , 2 0 0 7 b] (A p pe n di x  1 3 ). All re p orte d A Es will be c o de d usi n g 
Me d D R A a n d s u m mariz e d b y s yste m or ga n class a n d preferre d ter ms.  
E n d p oi nt  
St ati sti c al A n al ysi s M et h o d s  
S ec o nd ary  
•  T h e s afety e n dp oi nt will us e a tr e at m e nt p olicy str ate gy f or t h e I C E of 
wit h dr a w al fr o m tr eat m e nt, as s afety will b e ass ess ed at all p ost b aseli n e 
ass ess m e nts irres p ectiv e of w h et h er t he p articip a nt c o m pl et e d t h e tr e at me nt.  
•  T h e nu m b er an d p erc ent a ge of  tr e at m ent-e m er ge nt A Es, st u dy 
tr e at m e nt-r el at e d A Es, d eaths, S A Es, an d A Es l ea di ng t o st u dy tr eat m e nt or 
st u dy wit hdr a w al will b e pr ovi d e d . 
•  Tr e at m e nt -e m erg e nt A Es will b e s u m m ariz e d by s everity.  
C CI


T M F -1 3 8 1 7 5 4 3  
C O N FI D E N TI A L  
 
 
 
2 0 4 9 8 9  
 
8 3  
 
•  C h a n ge fr o m b as eli ne over ti m e i n l a bor at ory p ar a m eters  a n d vital si g ns w ill 
b e s u m m ariz e d wit h d escriptiv e st atistics.  
•  T h e fr eq u ency of l a bor at ory a b nor m ality ev ents alo n g wit h t he s hift fr o m 
b as eli ne t o t h e w orst -c as e post b aseli n e val u e will be provi d e d.  A bn or mal liv er 
c h e mistry r es ults will b e d eter mi n e d usi ng i ncr eases a bov e th e u p per li mit of 
n or mal.  C h a n ge fr o m bas elin e v alu es will b e su m m ariz e d wit h  d escriptiv e 
st atistics. 
•  T h e s everity of sp ecifi ed A Es a n d l a bor at ory ab nor maliti es will b e gr ad ed 
acc or di n g t o t h e m o difi ed D MI D t oxicity gr a di ng syste m  (A p p en dix  1 3 ). D ata  
will b e t a bul at ed a n d re p orte d by a bsol ut e gr ad e for Gr a d e s 3 a n d hi g h er a nd  
s hift t a bl es, as a p pr o priat e. 
•  A dv ers e ev e nts of s p ecial i nt er est will i ncl u de C V , g astroi nt estin al , an d C. 
difficil e i nf ectio n or c olitis eve nts. I n a d diti on, A Es associ at e d with 
ac etylc h oli nest eras e i nhi bitio n ar e als o co nsi der e d sp eci al i nt er est. As 
d escri b e d i n th e R A P, m a nual a nd pr ogr a m matic r evi e ws of A Es/ pr eferre d 
t er ms will b e us ed t o ass ess t h ese ev ents.  
•  B as eli n e E C G r esults will b e  pr ovi de d i n a listi n g.  
 
1 0. 4. 4.  
P K a n d P K/ P D  A n al y s e s  
Plas ma a n d uri ne c o n ce ntrati o ns f or t he P K P o p ulati o n will be s u m marize d usi n g 
descri pti ve statistics.  I n a d diti o n, ge p oti daci n plas ma c o nce ntr ati o ns will be a nal yz e d 
usi n g a p o p ulati o n a p pr oac h t o all o w f or t h e esti mati o n of ge p oti daci n e x p os ure i n eac h 
partici pa nt. A n o nli near mi x e d effects m o del will be use d t o deter mi ne p o p ulati o n P K 
para meters a n d t o i de ntif y rele va nt c o variates (e. g., a ge, wei g ht, or race). F or t his 
a nal ysis, a p pr oac hes s uc h as p o oli n g t he ver y s parse ge p oti daci n plas ma c o nce ntrati o n 
data o btai ne d fr o m t his st u d y wit h ric h d ata o btai n e d fr o m a d ult healt h y p artici pa nt 
P hase  I e val u ati ons (e. g., St u d y  B T Z 1 1 6 7 7 8) a n d a P hase IIa P K e val u ati o n i n 
partici pa nts wit h u nc o m plicate d U TI ( St u d y  2 0 6 8 9 9) ma y be necessar y . 
1 0. 5.  
I nt eri m A n al y si s 
O ne I A is pla n ne d  t o assess eit her b ot h efficac y a n d f utilit y or j ust f utilit y b y t he I D M C. 
T he I D M C will meet w h e n a p pr o xi matel y 6 0 % of partici pa nts i n t he micr o -I T T N T F-S 
P o p ulati o n ha ve ac hie v e d t he T O C Visit  t o e val uate t he pri mar y e n d p oi nt, i de ntif y 
p ote ntial treat me n t be nefit, a n d ma ke rec o m me n d ati o ns f or c o nti n ui n g or st o p pi n g t he 
st u d y, as per t he I D M C c harter. T h e I D M C me m b ers will i ncl u de at least 3 i n de pe n de nt 
e x perts, i ncl u di n g a n i nfecti o us disease s peci alist, a c hair p ers o n wit h e x peri e nce c hairi n g 
I D M C meeti n gs, a n d a st atisticia n. Details re gar di n g t he I D M C pr ocess will be descri be d 
i n t he I D M C c harter. 
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The SDAC will conduct and provide all unblinded analyses to the IDMC before the 
meeting is held. Details on the content and structure of the data output will be described 
in a separate IDMC analysis plan. The GSK and PPD study teams that are operating the 
study and conducting the final analysis will remain blinded. The IDMC and SDAC will 
maintain unblinded data in a secure area to ensure the integrity of the data until the study 
is completed. Details on protecting blind and data integrity will be described in a blinding 
plan.  
At the time the IA is conducted, the IDMC will review unblinded data to confirm that 
sufficient microbiological data exist for the unblinded gepotidacin treatment arm before 
deciding how to proceed. 
If the IDMC confirms there is sufficient microbiology data in the gepotidacin arm, an IA 
with stopping rules for both efficacy and futility will be performed. The nominal 
significance levels for the interim and final analyses will be determined by the 
Lan-DeMets spending functions approach [Lan, 1983]. This will be based on the Pocock 
stopping boundary for efficacy and the O’Brien-Flemming stopping boundary for futility. 
The futility bounds of this study are nonbinding and are considered guidance rather than 
strict bounds.  
During the course of the IA, the accrual of the study will continue. If efficacy success 
(i.e., noninferiority) is reached at the IA and the study is stopped early, the IA will be the 
primary analysis and data collected between the IA data cut and the time when the study 
is stopped will be considered overrun. Overrun data will be pooled with the IA data to 
repeat the primary efficacy analysis as sensitivity analysis. If efficacy success is not 
reached at the IA, the study will continue to the maximum target sample size for the 
micro-ITT NTF-S Population of approximately 884 participants. 
If, at the IA, the IDMC confirms that there is not sufficient microbiology data in the 
gepotidacin arm, then a futility-only IA will be conducted. The nominal significance 
levels for the interim and final analyses will be determined by the Lan-DeMets spending 
functions approach [Lan, 1983]. This will be based on the O’Brien-Flemming stopping 
boundary for futility. The futility bounds of this study are nonbinding and are considered 
guidance rather than strict bounds. The stopping boundaries will be calculated under the 
assumption of an approximate maximum sample size of 768 participants in the micro-ITT 
NTF-S Population.  
Details on timing, microbiological data criteria, design selection, and stopping boundaries 
for the IA are described in the IDMC charter. 
A GSK SRT will review the blinded safety data of this study at regular intervals. Details 
regarding the SRT process will be available in relevant SRT documents. The SRT will 
inform the IDMC if any safety signals are identified. 
10.6. 
Data Monitoring Committee or Other Review Board 
This study will have an IDMC as described in Section 10.5. In addition, there will be a 
GSK SRT and Microbiology Review Team. For details on these review teams, refer to 
Appendix 3. 


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-lactamase-producing enterobacteriaceae in community-acquired urinary tract infections 
in Sãn Luís, Brazil. Braz J Microbiol. 2013;44(2):469-7. 
Centers for Disease Control and Prevention (CDC). Antibiotic resistance threats in the 
United States, 2019. https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-
threats-report-508.pdf. Accessed 20-Mar-2021. 
European Association of Urology (EAU). EAU guidelines on urological infections. 
https://uroweb.org/guideline/urological-infections/?type=pocket-guidelines. Accessed 
12-Jun-2017. 
European Medicines Agency (EMA). Addendum to the guideline on the evaluation of 
medicinal products indicated for treatment of bacterial infections. CPMP/EWP/558/95 
rev 2. 24-Oct-2013. 
Fihn SD. Clinical practice. Acute uncomplicated urinary tract infection in women. 
N Engl J Med. 2003;349(3):259-66. 
Flamm RK, Sader HS, Farell DJ, Jones RN. Ceftazidime-avibactam and comparator 
agents tested against urinary tract isolates from a global surveillance program (2011). 
Diagn Microbiol Infect Dis. 2014;80(3):233-8. 
Foxman B, Barlow R, D’Arcy H, et al. Urinary tract infection: self-reported incidence 
and associated costs. Ann Epidemiol. 2000;10(8):509-15. 
Foxman B. Epidemiology of urinary tract infections: incidence, morbidity, and economic 
costs. Am J Med. 2002;113(Suppl 1A):5S-13S. 
Foxman B. The epidemiology of urinary tract infection. Nat Rev Urol. 
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Gupta K, Hooton TM, Miller L; Uncomplicated UTI IDSA Guideline Committee. 
Managing uncomplicated urinary tract infection⎯making sense out of resistance data. 
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Gupta K, Hooton TM, Naber KG, Wullt B, Colgan R, Miller LG, 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. 
2011b;52(5):e103-20. 
Gupta K, Hooton TM, Roberts PL, Stamm WE. Short-course nitrofurantoin for the 
treatment of acute uncomplicated cystitis in women. Arch Intern Med. 
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Ho PL, Poon WW, Loke SL, Leung MS, Chow KH, Wong RC, et al; COMBAT study 
group. Community emergence of CTX-M type extended-spectrum -lactamases among 
urinary Escherichia coli from women. J Antimicrob Chemother. 2007;60(1):140-4. 
Hooton TM. Clinical practice. Uncomplicated urinary tract infection. N Engl J Med. 
2012;366(11):1028-37. 
Johnson JR, Nicolas-Chanoine MH, DebRoy C, Castanheira M, Robicsek A, Hansen G, 
et al. Comparison of Escherichia coli ST131 pulsotypes, by epidemiologic traits, 
1967-2009. Emerg Infect Dis. 2012;18(4):598-607. 
Lan KK, DeMets D. Discrete sequential boundaries for clinical trials. Biometrika. 1983; 
70:659-63. 
Lob SH, Nicolle LE. Hoban DJ, Kazmierczak KM, Badal RE, Sahm DF. Susceptibility 
patterns and ESBL rates of Escherichia coli from urinary tract infections in Canada and 
the United States, SMART 2010-2014. Diagn Microbiol Infect Dis. 2016;85(4):459-65. 
Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med. 1985;4(2):213-
26. 
National Institute for Health Care Excellence (NICE). Public Health England. Summary 
of antimicrobial prescribing guidance – managing common infections. Feb 2019. 
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guidance/antimicrobial%20guidance/summary-antimicrobial-prescribing-
guidance.pdf?UNLID=3157626232019111861. Accessed 14-Feb-2019. 
Nicolas-Chanoine MH, Bertrand X, Madec JY. Escherichia coli ST131, an intriguing 
clonal group. Clin Microbiol Rev. 2014;27(3):543-74. 
Oteo J, Bautista V, Lara N, Cuevas O, Arroyo M, Fernández S, et al; Spanish 
ESBL-EARS-Net Study Group. Parallel increase in community use of fosfomycin and 
resistance to fosfomycin in extended-spectrum beta-lactamase (ESBL)-producing 
Escherichia coli. J Antimicrob Chemother. 2010;65(11):2459-63. 
Peirano G, Richardson D, Nigrin J, McGreer A, Loo V, Toye B, et al. High prevalence of 
ST131 isolates producing CTX-M-15 and CTX-M-14 among extended-spectrum-beta-
lactamase-producing Escherichia coli isolates from Canada. Antimicrob Agents 
Chemother. 2010;54(3):1327-30.  
Sanchez GV, Babiker A, Master RN, Luu T, Mathur A, Bordon J. Antibiotic resistance 
among urinary isolates from female outpatients in the United States in 2003 and 2012. 
Antimicrob Agents Chemother. 2016;60(5):2680-3. 
Sanchez GV, Master RN, Karlowsky JA, Bordon JM. In vitro antimicrobial resistance of 
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C O N FI D E N TI A L  
 
 
 
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8 7  
 
Sc hit o G C, Na ber K G, B ott o H, Pal o u J, Mazzei T, G ualc o L,  et al. T he A R E S C st u d y: 
a n i nter nati o nal s ur ve y o n t he a nti micr o bial resista nce of pat h o ge ns i n v ol v e d i n 
u nc o m plicate d uri nar y tr act i nfecti o ns. I nt J A nti micr o b A ge nts. 2 0 0 9; 3 4 ( 5): 4 0 7-1 3.  
Sta m m W E, H o ot o n T M. Ma na ge me nt of uri nar y tract i nfecti o ns i n a d u lts. N E n gl J 
Me d. 1 9 9 3; 3 2 9 ( 1 8): 1 3 2 8-3 4.  
Tala n D A, Sta m m W E, H o ot o n T M, M ora n GJ, B ur ke T, Ira v a ni A, et al. C o m paris o n of 
ci pr ofl o x aci n ( 7 da ys) a n d tri met h o pri m -s ulfa met h o x az ole ( 1 4 da ys) f or ac ute 
u nc o m plicate d p yel o ne p hritis i n w o me n: a ra n d o mize d tria l. J A M A. 
2 0 0 0; 2 8 3 ( 1 2): 1 5 8 3-9 0.  
U S De part me nt of Healt h a n d H u ma n Ser vices, D H H S, F o o d a n d Dr u g A d mi nistrati o n, 
Ce nter f or Dr u g E val uati o n a n d Researc h, Cli nical/ A nti micr o bial. G ui da nce f or i n d ustr y. 
U nc o m plicate d uri nar y tr act i nfecti o ns : de v el o pi n g dr u gs f or treat me nt. 
htt ps:// w w w.f da. g o v/ me dia/ 1 2 9 5 3 1/ d o w nl oa d . Last u p date d A u g ust 2 0 1 9.Accesse d 
0 9 -A pr -2 0 2 1 . 
U S De part me nt of Healt h a n d H u ma n Ser vices, D H H S, F o o d a n d Dr u g A d mi nistrati o n, 
Ce nter f or Dr u g E val uati o n a n d Researc h, Cli nical/ A nti micr o bial. G ui da n ce f or i n d ustr y. 
C o m plicate d uri nar y tract i nfecti o ns: de vel o pi n g dr u gs f or treat me nt. 
htt ps:// w w w.f da. g o v/ me dia/ 7 1 3 1 3/ d o w nl oa d . Last u p date d J u ne 2 0 1 8. Accesse d 
0 9 -A pr -2 0 2 1 . 
U S Nati o nal I nstit ute f or Aller g y a n d I nfecti o us Disease s, Di visi o n of Micr o bi ol o g y a n d 
I nfecti o us Dise ases. Di visi o n of Micr o bi ol o g y a n d I nfecti o us Diseases ( D MI D) A d ult 
T o xicit y Ta bl e. Draft. htt ps:// w w w. niai d. ni h. g o v/sites/ defa ult/files/ d mi da d ultt o x. p df. 
Last u p d ate d N o ve m b er 2 0 0 7 a. Accesse d 1 0-M ar -2 0 1 7.  
U S Nati o nal I nstit ute f or Al ler g y a n d I nfecti o us Disease Di visi o n of Micr o bi ol o g y a n d 
I nfecti o us Dise ase. Di visi o n of Micr o bi ol o g y a n d I nfecti o us Disease ( D MI D) Pe diatric 
T o xicit y Ta bl e. Draft. htt ps:// w w w. niai d. ni h. g o v/sites/ defa ult/files/ d mi d pe dt o x. p df. Last 
u p date d N o ve m ber 2 0 0 7 b . Access e d 1 0 -Mar -2 0 1 7.  
 
 
 
 
W orl d Healt h Or ga niz ati o n ( W H O). A nti micr o bial resista nce gl o bal re p ort o n 
s ur veilla nce, 2 0 1 4. 
htt p://a p ps. w h o.i nt/iris/ bitstrea m/ 1 0 6 6 5/ 1 1 2 6 4 2/ 1/ 9 7 8 9 2 4 1 5 6 4 7 4 8 _e n g. p df. Access e d 
2 9 -Mar -2 0 1 7.  
W orl d Healt h Or ga niz ati o n ( W H O ). Gl o bal pri orit y list of a nti bi otic-resista nt bacteri a t o 
g ui de researc h, disc o v er y, a n d de vel o p me nt of n e w a nti bi otics. 2 0 1 7. 
htt p:// w w w. w h o.i nt/ me dici nes/ p u blicati o ns/ W H O -P P L -S h ort _ S u m mar y _ 2 5 Fe b -
E T _ N M _ W H O. p df? ua = 1. Access e d 1 2 -A pr -2 0 1 7.  
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APPENDICES 
12.1. 
Appendix 1: Clostridium Difficile Testing Procedure and 
Algorithm 
 
CRA = clinical research associate (PPD site monitor); SRM = Study Reference Manual 
Note:  This algorithm is subject to investigator discretion when the clinical 
presentation and time course of diarrhea (e.g., during or within 12 hours immediately 
after dosing) do not fit the Clostridium difficile-associated diarrhea definition; 
consideration should be given to diarrhea occurring in this early time frame to be 
suggestive of a cholinergic effect. 
 


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12.2. 
Appendix 2: Contraceptive Guidance and Collection of 
Pregnancy Information 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below). 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with ONE of the following: 
• 
Documented hysterectomy 
• 
Documented bilateral salpingectomy 
• 
Documented bilateral oophorectomy 
Note:  Documentation can come from the study site personnel’s: review of 
participant’s medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
• 
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle-stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.  
• 
Females on HRT and whose menopausal status is in doubt will be required to 
use 1 of the nonhormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment. 
Pregnancy Testing 
• 
WOCBP should only be included after a confirmed menstrual period and a negative 
urine pregnancy test. 
• 
Pregnancy testing will be performed at Baseline (Day 1) before study treatment 
administration. The urine pregnancy test at Baseline will determine study 
contraception and abstinence requirements as follows: 
• 
Pregnancy testing at Baseline (Day 1) should be performed using the urine test 
kit provided to the study site (FIRST RESPONSE Early Result Pregnancy Test 
with a high sensitivity of ≤6.3 mIU/mL). Participants with a negative urine 
pregnancy test result from this test kit may be included in the study with no 
pretreatment contraception or abstinence requirements. Women of childbearing 
protentional are not required to be using contraception or to have practiced 
abstinence within 14 days prior to study entry if the high sensitivity urine 
pregnancy test results are negative at Baseline (Day 1). 


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Note:  ONLY if the study-specific pregnancy kit provided to the study site is 
unavailable, a standard urine pregnancy test with a sensitivity of 25 mIU/mL 
may be used as an exception. A participant with a negative urine pregnancy test 
result from the standard test may be included in the study only if the participant 
has used a highly effective contraception method as described in Table 16 or has 
practiced abstinence from penile/vaginal intercourse for at least 14 days before 
receiving study treatment. 
• 
After Dose 4 and before Dose 8, an additional pregnancy test using the urine test kit 
provided to the study site (FIRST RESPONSE Early Result Pregnancy Test with a 
sensitivity of ≤6.3 mIU/mL) is required to be performed for WOCBP who have not 
used a highly effective contraception method (Table 16) or have not practiced 
abstinence from penile/vaginal intercourse for at least 14 days prior to the first dose 
of study treatment. It is preferable for this pregnancy test to be performed at the 
study site; however, for participants for whom this is not possible, the urine 
pregnancy kit will be provided to the participant to perform as an outpatient during 
the defined window. For any participant with a positive pregnancy test result, study 
treatment must be immediately discontinued. 
• 
A pregnancy test will also be performed at the Test-of-Cure (Day 10 to 13) Visit, 
5 to 8 days after the last dose of study treatment.  
• 
Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected. 
• 
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the subject's participation in the study. 
Contraception Guidance 
Refer to the text directly above regarding pregnancy testing for female participants at 
Baseline (Day 1) and associated pretreatment contraception and abstinence requirements. 
Female participants of childbearing potential who enter the study using contraception 
must continue to do so throughout the study. 
As described in Section 6.3, participants will be requested to abstain from sexual activity 
from the Baseline Visit through the TOC Visit to prevent possible re-infection. 
 


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Table 16 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependenta 
Failure rate of <1% per year when used consistently and correctly.  
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb 
• oral 
• intravaginal  
• transdermal  
Progestogen-only hormonal contraception associated with inhibition of ovulationb 
• injectable  
Highly Effective Methods That Are User Independent  
• implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb 
• intrauterine device (IUD) 
• intrauterine hormone-releasing system (IUS) 
• bilateral tubal occlusion 
Vasectomized partner  
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.)  
Sexual abstinence  
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.)  
WOCBP=woman of childbearing potential. 
a. 
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants in clinical studies.  
b. 
Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of 
the contraceptive method.  
 


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Collection of Pregnancy Information 
Female participants who become pregnant 
• 
Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study.  
• 
Information will be recorded on the appropriate form and submitted to 
GlaxoSmithKline (GSK)/PPD within 24 hours of learning of a participant’s 
pregnancy.  
• 
Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on participant and neonate, which will 
be forwarded to GSK. Generally, follow-up will not be required for longer than 6 to 
8 weeks beyond the estimated delivery date. 
• 
Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.  
• 
While pregnancy itself is not considered to be an adverse event (AE) or serious AE 
(SAE), any pregnancy complication or elective termination of a pregnancy for 
medical reasons will be reported as an AE or SAE.  
• 
A spontaneous abortion is always considered to be an SAE and will be reported as 
such. 
• 
Any SAE occurring as a result of a poststudy pregnancy that is considered 
reasonably related to the study treatment by the investigator will be reported to 
GSK/PPD as described in Appendix 10. While the investigator is not obligated to 
actively seek this information in former study participants, he or she may learn of an 
SAE through spontaneous reporting.  
Any female participant who becomes pregnant while participating will discontinue study 
treatment. 
 


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12.3. 
Appendix 3: Study Governance Considerations 
Regulatory and Ethical Considerations 
• 
This study will be conducted in accordance with the protocol and with: 
• Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines 
• Applicable International Council on Harmonisation (ICH) Good Clinical 
Practice (GCP) Guidelines 
• Applicable laws and regulations 
• 
The protocol, protocol amendments, informed consent form (ICF)/assent 
form/eConsent (if applicable), investigator’s brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an institutional review 
board/independent ethics committee (IRB/IEC) by the investigator and reviewed 
and approved by the IRB/IEC before the study is initiated.*  
• 
Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants.  
• 
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/IEC* 
• Notifying the IRB/IEC of serious adverse events (SAEs) or other 
significant safety findings as required by IRB/IEC procedures* 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, 
the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations 
*Note:  In countries where the responsibility to perform these submissions and 
notifications resides with the sponsor rather than the investigator, GSK or their 
designee PPD (as described in the applicable powers of attorney) will take these 
responsibilities. 
Financial Disclosure 
Investigators and subinvestigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 


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Informed Consent/Assent Process 
• 
The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study.  
• 
Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent and/or eConsent (if applicable) that meets the requirements of 
21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC 
or study site.  
• 
The medical record must include a statement that written informed consent 
and/or eConsent (if applicable) was obtained before the participant was enrolled 
in the study and the date informed consent was obtained. The authorized person 
obtaining the informed consent must also sign the ICF. 
• 
Participants must be re-consented to the most current version of the 
ICF(s)/eConsent during their participation in the study.  
• 
A copy of the ICF(s)/eConsent must be provided to the participant or the 
participant’s legally authorized representative.  
• 
Adolescent participants should be asked for their written assent or eConsent (if 
applicable) to participate in the study. 
• 
As applicable, the IRB/IEC will be consulted before assent form development 
for guidance around age-appropriate groupings and any specific IRB/IEC 
requirements or local laws for conducting and documenting assent. 
Participants who are rescreened are required to sign a new ICF or provide eConsent (if 
applicable). 
 
Data Protection 
• 
Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred.  
• 
The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant.  
• 
The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities. 


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Committees Structure 
To protect the safety interests of participants, a GlaxoSmithKline (GSK) Safety Review 
Team will review blinded safety data instream on a regular basis throughout study 
conduct. Data reviewers will include but are not limited to the following participants: 
medical monitor, safety team lead, statistician, clinical team lead, and data quality lead.  
A Microbiology Review Team will monitor blinded uropathogen identification and 
susceptibility data instream, including the enrollment rate of participants with a 
qualifying bacterial uropathogen at Baseline and the resistance profile of uropathogens.  
Procedures will be described in a separate microbiology sample monitoring plan. 
An Independent Data Monitoring Committee will manage the interim analysis, with 
details provided in a separate charter and analysis plan. 
Written documentation regarding key decisions made by the review teams/committee will 
be promptly distributed to participating investigators and IRB/IECs. 
Publication Policy 
• 
The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.  
• 
The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual study site data. In this case, a coordinating investigator will be 
designated by mutual agreement. 
• 
Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements. 
Dissemination of Clinical Study Data 
• 
Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report. The investigator 
will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a 
GSK site or other mutually agreeable location. 
• 
GSK will also provide the investigator with the full summary of the study 
results. The investigator is encouraged to share the summary results with the 
study participants, as appropriate. 
• 
GSK will provide the investigator with the randomization codes for their site 
only after completion of the full statistical analysis. 


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• 
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK 
policy. 
Data Quality Assurance 
• 
All participant data relating to the study will be recorded on printed case report 
forms (CRFs) or electronic CRFs (eCRFs) unless transmitted to the sponsor or 
designee electronically (e.g., laboratory data). The investigator is responsible for 
verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF.  
• 
The investigator must maintain accurate documentation (source data) that 
supports the information entered in the eCRF.  
• 
The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents.  
• 
The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. Detailed information about study data 
collection and management process can be found in the Data Validation Manual. 
• 
Study monitors will perform ongoing source data verification to confirm that 
data entered into the eCRF by authorized study site personnel are accurate, 
complete, and verifiable from source documents; that the safety and rights of 
participants are being protected; and that the study is being conducted in 
accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.  
• 
Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
clinical study report/equivalent summary unless local regulations or institutional 
policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may 
be transferred to another location or party without written notification to the 
sponsor.  
Source Documents 
• 
Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
• 
Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
• 
Definition of what constitutes source data can be found in the Study Reference 
Manual. 


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Study and Site Closure 
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor’s procedures, or GCP guidelines 
• 
Inadequate recruitment of participants by the investigator 
• 
Discontinuation of further study treatment development 
 


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12.4. 
Appendix 4: Algorithm for Determining Qualifying 
Uropathogens 
In addition to other criteria indicated in Section 10.3, to be included in the micro-ITT 
Population, participants must have a qualifying bacterial uropathogen (defined in 
Figure 4) at Baseline from a quantitative bacteriology culture of a pretreatment 
clean-catch midstream urine specimen. For inclusion into the micro-ITT NTF-S 
Population, all baseline qualifying uropathogen(s) must also be susceptible to 
nitrofurantoin. Qualifying uropathogen susceptibilities will be monitored instream to 
ensure sufficient and balanced enrollment of participants with uropathogens resistant to 
specific microbiological classes. Please refer to the RAP for specific details. 
The algorithm for determining qualifying uropathogens based on microbiology laboratory 
quantitative culture results is provided in Figure 4, with additional algorithm details 
provided in the RAP. 
Figure 4 
Baseline Algorithm for Determining Qualifying Uropathogens 
 
CFU=colony-forming units. 
Note:  Only the following uropathogen species/groups will be considered for inclusion in the micro-ITT and other 
microbiological populations: Gram-negative bacilli (e.g., E. coli, K. pneumoniae, P. mirabilis), S. saprophyticus, 
and Enterococcus spp. Analysis details for the other uropathogens and uropathogen groups will be described in 
the RAP, as applicable. 
 
References 
Chan WW. Chapter 3.12: Urine cultures. In: Leber AL, editor. Clinical microbiology 
procedures handbook, 4th ed. Vol 1-3. Washington, DC; ASM Press; 2016. 
McCarter YS, Burd EM, Hall GS, Zervos M. Cumitech 2C, Laboratory diagnosis of 
urinary tract infections. Coordinating ed., Sharp SE. Washington, DC; ASM Press; 
2009.1-26. 
 


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12.5. 
Appendix 5: COVID-19 Protocol Information 
12.5.1. 
Overall Rationale for this Appendix  
The COVID-19 pandemic may impact the conduct of clinical studies. Challenges may 
arise from quarantines, site closures, travel limitations, interruptions to the supply chain 
for the investigational product or other considerations if site personnel or study 
participants become infected with COVID-19. These challenges may lead to difficulties 
in meeting protocol-specified procedures.  
This appendix outlines measures that may be applicable for any study site impacted by 
the COVID-19 pandemic. The purpose of the appendix is to provide information on the 
measures to be taken to protect participants’ safety, welfare and rights, and promote data 
integrity. These measures are expected to be temporary and study sites will be notified of 
any change to these allowances as the COVID-19 pandemic evolves. 
 
12.5.2. 
Study Procedures During the COVID-19 Pandemic 
During the special circumstances caused by the current COVID-19 pandemic, sites 
should consider specific public health guidance, the impact of any travel restrictions 
implemented by local/regional health authorities and local institutions, and individual 
benefit/risk when making enrollment and treatment decisions for study participants. 
Every effort should be made to adhere to protocol-specified assessments for participants 
on study treatment, including follow-up assessments; however, when not possible, for the 
duration of these special circumstances, the following measures may be implemented: 
• 
Only where applicable country and local regulations and infrastructure allow, home 
healthcare (home visits and telemedicine visits) may be performed at the discretion 
of the investigator and following the participant signing of an informed 
consent/assent form specific for home healthcare. Specific details will be described 
in the Study Reference Manual. The participant should be informed of the home 
healthcare plan and any potential risks associated with home visits and telemedicine. 
The participant must sign an informed consent form specific to home healthcare. 
• 
For all study visits, to minimize the amount of time that participants spend at the 
clinic, eConsent may be utilized and remote collection of study-related data may be 
obtained as described in the Study Reference Manual. Thus, some visit data may be 
collected through a combination of telemedicine and on-site visits. Collection of 
information via telemedicine will be performed only where local regulations permit. 
• 
Clinical investigators should document in site/participant/source files how 
restrictions related to COVID-19 led to changes in study conduct, the duration of 
those changes, and indicate which trial participants were impacted and how those 
trial participants were impacted (as per the current local COVID-19 related 
regulatory guidance).  
• 
Missing protocol-required data/visits due to COVID-19 should be noted in 
site/participant/source files and recorded as a COVID-19 protocol deviation.  


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Specifically for data management and monitoring the following will apply: 
• 
If on-site monitoring is no longer permitted, GSK/PPD will consider remote Source 
Data Verification/Source Document Review (SDV/SDR) where permitted by the 
clinical site/institution. Remote SDV/SDR will be proposed to study sites to meet a 
participant and/or critical quality need, e.g., to assess participant safety or to ensure 
data integrity. In case of remote SDV/SDR, GSK/PPD will work with the site to 
ensure participant privacy.  
• 
eCRF/CRF Final or Interim Sign-Off Process: The principal investigator is 
responsible for ensuring that the data within the eCRF casebook and any other data 
sources utilized during the study for each study participant is complete and 
consistent with source documents throughout the study (ICH GCP 4.9.1 4.9.2). The 
principal investigator may sign/re-sign the eCRF from any computer/location by 
accessing the validated system using his/her unique eCRF log-in credentials. The 
principal investigator may delegate this activity to another medically qualified and 
trained subinvestigator and this must be documented on the Delegation of 
Responsibilities Log. It is recommended that the principal investigator identifies a 
subinvestigator as a back-up for eCRF signatures and that appropriate training on the 
protocol and eCRF requirements is provided and documented.  
• 
Essential Document Sign-Off Process: If an investigator is unable to print and sign 
essential documents such as Protocol/Amendment signature page then e-mail 
approval can be accepted by replying to the relevant e-mail that is sent by GSK/PPD. 
 


T M F -1 3 8 1 7 5 4 3  
C O N FI D E N TI A L  
 
 
 
2 0 4 9 8 9  
 
1 0 1  
 
1 2. 6.  
A p p e n di x  6:  Cli ni c al Si g n s a n d S y m pt o m s S c or e f or A c ut e 
C y stiti s  
Cli nical si g ns a n d s y m pt o ms of ac ute c ystitis will be rec or de d as f oll o ws:  
Cli ni c al Si g n s 
a n d S y m pt o m s  
N o n e  
 
Mil d  
Sy m pt o m is 
e asily t ol er at e d, 
c a usi n g mi ni mal 
disc o mf ort an d 
n ot i nt erf erin g 
wit h ev ery day 
activiti es  
M o d er at e  
Sy m pt o m is 
s uffici e ntly 
disc o mf orti n g t o 
i nt erf er e with 
n or mal ev ery day 
activiti es  
S e v er e  
Sy m pt o m 
pr ev e nts n or mal 
ev ery d ay 
activiti es  
 
S C O R E  0  
S C O R E  1 
S C O R E  2 
S C O R E 3 
Dys uri a  
 
 
 
 
Fr e q u ency  
 
 
 
 
Ur g e ncy  
 
 
 
 
L o w er a b d o mi nal 
or s u pr ap u bic p ai n  
 
 
 
 
 
C CI


T M F -1 3 8 1 7 5 4 3  
C O N FI D E N TI A L  
 
 
 
2 0 4 9 8 9  
 
1 0 2  
 
 
C CI


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12.7. 
Appendix 7: Additional Guidance on Permitted and 
Prohibited Medications and Crediblemeds.org 
For quick reference, a list of some common concomitant medications that are permitted 
for participants to take during the study for nausea, vomiting, pain, diarrhea, etc. per 
investigator discretion is provided below. A list of some of the commonly used 
medications that are prohibited is also provided in this appendix. Lastly, a topline 
overview of how to use crediblemeds.org is also provided. 
A further detailed list of medications will be provided in the Study Reference Manual. 
List of Concomitant Medications Permitted During the Study: 
Generic Namea 
Common Therapeutic Use(s) 
Acetylsalicylic acid 
Only allowed for the prevention of cardiovascular disease events at a 
low dose of ≤100 mg/day 
Dolasetron 
Nausea, vomiting 
Granisetron 
Nausea, vomiting 
Metoclopramide 
Nausea, vomiting 
Palonosetron 
Nausea, vomiting 
Promethazine 
Nausea, vomiting 
Tropisetron  
(Only on Non-US markets) 
Nausea, vomiting 
Acetaminophen or paracetamol 
Pain, fever 
Tramadol 
Pain 
Hydrocodone ER 
Pain, severe 
Loperamide 
Diarrhea 
Cetirizine 
Antihistamine (H1) 
Ebastine 
Antihistamine (H1) 
Fexofenadine 
Antihistamine (H1) 
Loratadine 
Antihistamine (H1) 
Clindamycin 
Antibiotic – topical, nonsystemic only 
Neomycin 
Antibiotic – topical, nonsystemic only 
Polymyxin 
Antibiotic – topical, nonsystemic only 
Clotrimazole 
Antifungal – topical, nonsystemic only 
Tolnaftate 
Antifungal – topical, nonsystemic only 
Ketoconazole 
Antifungal – topical, nonsystemic only 
ER=extended release; US=United States. 
a. 
Check within each local country to assess if other generic names apply. 
Note: See also Section 7.7.1 for other permitted medications.  
 


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List of Prohibited Concomitant Medications: 
Generic Name or Categorya 
Common Therapeutic Use(s) 
Ondansetron 
Nausea, vomiting 
Acetylsalicylic acid (doses >100 mg/day) 
Pain, other 
Celecoxib 
Pain 
Diclofenac 
Pain 
Diflunisal 
Pain 
Etodolac 
Pain 
Ibuprofen 
Pain, fever  
Indomethacin 
Pain 
Ketoprofen 
Pain 
Ketorolac 
Pain 
Nabumetone 
Pain 
Naproxen 
Pain 
Oxaprozin 
Pain 
Phenazopyridine 
Pain (urinary tract) 
Piroxicam 
Pain 
Rofecoxib 
Pain 
Salsalate 
Pain 
Sulindac 
Pain 
Tolmetin 
Pain 
Valdecoxib 
Pain 
Other investigational products 
Various 
Systemic antibiotics (e.g., ciprofloxacin, amoxicillin/clavulanate, cephalexin, 
doxycycline) 
Antibiotic – all systemic 
Systemic antifungals (e.g., itraconazole, fluconazole, terbinafine) 
Antifungal – all systemic 
Prednisolone or equivalent (refer to Section 7.7.2 for details) 
Immunosuppressive therapy 
Strong CYP3A4 inhibitors and strong CYP3A4 inducers 
See Study Reference Manual 
St John’s wort 
Herbal, various 
Uva ursi 
Herbal, various 
D-mannose 
Nutritional supplement, various  
Cranberry supplements 
Nutritional supplement, various 
Probenecid 
Uric acid reducer 
Sulfinpyrazone 
Uric acid reducer 
Magnesium trisilicate 
Antacid (common ingredient) 
Succinylcholine and other nondepolarizing paralytic agents 
Muscle relaxation, muscle paralysis 
CYP3A4=cytochrome P450 enzyme 3A4; NSAIDS=nonsteroidal anti-inflammatory medications. 
a. 
Check within each local country to assess if other generic names apply. 
Note: See also Section 7.7.2 for other prohibited medications and details for the when these medications are 
prohibited. All NSAIDS are prohibited; this list may not be an exhaustive list of all NSAIDS available globally. 


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Crediblemeds.org Instructions 
Instructions for accessing www.crediblemeds.org and searching for an exclusionary drug 
due to its “Known Risk of Torsades de Pointes (TdP)” category are summarized below.  
To access www.crediblemeds.org, copy and paste this link into the internet search bar: 
https://www.crediblemeds.org/ 
On the main home page, there are 2 search options available. Choose the first option to 
search for 1 drug at a time, which does not require registration.  
 
Choosing that option brings you to a screen that allows for you to enter a generic or brand 
drug name and choose Search. If it has a Known Risk of TdP (i.e., is a prohibited 
exclusionary medication), it will show a red triangle with an exclamation point as shown 
here: 
 
Always check the www.crediblemeds.org website for the most up-to-date information on 
drugs with a Known Risk of TdP for participant safety.  
 


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12.8. 
Appendix 8: Liver Safety: Required Actions and Follow-up 
Assessments 
Phase III liver chemistry stopping and increased monitoring criteria have been 
designed to assure participant safety and evaluate liver event etiology. 
Phase III liver chemistry stopping criteria and required follow-up assessments 
Liver Chemistry Stopping Criteria  
ALT Absolute ALT 8 x ULN 
ALT Increase 
ALT 5 x ULN but <8 x ULN persists for 2 weeks 
ALT 3 x ULN but <5 x ULN persists for 4 weeks 
Bilirubina,b 
ALT 3 x ULN and bilirubin 2 x ULN (>35% direct bilirubin)  
INRb 
ALT 3 x ULN and INR >1.5, if INR measured 
Cannot 
Monitor 
ALT 5 x ULN but <8 x ULN and cannot be monitored weekly for 2 weeks 
ALT 3 x ULN but <5 x ULN and cannot be monitored weekly for 4 weeks 
Symptomaticc ALT 3 x ULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity 
Required Actions and Follow-up Assessments  
Actions 
Follow-up Assessments 
• Immediately discontinue study treatment  
• Report the event to GSK/PPD within 
24 hours 
• Complete the liver event eCRF and 
complete an SAE data collection tool if the 
event also meets the criteria for an SAEb 
• Perform liver event follow-up assessments  
• Monitor the participant until liver chemistries 
resolve, stabilize, or return to within 
baseline (see MONITORING below) 
• Do not restart/rechallenge participant with 
study treatment  
• If restart/rechallenge not allowed or not 
granted, permanently discontinue study 
treatment and continue participant in the 
• Viral hepatitis serologyd 
• Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend 
• Only in those with underlying chronic 
hepatitis B at study entry (identified by 
positive hepatitis B surface antigen), 
quantitative hepatitis B DNA, and 
hepatitis delta antibodye 
• Obtain blood sample for PK analysis, 
within 24 hours after last dosef 
• Serum creatine phosphokinase and 
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study for any protocol-specified follow-up 
assessments  
 
 
 
MONITORING: 
For bilirubin or INR criteria:  
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow-up assessments within 
24 hours 
• Monitor participants twice weekly until liver 
chemistries resolve, stabilize, or return to 
within baseline 
• A specialist or hepatology consultation is 
recommended 
For All other criteria:  
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow-up assessments within 
24 to 72 hours  
• Monitor participants weekly until liver 
chemistries resolve, stabilize, or return to 
within baseline 
• Fractionate bilirubin, if total bilirubin 
2 x ULN 
• Obtain complete blood count with 
differential to assess eosinophilia 
• Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form 
• Record use of concomitant medications 
on the concomitant medications report 
form including acetaminophen, herbal 
remedies, other over-the-counter 
medications 
• Record alcohol use on the liver event 
alcohol intake eCRF page 
 
For bilirubin or INR criteria: 
• Antinuclear antibody, antismooth muscle 
antibody, type 1 antiliver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins. 
• Serum acetaminophen adduct HPLC 
assay (quantifies potential 
acetaminophen contribution to liver injury 
in participants with definite or likely 
acetaminophen use in the preceding 
week [James, 2009]). NOTE:  not 
required in China  
• Liver imaging (ultrasound, magnetic 
resonance, or computed tomography) 
and/or liver biopsy to evaluate liver 
disease; complete liver imaging and/or 
liver biopsy eCRFs. 
AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; eCRF=electronic case report 
form; GSK=GlaxoSmithKline; HPLC=high-performance liquid chromatography; IgG=immunoglobulin G; 
IgM=immunoglobulin M; INR=international normalized ratio; PK=pharmacokinetic; SAE=serious adverse event; 
ULN=upper limit of normal. 
a. 
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that participant if ALT 3 x ULN and bilirubin 2 x ULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury.  
b. 
All events of ALT 3 x ULN and bilirubin 2 x ULN (>35% direct bilirubin) or ALT 3 x ULN and INR >1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated will 
not apply to participants receiving anticoagulants. 


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c. 
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia). 
d. 
Includes: hepatitis A IgM antibody; hepatitis B surface antigen and hepatitis B core antibody (IgM); hepatitis C 
RNA; cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing); hepatitis E IgM antibody. 
e. 
If hepatitis delta antibody assay cannot be performed, it can be replaced with a polymerase chain reaction of 
hepatitis D RNA virus (where needed) [Le Gal, 2005]. 
f. 
The PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
treatments. Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
treatment prior to PK blood sample draw on the eCRF. If the date or time of the last dose is unclear, provide the 
participant’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot 
be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and 
shipping are in the Study Reference Manual.  
 
Phase III liver chemistry increased monitoring criteria with continued therapy 
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event 
Criteria 
Actions 
 
ALT 5 x ULN and <8 x ULN and 
bilirubin <2 x ULN without symptoms 
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 2 weeks. 
OR 
ALT 3 x ULN and <5 x ULN and 
bilirubin <2 x ULN without symptoms 
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks. 
• Notify the GSK/PPD medical monitor within 
24 hours of learning of the abnormality to discuss 
participant safety.  
• Participant can continue study treatment.  
• Participant must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilize, or return to 
within baseline.  
• If at any time participant meets the liver chemistry 
stopping criteria, proceed as described above. 
• If ALT decreases from ALT 5 x ULN and 
<8 x ULN to ≥3 x ULN but <5 x ULN, continue to 
monitor liver chemistries weekly.  
• If, after 4 weeks of monitoring, ALT <3 x ULN and 
bilirubin <2 x ULN, monitor participants twice 
monthly until liver chemistries normalize or return 
to within baseline. 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; GSK=GlaxoSmithKline; ULN=upper limit of normal. 
 


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References 
James LP, Letzig L, Simpson PM, et al. Pharmacokinetics of acetaminophen-protein 
adducts in adults with acetaminophen overdose and acute liver failure. Drug Metab 
Dispos. 2009;37:1779-1784. 
Le Gal F, Gordien E, Affolabi D, et al. Quantification of hepatitis delta virus RNA in 
serum by consensus real-time PCR indicates different patterns of virological response to 
interferon therapy in chronically infected patients. J Clin Microbiol. 2005;43:2363-2369.  
 


T M F -1 3 8 1 7 5 4 3  
C O N FI D E N TI A L  
 
 
 
2 0 4 9 8 9  
 
1 1 0  
 
 
C CI


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12.10. 
Appendix 10: Adverse Events: Definitions and Procedures 
for Recording, Evaluating, Follow-up, and Reporting 
Definition of Adverse Event 
Adverse Event Definition 
• 
An adverse event (AE) is any untoward medical occurrence in a clinical study 
participant, temporally associated with the use of a study treatment, whether or not 
considered related to the study treatment. 
• 
NOTE:  An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a study treatment. 
Events Meeting the AE Definition  
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., electrocardiograms, radiological 
scans, vital signs measurements), including those that worsen from baseline, 
considered clinically significant in the medical and scientific judgment of the 
investigator (i.e., not related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/serious AE (SAE) unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae. 
• 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not 
be reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting 
from lack of efficacy will be reported as AE or SAE if they fulfill the definition of 
an AE or SAE.  
 


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Events NOT Meeting the AE Definition  
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by 
the investigator to be more severe than expected for the participant’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
 
Definition of an SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life threatening 
The term “life threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 


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d. Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent 1 of the other outcomes listed in the above definition. These events should 
usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 
 
Cardiovascular Adverse Events of Special Interest and Cases of 
Clostridium Difficile 
Investigators will be required to fill out the specific event page of the electronic case 
report form (eCRF) for the following cardiovascular AEs and SAEs, and for cases of 
Clostridium difficile: 
Cardiovascular Events: 
• 
Myocardial infarction/unstable angina 
• 
Congestive heart failure 
• 
Arrhythmias 
• 
Valvulopathy 
• 
Pulmonary hypertension 
• 
Cerebrovascular events/stroke and transient ischemic attack 
• 
Peripheral arterial thromboembolism 
• 
Deep venous thrombosis/pulmonary embolism 
• 
Revascularization 
 


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Recording AE and SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
related to the event. 
• 
The investigator will then record all relevant AE/SAE information in the eCRF. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GlaxoSmithKline (GSK)/PPD in lieu of completion of the 
GSK/PPD AE/SAE eCRF page. 
• 
There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
• 
The severity of AEs and SAEs will be determined by the investigator according to 
the US National Institute of Allergy and Infectious Diseases Division of 
Microbiology and Infectious Diseases criteria for adult toxicity assessment 
[DMIDDMID, 2007a], with the exception of serum creatinine adolescent 
laboratory data, which will be assessed using pediatric toxicity criteria [DMID, 
2007b] (Appendix 13).  
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
Assessment of Causality 
• 
The investigator is obligated to assess the relationship between study treatment 
and each occurrence of each AE/SAE. 
• 
A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated. 
• 
The investigator will also consult the investigator’s brochure and/or product 
information, for marketed products, in his/her assessment. 
• 
For each AE/SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE/SAE and has provided an assessment of causality. 


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• 
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK/PPD. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to GSK/PPD. 
• 
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
Follow-up of AE and SAE 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK 
to elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• 
If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide GSK with a copy of any 
postmortem findings including histopathology. 
• 
New or updated information will be recorded in the originally completed eCRF. 
• 
The investigator will submit any updated SAE data to GSK/PPD within 24 hours 
of receipt of the information. 
Reporting of SAE to GSK/PPD 
SAE Reporting to GSK/PPD via Electronic Data Collection Tool 
• 
The primary mechanism for reporting SAE to GSK/PPD will be the electronic data 
collection tool. 
• 
The study site will enter the SAE data into the electronic system as soon as it 
becomes available. 
• 
The investigator or medically qualified subinvestigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to study treatment/study participation (causality) within 
72 hours of SAE entry into the eCRF. 
• 
After the study is completed at a given study site, the electronic data collection 
tool will be taken off-line to prevent the entry of new data or changes to existing 
data. 
• 
If a study site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic data collection tool 
has been taken off-line, then the study site can report this information to the 
medical monitor or SAE coordinator by telephone. 
• 
Contacts for SAE reporting can be found in the SRM. 


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12.11. 
Appendix 11: Clinical Laboratory Tests 
• 
The tests detailed in Table 17 will be performed by the central laboratory.  
• 
Local laboratory results are only required in the event that the central laboratory 
results are not available in time for a response evaluation. If a local sample is 
required, it is important that the sample for central analysis is obtained at the 
same time.  
• 
Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 6 of the protocol. 
• 
Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 


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Table 17 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet count  
RBC Indices: 
MCV 
MCH 
WBC Count With 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC count 
Hemoglobin 
Hematocrit 
Clinical 
Chemistrya 
Blood urea 
nitrogen 
Potassium 
AST/SGOT 
Total and direct 
bilirubin 
Creatinine 
Sodium 
ALT/SGPT 
Total protein 
Glucose 
nonfasting 
Calcium 
Alkaline 
phosphatase 
Albumin 
Chloride 
Magnesium 
Phosphorus 
 
Routine 
Urinalysis 
• Specific gravity 
• pH, glucose, protein, blood, ketones, nitrite, and leukocyte esterase by 
dipstick 
• Microscopic examination (if blood or protein is abnormal) 
Other 
Screening 
Tests 
• Serum or urine alcohol and drug screen (to include at minimum: 
amphetamines, barbiturates, cocaine, opiates, cannabinoids, and 
benzodiazepines) 
• Urine hCG pregnancy test (as needed for women of childbearing 
potential)b 
• Serology (HBsAg, hepatitis C virus antibody, and HIV). If serology testing 
was performed within 3 months prior to the first dose of study treatment 
and results were positive, testing at Baseline is not required. If testing 
was performed within 3 months and any result was negative, testing at 
Baseline is required. 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; eCRF=electronic case report form; 
HBsAg=hepatitis B surface antigen; hCG=human chorionic gonadotropin; HIV=human immunodeficiency virus; 
MCH=mean corpuscular hemoglobin; MCV=mean corpuscular volume; RBC=red blood cell; SGOT=serum 
glutamic-oxaloacetic transaminase; SGPT=serum glutamic-pyruvic transaminase; WBC=while blood cell. 
a. 
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping 
or monitoring event are given in Section 8.1.1 and Appendix 8. All events of ALT 3 × upper limit of normal 
(ULN) and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (INR) 
>1.5, if INR measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as a 
serious adverse event. 
b. 
See Appendix 2 for urine test requirement details. Local urine testing will be standard for the protocol unless 
serum testing is required by local regulation or the Institutional Review Board/Independent Ethics Committee. 
 
Laboratory results that could unblind the study will not be reported to study sites or other 
blinded personnel until the study has been unblinded. 


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12.12. 
Appendix 12: Genetics 
USE/ANALYSIS OF DNA 
• 
Genetic variation may impact a participant’s response to therapy, susceptibility, 
severity and progression of disease. Variable response to therapy may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and 
institutional review board/independent ethics committee allow, a blood sample will 
be collected for DNA analysis. 
• 
DNA samples will be used for research related to gepotidacin or uncomplicated 
urinary tract infections and related diseases. They may also be used to develop 
tests/assays including diagnostic tests) related to gepotidacin and uncomplicated 
urinary tract infections. Genetic research may consist of the analysis of 1 or more 
candidate genes or the analysis of genetic markers throughout the genome [or 
analysis of the entire genome] (as appropriate). 
• 
DNA samples will be analyzed if it is hypothesized that this may help further 
understand the clinical data.  
• 
The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to gepotidacin or study treatments of this class. The results 
of genetic analyses may be reported in the clinical study report or in a separate study 
summary. 
• 
The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality.  
• 
The samples will be retained while research on gepotidacin (or study treatments of 
this class) or uncomplicated urinary tract infections continues but no longer than 
15 years after the last participant last visit or other period as per local requirements. 
 


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12.13. 
Appendix 13: Division of Microbiology and Infectious 
Diseases Adult Toxicity Tables for Adverse Event 
Assessment 
ESTIMATING SEVERITY GRADE: For abnormalities NOT found elsewhere in the 
Toxicity Tables, use the scale below to estimate grade of severity: 
GRADE 1 
Mild 
Transient or mild discomfort (<48 hours); no medical 
intervention/therapy required 
GRADE 2 
Moderate 
Mild to moderate limitation in activity – some assistance 
may be needed; no or minimal medical 
intervention/therapy required 
GRADE 3 
Severe 
Marked limitation in activity, some assistance usually 
required; medical intervention/therapy required, 
hospitalizations possible 
GRADE 4 
Life-threatening 
Extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, 
hospitalization or hospice care probable 
 
SERIOUS OR LIFE-THREATENING AEs: ANY clinical event deemed by the 
investigator to be serious or life-threatening should be considered a Grade 4 event. 
Clinical events considered to be serious or life-threatening include, but are not limited to: 
seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular coagulation, 
diffuse petechiae, paralysis, acute psychosis, and severe depression. 
COMMENTS REGARDING THE USE OF THESE TABLES 
• Standardized and commonly used toxicity tables (Division of AIDS, National Cancer 
Institute’s Common Toxicity Criteria, and World Health Organization) have been 
adapted for use by the Division of Microbiology and Infectious Diseases (DAIDS) 
and modified to better meet the needs of participants in Division of Microbiology and 
Infectious Diseases (DMID) trials. 
• For parameters not included in the following Toxicity Tables, study sites should refer 
to the “Guide for Estimating Severity Grade” located above. 
• Criteria are generally grouped by body system. 
Some protocols may have additional protocol specific grading criteria, which will 
supersede the use of these tables for specified criteria. 
 
 
Note: Adult DMID toxicity criteria will be applied for all laboratory parameters, with the 
exception of serum creatinine adolescent laboratory data, which will be assessed using 
pediatric DMID toxicity criteria. The DMID pediatric toxicity table may be accessed at 
https://www.niaid.nih.gov/sites/default/files/dmidpedtox.pdf. 
 


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HEMATOLOGY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
9.5 to 10.5 gm/dL 
8.0 to 9.4 gm/dL 
6.5 to 7.9 gm/dL 
<6.5 gm/dL 
Absolute Neutrophil Count 
1000 to 1500 /mm3 
750 to 999 /mm3` 
500 to 749 /mm3 
<500 /mm3 
Platelets 
75,000 to 99,999 /mm3 
50,000 to 74,999 /mm3 
20,000 to 49,999 /mm3 
<20,000 /mm3 
White Blood Cells 
11,000 to 13,000 /mm3 
13,000 to 15,000 /mm3 
15,000 to 30,000 /mm3 
>30,000 or <1000 /mm3 
% Polymorphonuclear Leukocytes + 
Band Cells 
>80% 
90 to 95% 
>95% 
N/A 
Abnormal Fibrinogen 
Low: 100 to 200 mg/dL 
High: 400 to 600 mg/dL 
Low: <100 mg/dL 
High: >600 mg/dL 
Low: <50 mg/dL 
High: N/A 
Fibrinogen associated with gross bleeding or 
with disseminated coagulation 
Fibrin Split Product 
20 to 40 mcg/mL 
41 to 50 mcg/mL 
51 to 60 mcg/dL 
>60 mcg/dL 
Prothrombin Time (PT) 
1.01 to 1.25  ULN 
1.26 to 1.5  ULN 
1.51 to 3.0  ULN 
>3  ULN 
Activated Partial Thromboplastin (APTT) 
1.01 to 1.66  ULN 
1.67 to 2.33  ULN 
2.34 to 3  ULN 
>3  ULN 
Methemoglobin 
5.0 to 9.9% 
10.0 to 14.9% 
15.0 to 19.9% 
>20% 
N/A=not applicable; ULN=upper limit of normal.  


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CHEMISTRIES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hyponatremia 
130 to 135 mEq/L 
123 to 129 mEq/L 
116 to 122 mEq/L 
<116 mEq/L or abnormal sodium with 
mental status changes or seizures 
Hypernatremia 
146 to 150 mEq/L 
151 to 157 mEq/L 
158 to 165 mEq/L 
>165 mEq/L or abnormal sodium with 
mental status changes or seizures 
Hypokalemia 
3.0 to 3.4 mEq/L 
2.5 to 2.9 mEq/L 
2.0 to 2.4 mEq/L or intensive 
replacement therapy of 
hospitalization required 
<2.0 mEq/L or abnormal potassium with 
paresis, ileus, or life-threatening arrhythmia 
Hyperkalemia 
5.6 to 6.0 mEq/L 
6.1 to 6.5 mEq/L 
6.6 to 7.0 mEq/L 
>7.0 mEq/L or abnormal potassium with 
life-threatening arrhythmia 
Hypoglycemia 
55 to 64 mg/dL 
40 to 54 mg/dL 
30 to 39 mg/dL 
<30 mg/dL or abnormal glucose with mental 
status changes or coma 
Hyperglycemia 
(nonfasting and no prior 
diabetes) 
116 to 160 mg/dL 
161 to 250 mg/dL 
251 to 500 mg/dL 
>500 mg/dL or abnormal glucose with 
ketoacidosis or seizures 
Hypocalcemia 
(corrected for albumin) 
8.4 to 7.8 mg/dL 
7.7 to 7.0 mg/dL 
6.9 to 6.1 mg/dL 
<6.1 mg/dL or abnormal calcium with 
life-threatening arrhythmia or tetany 
Hypercalcemia 
(corrected for albumin) 
10.6 to 11.5 mg/dL 
11.6 to 12.5 mg/dL 
12.6 to 13.5 mg/dL 
>13.5 mg/dL or abnormal calcium with 
life-threatening arrhythmia 
Hypomagnesemia 
1.4 to 1.2 mEq/L 
1.1 to 0.9 mEq/L 
0.8 to 0.6 mEq/L 
<0.6 mEq/L or abnormal magnesium with 
life-threatening arrhythmia 
Hypophosphatemia 
2.0 to 2.4 mg/dL 
1.5 to 1.9 mg/dL or 
replacement Rx required 
1.0 to 1.4 mg/dL 
intensive therapy or hospitalization 
required 
<1.0 mg/dL or abnormal phosphate with 
life-threatening arrhythmia 
Hyperbilirubinemia (when 
accompanied by any increase in 
other liver function test) 
1.1 to <1.25  ULN 
1.25 to <1.5  ULN 
1.5 to 1.75  ULN 
>1.75  ULN 
Hyperbilirubinemia (when other 
liver function tests are in the 
normal range) 
1.1 to <1.5  ULN 
1.5 to <2.0  ULN 
2.0 to 3.0  ULN 
>3.0  ULN 
Blood urea nitrogen  
1.25 to 2.5  ULN 
2.6 to 5  ULN 
5.1 to 10  ULN 
>10  ULN 
Hyperuricemia (uric acid) 
7.5 to 10.0 mg/dL 
10.1 to 12.0 mg/dL 
12.1 to 15.0 mg/dL 
>15.0 mg/dL 
Creatinine 
1.1 to 1.5  ULN 
1.6 to 3.0  ULN 
3.1 to 6.0  ULN 
>6  ULN or dialysis required 
Rx=therapy; ULN=upper limit of normal. 


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ENZYMES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Aspartate aminotransferase (AST) 
1.1 to <2.0  ULN 
2.0 to <3.0  ULN 
3.0 to 8.0  ULN 
>8.0  ULN 
Alanine aminotransferase (ALT) 
1.1 to <2.0  ULN 
2.0 to <3.0  ULN 
3.0 to 8.0  ULN 
>8.0  ULN 
Gamma to glutamyl transferase (GGT) 
1.1 to <2.0  ULN 
2.0 to <3.0  ULN 
3.0 to 8.0  ULN 
>8.0  ULN 
Alkaline Phosphatase 
1.1 to <2.0  ULN 
2.0 to <3.0  ULN 
3.0 to 8.0  ULN 
>8.0  ULN 
Amylase 
1.1 to 1.5  ULN 
1.6 to 2.0  ULN 
2.1 to 5.0  ULN 
>5.1  ULN 
Lipase 
1.1 to 1.5  ULN 
1.6 to 2.0  ULN 
2.1 to 5.0  ULN 
>5.1  ULN 
ULN=upper limit of normal. 
URINALYSIS 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Proteinuria 
1+ or 
200 mg to 1 gm loss/day 
2 to 3+ or 
1 to 2 gm loss/day 
4+ or 
2 to 3.5 gm loss/day 
Nephrotic syndrome or 
>3.5 gm loss/day 
Hematuria 
Microscopic only 
<10 RBC/HPF 
Gross, no clots 
>10 RBC/HPF 
Gross, with or without clots, 
or red blood cells casts 
Obstructive or  
required transfusion 
HPF=high powered field; RBC=red blood cells. 


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CARDIOVASCULAR 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cardiac rhythm 
N/A 
Asymptomatic, transient signs, no 
Rx required 
Recurrent/persistent; symptomatic 
Rx required 
Unstable dysrhythmia; 
hospitalization and treatment 
required 
Hypertension 
Transient increase >20 mm/Hg; 
no treatment  
Recurrent, chronic increase 
>20 mm/Hg; 
treatment required  
Acute treatment required; 
outpatient treatment or 
hospitalization possible  
End organ damage or 
hospitalization required  
Hypotension 
Transient orthostatic hypotension 
with heart rate increased by 
<20 beat/min or decreased by 
<10 mmHg systolic BP. 
No treatment required 
Symptoms due to orthostatic 
hypotension or BP decreased by 
<20 mmHg systolic; correctable 
with oral fluid treatment 
Requires IV fluids; 
no hospitalization required 
Mean arterial pressure <60 mmHg 
or end organ damage or shock; 
requires hospitalization and 
vasopressor treatment 
Pericarditis 
Minimal effusion 
Mild/moderate asymptomatic 
effusion, no treatment 
Symptomatic effusion; pain; EKG 
changes 
Tamponade; pericardiocentesis or 
surgery required 
Hemorrhage, Blood Loss 
Microscopic/occult 
Mild, no transfusion 
Gross blood loss;  
1 to 2 units transfused 
Massive blood loss; >3 units 
transfused 
BP=blood pressure; IV=intravenous; EKG=electrocardiogram; N/A=not applicable; Rx=therapy. 
RESPIRATORY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cough 
Transient; no treatment 
Persistent cough; treatment 
responsive 
Paroxysmal cough; uncontrolled 
with treatment 
N/A 
Bronchospasm, Acute 
Transient; no treatment; FEV1 70 
to 80% of peak flow 
Requires treatment; normalizes 
with bronchodilator; FEV1 50 to 
70% of peak flow 
No normalization with 
bronchodilator; FEV1 25 to 50% of 
peak flow; or retractions present 
Cyanosis: FEV1 <25% of peak 
flow; or intubation necessary 
Dyspnea 
Dyspnea on exertion 
Dyspnea with normal activity 
Dyspnea at rest 
Dyspnea requiring oxygen therapy 
FEV1=forced expiratory volume in 1 second; N/A=not applicable. 


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GASTROINTESTINAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Nausea 
Mild or transient; maintains 
reasonable intake 
Moderate discomfort; intake 
decreased significantly; some 
activity limited 
No significant intake; requires IV fluids 
Hospitalization required 
Vomiting 
1 episode in 24 hours 
2 to 5 episodes in 24 hours 
>6 episodes in 24 hours or needing IV 
fluids 
Physiologic consequences requiring 
hospitalization or requiring parenteral 
nutrition 
Constipation 
Requiring stool softener or 
dietary modification 
Requiring laxatives 
Obstipation requiring manual evacuation 
or enema 
Obstruction or toxic megacolon 
Diarrhea 
Mild or transient; 3 to 
4 loose stools/day or mild 
diarrhea lasting <1 week 
Moderate or persistent; 5 to 
7 loose stools/day or diarrhea 
lasting >1 week 
>7 loose stools/day or bloody diarrhea; 
or orthostatic hypotension or electrolyte 
imbalance or >2L IV fluids required 
Hypotensive shock or physiologic 
consequences requiring hospitalization 
Oral discomfort/ 
Dysphagia 
Mild discomfort; no 
difficulty swallowing 
Some limits on eating/drinking 
Eating/talking very limited; unable to 
swallow solid foods 
Unable to drink fluids; requires IV fluids 
IV=intravenous. 
NEUROLOGICAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Neuro-Cerebellar 
Slight incoordination 
dysdiadochokinesis 
Intention tremor, dysmetria, 
slurred speech; nystagmus 
Locomotor ataxia 
Incapacitated 
Psychiatric 
Mild anxiety or depression 
Moderate anxiety or depression; 
therapy required; change in 
normal routine 
Severe mood changes requiring 
therapy; or suicidal ideation; or 
aggressive ideation 
Acute psychosis requiring 
hospitalization; or suicidal 
gesture/attempt or hallucinations 
Muscle strength 
Subjective weakness; no 
objective symptoms/signs 
Mild objective signs/symptoms; no 
decrease in function 
Objective weakness; function limited 
Paralysis 
Paresthesia 
(burning, tingling, etc.) 
Mild discomfort; no treatment 
required 
Moderate discomfort; 
non- narcotic analgesia required 
Severe discomfort; or narcotic analgesia 
required with symptomatic improvement 
Incapacitating; or not responsive 
to narcotic analgesia 
Neurosensory 
Mild impairment in sensation 
(decreased sensation, e.g., 
vibratory, pinprick, hot/cold in 
great toes) in focal area or 
symmetrical distribution; or 
change in taste, smell, vision, 
and/or hearing 
Moderate impairment (moderately 
decreased sensation, e.g., 
vibratory, pinprick, hot/cold to 
ankles) and/or joint position or 
mild impairment that is not 
symmetrical 
Severe impairment (decreased or loss 
of sensation to knees or wrists) or loss 
of sensation of at least moderate degree 
in multiple different body areas (i.e., 
upper and lower extremities) 
Sensory loss involves limbs and 
trunk; paralysis; or seizures 


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MUSCULOSKELETAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Arthralgia (joint 
pain) 
Mild pain not interfering with function 
Moderate pain, analgesics and/or pain 
interfering with function but not with ADL 
Severe paid; pain and/or analgesics 
interfering with ADL 
Disabling pain 
Arthritis 
Mild pain with inflammation, erythema or 
joint swelling, but not interfering with 
function 
Moderate pain with inflammation, erythema or 
joint swelling; interfering with function but not 
with ADL 
Severe pain with inflammation, 
erythema or joint swelling, and 
interfering with ADL 
Permanent and/or 
disabling joint 
destruction 
Myalgia 
Myalgia with no limitation of activity 
Muscle tenderness (at other than injection site) 
or with moderate impairment of activity 
Severe muscle tenderness with marked 
impairment of activity 
Frank myonecrosis 
ADL=activities of daily living. 
SKIN 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Mucocutaneous 
Erythema; pruritus 
Diffuse, maculo papular rash, dry 
desquamation 
Vesiculation or moist 
desquamation or ulceration 
Exfoliative dermatitis, mucous membrane 
involvement or erythema, multiforme or suspected 
Stevens-Johnson or necrosis requiring surgery 
Induration 
<15 mm 
15 to 30 mm 
>30 mm 
N/A 
Erythema 
<15 mm 
15 to 30 mm 
>30 mm 
N/A 
Edema 
<15 mm 
15 to 30 mm 
>30 mm 
N/A 
Rash at injection site 
<15 mm 
15 to 30 mm 
>30 mm 
N/A 
Pruritus 
Slight itching at injection site 
Moderate itching at injection extremity 
Itching over entire body 
N/A 
N/A=not applicable. 
 
 
SYSTEMIC 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Allergic reaction 
Pruritus without rash 
Localized urticarial 
Generalized urticarial; angioedema 
Anaphylaxis 
Headache 
Mild, no treatment required 
Transient, moderate; treatment 
required 
Severe; responds to initial narcotic 
therapy 
Intractable; requires repeated
narcotic therapy 
Fever: oral 
37.7 to 38.5C or 100.0 to 101.5F 
38.6 to 39.5C or 101.6 to 102.9F 
39.6 to 40.5C or 103 to 105F 
>40C or >105F 
Fatigue 
Normal activity reduced <48 hours 
Normal activity decreased 25 to 50%; 
>48 hours 
Normal activity decreased >50%; 
cannot work 
Unable to care for self 
 


T M F -1 3 8 1 7 5 4 3  
C O N FI D E N TI A L  
 
 
 
2 0 4 9 8 9  
 
 
 
1 2 6  
 
1 2. 1 4.  
A p p e n di x  1 4: A b br e vi ati o n s a n d Tr a d e m ar k s  
A B S S SI  
ac ute bacterial s ki n a n d s ki n str uct ure i nfecti o n  
A E  
a d verse e ve nt  
A L T  
ala ni ne a mi n otra nsferas e  
A U C 1 2 h  
area u n d er t he dr u g c o nce ntrati o n -ti me c ur ve o ver 1 2 
h o urs  
A U C 2 4 h  
area u n d er t he dr u g c o nce ntrati o n-ti me c ur ve o ver 2 4 
h o urs  
BI D  
t wice dail y 
C D C  
Ce nters f or Disease C o ntr ol a n d Pre ve nti o n  
C E  
Cli nicall y E val ua ble  
C F U  
c ol o n y-f or mi n g u nits 
CI  
c o nfi de nce i nter val  
C O N S O R T  
C o ns oli date d Sta n dar ds of Re p orti n g Trials  
C O VI D -1 9  
c or o na vir us disease  
C R F  
case re p ort f or m  
C V  
car di o vas c ular  
C Y P 3 A 4  
c yt o c hr o me P 4 5 0 e nz y m e 3 A 4  
D MI D  
Di visi o n of Micr o bi ol o g y a n d I nfecti o us Diseases  
E A G L E  
Efficac y of A nti bacterial Ge p oti daci n E val uat e d  
E C G  
electr ocar di o gra m  
e C R F 
electr o nic case re p ort f or m  
E M A  
E ur o pea n Me dici nes A ge nc y  
E S B L  
e xte n de d -s pectr u m -lacta mase 
F  
Fa hre n heit  
fA U C/ MI C  
rati o of t he area u n d er t h e free-dr u g c o nce ntrati o n -ti me 
c ur ve t o mi ni m u m i n hi bit or y c o n ce ntr ati o n  o ver 2 4 h o urs  
F D A  
F o o d a n d Dr u g A d m i nistrati o n  
G C P  
G o o d Cli nical Practice  
G S K  
Gla x o S mit h Kli ne  
H P F  
hi g h -p o wer fi el d  
I A 
i nteri m a nal ysis 
I B 
i n vesti gat or’s br oc h ure  
I C E 
i nterc urre nt e ve nt 
I C F 
i nf or me d c o nse nt f or m  
I C H  
I nter nati o nal C o u ncil o n Har m o nisati o n 
I D M C 
I n d e pe n de nt Data M o nit ori n g C o m mittee  
I E C 
i n de pe n de nt et hics c o m mittee 
I R B 
i nstit uti o nal re vie w b oar d 
I R T 
i nteracti ve res p o nse tec h n ol o g y  
I T T 
I nte nt-t o-Treat  
I V 
i ntra ve n o us  
k g  
kil o gra m  
m  
meter  
C CI


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MDR 
multidrug-resistant 
MedDRA 
Medical Dictionary for Regulatory Activities  
mg 
milligram 
MIC 
minimum inhibitory concentration 
micro-ITT 
Microbiological Intent-to-Treat  
min 
minute 
mL 
milliliter 
mm 
millimeter 
msec 
millisecond 
NTF 
nitrofurantoin  
NTF-NS 
not susceptible to nitrofurantoin 
NTF-S 
susceptible to nitrofurantoin 
PD 
pharmacodynamic 
PK 
pharmacokinetic  
QTc 
corrected QT interval 
QTcB 
QT interval corrected for heart rate according to Bazett 
QTcF 
QT interval corrected for heart rate according to 
Fridericia  
RAP 
reporting and analysis plan  
SAE 
serious adverse event 
SDAC 
Statistical Data Analysis Center 
SoA 
Schedule of Activities 
SRM 
Study Reference Manual  
ST 
sequence type 
TdP 
torsades de pointes  
TOC 
Test-of-Cure  
TMP-SXT 
trimethoprim-sulfamethoxazole 
µg 
microgram 
ULN 
upper limit of normal 
UTI 
urinary tract infection 
WHO 
World Health Organization 
WOCBP 
woman of childbearing potential  
 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
None 
 
FIRST RESPONSE 
 
 
MedDRA 
 


T M F -1 3 8 1 7 5 4 3  
C O N FI D E N TI A L  
 
 
 
2 0 4 9 8 9  
 
 
 
1 2 8  
 
1 2. 1 5.  
A p p e n di x  1 5 : Pr ot o c ol A m e n d m e nt Hi st or y 
T he Pr ot oc ol A me n d me nt S u m mar y of C ha n ges T a ble f or t he c urre nt a me n d me nt is 
l ocate d directl y b ef ore t he Ta ble of C o nte nts. 
A me n d me nt 1   0 6 -M A Y -2 0 2 1  
T his gl o bal a me n d m e nt is c o nsi dere d t o be s u bsta ntial.  
O ver all R ati o n ale f or t he A me n d me nt:  
 
 
 
; i n dicat e d st u d y o p erati o nal all o wa nces wit h re gar d t o c or o na vir us 
disease ( C O VI D -1 9); i nc or p orate d past a d mi nistrati ve letters t o t he sites; a d de d esti ma n d 
te xt; re m o ve d t he p har mac o ki netic ( P K) s a m ple c ollecti o n at Bas eli ne; re m o ve d t he 
pre d ose re q uire me nt f or c ollecti o n  of t he P K a n d micr o bi ol o gical s a m ples at t he O n -
t hera p y Visit; re m o ve d t he o n-site d osi n g re q uire me nt at t he O n-T hera p y Visit; pr o vi de d 
mi n or statistical clarificati o ns t o t he a nal ysis p o p ul ati o ns, res p o nse a n d o utc o mes ta bles, 
a n d acc o u nte d f or s u p ple me n tar y a nal ysis, w hic h will be detaile d i n t he re p orti n g a n d 
a nal ysis pla n ( R A P); i ncrease d t he pla n n e d t otal e nr oll me nt p o p ulati o n; a n d i nc or p orate d 
u p dates per t he m ost rece nt i n vesti gat or’s br oc h ure (I B) versi o n 0 7. T he a me n d me nt als o 
i ncl u des a d diti o nal mi n or a d mi nistrati ve a n d w or di n g e dits.  
S e cti o n # a n d N a me  
D e s cri pti o n of C h a n g e  
Bri ef R ati o n al e  
Sy n o psis  
4 O bj ectiv es a n d 
Esti m a n ds/ E n dp oi nts  
T a bl e 2 Esti m a nd for 
t h e S ec on d ary 
E n d poi nts  
1 0. 3. 1 Ge n eral 
C o nsi d er atio ns  
1 0. 3. 2 Effic acy 
A n alysis  
1 0. 3. 3 Saf ety 
A n alys es  
T hr o u gh o ut  
A d d ed esti m a n d t ext f or th e 
pri m ary a n d sec o nd ary en dp oi nts  
T o m e et curre nt I C H g ui deli n es o n 
esti m a n ds  
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Section # and Name 
Description of Change 
Brief Rationale 
Synopsis 
4 Objectives and 
Estimands/Endpoints 
For the secondary (updated only 
in the Synopsis) and exploratory 
objectives, an additional objective 
and endpoint were added to each 
section to examine the clinical 
response in female participants 
with acute cystitis with qualifying 
bacterial uropathogen(s) at 
Baseline that all are susceptible to 
nitrofurantoin 
Consistency with the primary 
objective population 
Synopsis 
10.1.1 Justification of 
Sample Size 
Increased the total enrollment 
sample size to up to 2500 
participants and expanded sample 
size justification text 
To reflect the expected number of 
participants for full enrollment to 
support the required number of 
evaluable participants for the 
primary analysis and to provide 
additional sample size details 
Schedule of Activities 
Removed postdose PK collection 
at the Baseline Visit; thus, also 
removed “(peak and trough)” from 
the secondary PK endpoint  
Clinical conduct feasibility  
Schedule of Activities 
4 Objectives and 
Estimands/Endpoints 
9 Study Assessments 
and Procedures 
9.5 Pharmacokinetics 
10.3.4 PK and PK/PD 
Analyses 
Throughout 
 
 
Revised On-therapy Visit 
procedures as follows:  
• Removed requirement for 
participants to take their study 
treatment at the study site 
• Removed the predose 
collection requirement for 
microbiological and PK 
samples; thus, also removed 
“(peak and trough)” from the 
secondary PK endpoint 
• Recommended the 
On-Therapy Visit should 
ideally be scheduled 1 to 2 
hours after the participant’s 
most recent dose of study 
treatment was taken 
Clinical conduct feasibility 
Schedule of Activities 
6.2 Inclusion Criteria 
#3 
Updated criterion to state 
“3+/large” rather than 
“3+/moderate” for the presence of 
leukocyte esterase  
Incorporation of Protocol 
Administration Letter 1 


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Section # and Name 
Description of Change 
Brief Rationale 
3.3.1 Risk 
Assessment 
6.2 Exclusion Criteria 
#5 
Added acute porphyria as an 
example of a risk for the 
nitrofurantoin comparator and 
excluded the medical condition for 
participant enrollment  
Incorporation of the letter to sites 
dated 09-DEC-2019 
Section 3.3.1 Risk 
Assessment 
6.2 Exclusion Criteria 
#21 
7.7.2 Prohibited 
Medications and 
Nondrug Therapies 
Section 12.7 
Appendix 7 
Removed exclusion for strong 
P-glycoprotein inhibitors 
Consistency with the most current 
Version 07 of the investigator’s 
brochure 
6.2 Exclusion Criteria 
#10 
Expanded text to include, “or 
preclude complete resolution of 
cystitis symptoms” 
Clarification purposes 
7.7 Concomitant 
Therapy 
Clarified that any antibiotic use 
within 6 months of the Baseline 
Visit should be recorded 
To support the study analysis 
7.7.1 Permitted 
Medications and 
Nondrug Therapies 
7.7.2 Prohibited 
Medications and 
Nondrug Therapies 
Section 12.7 
Appendix 7 
Clarified that low-dose 
acetylsalicylic acid is permitted as 
a concomitant medication if taken 
to prevent cardiovascular disease 
events 
To support study conduct and 
enrollment for a medication used 
in a manner that should not have 
an impact on the efficacy 
evaluations  
7.7.2 Prohibited 
Medications and 
Nondrug Therapies 
Section 12.7 
Appendix 7 
Added strong CYP3A4 inducers to 
the prohibited medications 
Alignment with preliminary results 
from a recently completed Phase I 
study  
Schedule of Activities 
9.4.1 Physical 
Examinations 
Clarified that the physical 
examination at the Test-of-Cure 
Visit may be symptom directed 
and was only required if indicated 
for a specific participant 
Incorporation of Protocol 
Administration Letter 3 


T M F -1 3 8 1 7 5 4 3  
C O N FI D E N TI A L  
 
 
 
2 0 4 9 8 9  
 
 
 
1 3 1  
 
S e cti o n # a n d N a me  
D e s cri pti o n of C h a n g e  
Bri ef R ati o n al e  
9. 1.2. 1 
Micr o bi ol o gic al 
O utc o m e a nd 
R es p o nse  
Mi n or t ext cl arific ati ons w ere 
a d de d to th e o utc o me a n d 
r es p o nse t abl es, a nd a n e w t a bl e 
( T a bl e 6) w as a dd e d t o d efin e 
p artici p a nt -l ev el micro bi ol ogic al 
o utc o m es a nd r es po nses  
T o pr ovi de cl arific ati o n t o sup p ort 
t h e pl a n n e d st atistic al a nalys es 
a n d pr o gr a m mi n g d etails  
9. 1.3 Cli nic al 
Ev al u atio n  
S u bs ecti o ns wer e ad d ed for t h e 
diff er e nt cli nic al eval u atio ns 
pl a n ne d f or pri m ary a nd 
ex pl or ato ry o bj ectiv es, mi n or t ext 
cl arific ati o ns w er e a dd e d t o t h e 
o utc o m e a nd r es po nse t ables  
T o pr ovi de cl arific ati o n t o sup p ort 
t h e pl a n n e d st atistic al a nalys es 
a n d pr o gr a m mi n g d etails  
Sy n o psis  
Sc h e dul e of Activiti es  
9. 1.3. 3 Uri n ary Tr act 
I nf ectio n Activity 
I mp air m e nt 
Ass ess m e nt  
I n dic ate d t his assess m e nt sh o ul d 
b e p erf or me d at th e e nd of th e 
st u dy visits a n d by a differ ent 
st u dy staff m e m ber t ha n th e 
p ers o n co nd ucti ng th e cli nical 
sy m pt o ms ass ess m ent an d 
sc ori n g 
T o prioritiz e c oll ecti on of t h e 
pri m ary effic acy cli nic al 
m e as ur e m e nts wit h se p ar ati o n 
fr o m t h e ex pl or at ory cli nic al 
m e as ur e m e nts  
Sc h e dul e of Activiti es  
9. 1.3. 1 Cli nic al Si g ns 
a n d Sy m pt o ms 
Sc or es, Cli nic al 
O utc o m es, a nd 
Cli nic al R es p o nse  
T hr o u gh o ut  
S ecti o n 6 A p pe n dix 6  
Cl arifi e d t h at t h e cli nic al si gns  a nd 
sy m pt o ms sc or es s ho ul d b e 
p erf or me d by a p hysici an or 
ot h er wis e a p pro priat ely m edic ally 
tr ai n e d st aff, an d th at t he s a m e 
sc or er s h o uld p erf or m t he 
ass ess m e nt at all ti me p oi nts 
w h e n ever p ossibl e, a n d cl arifi e d 
a d diti on al i nstructi o ns f or the 
c oll ecti on of dat a v er b ally to 
s u p port t he assess m e nt 
I nc or p orati o n of Pr ot ocol 
A d mi nistr ativ e L etter 3, whic h will 
s u p port c o nsiste nt d ata c ollecti o n 
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Section # and Name 
Description of Change 
Brief Rationale 
Schedule of Activities 
Throughout 
Appendix 5  
Added text to allow for eConsent, 
telemedicine study-related data 
collection, collection of visit data 
as a combination of telemedicine 
and on-site visits, remote source 
data verification, and eCRF sign-
off flexibility for investigators 
To support ongoing study conduct 
from safety and operational 
perspectives during the COVID-19 
pandemic 
10.2 Populations for 
Analyses 
Minor clarifications to the 
description of populations, 
including updates to analyze per 
randomized study treatment, 
where applicable  
Consistency with the planned 
statistical analysis and required 
outputs 
10.3.1 General 
Considerations 
Added text regarding 
supplemental analysis and 
additional analysis that may be 
needed per COVID-19 impact on 
the study 
Consistency with the planned 
statistical analysis and required 
outputs 
10.3.2 Efficacy 
Analyses 
10.3.3 Safety 
Analyses 
Minor clarifications to the plans for 
analysis 
Consistency with the planned 
statistical analysis and required 
outputs 
3.3.1 Risk 
Assessment 
Throughout 
Updates to protocol text, including 
risk/benefit and dose justification 
rationale text (i.e., added topline 
PK and safety results from a study 
in healthy adult and adolescent 
participants) per the most current 
investigator’s brochure; no new 
safety signals were identified or 
added 
Consistency with the most current 
Version 07 of the investigator’s 
brochure 
Appendix 4 Algorithm 
for Determining 
Qualifying 
Uropathogens 
Minor clarifications per the current 
plans for analysis 
Consistency with regulatory 
authority feedback and statistical 
analysis plans 
Throughout 
Clarified each treatment day 
would be assessed over 24 hours, 
clarified pregnancy testing 
requirements, and that the 
On-therapy Visit will occur on 
“Days 2 to 4” 
Incorporation of Protocol 
Administration Letter 2 


TMF-13817543 
CONFIDENTIAL 
 
 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Throughout  
Revised the in-text definitions of 
microbiological and clinical 
success to remove “specific to the 
disease under study” regarding 
the use of other systemic 
antimicrobials 
Corrected text to align with the 
original definitions of success in 
the endpoint definition tables 
Throughout 
Updated text to state Clostridium 
difficile and acetylcholinesterase 
inhibition events are considered 
adverse events of special interest 
To support the planned safety 
analysis 
Throughout 
Updated appendices order 
globally 
Consistency with in-text 
presentation order 
Throughout 
Minor editorial and document 
formatting revisions 
Minor, therefore, have not been 
summarized 
 

SAP_001.pdf: 
 
C O N FI D E N TI A L  
 
Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s  
 
2 0 4 9 8 9  
 
 
1  
 
Di visi o n  
: W orl d wi de De vel o p me nt  
I nf or m ati o n T y pe 
: Re p orti n g a n d A nal ysis Pla n ( R A P)  
 
Title  
: Re p orti n g a n d A nal ysis Pla n A me n d me nt 2  f or A P hase III, 
Ra n d o mize d, M ultice nter, Parallel -Gr o u p, D o u ble -Bli n d, 
D o u ble -D u m m y St u d y i n A d olesce nt a n d A d ult Fe male 
Partici pa nts C o m pari n g t he Efficac y a n d Safet y of 
Ge p oti daci n t o Nitr of ura nt oi n i n t he Treat me nt of 
U nc o m plicate d Uri n ar y Tract I nfecti o n ( Ac ute C ystitis)  
C o m p o u n d N u m ber  : G S K 2 1 4 0 9 4 4  
Cli nic al St u d y 
I de ntifier 
: 2 0 4 9 8 9  
Effecti ve D ate  
: 0 8 Se p 2 0 2 2  
 
Descri pti o n:  
•  T he p ur p ose of t his R A P is t o descri be t he pla n ne d a nal ys es a n d o ut p ut t o b e 
i ncl u de d i n t he Cli nical St u d y Re p ort f or Pr ot oc ol 2 0 4 9 8 9.  
•  T his R A P is i nte n de d t o descri be t he f ull a nal yses re q uire d f or t he st u d y.  
•  T his R A P will be pr o vi de d t o t he st u d y tea m me m bers t o c o n ve y t he c o nte nt of t he 
Statistical A nal ysis C o m plete ( S A C) deli vera ble.  
R A P A ut h or(s):  
A ut h or  
D ate  
A p pr o v al 
Met h o d  
 
Refer t o 
Si g nat ure  
Si g nat ure  
Se ni or Bi ostatisticia n ( Bi ostatistics, P P D)  
 
Refer t o 
Si g nat ure  
Si g nat ure  
Se ni or P har mac o ki neticist ( Bi ostatistics, P P D)  
 
C o p yri g ht 2 0 2 2  t he Gla x o S mit h Kli ne gr o u p of c o m pa nies. All ri g hts r eser ve d. 
U na ut h orize d c o p yi n g or use of t his i nf or mati o n is pr o hi bite d.  
P P D
P P D


 
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R A P Te a m A p pr o v als:  
A p pr o ver  
D ate  
A p pr o v al 
Met h o d  
 
1 2 A u g 2 0 2 2  
E mail  
Pri nci pal Statistic ia n ( Cli nical Statistics) 
 
2 6 A u g 2 0 2 2  
E mail  
Pri nci pal Pr o gra m mer/ A nal yst ( Cli nical 
Pr o gra m mi n g)  
 
0 1 Se p 2 0 2 2  
E mail  
 ( Cli nical 
Scie nces, I nfecti o us Dise ase)   
 
2 6 A u g 2 0 2 2  
E mail  
 ( Cli nical Data M a na ge m e nt) 
 
1 5 A u g 2 0 2 2  
E mail  
 
 
1 2 A u g 2 0 2 2  
E mail  
 ( C P M S) 
 
3 1 A u g 2 0 2 2  
E mail  
 ( S M G P har ma Safet y) 
 
2 6 A u g 2 0 2 2  
E mail  
 ( Cli nical Micr o bi ol o g y, 
I nfecti o us Dise ases Researc h U nit)  
Cli nic al St atistics a n d Cli nic al Pr o gr a m mi n g Li ne A p pr o v als:  
A p pr o ver  
D ate  
A p pr o v al 
Met h o d  
 
Refer t o 
Si g nat ure  
Si g nat ure  
 ( Cli nical Statistics) 
 
Refer t o 
Si g nat ure  
Si g nat ure  
Pr o gra m mi n g Lea der ( Cli nical Pr o gra m mi n g)  
 
Refer t o 
Si g nat ure  
Si g nat ure  
Pri nci pal Statistic ia n, Bi ostatistics ( Bi ostatistics, 
P P D)  
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
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TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 6 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 7 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 7 
2.2. 
Study Objective(s) and Estimand(s) / Endpoint(s) ......................................... 9 
2.2.1. 
Primary Estimand ........................................................................ 10 
2.2.2. 
Estimand for Secondary Endpoints .............................................. 12 
2.3. 
Study Design .............................................................................................. 16 
2.4. 
Statistical Hypotheses / Statistical Analyses ............................................... 17 
3. 
PLANNED ANALYSES .......................................................................................... 19 
3.1. 
Interim Analyses ......................................................................................... 19 
3.2. 
Final Analyses ............................................................................................ 21 
4. 
ANALYSIS POPULATIONS ................................................................................... 23 
4.1. 
Protocol Deviations ..................................................................................... 28 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 30 
5.1. 
Study Treatment & Subgroup Display Descriptors ...................................... 30 
5.2. 
Baseline Definitions .................................................................................... 31 
5.2.1. 
Qualifying Uropathogens ............................................................. 31 
5.3. 
Multicenter Studies ..................................................................................... 31 
5.4. 
Examination of Covariates, Other Strata and Subgroups ............................ 32 
5.4.1. 
Covariates and Other Strata ........................................................ 32 
5.4.2. 
Examination of Subgroups ........................................................... 33 
5.5. 
Multiple Comparisons and Multiplicity ......................................................... 34 
5.6. 
Analysis Visits ............................................................................................. 35 
5.7. 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 36 
6. 
STUDY POPULATION ANALYSES ....................................................................... 37 
6.1. 
Overview of Planned Study Population Analyses ........................................ 37 
6.1.1. 
Disposition and Protocol Deviations ............................................. 37 
6.1.2. 
Demographic and Baseline Disease Characteristics .................... 38 
6.1.3. 
Prior and Concomitant Medications ............................................. 39 
6.1.4. 
Medical History and Current Medical Conditions .......................... 39 
6.1.5. 
Treatment Exposure .................................................................... 39 
7. 
EFFICACY ANALYSES .......................................................................................... 41 
7.1. 
Primary Efficacy Analyses .......................................................................... 41 
7.1.1. 
Endpoint / Variables ..................................................................... 41 
7.1.2. 
Summary Measure ...................................................................... 44 
7.1.3. 
Population of Interest ................................................................... 44 
7.1.4. 
Strategy for Intercurrent Events ................................................... 44 
7.1.5. 
Treatment Condition .................................................................... 45 
7.1.6. 
Statistical Analyses / Methods ..................................................... 45 


 
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4  
 
7. 2.  
S e c o n d ar y Effi c a c y A n al y s e s  ...................................................................... 5 2  
7. 2. 1.  
E n d p oi nt / V ari a bl e s  ..................................................................... 5 2  
7. 2. 2.  
S u m m ar y M e a s ur e  ...................................................................... 5 5  
7. 2. 3.  
P o p ul ati o n of I nt er e st  ................................................................... 5 5  
7. 2. 4.  
Str at e g y f or I nt er c urr e nt E v e nt s  ................................................... 5 6  
7. 2. 5.  
Tr e at m e nt C o n diti o n  .................................................................... 5 6  
7. 2. 6.  
St ati sti c al A n al y s e s / M et h o d s  ..................................................... 5 6  
8.  
S A F E T Y A N A L Y S E S  ............................................................................................. 7 2  
8. 1.  
A d v er s e E v e nt s A n al y s e s  ........................................................................... 7 2  
8. 2.  
A d v er s e E v e nt s of S p e ci al I nt er e st A n al y s e s ( A E SI)  ................................... 7 3  
8. 2. 1.  
Cl o stri di u m diffi cil e  A E SI s  ............................................................ 7 3  
8. 2. 2.  
C ar di o v a s c ul ar a n d G a str oi nt e sti n al A E SI s  .................................. 7 3  
8. 2. 3.  
P ot e nti al A c et yl c h oli n e st er a s e -I n hi biti o n A E SI s ........................... 7 3  
8. 3.  
Cli ni c al L a b or at or y A n al y s e s  ....................................................................... 7 4  
8. 4.  
Vit al Si g n s a n d El e ctr o c ar di o gr a m ( E C G)  ................................................... 7 5  
8. 5.  
P h y si c al E x a mi n ati o n s  ................................................................................ 7 6  
9.  
P H A R M A C O KI N E TI C A N A L Y S E S  ......................................................................... 7 7  
9. 1.  
Pri m ar y P h ar m a c o ki n eti c A n al y s e s  ............................................................. 7 7  
9. 1. 1.  
E n d p oi nt / V ari a bl e s  ..................................................................... 7 7  
9. 1. 2.  
S u m m ar y M e a s ur e  ...................................................................... 7 7  
9. 1. 3.  
P o p ul ati o n of I nt er e st  ................................................................... 7 8  
9. 1. 4.  
Str at e g y f or I nt er c urr e nt E v e nt s  ................................................... 7 8  
9. 1. 5.  
St ati sti c al A n al y si s / M et h o d s  ....................................................... 7 8  
1 0.  A D DI TI O N A L A N A L Y S E S D U E T O T H E C O VI D -1 9 P A N D E MI C  ........................... 7 9  
1 0. 1.  St u d y P o p ul ati o n  ......................................................................................... 7 9  
1 0. 1. 1.  
S u bj e ct Di s p o siti o n  ...................................................................... 7 9  
1 0. 1. 2.  
Pr ot o c ol D e vi ati o n s  ...................................................................... 7 9  
1 0. 2.  S af et y  ......................................................................................................... 7 9  
1 1.  R E F E R E N C E S  ....................................................................................................... 8 0  
1 2.  A P P E N DI C E S  ........................................................................................................ 8 1  
1 2. 1.  A p p e n di x 1: S c h e d ul e of A cti viti e s  .............................................................. 8 1  
1 2. 2.  A p p e n di x 2: St u d y P h a s e s a n d Tr e at m e nt E m er g e nt A d v er s e 
E v e nt s  ........................................................................................................ 8 4  
1 2. 2. 1.  
St u d y P h a s e s  .............................................................................. 8 4  
1 2. 2. 2.  
Tr e at m e nt E m er g e nt Fl a g f or A d v er s e E v e nt s  ............................. 8 4  
1 2. 2. 3.  
P arti ci p a nt a n d St u d y C o m pl eti o n  ................................................ 8 5  
1 2. 3.  A p p e n di x 3: D at a Di s pl a y S t a n d ar d s & H a n dli n g C o n v e nti o n s .................... 8 6  
1 2. 3. 1.  
R e p orti n g Pr o c e s s  ....................................................................... 8 6  
1 2. 3. 2.  
R e p orti n g St a n d ar d s  .................................................................... 8 6  
1 2. 3. 3.  
R e p orti n g St a n d ar d s f or P h ar m a c o ki n eti c  .................................... 8 7  
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12.4. 
Appendix 4: Derived and Transformed Data ............................................... 88 
12.4.1. 
General ........................................................................................ 88 
12.4.2. 
Study Population .......................................................................... 88 
12.4.3. 
Safety .......................................................................................... 88 
12.4.4. 
Efficacy ........................................................................................ 91 
12.5. 
Appendix 5: Reporting Standards for Missing Data ................................... 101 
12.5.1. 
Premature Withdrawals .............................................................. 101 
12.5.2. 
Handling of Missing Data ........................................................... 101 
12.6. 
Appendix 6: Values of Potential Clinical Importance ................................. 103 
12.6.1. 
ECG ........................................................................................... 103 
12.6.2. 
Vital Signs .................................................................................. 103 
12.7. 
Appendix 7: Division of Microbiology and Infectious Diseases Adult 
Toxicity Tables for Adverse Event Assessment......................................... 104 
12.7.1. 
Laboratory Values ...................................................................... 104 
12.8. 
Appendix 8: Abbreviations & Trademarks ................................................. 108 
12.8.1. 
Abbreviations ............................................................................. 108 
12.8.2. 
Trademarks ............................................................................... 109 
12.9. 
Appendix 9: List of Data Displays ............................................................. 110 
12.9.1. 
Data Display Numbering ............................................................ 110 
12.9.2. 
Mock Example Shell Referencing .............................................. 110 
12.9.3. 
Deliverable, Priority and Conditional Column ............................. 110 
12.9.4. 
Footnotes................................................................................... 110 
12.9.5. 
Study Population Tables ............................................................ 111 
12.9.6. 
Study Population Figures ........................................................... 116 
12.9.7. 
Efficacy Tables .......................................................................... 117 
12.9.8. 
Efficacy Figures ......................................................................... 132 
12.9.9. 
Safety Tables ............................................................................. 134 
12.9.10. Safety Figures ........................................................................... 139 
12.9.11. Pharmacokinetic Tables ............................................................. 140 
12.9.12. ICH and Non-ICH Listings .......................................................... 141 
12.10. Appendix 10: Qualifying Uropathogen Algorithm ....................................... 150 
12.11. Appendix 11: Uropathogen Phenotype Algorithm ...................................... 155 
12.12. Appendix 12: Uropathogen Genotype Algorithm ....................................... 160 
12.13. Appendix 13: Uropathogen Grouping and Order Example ........................ 165 
12.13.1. Uropathogen Grouping and Gram Positive/Negative 
Example .................................................................................... 165 
12.13.2. Qualifying Uropathogen Grouping Example ............................... 166 
12.13.3. Display Order Example .............................................................. 166 
 


 
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1. 
INTRODUCTION 
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol 204989. 
Revision Chronology: 
Version 
Date 
Original 
14JAN2022 
Amendment No. 1 
26JUL2022 
Updates include: 
• 
Clarifications that the primary analysis population will be “micro-ITT NTF-S (IA Set)” if the study 
is stopped early for success (and inclusion of corresponding outputs). 
• 
Clarifications that <18 years and ≥18 to 50 years strata will be combined for use as an analysis 
covariate to ensure participants with valid data are not excluded. 
• 
Other minor edits for clarification. 
Amendment No. 2 
Refer to Last Signature 
Updates include: 
• 
Updates to the IA recommendation framework to include a supplementary analysis performed 
on a supplementary analysis population defined as the primary analysis population excluding 
participants from investigators/sites which have had a corrective and preventative action (CAPA) 
put in place requiring that a supplementary analysis excluding data from these sites be 
performed. This population will be labeled micro-ITT NTF-S (CAPA) population and will be 
performed on the IA Set if applicable. The updated IA recommendation framework requires both 
the primary and supplementary analyses to meet the NI boundary to stop the study for efficacy 
at the interim analysis. If the study continues at the interim, demonstration of NI at the final 
analysis will remain based on the primary analysis only (micro-ITT NTF-S) and the 
supplementary analysis (micro-ITT NTF-S (CAPA)) performed at the final analysis will be 
provided for descriptive purposes only. This is detailed in Section 2.4 and Section 5.5.  
o Note: demonstration of NI at the final analysis will remain based on the primary 
analysis only. 
o Note: At the IA, for testing futility against the boundary only the primary population 
(micro-ITT NTF-S (IA Set) population) should be used to determine if the futility 
boundary has been met. The micro-ITT NTF-S (CAPA) (IA Set) supplementary analysis 
will also be available to the IDMC. The Z-Statistic boundaries in this supplementary 
analysis will be consistent with the primary analysis and presented for reference (i.e., 
should not be used as formal hypothesis testing for futility). 
o Note: Sensitivity analyses (i.e., unadjusted treatment difference and treatment 
difference adjusting for strata as randomized) will also be available to the IDMC. The Z-
Statistic boundaries (for efficacy and/or futility) in these sensitivity analyses will be 
consistent with the primary analysis and presented for reference (i.e., should not be 
used as formal hypothesis testing). 
 


 
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2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
Changes to the planned statistical analysis specified in the protocol (Dated: 03-NOV-
2021) are listed below. 
• Whilst demonstration of NI at the final analysis (if the study continues at the IA) 
will remain based on the primary analysis only, the IA recommendation framework 
at the IA has been updated to include a supplementary analysis performed on a 
supplementary analysis population defined as the primary analysis population 
excluding participants from investigators/sites which have had a corrective and 
preventative action (CAPA) put in place requiring that a supplementary analysis 
excluding data from these sites be performed. This population will be labeled 
micro-ITT NTF-S (CAPA) population and will be performed on the IA Set if 
applicable. The updated IA recommendation framework requires both the primary 
and supplementary analyses to meet the NI boundary to stop the study for efficacy 
at the interim analysis. If the study continues at the interim analysis, 
demonstration of NI at the final analysis will remain based on the primary 
analysis only (micro-ITT NTF-S) and the supplementary analysis (micro-ITT 
NTF-S (CAPA)) performed at the final analysis will be provided for descriptive 
purposes only. This is detailed in Section 2.4 and Section 5.5. 
• Note: At the IA, for testing futility against the boundary only the primary 
population (micro-ITT NTF-S (IA Set) population) should be used to 
determine if the futility boundary has been met. The micro-ITT NTF-S 
(CAPA) (IA Set) supplementary analysis will also be available to the 
IDMC. The Z-Statistic boundaries in this supplementary analysis will be 
consistent with the primary analysis and presented for reference (i.e., 
should not be used as formal hypothesis testing for futility). 
• Note: Sensitivity analyses (i.e., unadjusted treatment difference and 
treatment difference adjusting for strata as randomized) will also be 
available to the IDMC. The Z-Statistic boundaries (for efficacy and/or 
futility) in these sensitivity analyses will be consistent with the primary 
analysis and presented for reference (i.e., should not be used as formal 
hypothesis testing). 
• The covariates used for adjusting the primary analyses have been updated to 
combine the <18 and ≥18- to 50-year-old participants. Due to small number of 
participants if the age groups weren’t combined <18-year-old participants with 
valid data may have been excluded from the primary analysis. This is because 
Miettinen and Nurminen method calculates the treatment difference within each 
stratum prior to combining stratum estimates to calculate a common risk 
difference. Therefore, as the treatment difference cannot be calculated within a 
stratum if there are only participants on one treatment arm within a stratum, and 
per current recruitment projections we do not expect the number of participants in 
the “<18 years, Nonrecurrent infection” and “<18 years, Recurrent infection” to 
increase substantially so there is a risk that there may be participants on only one 
treatment arm hence participants with valid data may have been excluded from 


 
C O N FI D E N TI A L  
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8  
 
t he pri mar y a n al ysis. To a v oi d t his, it is statisticall y a p pr o priate t o c o m bi ne t hese 
a ge gr o u ps. It is cli nicall y a p pr o priate t o c o m bi ne t hese a ge gr o u ps as t here is n o 
reas o n f or differe ntial s usce pti bilit y i n a d ults c o m pare d t o  a d oles ce nts a n d n o 
reas o n w h y t he treat me nt differe n ce b et wee n g e p o ti daci n a n d nitr o f ura nt oi n 
w o ul d be differe nt i n t hese gr o u ps . F or t h e pri mar y a n al ysis, t he test statistics of 
t he t hera pe utic s u ccess rate differe nce b et wee n t he 2 treat me nt gr o u ps 
( ge p oti daci n - nitr o f ura nt oi n) f or n o ni nferi orit y (-1 0 % mar gi n) will be calc ulate d 
usi n g t he Mietti ne n a n d N ur mi ne n met h o d stratifi e d b y a ge cate g or y ( ≤5 0 years, 
or > 5 0 years) a n d ac ute c ystitis rec urre nce ( n o nrec urre nt i nfecti o n or rec urre nt 
i nfecti o n) c o m bi nati o ns ( 4 strata) . 
•  A d diti o nal e x pl orat or y e n d p oi nt s were a d d e d, 
 
•  F or s u peri orit y testi n g, p -val ue will be use d i nstea d of Z statistic.  
•  Clarit y t hat a p artici pa nt will be c o nsi dere d t o ha ve c o m plete d treat me nt if s he has 
ta ke n all d oses of t he ra n d o ml y assi g ne d st u d y treat me nt, i.e. re gar dless of T O C 
Visit.  
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2.2. 
Study Objective(s) and Estimand(s) / Endpoint(s) 
Objectives 
Endpoints 
Primary 
Primary 
To assess the combined clinical and 
microbiological efficacy of gepotidacin 
compared to nitrofurantoin, at the Test-of-Cure 
(TOC) Visit, in female participants with acute 
cystitis with qualifying uropathogen(s) at 
Baseline that all are susceptible to 
nitrofurantoin 
Therapeutic response (combined per-participant 
microbiological and clinical response) at the TOC 
Visit. 
Secondary 
Secondary 
To assess the clinical efficacy of gepotidacin 
compared to nitrofurantoin, at the TOC and 
Follow-up Visits, in female participants with 
acute cystitis 
Clinical outcome and response at the TOC and 
Follow-up Visits. 
To assess the clinical efficacy of gepotidacin 
compared to nitrofurantoin, at the TOC and 
Follow-up Visits, in female participants with 
acute cystitis with qualifying uropathogen(s) at 
Baseline that all are susceptible to 
nitrofurantoin 
Clinical outcome and response at the TOC and 
Follow-up Visits. 
To assess the microbiological efficacy of 
gepotidacin compared to nitrofurantoin, at the 
TOC and Follow-up Visits, in female 
participants with acute cystitis with qualifying 
uropathogen(s) at Baseline that all are 
susceptible to nitrofurantoin 
Microbiological outcome and response at the 
TOC and Follow-up Visits. 
To assess the combined clinical and 
microbiological efficacy of gepotidacin 
compared to nitrofurantoin, at the Follow-up 
Visit, in female participants with acute cystitis 
with qualifying uropathogen(s) at Baseline that 
all are susceptible to nitrofurantoin 
Therapeutic response (combined per-participant 
microbiological and clinical response) at the 
Follow-up Visit. 
To determine the plasma and urine 
pharmacokinetic (PK) concentrations of 
gepotidacin in female participants with acute 
cystitis 
Gepotidacin plasma and urine concentrations  
To assess the safety and tolerability of 
gepotidacin compared to nitrofurantoin in 
female participants with acute cystitis 
Treatment-emergent AEs (TEAEs) and serious 
AEs (SAEs) and change from baseline results for 
clinical laboratory tests and vital sign 
measurements 
 
 
 


 
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1 0  
 
O bj e cti ve s  
E n d p oi nt s  
2. 2. 1.  
Pri m ar y E sti m a n d  
T he pri mar y cli nic al q uesti o n of i nterest is: W hat is t he treat me nt effect o n t hera pe utic 
s uccess r ate aft er 5 da ys treat me nt wit h ge p oti daci n 1 5 0 0 m g t wice d ail y c o m pare d t o 5 
da ys tr eat me nt wit h nitr of ura nt oi n 1 0 0  m g t wi ce d ail y i n partici p a nts wit h ac ute c ystitis  
wit h q ualif yi n g ur o p at h o ge n (s) at B aseli ne t h at all are s usce pti ble t o nitr of ura nt oi n, 
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regardless of treatment discontinuation for any reason. Receipt of systemic antimicrobials 
impacts the endpoint definition (see Section 7.1.1.2 to Section 7.1.1.3). 
The primary estimand is described by the following attributes: 
• Population: Female participants with acute cystitis with qualifying uropathogen(s) 
at Baseline that all are susceptible to nitrofurantoin.   
• Treatment condition: Gepotidacin 1500 mg twice daily for 5 days versus 
nitrofurantoin 100 mg twice daily for 5 days, regardless of adherence. 
• Variable: Therapeutic response (combined per participant microbiological and 
clinical response) at the Test of Cure (TOC) Visit. Microbiological success is 
defined as eradication (i.e. reduction) of all qualifying uropathogens recovered at 
Baseline to <103 CFU/ml as observed on quantitative urine culture without the 
participant receiving other systemic antimicrobials. Clinical success is defined as 
resolution of signs and symptoms of acute cystitis present at Baseline (and no new 
signs and symptoms) without the participant receiving other systemic 
antimicrobials. 
• Summary measure: difference in the therapeutic success rate in the gepotidacin 
and nitrofurantoin treatment groups (gepotidacin – nitrofurantoin).  
• Intercurrent events (ICE): 
o Study treatment discontinuation (due to any reason) – treatment policy 
strategy (interest is in the treatment effect regardless of study treatment 
discontinuation). 
o Use of systemic antimicrobials - composite strategy.  This intercurrent event 
is captured through the definitions of microbiological and clinical response 
(see Section 7.1.1.2 to Section 7.1.1.3) and will be counted as therapeutic 
failures.    
If the patient experiences both of these ICE then a composite strategy (assigning 
therapeutic response as a failure) will be used from the point that the relevant 
systemic antimicrobial was taken. 
Rationale for estimand: 
Interest lies in the treatment effect irrespective of whether the full course of 5 days of 
treatment was taken or not which reflects how patients may be treated in clinical practice.  
Hence a treatment policy strategy is appropriate for treatment withdrawal before 
completing 5 days of treatment. Use of other systemic antimicrobials may confound the 
bacterial culture results thus the microbiological response will be considered failure. For 
clinical data the use of a systemic antimicrobial for uUTI is a sign of treatment failure 
and use of a systemic antimicrobial for another infection can’t be considered a success as 
it confounds the assessment of efficacy. Therefore, the definition of a successful 
therapeutic response precludes the use of other systemic antimicrobials. 


 
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2.2.2. 
Estimand for Secondary Endpoints 
The secondary clinical questions of interest are: What is the treatment effect on each of 
the secondary efficacy endpoints after 5 days treatment with gepotidacin 1500 mg twice 
daily compared to 5 days treatment with nitrofurantoin 100 mg twice daily in participants 
with acute cystitis (clinical endpoints) and in participants with acute cystitis with 
qualifying uropathogen(s) at Baseline that all are susceptible to nitrofurantoin 
(therapeutic, clinical, and microbiological endpoints), regardless of treatment 
discontinuation for any reason. Receipt of systemic antimicrobials impacts the endpoint 
definitions (see Section 7.2.1.1, Section 7.2.1.2, and Section 7.2.1.3).   
For each of the secondary efficacy endpoints the estimand will follow a similar approach 
to the estimand for the primary endpoint and use the same strategies for the intercurrent 
events. The exception is the summary measure for the outcome endpoints. These 
endpoints are descriptively summarized and therefore the summary measure will be the 
percentage in each clinical and microbiological outcome category in the gepotidacin and 
nitrofurantoin arms separately (as no direct comparison between treatment groups will be 
made).  
The PK endpoint will use a while on treatment strategy for the intercurrent event of 
withdrawal from treatment since the PK will be assessed at all post baseline assessments 
irrespective of whether the patient completed the treatment. 
The safety endpoint will use a treatment policy strategy for the intercurrent event of 
withdrawal from treatment since the safety will be assessed at all post baseline 
assessments irrespective of whether the patient completed the treatment. Components of 
estimand for all secondary endpoints are listed in Table 1. 
 


 
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Table 1 
Estimand for Secondary Endpoints 
 
Population 
Treatment condition 
Variable 
Summary measure 
ICE 
Clinical response at 
the TOC and FU Visits 
Female participants 
with acute cystitis 
Gepotidacin 1500 mg 
twice daily for 5 days 
versus nitrofurantoin 
100 mg twice daily for 
5 days regardless of 
adherence. 
See Table 8 (Section  
7.1.1) and Table 11 
(Section 7.2.1) 
Difference in the 
Clinical success rate in 
the gepotidacin and 
nitrofurantoin 
treatment groups. 
Study treatment 
discontinuation (due to 
any reason) – 
treatment policy 
Use of systemic 
antimicrobials - 
composite strategy 
Clinical outcome at the 
TOC and FU Visits 
Female participants 
with acute cystitis 
Gepotidacin 1500 mg 
twice daily for 5 days 
versus nitrofurantoin 
100 mg twice daily for 
5 days regardless of 
adherence. 
See Table 8 (Section  
7.1.1) and Table 
11(Section 7.2.1) 
Percentage of 
participants in each 
outcome category in 
the gepotidacin and 
nitrofurantoin arms 
separately 
Study treatment 
discontinuation (due to 
any reason) – 
treatment policy 
Use of systemic 
antimicrobials - 
composite strategy 
Clinical response at 
the TOC and FU Visits 
Female participants 
with acute cystitis with 
qualifying 
uropathogen(s) at 
Baseline that all are 
susceptible to 
nitrofurantoin. 
Gepotidacin 1500 mg 
twice daily for 5 days 
versus nitrofurantoin 
100 mg twice daily for 
5 days regardless of 
adherence. 
See Table 8 (Section  
7.1.1) and Table 
11(Section 7.2.1) 
Difference in the 
Clinical success rate in 
the gepotidacin and 
nitrofurantoin 
treatment groups. 
Study treatment 
discontinuation (due to 
any reason) – 
treatment policy 
Use of systemic 
antimicrobials - 
composite strategy 


 
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Population 
Treatment condition 
Variable 
Summary measure 
ICE 
Clinical outcome at the 
TOC and FU Visits 
Female participants 
with acute cystitis with 
qualifying 
uropathogen(s) at 
Baseline that all are 
susceptible to 
nitrofurantoin 
Gepotidacin 1500 mg 
twice daily for 5 days 
versus nitrofurantoin 
100 mg twice daily for 
5 days regardless of 
adherence 
See Table 8 (Section  
7.1.1) and Table 11 
(Section 7.2.1) 
Percentage of 
participants in each 
outcome category in 
the gepotidacin and 
nitrofurantoin arms 
separately 
Study treatment 
discontinuation (due to 
any reason) – 
treatment policy 
Use of systemic 
antimicrobials - 
composite strategy 
Microbiological 
response at the TOC 
and FU Visits 
 
Female participants 
with acute cystitis with 
qualifying 
uropathogen(s) at 
Baseline that all are 
susceptible to 
nitrofurantoin. 
Gepotidacin 1500 mg 
twice daily for 5 days 
versus nitrofurantoin 
100 mg twice daily for 
5 days regardless of 
adherence. 
See Table 7 (Section 
7.1.1) and Table 10 
(Section 7.2.1) 
Difference in the 
microbiological 
success rate in the 
gepotidacin and 
nitrofurantoin 
treatment groups. 
Study treatment 
discontinuation (due to 
any reason) – 
treatment policy 
Use of systemic 
antimicrobials - 
composite strategy 
Microbiological 
outcome at the TOC 
and FU Visits 
Female participants 
with acute cystitis with 
qualifying 
uropathogen(s) at 
Baseline that all are 
susceptible to 
nitrofurantoin. 
Gepotidacin 1500 mg 
twice daily for 5 days 
versus nitrofurantoin 
100 mg twice daily for 
5 days regardless of 
adherence. 
See Table 7 (Section 
7.1.1) and Table 10 
(Section 7.2.1) 
Percentage of 
participants in each 
outcome category in 
the gepotidacin and 
nitrofurantoin arms 
separately 
Study treatment 
discontinuation (due to 
any reason) – 
treatment policy 
Use of systemic 
antimicrobials - 
composite strategy 
Therapeutic response 
at the FU Visit 
Female participants 
with acute cystitis with 
qualifying 
uropathogen(s) at 
Baseline that all are 
Gepotidacin 1500 mg 
twice daily for 5 days 
versus nitrofurantoin 
100 mg twice daily for 
See Table 10 and 
Table 11(Section 
7.2.1) 
Difference in the 
therapeutic success 
rate in the gepotidacin 
and nitrofurantoin 
treatment groups. 
Study treatment 
discontinuation (due to 
any reason) – 
treatment policy 


 
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Population 
Treatment condition 
Variable 
Summary measure 
ICE 
susceptible to 
nitrofurantoin. 
5 days regardless of 
adherence. 
Use of systemic 
antimicrobials - 
composite strategy 
Pharmacokinetic (PK) 
Female participants 
with acute cystitis  
Gepotidacin 1500 mg 
twice daily for 5 days 
See Section 9.1.1.1 
Summary statistics 
(appropriate for each 
type of endpoint) in the 
gepotidacin arm  
Study treatment 
discontinuation (due to 
any reason) – while on 
treatment strategy 
(treatment phase 
defined as from first 
dose to OT Visit) 
Safety  
Female participants 
with acute cystitis 
Gepotidacin 1500 mg 
twice daily for 5 days 
versus nitrofurantoin 
100 mg twice daily for 
5 days regardless of 
adherence. 
TEAEs, SAEs, as well 
as change from 
baseline results for 
clinical laboratory 
tests, and vital sign 
measurements. 
Summary statistics 
(appropriate for each 
type of endpoint) in the 
gepotidacin and 
nitrofurantoin arms 
separately 
Study treatment 
discontinuation (due to 
any reason) – 
treatment policy 
 
 


 
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2.3. 
Study Design 
Overview of Study Design and Key Features 
The study design schematic is shown in Figure 1. 
Figure 1 
Study Design Schematic 
 
BID=twice daily; HPF=high-power field; TOC=Test-of-Cure; WBC=white blood cell. 
a. There will be central randomization with stratification by age category (<18 years, ≥18 to 50 years, or >50 
years) and acute cystitis recurrence (nonrecurrent infection or recurrent infection, defined as a confirmed 
infection [not including the current infection in the calculation] with at least 1 prior episode within the past 3 
months, at least 2 prior episodes within the past 6 months, or at least 3 prior episodes within the past 12 months 
before study entry). 
b. Study treatment will be administered under double-blind, double-dummy conditions. Each dose should be taken 
after food consumption and with water. 
Design 
Features 
• Phase III, randomized, multicenter, parallel-group, double blind, double-dummy, 
comparator-controlled, noninferiority study 
• The study duration is approximately 28 days with 4 planned study visits 
• Baseline (Day 1) Visit 
• On-Therapy (Day 2 to 4) Visit 
• TOC (Day 10 to 13) Visit 
• Follow-up (Day 28±3) Visit 
• The study will enroll approximately 2500 participants to fulfill the maximum target 
sample size of 884 participants with acute cystitis in the micro-ITT NTF-S 
Population, for an estimated total of approximately 442 evaluable participants per 
treatment group. The final number of randomized subjects may vary depending on 
the actual evaluability rate and review of qualifying uropathogens by an unblinded 
Statistical Data Analysis Center (SDAC). Therefore, enrollment will continue until 
the approximate target number of participants in the primary analysis population 
(micro-ITT NTF-S Population) has been reached. 


 
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Overview of Study Design and Key Features 
Dosing 
• Participants will receive oral study treatment (gepotidacin [2 tablets] + 
nitrofurantoin matching placebo [1 capsule] or nitrofurantoin [1 capsule] + 
gepotidacin matching placebo [2 tablets]) BID (approximately every 12 hours) for 5 
days. The first oral dose will be administered at the study site during the Baseline 
Visit; participants will self-administer subsequent doses as outpatients thereafter, 
beginning with the second dose, with the exception of 1 dose at the OT Visit that 
will be taken at the study site whenever possible.  
Time & Events 
• Refer to Appendix 1 
Treatment 
Assignment 
• Participants will be stratified, as described in Figure 1, and will be randomly 
assigned in a 1:1 ratio to receive one of the following study treatments: 
• Gepotidacin: 1500 mg administered orally twice daily (BID) for 5 days  
• Nitrofurantoin: 100 mg administered orally BID for 5 days 
Interim 
Analysis 
• One interim analysis will be planned to assess futility and efficacy or futility only. 
An independent data monitoring committee (IDMC) will review unblinded data to 
make recommendations to GSK. Details regarding the IDMC process will be 
available in relevant IDMC documents. 
2.4. 
Statistical Hypotheses / Statistical Analyses 
The study is designed to determine whether gepotidacin administered orally is 
noninferior compared with nitrofurantoin administered orally on the primary efficacy 
endpoint of therapeutic response (combined per-participant microbiological and clinical 
response) at the TOC Visit in participants with a qualifying uropathogen at Baseline that 
is susceptible to nitrofurantoin. Microbiological success per-participant is defined as 
eradication (i.e., reduction of all qualifying uropathogens recovered at Baseline to 
<103 CFU/mL as observed on quantitative urine culture) without the participant receiving 
other systemic antimicrobials prior to the urine culture assessment conducted at the TOC 
Visit (evaluated at the resolution of minutes). Clinical success is defined as resolution of 
all signs and symptoms of acute cystitis present at Baseline (and no new signs and 
symptoms) without the participant receiving other systemic antimicrobials. For systemic 
antimicrobials received for the current infection (as rescue treatment) prior to or on the 
TOC Visit will be considered a clinical failure. For systemic antimicrobials received for 
other infection (as non-rescue treatment) prior to the TOC Visit will be considered a 
clinical failure. 
The following are null and alternative hypotheses for the primary analysis of the 
therapeutic success rates at the prespecified noninferiority margin of -10.0%: 
H0: therapeutic success rate of Gepotidacin 1500 mg BID – therapeutic success rate 
of Nitrofurantoin 100 mg BID ≤ -10.0% 
H1: therapeutic success rate of Gepotidacin 1500 mg BID – therapeutic success rate 
of Nitrofurantoin 100 mg BID >-10.0% 
At the interim, if the Z statistic (for the primary analysis population) is higher than the Z 
statistic boundary for noninferiority, noninferiority will be tested in a supplementary 
analysis population (micro-ITT NTF-S (IA Set) (CAPA)) to ensure consistency. If the Z 
statistic (for the supplementary analysis population) is also higher than the Z statistic 
boundary for noninferiority the study will be stopped for efficacy and noninferiority will 


 
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be declared.  
Note: The stopping boundaries for this key supplementary analysis will be consistent 
with the primary analysis (as will the null and alternative hypotheses), the futility bounds 
will be presented for reference only (and not to be used as formal futility hypothesis 
testing).  
At the final analysis (if the study continues at the IA), if the Z statistic (for the primary 
analysis population) is higher than the Z statistic boundary for noninferiority the study 
will be declared successful and noninferiority will be declared. Refer to Section 5.5 for 
further details on study success definition and IA recommendation framework. 
If noninferiority is declared between gepotidacin and nitrofurantoin, superiority will be 
tested in the primary analysis population with the following null and alternative 
hypotheses: 
H0: therapeutic success rate of gepotidacin 1500 mg BID – therapeutic success rate 
of nitrofurantoin 100 mg BID ≤0% 
H1: therapeutic success rate of gepotidacin 1500 mg BID – therapeutic success rate 
of nitrofurantoin 100 mg BID >0% 
If the one-sided p-value is less than the p-value boundary superiority of gepotidacin will 
be declared.  
The difference in therapeutic success rates between the two study treatment groups and 
its Z statistic use the Miettinen-Nurminen (MN) method Miettinen, 1985) stratified by 
age category (≤50 years, or >50 years) and acute cystitis recurrence (nonrecurrent 
infection or recurrent infection) combinations. In the event that any participants are mis-
stratified, for the primary efficacy analysis, the actual age and acute cystitis collected in 
eCRF will be used to create actual pooled stratification. A sensitivity analysis of the 
primary efficacy analysis will also be conducted from the pooled stratification as 
randomized. 


 
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3. 
PLANNED ANALYSES 
3.1. 
Interim Analyses 
One IA is planned to assess either both efficacy (noninferiority) and futility or just futility 
by the IDMC. The IDMC will meet when approximately 60% of participants in the 
micro-ITT NTF-S Population have achieved the TOC Visit to evaluate the primary 
endpoint, identify potential treatment benefit, and make recommendations for continuing 
or stopping the study, as per the IDMC charter. The scope of data for the IA reporting 
will include (a) participants who had the opportunity to reach their Test of Cure (TOC) 
visit and (b) participants who have not yet reached their TOC visit, but are already known 
to be failures (e.g., subjects who took other systemic antimicrobial or withdrew from the 
study before the TOC visit). The IDMC members will include at least 3 independent 
experts (from a total of 5 planned), including an infectious disease specialist, a 
chairperson with experience chairing IDMC meetings, and a statistician. Details 
regarding the IDMC process will be described in the IDMC charter. 
The Statistical Data Analysis Centre (SDAC), a PPD unblinded statistical team, will 
conduct and provide all unblinded analyses to the IDMC before the meeting is held. The 
GSK and PPD study teams that are operating the study and conducting the final analysis 
will remain blinded. The IDMC and SDAC will maintain unblinded data in a secure area 
to ensure the integrity of the data until the study is completed. Details on protecting blind 
and data integrity will be described in a blinding plan.  
At the time the IA is conducted, the IDMC will review unblinded data to confirm that 
sufficient microbiological data exist for the unblinded gepotidacin treatment arm before 
deciding how to proceed as detailed in the IA RAP. 
If the IDMC confirms there is sufficient microbiology data in the gepotidacin arm, an IA 
with stopping rules for both efficacy and futility will be performed. The nominal 
significance levels for the interim and final analyses will be determined by the 
Lan-DeMets spending functions approach [Lan , 1983]. This will be based on the Pocock 
stopping boundary for efficacy and the O’Brien-Fleming stopping boundary for futility. 
The futility bounds of this study are nonbinding and are considered guidance rather than 
strict bounds. The IA recommendation framework requires both the primary and 
supplementary analyses to meet the NI boundary to stop the study for efficacy at the 
interim analysis as described in Section 5.5. For futility, only the micro-ITT NTF-S 
population will be used to determine if the futility boundary has been met (i.e., not the 
micro-ITT NTF-S (CAPA) population). 
During the course of the IA, patients will continue to be randomized. If efficacy success 
(i.e., noninferiority) is reached at the IA and the study is stopped early, the IA efficacy 
results will be the primary analysis to support the effectiveness of the study. If efficacy 
success is not reached at the IA, the study will continue to the maximum target sample 
size for the micro-ITT NTF-S Population of approximately 884 participants. 
If, at the IA, the IDMC confirms that there is not sufficient microbiology data in the 
gepotidacin arm, then a futility-only IA will be conducted. The nominal significance 
levels for the interim and final analyses will be determined by the Lan-DeMets spending 


 
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functions approach [Lan , 1983]. This will be based on the O’Brien-Fleming stopping 
boundary for futility. The futility bounds of this study are nonbinding and are considered 
guidance rather than strict bounds. Note: only the micro-ITT NTF-S population will be 
used to determine if the futility boundary has been met (i.e., not the micro-ITT NTF-S 
(CAPA) population). The stopping boundaries will be calculated under the assumption of 
an approximate maximum sample size of 768 participants in the micro-ITT NTF-S 
Population, a 76% therapeutic success rate for nitrofurantoin, a -10.0% noninferiority 
margin and a 0.025 one-sided alpha level. If the decision is to continue at IA, the 
boundary for final analyses will not be updated as it is based on the planned sample size. 
Table 2 summarizes the information fraction, sample size and decision guidance 
(boundaries in Z-statistics and p-value, cumulative alpha, and beta) for the planned IA at 
60% timing (i.e., a planned end of study sample size of 884 participants in the micro-ITT 
NTF-S Population) with a -10.0% noninferiority margin, 0.025 one-sided type I error and 
a 0.1 type II error approximately and assuming a 76% therapeutic success rate for 
nitrofurantoin. If the decision is to continue at IA, the boundary for final analyses will not 
be updated as it is based on the planned sample size of 884. 
Table 2 
Information Fraction and Stopping Boundaries  for Efficacy and 
Futility IA  
Informatio
n Fraction 
Target 
Sampl
e Size 
for 
each 
study 
Efficacy Boundary 
Non-Binding Futility 
Boundary 
Z 
statistic
s 
p-
value 
Cumulativ
e alpha 
Z 
statistic
s 
p-
value 
Cumulativ
e beta 
60% 
530 
>2.104 
<0.01
8 
0.018 
<0.854 
>0.19
7 
0.033 
100% 
884 
>2.23 
<0.01
3 
0.025 
<2.23 
>0.01
3 
0.098 
Information fraction is determined using CLSI based micro-ITT NTF-S. Testing for 
noninferiority and superiority share the same Z statistics and p-value boundaries.  
Table 3 summarizes the information fraction, sample size, and decision guidance 
(boundaries in Z-statistics and p-values, cumulative beta) for the planned IA for futility 
only. The IA will occur at 530 participants and this corresponds to 69% information 
fraction for futility-only IA (i.e., a planned end of study sample size of 768 participants in 
the micro-ITT NTF-S Population) with a -10.0% noninferiority margin, 0.025 one-sided 
type I error and assuming a 76% therapeutic success rate for nitrofurantoin. The actual 
boundaries will be determined based on the actual information fraction in the micro-ITT 
NTF-S (IA Set) population at the time of IA. If the decision is to continue at IA, the 
boundary for final analyses will not be updated as it is based on the planned sample size 
of 768. Boundaries are calculated in software EAST using Wald statistics without 
adjusting for strata. 


 
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Table 3 
Information Fraction and Stopping Boundaries for Futility Only IA  
Information 
Fraction 
Target 
Sample 
Size for 
each study 
Non-Binding Futility Boundary 
Z statistics 
p-value 
Cumulative beta 
69% 
530 
<1.128 
>0.13 
0.059 
100% 
768 
<1.96 
>0.025 
0.116 
Information fraction is determined using CLSI based micro-ITT NTF-S 
The efficacy boundaries and non-binding futility boundaries in Table 2 and Table 3 are 
based on initially assigned information fraction and are calculated in software EAST 
using Wald statistics without adjusting for strata. The actual boundaries will be 
determined based on the actual information fraction in the micro-ITT NTF-S (IA Set) 
population at the time of IA. If the decision is to continue at IA, the boundary for end of 
study analyses will not be updated as it is based on the planned sample size. 
Sensitivity analyses (i.e., unadjusted treatment difference and treatment difference 
adjusting for strata as randomized) will also be available to the IDMC. The Z-Statistic 
boundaries (for efficacy and/or futility) in these sensitivity analyses will be consistent 
with the primary analysis and presented for reference (i.e., should not be used as formal 
hypothesis testing). 
Conditional power will be calculated based on the observed data at the time of the IA for 
each study individually and will be provided purely for additional information to 
facilitate the decision around stopping for futility. It will not be used to facilitate any 
decision on stopping for success. 
Additional details on IA designs, microbiological data criteria, stopping boundaries, 
content, and structure of the data output for IA are described in the IDMC charter and a 
separate IA analysis plan. 
3.2. 
Final Analyses 
The final planned primary analyses will be performed after the completion of the 
following sequential steps: 
1. All participants have completed the study as defined in the protocol at the FU Visit.  
2. If the study is stopped for success at the IA, primary inferential analysis and a small 
set of supporting analyses will be repeated on the complete data for participants 
included in the IA to ensure consistency. Data collected after the IA data cut are 
considered overrun. Overrun participants will be pooled with the IA participants for 
all analyses defined in this document except the primary inferential analysis. If the 
study is not stopped for success, all analyses will be performed on all participant data 
after study completion.   


 
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3. All protocol deviations captured and categorized, and analysis populations defined. 
4. All final database cleaning and data lock activities completed by data management. 
5. All criteria for the unblinding of subject randomization codes have been achieved. 
6. All randomization codes have been distributed per standard operating procedures. 


 
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4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses Evaluated 
Screened 
Population 
• All participants who were screened for 
eligibility 
• Participants will be analyzed according to their 
randomized study treatment. 
• Study Population 
•  
Intent-to-Treat 
(ITT) Population 
• All participants randomly assigned to study 
treatment.  
• Participants will be analyzed according to their 
randomized study treatment. 
• Study Population 
• Efficacy 
Microbiological 
ITT (micro-ITT) 
Population 
• All participants randomly assigned to study 
treatment who receive at least 1 dose of study 
treatment and have a qualifying baseline 
uropathogen from a quantitative bacteriological 
culture of a pretreatment clean-catch midstream 
urine specimen.  
• Participants will be analyzed according to their 
randomized study treatment. 
• Study Population 
• Efficacy 
micro-ITT NTF-S 
Population 
• All participants in the micro-ITT Population 
whose baseline qualifying uropathogens are all 
susceptible to nitrofurantoin (NTF-S)1. 
Participants with missing MIC susceptibility 
results for any qualifying uropathogens will not 
be included in the NTF-S sub-Population.  
• Participants will be analyzed according to their 
randomized study treatment. 
• Study Population 
• Efficacy 
(including the 
primary efficacy 
analysis if the 
study does not 
stop for efficacy) 
micro-ITT NTF-S 
(IA Set) 
Population 
• All participants in the micro-ITT NTF-S 
Population who, per the interim analysis data, 
had: 
a) the opportunity to reach their Test of Cure 
(TOC) visit, or 
b) had not yet reached their TOC visit, but 
were already known to be failures (e.g., 
subjects who took other systemic 
antimicrobial or withdrew from the study 
before the TOC visit) 
• Participants will be analyzed according to their 
randomized study treatment. 
Note: this population will only be used as the 
primary analysis population if the study stops for 
efficacy. 2 
 
• Study Population 
• Efficacy 
(including the 
primary efficacy 
analysis if the 
study stops for 
efficacy) 
micro-ITT NTF-
NS Population 
• All participants in the micro-ITT Population 
who have any baseline qualifying uropathogens 
that are NTF-NS, defined as resistant to 
nitrofurantoin (NTF-R), or intermediate to 
nitrofurantoin (NTF-I), or no interpretation to 
nitrofurantoin (NTF-NI), Participants missing 
MIC susceptibility results for all qualifying 
• Study Population 
• Efficacy 


 
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Population 
Definition / Criteria 
Analyses Evaluated 
uropathogens will not be included in the NTF-
NS sub-Population.  
• Participants will be analyzed according to their 
randomized study treatment. 
Microbiologically 
Evaluable at OT 
(ME-OT) 
Population 
• Participants who meet the definition of the 
micro-ITT Population, follow important 
components of the study (i.e., (1) receive at least 
80% of planned doses as randomized and actual 
treatment received is the same as randomized, 
(2) have an interpretable quantitative urine 
culture at the OT Visit and evaluable clinical 
scores at the baseline and the OT Visit, (3) have 
not taken any other systemic antimicrobial 
before OT unless it was taken for the current 
infection (therapeutic failure), and (4) have no 
other major protocol deviation that prevents 
evaluation of efficacy. 
• Participants will be analyzed according to their 
randomized study treatment, however, by 
definition, for all participants in this analysis 
population the actual treatment received is the 
same as randomized. 
• Efficacy 
Microbiologically 
Evaluable at TOC 
(ME-TOC) 
Population 
• Participants who meet the definition of the 
micro-ITT Population, follow important 
components of the study (i.e., (1) receive at least 
80% of planned doses as randomized and actual 
treatment received is the same as randomized, 
(2) have an interpretable quantitative urine 
culture at the TOC Visit and evaluable clinical 
scores at the baseline and the TOC Visit, (3) 
have not taken any other systemic antimicrobial 
before TOC unless it was taken for the current 
infection, and (4) have no other major protocol 
deviation that prevents evaluation of efficacy. 
• Participants will be analyzed according to their 
randomized study treatment, however, by 
definition, for all participants in this analysis 
population the actual treatment received is the 
same as randomized. 
• Efficacy 
Microbiologically 
Evaluable at FU 
(ME-FU) 
Population 
• Participants who meet the definition of the 
micro-ITT Population, follow important 
components of the study (i.e., (1) receive at least 
80% of planned doses as randomized and actual 
treatment received is the same as randomized, 
(2) have an interpretable quantitative urine 
culture at FU Visit (unless microbiological 
outcome at TOC is persistence or recurrence) 
and evaluable clinical scores at the baseline and 
the FU Visit (unless clinical outcome at TOC is 
clinical improvement or worsening), (3) have 
not taken any other systemic antimicrobial 
• Efficacy 


 
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Population 
Definition / Criteria 
Analyses Evaluated 
before FU unless it was taken for the current 
infection (therapeutic failure), and (4) have no 
other major protocol deviation that prevents 
evaluation of efficacy. 
• Participants will be analyzed according to their 
randomized study treatment, however, by 
definition, for all participants in this analysis 
population the actual treatment received is the 
same as randomized. 
ME-OT NTF-S 
Population 
• All participants in the ME-OT Population whose 
baseline qualifying uropathogens are all 
susceptible to nitrofurantoin. 
• Participants will be analyzed according to their 
randomized study treatment, however, by 
definition, for all participants in this analysis 
population the actual treatment received is the 
same as randomized. 
• Efficacy 
ME-OT NTF-NS 
Population 
• All participants in the ME-OT Population who 
have any baseline qualifying uropathogens that 
are NTF-NS. 
• Participants will be analyzed according to their 
randomized study treatment, however, by 
definition, for all participants in this analysis 
population the actual treatment received is the 
same as randomized. 
• Efficacy 
ME-TOC NTF-S 
Population 
• All participants in the ME-TOC Population 
whose baseline qualifying uropathogens are all 
susceptible to nitrofurantoin. 
• Participants will be analyzed according to their 
randomized study treatment, however, by 
definition, for all participants in this analysis 
population the actual treatment received is the 
same as randomized. 
• Efficacy 
ME-TOC NTF-NS 
Population 
• All participants in the ME-TOC Population who 
have any baseline qualifying uropathogens that 
are NTF-NS. 
• Participants will be analyzed according to their 
randomized study treatment, however, by 
definition, for all participants in this analysis 
population the actual treatment received is the 
same as randomized. 
• Efficacy 
ME-FU NTF-S 
Population 
• All participants in the ME-FU Population whose 
baseline qualifying uropathogens are all 
susceptible to nitrofurantoin. 
• Participants will be analyzed according to their 
randomized study treatment, however, by 
definition, for all participants in this analysis 
population the actual treatment received is the 
same as randomized. 
• Efficacy 


 
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Population 
Definition / Criteria 
Analyses Evaluated 
ME-FU NTF-NS 
Population 
• All participants in the ME-FU Population who 
have any baseline qualifying uropathogens that 
are NTF-NS. 
• Participants will be analyzed according to their 
randomized study treatment, however, by 
definition, for all participants in this analysis 
population the actual treatment received is the 
same as randomized. 
• Efficacy 
Clinically 
Evaluable at OT 
(CE-OT) 
Population 
• All participants in the ITT Population who 
follow important components of the study as 
specified in the protocol (i.e., (1) receive at least 
80% of planned doses as randomized and actual 
treatment received is the same as randomized, 
(2) have evaluable clinical scores of signs and 
symptoms at the baseline and the OT Visit, (3) 
have not received other systemic antimicrobials 
before OT unless it was for the current infection 
(therapeutic failure), and (4) have no other major 
protocol deviation that prevents evaluation of 
efficacy). 
• Participants will be analyzed according to their 
randomized study treatment, however, by 
definition, for all participants in this analysis 
population the actual treatment received is the 
same as randomized. 
• Efficacy 
Clinically 
Evaluable at TOC 
(CE-TOC) 
Population 
• All participants in the ITT Population who 
follow important components of the study as 
specified in the protocol (i.e., (1) receive at least 
80% of planned doses as randomized and actual 
treatment received is the same as randomized, 
(2) have evaluable clinical scores of signs and 
symptoms at the baseline and the TOC Visits, 
(3) have not received other systemic 
antimicrobials before TOC unless it was for the 
current infection (therapeutic failure), and (4) 
have no other major protocol deviation that 
prevents evaluation of efficacy.  
• Participants will be analyzed according to their 
randomized study treatment, however, by 
definition, for all participants in this analysis 
population the actual treatment received is the 
same as randomized. 
• Study Population 
• Efficacy 
Clinically 
Evaluable at FU 
(CE-FU) 
Population 
• All participants in the ITT Population who 
follow important components of the study as 
specified in the protocol (i.e., (1) receive at least 
80% of planned doses as randomized and actual 
treatment received is the same as randomized, 
(2) have evaluable clinical scores of signs and 
symptoms at the baseline and the FU Visit 
(unless clinical outcome at TOC is clinical 
• Efficacy 


 
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Population 
Definition / Criteria 
Analyses Evaluated 
improvement or worsening), (3) have not 
received other systemic antimicrobials before 
FU unless it was for the current infection 
(therapeutic failure), and (4) have no other major 
protocol deviation that prevents evaluation of 
efficacy). 
• Participants will be analyzed according to their 
randomized study treatment, however, by 
definition, for all participants in this analysis 
population the actual treatment received is the 
same as randomized. 
Safety Population 
• All randomized participants who receive at least 
1 dose of study treatment.  
• Participants will be analyzed according to their 
actual treatment received. 
Note: if a participant receives both gepotidacin and 
nitrofurantoin they will be summarized within 
gepotidacin 1500 mg BID.  
• Safety 
Pharmacokinetic 
(PK) Population 
• All randomized participants who receive at least 
1 dose of study treatment and have at least 1 
nonmissing plasma or urine PK concentration. 
This population will be used for listing and 
summary of plasma and urine gepotidacin 
concentration-time data and population PK 
(plasma) analysis, as data permit. 
• Participants will be reported according to their 
actual treatment received. 
Note: if a participant receives both gepotidacin and 
nitrofurantoin they will be listed only (i.e., not 
summarized within gepotidacin 1500 mg BID). .   
Note: Plasma and/or urine samples for participant 
randomized to Nitrofurantoin will not be measured. 
• PK 
1. Broth microdilution nitrofurantoin MIC result from JMI Laboratories (if available) will take 
precedence over global central laboratory (GCL) nitrofurantoin MIC result for determining 
susceptibility to nitrofurantoin. 
2. The micro-ITT NTF-S (IA Set) Population will include participants who have completed their 
TOC Visit or had the opportunity to reach their TOC visit (determined by the last day of the 
TOC visit analysis window per Table 5) as of the IA data cut-off. Participants who have not 
had the opportunity to reach their TOC Visit but are known failures (per the SDTM datasets 
used in the interim analyses) will be in scope of the IA Set if they are randomized prior to the 
IA data cut-off.  
Notes: 
• 
Refer to Appendix 9: List of Data Displays. 
• 
Qualifying uropathogens specified in any study populations above include only the 
uropathogen species/groups [Gram-negative bacilli (e.g. E. coli, K. pneumoniae, P. 
mirabilis), S. saprophyticus, and Enterococcus spp.], as described in Section 7.3.2. 
• 
Evaluable clinical score means non-missing clinical score. 
• 
Significant deviations which prevent evaluation of efficacy and result in exclusion from 
CE/ME analysis populations will be determined by the study team throughout the conduct 
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The term “CE Population” is used to refer to all CE Populations. The term “ME 
Population” is used to refer to all ME Populations. 
Inclusion into the ITT, Safety, and PK Population will be determined programmatically 
from eCRF data. 
Inclusion criteria for the micro-ITT/NTF-S/NTF-NS, ME Populations, and CE 
Populations will be determined programmatically and through manual review conducted 
by the Sponsor. The Sponsor will be blinded to treatment assignment and may review the 
data concurrent with conduct of the study. Final determination of population inclusion 
will be performed after database lock and prior to unblinding. Exclusion from ME/CE 
Populations related to receipt of incorrect study drug will be determined 
programmatically after unblinding. 
Nitrofurantoin susceptibility interpretations will be based on the Clinical and Laboratory 
Standards Institute (CLSI) guidelines to determine participant inclusion into the NTF-
S/NTF-NS subpopulations except as described in Section 7.1.6.3. 
If the study stops for efficacy the primary analysis population will be the micro-ITT 
NTF-S (IA Set) Population, and the micro-ITT NTF-S Population (complete trial data 
including participants included in the IA and overrun participants) will be used for 
sensitivity analyses (as described in Section 7.1.6.2) to provide a nominal estimate of the 
treatment difference and 95% CI. If the study does not stop for efficacy the primary 
analysis population will be the micro-ITT NTF-S Population (complete trial data). 
In the event that one or more investigators/sites have had a corrective and preventative 
action (CAPA) put in place requiring that a supplementary analysis excluding data from 
these sites be performed, a supplementary analysis will be performed. A flag will be 
included to identify subjects enrolled by those investigators/sites. This will enable further 
subpopulations to be defined for the primary analysis populations (micro-ITT NTF-S if 
the study continues / micro-ITT NTF-S (IA Set) if the study stops for futility). The sub 
population will consist of all subjects in the primary analysis population except subjects 
from those investigative sites (e.g., micro-ITT NTF-S (CAPA)/ micro-ITT NTF-S (IA 
Set) (CAPA) respectively) and will be used to perform the additional supplemental 
analysis for the primary efficacy endpoint only. Note: this analysis is included in the IA 
recommendation framework per Section 5.5. 
4.1. 
Protocol Deviations 
Significant protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, participant management or participant assessment) will be 
summarized and listed. Separately, significant deviations which result in exclusion from 
analysis populations and events that result in exclusion from analysis populations will be 
summarized and listed. 
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan, entitled Study Deviation 
Tool and Rules. 


 
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o Data will be reviewed prior to freezing the database to ensure all significant 
deviations and deviations which may lead to exclusion of a participant from the 
analysis populations are captured and categorized in the protocol deviations 
dataset. This will occur prior to unblinding. 
o This dataset will be the basis for the summaries and listings of significant protocol 
deviations. 
A separate listing of all inclusion/exclusion criteria deviations will also be provided. This 
listing will be based on data as recorded on the inclusion/exclusion page of the eCRF. 


 
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5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
5.1. 
Study Treatment & Subgroup Display Descriptors 
Randomized and actual treatment will be reported per Table 4. This accounts for potential 
treatment misallocations due to double-dummy treatments, if applicable. 
Table 4 
Randomized and Actual Treatment Group Descriptions 
Randomized Treatment Group Descriptions  
Randomized Treatments (double-dummy) 
Data Displays for Reporting 
Tablet 
Capsule 
Description 
Order in TFL 
Gepotidacin 
Placebo  
(matched to Nitrofurantoin) 
Gepotidacin 1500 mg BID 
1 
Placebo  
(matched to Gepotidacin) 
Nitrofurantoin 
Nitrofurantoin 100 mg BID 
2 
Actual Treatment Group Descriptions (Listing of actual and randomized treatment, PK) 
Actual Treatments (double-dummy) 
Data Displays for Reporting1 
Tablet 
Capsule 
Description 
Order in TFL 
Placebo  
(matched to Gepotidacin) 
Placebo  
(matched to Nitrofurantoin) 
Placebo 
1 
Gepotidacin 
Nitrofurantoin 
Gepotidacin 1500 mg BID +  
Nitrofurantoin 100 mg BID 
2 
Gepotidacin 
Placebo  
(matched to Nitrofurantoin) 
Gepotidacin 1500 mg BID 
3 
Placebo  
(matched to Gepotidacin) 
Nitrofurantoin 
Nitrofurantoin 100 mg BID 
4 
Actual Treatment Group Descriptions (Safety TFL) 
Actual Treatments (double-dummy) 
Data Displays for Reporting2 
Tablet 
Capsule 
Description 
Order in TFL 
Placebo  
(matched to Gepotidacin) 
Placebo  
(matched to Nitrofurantoin) 
Placebo 
1 
Gepotidacin 
Nitrofurantoin 
Gepotidacin 1500 mg BID 
2 
Gepotidacin 
Placebo  
(matched to Nitrofurantoin) 
Gepotidacin 1500 mg BID 
2 
Placebo  
(matched to Gepotidacin) 
Nitrofurantoin 
Nitrofurantoin 100 mg BID 
3 
1. PK Summaries will only include “Gepotidacin 1500 mg BID” arms only, all other 
data will be listed only  
2. Safety Summaries will include “Gepotidacin 1500 mg BID” and “Nitrofurantoin 
100 mg BID” arms only, all other data will be listed only  
 


 
C O N FI D E N TI A L  
2 0 4 9 8 9  
 
3 1  
 
T otal  (acr oss all treat me nt gr o u ps) will be prese nte d  f or st u d y p o p ul ati o n, safet y, a n d 
selecte d micr o bi ol o g y dis pla ys.  
5. 2.  
B a s eli n e D efi niti o n s  
F or all e n d p oi nts , t he bas eli ne val ue will be t he lat est pre d ose ass ess me nt wit h a n o n-
missi n g val ue ( or ra n d o mizati o n date i n partici pa nts w h o are ra n d o mize d b ut di d n ot 
recei v e st u d y tr eat me nt), i ncl u di n g t h ose fr o m u ns c he d ule d visits. If ti me is n ot c ollecte d, 
Da y 1 assess me nts are ass u me d t o be ta ke n pri or t o first d ose a n d use d as baseli ne.  F or 
cli nical si g ns a n d sy m pt o ms asse ssme nts , 
 
a n d micr o bi ol o gic al assess me nts, all Da y 1 s y m pt o m assess me nts a n d uri n e sa m ples 
(c ollecte d f or i de ntificati o n of ur o pat h o ge ns) are use d as baseli ne re gar dless of if t he y 
were ta k e n pre or p ost d ose.  Uri ne sa m ple s c ollect e d o n Da y -1 or Da y 1  ca n be 
c o nsi dere d as baseli ne. If baseli ne data is missi n g, t he n c ha n ge fr o m baseli n e calc ul ati o ns 
will n ot be perf or me d a n d will be set t o missi n g.  
N o c ha n ge fr o m bas eli ne will be deri ve d f or E C Gs si nce t he pr ot oc ol o nl y re q uires E C G 
e val uati o ns at t he Baseli ne Visit.  
5. 2. 1.  
Q u alif yi n g Ur o p at h o g e n s  
T he al g orit h m f or det er mi ni n g baseli ne q u alif yi n g ur o pat h o ge ns bas e d o n micr o bi ol o g y 
la b orat or y q ua ntitati ve c ult ure res ults is pr o vi de d i n Fi g ure 2  a n d Secti o n 1 2. 1 0 : 
Fi g ur e 2  
B a s eli n e Al g orit h m f or D et er mi ni n g Q u alif yi n g Ur o p at h o g e n s  
 
O nl y t he f oll o wi n g ur o pat h o ge n s p ecies/ gr o u ps , i n cl u di n g Gra m -ne gati ve b acilli (e. g., E. 
c oli, K. p ne u m o ni ae, P. mir a bilis ), S. s a pr o p hytic us, a n d E nter oc occ us  s p p., will be 
c o nsi dere d f or i ncl usi o n i n t he micr o -I T T a n d ot her micr o bi ol o gical p o p ulati o ns. 
5. 3.  
M ulti c e nt er St u di e s  
I n t his m ultice nter gl o bal st u d y, e nr ollme nt will b e prese nt e d b y i n vesti gati ve site, 
c o u ntr y, a n d re gi o n f or  d escri pti ve s u m maries. Data fr o m all sites will be c o m bi ne d f or 
statistical a nal ys es; a nal yses will n ot be a dj uste d b y site. 
C CI


 
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5.4. 
Examination of Covariates, Other Strata and Subgroups 
5.4.1. 
Covariates and Other Strata 
The list of covariates and other strata may be used in descriptive summaries and 
statistical analyses, some of which may also be used for subgroup analyses. Additional 
covariates and other strata of clinical interest may also be considered. 
• 
If the number of participants is small within a category of a covariate or strata, then 
the covariate/strata categories may be refined prior to unblinding the trial. 
• 
If the category cannot be refined further, then the covariate may be included as a 
continuous measure. 
Participants will be randomized to a study treatment using stratification by age category 
(<18 years, ≥18 to 50 years, or >50 years) and acute cystitis recurrence (nonrecurrent 
infection or recurrent infection). In the case of a difference between the stratification 
assigned at the time of randomization and the data collected in the eCRF, the data 
collected in the eCRF will be considered actual and used unless specified. 
Stratification Factor 
Stratification Level 
Age Category 
<18 years 
 
≥18 to 50 years 
 
>50 years 
Acute Cystitis Recurrence 
Nonrecurrent infection 
 
Recurrent infection 
 
Stratification combinations will thus include: 
Stratification Value 
Stratification Description 
1 
<18 years, Nonrecurrent infection 
2 
<18 years, Recurrent infection 
3 
≥18 to 50 years, Nonrecurrent infection 
4 
≥18 to 50 years, Recurrent infection 
5 
>50 years, Nonrecurrent infection 
6 
>50 years, Recurrent infection 
 
For use as an analysis covariate, pooled strata combining the <18 and ≥18 to 50-year-old 
participants are defined as follows: 
Pooled Stratification Factor 
Stratification Level 
Age Category 
≤ 50 years 
 
>50 years 
Acute Cystitis Recurrence 
Nonrecurrent infection 
 
Recurrent infection 
 


 
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Pooled stratification combinations will thus include: 
Pooled Stratification Value 
Stratification Description 
1 
≤50 years, Nonrecurrent infection 
2 
≤50 years, Recurrent infection 
3 
>50 years, Nonrecurrent infection 
4 
>50 years, Recurrent infection 
 
 
Covariates 
Treatment 
Pooled strata (≤50 years, Nonrecurrent infection; ≤50 years, Recurrent infection; >50 years, 
Nonrecurrent infection; or >50 years, Recurrent infection† 
Age (≤50 years, or >50 years)* 
Acute cystitis recurrence (nonrecurrent infection or recurrent infection) at Baseline* 
Baseline clinical signs and symptoms total score* (clinical response only) 
Interaction term between treatment, Baseline uropathogen species/group and MIC (gepotidacin 
or nitrofurantoin) for randomized treatment* (microbiology response only).  
Prior visit (On-therapy Visit) clinical outcome* (clinical response only) 
Prior visit (On-therapy Visit) microbiological outcome* (microbiological response only) 
Site (Sites with <10 participants in the micro-ITT NTF-S Population may be combined prior to 
unblinding)* (clinical response only) 
†In the case of a difference between the stratification assigned at the time of randomization and 
the data collected in the eCRF, the data collected in the eCRF will be considered actual and 
used unless specified. 
*Included in the multiple imputation logistic regression models only 
 
5.4.2. 
Examination of Subgroups 
Subgroup analyses will be performed using the following categories for efficacy analysis; 
treatment group differences will be displayed for subgroups with ≥10 participants across 
both treatment groups. For the subgroup analyses related to age category and acute 
cystitis, in the event that participants are mis-stratified, the actual stratification will be 
created using actual age and recurrent status collected from eCRF. If the number of 
participants is small within a subgroup, then the subgroup categories may be refined prior 
to unblinding the trial. 
• Age category (<18, ≥18 to 50, >50) (only for therapeutic, clinical and 
(participant-level) microbiological response analyses)  
• Acute cystitis recurrence (nonrecurrent infection, recurrent infection) 
(nonrecurrent infection or recurrent infection, defined as a confirmed infection 
with at least 1 episode within the past 3 months, at least 2 episodes within the past 
6 months, or at least 3 episodes within the past 12 months before study entry) 


 
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(only for therapeutic, clinical and (participant-level) microbiological response 
analyses) 
• (Unpooled) Stratification combinations as above for age and acute cystitis 
recurrence (only for therapeutic, clinical and (participant-level) microbiological 
response analyses) 
• Qualifying uropathogen species/group isolated at Baseline (including phenotypic 
and genotypic subcategories), which is defined in Section 7.3.2. (only for 
therapeutic, clinical and (uropathogen-level) microbiological response analyses) 
• Number of Qualified Uropathogens at Baseline (only 1 qualifying uropathogen, 
two qualified uropathogens, one qualified plus additional any number of non-
qualified uropathogens ) (only for therapeutic response analyses) 
• Region (only for therapeutic, clinical and (participant-level) microbiological 
response analyses): 
• Americas: United States and Mexico 
• Europe: Bulgaria, Czech Republic, Germany, Greece, Hungary, Romania, 
Slovakia, Spain, and United Kingdom  
• Asia-Pacific: India 
• Others 
• Race (only for therapeutic, clinical and (participant-level) microbiological 
response analyses) 
• Ethnicity (only for therapeutic, clinical and (participant-level) microbiological 
response analyses) 
• Menopausal status: Post-menopausal vs. Non post-menopausal (only for 
therapeutic, clinical and (participant-level) microbiological response analyses) 
• Baseline symptom total scores (2-5, 6-8, 9-12) (only for therapeutic, clinical and 
(participant-level) microbiological response analyses). 
For primary efficacy endpoint, additional subgroup analyses by age, acute cystitis 
recurrence and their combinations as randomized will be included.  
For safety analysis, the below subgroup analysis related to age will be explored: 
• Age: <18, ≥18 to 64, ≥ 65 to 74, ≥75 
5.5. 
Multiple Comparisons and Multiplicity 
The primary comparison of interest is the comparison between gepotidacin to 
nitrofurantoin for the primary endpoint of therapeutic response rate at TOC in the micro-
ITT NTF-S Population. This analysis will be adjusted for stratification factors. The issue 
of multiple comparisons in the primary analysis will be addressed by testing the 
noninferiority of gepotidacin to treatment with nitrofurantoin prior to testing for 
superiority as described in Section 2.4. Further to this, the IA recommendation 
framework is defined per Figure 3. The IA recommendation framework required that 
both the noninferiority criteria is met in both the primary analysis population and the 
supplementary population for the study to be stopped for efficacy and noninferiority to be 
declared. Note: If the study continues at the interim, demonstration of NI at the final 
analysis will remain based on the primary analysis only (micro-ITT NTF-S) and the 


 
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supplementary analysis (micro-ITT NTF-S (CAPA)) performed at the final analysis will 
be provided for descriptive purposes only. 
Figure 3 
Study Success Definition and IA Recommendation Framework 
 
The statistical analyses of all other efficacy endpoints will be descriptive in nature, and 
therefore, will not be subject to multiplicity adjustments. 
5.6. 
Analysis Visits 
Analysis visit windows will be defined for by-visit summary and analysis purposes as 
illustrated in Table 5. Data not reported by-visit, including adverse events and 
concomitant medications, will not employ analysis visits. Analysis visit labels will be 
assigned to each post-baseline record (including records from unscheduled and early 
termination visits) based on the corresponding study day (relative to first study treatment 
or randomization if not treated). For post-baseline records collected outside the analysis 
visit window, a blank analysis visit label will be assigned. For example, a record 
collected at study Day 6 will not be utilized in any analyses or by visit descriptive 
summaries conducted at the OT or TOC scheduled visit. Descriptive summaries that are 
shown for “any assessment post baseline” e.g. maximum/minimum/ worst case post 
baseline, will use all assessments irrespective of whether they fall in an analysis visit 
window. 


 
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Table 5 
Analysis Visit Windows 
Post-Baseline 
Scheduled Visit 
Protocol 
Window 
(Days) 
Target Day 
Analysis Visit 
Window (Days) 
On-therapy 
2 to 4 
3 
2 to 5 
Test-of-Cure 
10 to 13 
12 
9 to 16 
Follow-up 
25 to 31 
28 
21 to 31 
If multiple records exist within the same analysis visit window, then the record occurring 
closest to the target day will be utilized in all analyses and analysis population 
determinations. If multiple records are equally close to the target day, then the later 
record will be utilized. If multiple records occur on the same day and time is not 
collected, then the record with the larger Study Data Tabulation Model (SDTM) record 
sequence number will be utilized in all analyses. All protocol assessments (including 
unscheduled and early termination visits) will be presented in subject listings. Both the 
nominal and analysis visit will be presented in listings. 
5.7. 
Other Considerations for Data Analyses and Data Handling 
Conventions 
Other considerations for data analyses and data handling conventions are outlined in the 
appendices: 
Section 
Component 
Section 12.1 
Appendix 1: Schedule of Activities 
Section 12.2 
Appendix 2: Study Phases and Treatment Emergent Adverse Events 
Section 12.3 
Appendix 3: Data Display Standards & Handling Conventions 
Section 12.4 
Appendix 4: : Derived and Transformed Data 
Section 12.5 
Appendix 5: Reporting Standards for Missing Data  
Section 12.6 
Appendix 6: Values of Potential Clinical Importance 
Section 12.7 
Appendix 7: Division of Microbiology and Infectious Diseases Adult Toxicity 
Tables for Adverse Event Assessment 
Section 12.8 
Appendix 8: Abbreviations & Trademarks 
Section 12.9 
Appendix 9: List of Data Displays 
Section 12.10 
Appendix 10: Qualifying Uropathogen  
Section 12.11 
Appendix 11: Uropathogen Phenotype  
Section 12.12 
Appendix 12: Uropathogen Genotype  
Section 12.13 
Appendix 13: Uropathogen Grouping and Order Example 
 


 
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6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Study Population Analyses 
The study population analyses will be mainly based on the ITT Population and the 
primary analysis population (micro-ITT NTF-S/micro-ITT NTF-S (IA Set)), unless 
otherwise specified. Study population analyses including subject disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure and treatment compliance will be based on GSK Core Data Standards. 
Baseline disease characteristics including baseline clinical symptom score, baseline 
uropathogens (including phenotypic and genotypic subcategories), past and current 
medical conditions, history of uncomplicated UTI, and exposure data will also be 
summarized. 
6.1.1. 
Disposition and Protocol Deviations 
All participants who provided informed consent will be accounted for. Participant 
disposition will be tabulated for each treatment group and overall, with the number of 
participants who completed the study, or prematurely withdrew, with the reason for early 
withdrawal presented for the ITT and micro-ITT NTF-S Populations and micro-ITT 
NTF-S (IA Set) Population if the study stops for efficacy. Separately, a summary of 
treatment status and reasons for discontinuation of study treatment will be provided for 
each treatment group and overall, with the number of participants who completed 
treatment, or prematurely discontinued treatment, and the primary reasons for treatment 
discontinuation tabulated for the ITT and micro-ITT NTF-S Populations and micro-ITT 
NTF-S (IA Set) Population if the study stops for efficacy.  
The number and percentage of participants enrolled by country and site will be 
summarized for each treatment group and overall for the ITT Population.  
For the Screened Population, a summary of reasons for screen failure (did not meet 
inclusion/exclusion criteria, adverse event, protocol deviation, lost to follow up, 
investigator discretion, withdrew consent, or other) will be provided.  
A table will be produced summarizing the number of participants in each analysis 
population for all participants who provided informed consent. A separate table will also 
be constructed that summarizes the reasons for exclusion from each study population for 
all participants in the ITT Population. For each study population, failure to meet specific 
study population requirements will be summarized by treatment group and overall. Note 
that only participants with pre-defined uropathogens [Gram-negative bacilli (e.g. E. coli, 
K. pneumoniae, P. mirabilis), S. saprophyticus, and Enterococcus spp. as described in 
Section 7.3.2] will be considered for inclusion in the relevant microbiological 
populations.  
The number and percentage of participants in the ITT Population with significant 
protocol deviations will be summarized by category and coded term.  
All data will be listed by participant (paginated by treatment group). 


 
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6.1.2. 
Demographic and Baseline Disease Characteristics 
Demographic and other baseline characteristics such as age, sex, race, ethnicity, 
childbearing potential, height, weight, body mass index (BMI), baseline acute cystitis 
recurrence and baseline renal impairment category will be summarized and tabulated by 
treatment group and for all participants in ITT, micro-ITT NTF-S, CE-TOC, and ME-
TOC NTF-S Populations and micro-ITT NTF-S (IA Set) Population if the study stops for 
efficacy. Descriptive statistics will be presented for age, height, weight, and BMI. 
Frequency counts and percentages will be presented for age category, sex, race, ethnicity, 
childbearing potential, and baseline acute cystitis recurrence. Age is computed as integer 
part of (First Dose Date - JUN30 of Collected Birth Year + 1)/365.25; when first dose 
date is missing, the informed consent date is used. Individual participant demographics 
(including baseline acute cystitis status) will be presented in listings. 
Baseline disease characteristics will summarize baseline quantitative bacterial counts, 
number of subjects with at least one baseline qualifying uropathogen identified, number 
of baseline qualifying uropathogens identified per subject, baseline qualifying 
uropathogens identified, and baseline clinical symptom score in ITT, micro-ITT and its 
derivatives (including micro-ITT NTF-S (IA Set) Population if the study stops for 
efficacy), CE-TOC, ME-TOC and its derivatives, ME-FU and its derivative populations. 
Separately, baseline uropathogens and qualifying uropathogens (including phenotypic 
and genotypic subcategories) will be summarized for ITT, micro-ITT and its derivatives, 
ME-TOC and its derivatives, ME-FU and its derivative populations. Baseline qualifying 
uropathogens will also be summarized separately by species and group (e.g., Klebsiella 
spp., other Enterobacterales, gram-negative nonfermenters, gram-positive species) for 
micro-ITT and its derivatives, ME-TOC and its derivatives, ME-FU and its derivative 
populations. Data will be listed and summarized using descriptive statistics or frequency 
counts and percentages as applicable.  
The severity of renal impairment will be evaluated using estimated by creatinine 
clearance (CCr) using the Cockcroft and Gault formula (1973): 
 
where 
• Scr is serum creatinine in (mg/dL) 
• Age in years 
• Weight in kg 
 Severity of renal impairment will be categorized based on creatinine clearance as 
below (rounded to the nearest integer): 
• Normal (≥90 mL/min) 
• Mild (≥60 to 89 mL/min) 
• Moderate (≥30 to 59 mL/min) 
• Severe (<30 mL/min) 


 
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Substance use such as smoking history, cigarettes per day, alcohol consumption, alcohol 
weekly use, caffeine consumption, and average caffeinated servings per day will also be 
summarized and listed. 
The details of data displays are presented in Appendix 9 
6.1.3. 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using GSK Drug coding dictionary, 
summarized, and listed using generic term, verbatim text, and indication. Separate 
summaries of prior and concomitant medications will show the number and percentage of 
participants in the ITT and micro-ITT NTF-S Populations (and micro-ITT NTF-S (IA 
Set) Population (for concomitant medications only) if the study stops for efficacy) taking 
each prior and concomitant medication by corresponding Anatomical Therapeutic 
Chemical (ATC) classification Level 1 (Body System) information. The summary of 
prior medications will include a separate summary of prior antibiotic medications. The 
summary of concomitant medications will display separate summaries for systemic 
concomitant medications, non-systemic concomitant medications, systemic antibiotics 
taken for the disease under study (started on/after Study Day 1), systemic antibiotics 
taken for another disease/condition (started on/after Study Day 1), and prohibited (non-
antibiotic) medications. 
An antibiotic is considered systemic if the route is oral, subcutaneous, intramuscular, 
intravenous, or rectal. 
All prior and concomitant medications, as well as prior and concomitant antibiotic 
medications for uUTI, will be provided in separate listings. 
6.1.4. 
Medical History and Current Medical Conditions 
Medical history and current medical conditions will be summarized and displayed with 
the number and percentage of participants for each body system for ITT and micro-ITT 
NTF-S Populations (and micro-ITT NTF-S (IA Set) Population if the study stops for 
efficacy). General medical history, previous Clostridium difficile infection, and 
liver/cardiovascular related medical conditions will be summarized separately in tables 
and listings. A distinct summary table will also be produced for history of previous 
uncomplicated UTIs during the past 3 months, past 3-6 months, past 6-12 months, and 
past 5 years, and pre-existing conditions with similar symptoms in past 12 months for the 
ITT and micro-ITT NTF-S Populations (and micro-ITT NTF-S (IA Set) Population if the 
study stops for efficacy). All data will be listed. 
6.1.5. 
Treatment Exposure 
Treatment exposure will be summarized by treatment group for the Safety and micro-ITT 
NTF-S Populations (and micro-ITT NTF-S (IA Set) Population if the study stops for 
efficacy). The summary will include duration of treatment (days), the number of doses 
administered, number of tablets/capsules, average daily dose, cumulative actual dose, and 
compliance rate. The number of participants with <80%, ≥80% - <100%, and 100% 
compliance rate will also be summarized. Dose administration for all participants will be 
displayed in the listing. 
Compliance rate (%) will be calculated as: 


 
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• Gepotidacin/gepotidacin placebo:  
 
total number of tablets taken
20
∗100% 
• Nitrofurantoin/nitrofurantoin placebo: 
 
total number of capsules taken
10
∗100% 
The details of data displays are presented in Appendix 9 


 
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7. 
EFFICACY ANALYSES 
7.1. 
Primary Efficacy Analyses  
The primary clinical question of interest is: what is the treatment effect on therapeutic 
success rate after 5 days treatment with gepotidacin 1500 mg twice daily compared to 5 
days treatment with nitrofurantoin 100 mg twice daily in participants with acute cystitis 
who have a qualifying uropathogen at Baseline that is susceptible to nitrofurantoin 
regardless of treatment discontinuation for any reason. Receipt of systemic antimicrobials 
impacts the endpoint definition (see Table 6 to Table 8). Further details on the primary 
estimand are given in Section 2.2.1. 
7.1.1. 
Endpoint / Variables 
7.1.1.1. 
Therapeutic Response at TOC 
The primary efficacy endpoint is therapeutic response (combined per participant 
microbiological and clinical response) at the Test of Cure (TOC) Visit. Therapeutic 
response is a dichotomous measure of overall efficacy response, either a success or 
failure, and will be determined programmatically. A therapeutic success refers to 
participants who have been deemed both a participant level “microbiological success” 
and a “clinical success”. All other combinations will be deemed failures for therapeutic 
response. The detailed definitions of microbiological and clinical response are given in 
Table 6, Table 7, and Table 8.  
7.1.1.2. 
Microbiological Outcome and Response at TOC 
• Only those participants who have a qualifying uropathogen (Section 5.2.1) identified 
at Baseline will be evaluated for microbiological outcome and response by baseline 
qualifying uropathogen for the primary efficacy endpoint. 
• The microbiological success at the uropathogen level is defined as a reduction of 
bacterial count to <103 CFU/mL for a specific qualifying uropathogen recovered at 
Baseline without the participant receiving any other systemic antimicrobials before 
the TOC Visit (started on/after Study Day 1). The criteria of microbiological outcome 
and response are shown in Table 6. 
• Participant level microbiological response is a measure of the combined “by 
uropathogen” response(s). Per-participant level microbiological success refers to 
participants who have been deemed “microbiological success” for all of their 
qualifying baseline uropathogen(s) microbiological responses. All other combinations 
are deemed failures for per-participant level microbiological response. Participant-
level microbiological outcome and response definitions at TOC are shown in Table 7. 


 
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Table 6 
Microbiological Outcome and Response by Baseline Qualifying 
Uropathogen at the TOC Visit - uropathogen level 
Defining Criteria 
Outcome 
Response 
Participants considered microbiological failures at the TOC Visit will also be considered 
microbiological failures at the Follow-up Visit. 
A quantitative urine culture taken at the TOC 
Visit shows reduction of the qualifying 
uropathogen recovered at Baseline to <103 
CFU/mL without the participant receiving 
other systemic antimicrobials before the TOC 
Visit 
Microbiological 
eradication 
Microbiological 
success 
A quantitative urine culture taken at the TOC 
Visit shows that the qualifying uropathogen 
recovered at Baseline, and which was also 
shown to persist or is unable to determine at 
the On-therapy Visit, grows ≥103 CFU/mL 
without the participant receiving other 
systemic antimicrobials before the TOC Visit 
Microbiological 
persistence 
Microbiological 
failure 
A quantitative urine culture taken at the TOC 
Visit shows that the qualifying uropathogen 
recovered at Baseline, and which was also 
shown to be eradicated at the On-therapy 
Visit, grows ≥103 CFU/mL without the 
participant receiving other systemic 
antimicrobials before the TOC Visit 
Microbiological 
recurrence 
Microbiological 
failure 
(1) The TOC urine culture result is missing or 
(2) The participant received other systemic 
antimicrobials before the TOC Visit 
Unable to 
determine 
Microbiological 
failure 
CFU=colony-forming units; TOC=Test-of-Cure. 
Table 7 
Participant-level microbiological outcome and response at the TOC 
Visit 
Defining Criteria 
Outcome 
Response 
All qualifying baseline uropathogens have a microbiological 
outcome of eradication at TOC 
Microbiological 
eradication 
Microbiological 
success 
At least one qualifying baseline uropathogen has an outcome 
of persistence at TOC 
Microbiological 
persistence 
Microbiological 
failure 
At least one qualifying baseline uropathogen has an outcome 
of recurrence and none have an outcome of persistence at 
TOC 
Microbiological 
recurrence 
Microbiological 
failure 
All qualifying baseline uropathogen outcomes are unable to 
determine at TOC 
Unable to 
determine 
Microbiological 
failure 
TOC=Test of Cure 
 


 
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7.1.1.3. 
Clinical Outcome and Response at TOC 
• Clinical signs and symptoms of acute cystitis will be recorded by site staff based on 
participant interview using the following scoring system: 
Clinical Signs 
and Symptoms 
None 
Mild 
Symptom is 
easily tolerated, 
causing minimal 
discomfort and 
not interfering 
with everyday 
activities 
Moderate 
Symptom is 
sufficiently 
discomforting to 
interfere with 
normal everyday 
activities 
Severe 
Symptom 
prevents normal 
everyday 
activities 
SCORE 0 
SCORE 1 
SCORE 2 
SCORE 3 
Dysuria 
 
 
 
 
Frequency 
 
 
 
 
Urgency 
 
 
 
 
Lower abdominal 
or suprapubic 
pain 
 
 
 
 
• The clinical signs and symptoms include dysuria, frequency, urgency, and lower 
abdominal or suprapubic pain. Each of the signs and symptoms will be scored from 0 
to 3. 
• At Baseline, the participant must present with at least 2 signs and symptoms and have 
a total cumulative symptom score ≥ 2. The total cumulative symptom score is derived 
by summing the score for each individual sign and symptom. If any individual sign 
and symptom scores are missing, then total symptom score will also be missing. At 
TOC, success is defined as normal presentation of signs and symptoms with a total 
cumulative symptom score of zero. If the participant is missing baseline assessment, 
they will be considered ‘Unable to determine’ for outcome, and ‘Clinical failure’ for 
response at the respective visit. 
• The clinical outcome and response will be programmatically determined by 
comparing the total scores of the signs and symptoms of acute cystitis at the TOC 
Visit to those present at Baseline as shown in Table 8. 
 
 


 
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Table 8 
Clinical Outcome and Response at the TOC Visit 
Defining Criteria 
Outcome 
Response 
Test-of-Cure Visit 
Resolution of signs and symptoms of acute 
cystitis present at Baseline (and no new signs 
and symptoms), without the participant 
receiving any other systemic antimicrobials 
before the TOC Visit 
Clinical resolution 
Clinical success 
Improvement in total symptom scores from 
Baseline, but not complete resolution, without 
the participant receiving other systemic 
antimicrobials before the TOC Visit 
Clinical 
improvement 
Clinical failure 
Worsening or no change in total symptom 
scores from Baseline or the participant 
received other systemic antimicrobials for the 
current infection before or on the date of the 
TOC Visit 
Clinical worsening 
Clinical failure 
(1) The baseline score is missing or  
(2) The TOC assessment is missing or 
(3) The participant received other systemic 
antimicrobials not for the current infection 
before the TOC Visit (unless clinical 
worsening outcome criteria were met) 
Unable to 
determine 
Clinical failure 
TOC=Test-of-Cure.  
 
If participant took both other systemic antimicrobials for the current infection on or 
before the date of the TOC Visit (started on/after Study Day 1), and other systemic 
antimicrobials not for the current infection before the date of the TOC Visit (started 
on/after Study Day 1), then participant will be derived as ‘Clinical worsening’. 
7.1.2. 
Summary Measure 
Difference in the therapeutic success rate in the gepotidacin and nitrofurantoin treatment 
groups (gepotidacin 1500 mg BID – nitrofurantoin 100 mg BID). 
7.1.3. 
Population of Interest 
Female participants with acute cystitis with qualifying uropathogen(s) at Baseline that all 
are susceptible to nitrofurantoin.  
7.1.4. 
Strategy for Intercurrent Events 
There are two kinds of intercurrent events (ICE): 
o Study treatment discontinuation (due to any reason) – treatment policy 
strategy (the occurrence of the ICE is considered irrelevant in defining the 
treatment effect of interest). 


 
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o Use of systemic antimicrobials - composite strategy. This intercurrent event is 
captured through the definitions of microbiological and clinical response (see 
Section 7.1.1.1 and Section 7.1.1.3) and will be counted as therapeutic 
failures.    
If the patient experiences both of these ICE then a composite strategy (assigning 
therapeutic response as a failure) will be used from the point that the relevant systemic 
antimicrobial was taken). 
7.1.5. 
Treatment Condition 
Gepotidacin 1500 mg twice daily for 5 days versus nitrofurantoin 100 mg twice daily for 
5 days regardless of adherence. 
7.1.6. 
Statistical Analyses / Methods 
7.1.6.1. 
Statistical Methodology Specification 
The primary efficacy endpoint is the therapeutic response (combined per-participant 
microbiological and clinical response) at the TOC Visit. The primary analysis population 
is the micro-ITT NTF-S Population if the study does not stop for efficacy and micro-ITT 
NTF-S (IA Set) if the study stops for efficacy. 
For the statistical analysis, four pooled strata will be formed according to the 
combinations of levels of the following categorical variables: age category (≤50 years, or 
>50 years) and acute cystitis recurrence (nonrecurrent infection or recurrent infection) at 
Baseline. If a participant is mis-stratified then the actual pooled strata collected in the 
eCRF will be used in the analysis instead of the randomized pooled strata, unless 
specified. 
The Miettinen-Nurminen (score) confidence limits for the treatment difference 
[Miettinen, 1985] are computed (SAS PROC FREQ [SAS, 2018] uses iterative 
computation for this). Stratum based point estimates and variances can be estimated from 
these CIs. The MN estimate of the common risk difference and variance is computed by 
combining the point estimates and variances from the individual pooled strata using MN 
weights. The estimate uses inverse variance stratum weights to produce MN confidence 
limits for the stratum risk differences. The mathematics and algorithm of MN method can 
be found in the SAS procedure guide under “Summary Score Estimate of the Common 
Risk Difference” [SAS, 2018]. 
Z statistics for noninferiority are calculated by using the MN common risk difference and 
the variance estimator and the –10% NI margin to compare with the Z-statistics 
boundaries. Testing for superiority will occur if noninferiority is achieved. A one-sided p-
value will be calculated to compare with the p-value boundaries.  
Statistical testing will occur at the IA. If the study is not stopped for efficacy or futility, 
statistical testing will be repeated after the study is completed. Boundaries will be 
calculated at the time of the IA for both testing at the IA and at the end of study based on 
the actual information fraction at the time of the IA.  


 
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The point estimate of the difference in the proportion of therapeutic responders between 
each treatment group and its two-sided 95% CIs (using MN method adjusting for 
treatment and actual pooled strata) and Z statistic for noninferiority will be presented. 
Note: all CI are nominal without multiplicity adjustment for alpha spend at interim. 
The number and proportion of participants with therapeutic success at the TOC Visit will 
be presented by treatment group along with the 95% Exact Clopper-Pearson  CI for the 
success rate. 
A summary of therapeutic success, failure, and reasons for failure at the TOC Visits 
(including receipt of non-study antibacterial therapy for uUTI) will also be presented for 
each treatment group at participant level. 
Supportive analyses will be performed to enable the assessment of the homogeneity of 
the treatment difference across pooled strata used in the primary analysis. This will be 
conducted on the primary analysis population (micro-ITT NTF-S (IA Set) if the study 
stops for efficacy else the micro-ITT NTF-S Population) 
The weighted least squares chi-squared statistic of Fleiss [Fleiss, 1981] will be used to 
test for one-way homogeneity of the treatment difference across the levels of the pooled 
strata used for the primary analysis. The overall test for homogeneity will use the 
combined strata levels constructed by cross-classification of pooled strata. Additional 
tests for homogeneity of the treatment difference across the levels of each pooled strata 
will be performed, with each pooled stratum considered separately. Following Lui and 
Kelly [Lui, 2000], ½ will be added to each cell in any (pooled) stratum for which the 
stratum-specific success rate estimates of either gepotidacin or nitrofurantoin are zero or 
one, and tests will be one-sided. Tests of homogeneity will be assessed at the one-sided 
10% level of significance. 
For each stratum, the percent of participants with therapeutic successes by treatment 
group and unadjusted difference in percent between treatment groups with corresponding 
two-sided 95% CI (using MN method adjusting for treatment only) will be reported. In 
addition, the p-value from the overall test of homogeneity will be reported, as well as the 
p-value for the additional tests of homogeneity considering each pooled strata separately. 
7.1.6.2. 
Sensitivity Analyses 
Sensitivity analyses will be performed to investigate the robustness of the primary 
efficacy results for the primary estimand. The following sensitivity analyses will be 
performed in the primary analysis population (micro-ITT NTF-S (IA Set) Population if 
the study stops for efficacy else micro-ITT NTF-S Population) unless otherwise 
specified. Z statistics for noninferiority will be compared to the boundaries used for 
primary efficacy testing. 
1) If the study stops for efficacy, an analysis of therapeutic response at TOC adjusted 
for the pooled stratification factors based on the actual stratum will be performed 
on the micro-ITT NTF-S Population (complete trial data). Difference in the 
proportion of therapeutic responders between each treatment group adjusted by 
MN weights (using actual pooled strata) will be presented along with two-sided 


 
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95% CIs (using MN method adjusting for treatment and actual pooled strata) and 
Z statistics for noninferiority to provide a nominal estimate. 
2) An analysis of therapeutic response at TOC unadjusted for the stratification 
factors. Unadjusted difference in proportions between treatment groups 
(gepotidacin – nitrofurantoin), Z statistic for noninferiority using the unadjusted 
difference, and corresponding two-sided 95% CI (using MN method adjusting for 
treatment only) will be presented.  
If the study stops for efficacy, this analysis will be performed on the micro-ITT 
NTF-S (IA Set) Population and micro-ITT NTF-S Population. 
3) An analysis of therapeutic response at TOC adjusted for the stratification factors 
based on the randomization stratum the participant was randomized to (instead of 
the actual stratum the participant should be assigned to). Difference in the 
proportion of therapeutic responders between each treatment group adjusted by 
MN weights (using randomized stratification) will be presented along with two-
sided 95% CIs (using MN method adjusting for treatment and pooled strata as 
randomized) and Z statistics for noninferiority.  
If the study stops for efficacy, this analysis will be performed on the micro-ITT 
NTF-S (IA Set) Population and micro-ITT NTF-S Population. 
4) A sensitivity analysis for the primary endpoint will be carried out to assess the 
impact of missing data. If the entire TOC Visit, bacteriology samples or clinical 
signs and symptoms assessment were missed due to COVID-19 pandemic, then 
the missing value will be imputed under the MAR assumption. If the TOC 
bacteriology sample was taken but a result is not available for the sample for any 
reason, then the missed value will also be imputed under the MAR assumption. 
All other missing data will be considered as a failure (i.e., non-responders) in the 
primary analysis. Multiple imputations will be implemented with the following 
steps: 
o Step 1: Missing microbiology response values and clinical response values 
will be imputed using separate logistic regression models under a missing 
at random assumption in the micro-ITT NTF-S Population. The number of 
imputations will be 1,000 and SEED = 204989. The variables to be 
included in the imputation model are: 
• Age (≤50 years, or >50 years) 
• Acute cystitis recurrence (nonrecurrent infection or recurrent 
infection) at Baseline 
• Baseline clinical signs and symptoms total score (clinical response 
only) 
• Interaction term between treatment, Baseline qualifying 
uropathogen species/group and MIC (gepotidacin or 
nitrofurantoin) for randomized treatment (microbiology response 
only). If needed, this may be refined prior to unblinding. 
Note: Baseline uropathogen species/group will be determined by 
GSK microbiology prior to unblinding and will include separate 
holistic reviews to: 
o identify dominant uropathogen for subjects with more than 
one qualifying uropathogen at Baseline. This selection will 
be completed for all subjects with more than one qualifying 
uropathogen at Baseline in the micro-ITT NTF-S 


 
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Population, regardless of missing data and will be based on 
species and gepotidacin or nitrofurantoin MIC value and 
will identify the dominant uropathogen for gepotidacin and 
for nitrofurantoin treatment groups as these may differ. 
This will be documented prior to unblinding.  Post 
unblinding, the dominant uropathogen for the randomized 
treatment will be used and the corresponding Baseline 
uropathogen species/group and MIC will be used in the 
analysis. 
o Group similar uropathogens. This may include groupings 
by species and, if needed, grouping of uropathogens with 
smaller frequencies with other similar uropathogens. This 
will be documented prior to unblinding. 
o Group MICs (gepotidacin or nitrofurantoin) by randomized 
treatment which may be based on Baseline uropathogen 
species/group. This will be documented prior to unblinding. 
• Prior visit (On-therapy Visit) clinical outcome (clinical response 
only) 
• Prior visit (On-therapy Visit) microbiological outcome 
(microbiological response only) 
• Site (Sites with <10 participants in the micro-ITT NTF-S 
Population may be combined prior to unblinding) (clinical 
response only) 
• Randomized treatment received 
Any subjects that have a missing value for one or more variables listed 
above will be excluded from the relevant imputation model(s).  
o Step 2: Step 1 will produce 1,000 imputed datasets with complete data. 
For each dataset, participants therapeutic response will then be derived 
using the imputed and non-missing data per Section 7.1.1.1. We will 
estimate the proportion of success in each treatment group and its standard 
error using the exact Clopper-Pearson method, and the difference in the 
proportion of success between the two treatment groups and its standard 
error using the MN method weighted on actual pooled strata as in the 
primary efficacy analysis for each imputed dataset separately. All 
estimated quantities (proportion of success in each treatment group, 
difference between two groups, and their associated standard errors) will 
be saved for step 3.  
o Step 3: The estimated quantities in Step 2 will be combined across the 
imputed datasets using Rubin’s rules to provide pooled estimates for the 
success rate in each treatment group and for the difference in the 
proportion of success between the two treatment groups. The 95% (Wald) 
CIs will be calculated for the proportions of successes in each arm as well 
as for the risk difference between the two treatment groups. Z statistic for 
noninferiority between the two treatment groups will also be calculated. 
Testing for superiority may occur if noninferiority is achieved. A one-
sided p-value for superiority will be calculated to compare with the p-
value boundary.  


 
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5) To assess the impact of failure imputation of missing data on the therapeutic 
response at TOC, a tipping point analysis may be performed for the primary 
endpoint in the micro-ITT NTF-S Population. The scope of missing data will be 
consistent with the multiple imputation analyses, specifically, if the entire TOC 
Visit, bacteriology samples or clinical signs and symptoms assessment were 
missed due to COVID-19 pandemic, then the missed value will be imputed under 
the MAR assumption. If the TOC bacteriology sample was taken but a result is 
not available for the sample for any reason, then the missed value will also be 
imputed under the MAR assumption. All other missing data will be considered as 
a failure (i.e., non-responders) per the primary analysis. The tipping point analysis 
will vary assumptions on the proportion of subjects achieving success in the two 
treatment groups. For each combination of assumed success rates in the two 
treatment groups, the number of additional subjects achieving success among 
subjects with missing therapeutic response will be imputed by drawing from a 
binomial distribution.  
o A grid of paired values will be established, ranging from 0.025 to 0.975 in 
steps of 0.025, establishing the assumed response rates for each treatment 
group in subjects with missing therapeutic response. 
o For each pair of assumed response rates corresponding to treatment group, 
(𝜃𝐺𝑒𝑝𝑜𝑡𝑖𝑑𝑎𝑐𝑖𝑛
(𝑖)
, 𝜃𝑁𝑖𝑡𝑟𝑜𝑓𝑢𝑟𝑎𝑛𝑡𝑜𝑖𝑛
(𝑗)
), repeat the following steps 100 times: 
o Sample additional responders among subjects with missing 
responses by drawing from a binomial distribution, using the 
assumed response rate assigned to each treatment group. Sampling 
will be completed separately by treatment,   
𝑟𝐺𝑒𝑝𝑜𝑡𝑖𝑑𝑎𝑐𝑖𝑛,
𝑎
 ~ Binomial (𝑛𝐺𝑒𝑝𝑜𝑡𝑖𝑑𝑎𝑐𝑖𝑛
𝑚𝑖𝑠𝑠
, 𝜃𝐺𝑒𝑝𝑜𝑡𝑖𝑑𝑎𝑐𝑖𝑛
(𝑖)
) 
𝑟𝑁𝑖𝑡𝑟𝑜𝑓𝑢𝑟𝑎𝑛𝑡𝑜𝑖𝑛 
𝑎
 ~ Binomial (𝑛𝑁𝑖𝑟𝑜𝑓𝑢𝑟𝑎𝑛𝑡𝑜𝑖𝑛
𝑚𝑖𝑠𝑠
, 𝜃𝑁𝑖𝑡𝑟𝑜𝑓𝑢𝑟𝑎𝑛𝑜𝑡𝑖𝑛
(𝑗)
) 
o The proportion of success in each treatment group and the 
difference in the proportion of success between two treatment 
groups as well as the respective associated standard errors will be 
computed. Standard error of the risk difference estimate will be 
calculated using the MN method weighted on actual pooled strata. 
o Using Rubin’s rules we will combine the estimated quantities (success rate 
in each treatment group, difference in proportions between two groups, 
and their respective standard errors). The calculations for pooled estimates 
will be implemented using SAS PROC MIANALYZE. 95% (Wald) CIs 
will be calculated for the proportions of successes in each arm as well as 
for the risk difference between the two treatment groups. Z statistic for 
noninferiority between the two treatment groups will also be calculated. 
The noninferiority conclusion will be drawn if the Z statistic is larger than 
the Z statistic boundary. Testing for superiority may occur if 
noninferiority is achieved. A one-sided p-value will be calculated to 
compare with the p-value boundaries. 
o The process described above will be repeated for each pair of assumed 
response rates, (𝜃𝐺𝑒𝑝𝑜𝑡𝑖𝑑𝑎𝑐𝑖𝑛
(𝑖)
, 𝜃𝑁𝑖𝑡𝑟𝑜𝑓𝑢𝑟𝑎𝑛𝑡𝑜𝑖𝑛
(𝑗)
). 


 
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o Visual representations of treatment difference and noninferiority decisions 
will be produced using a colored heatmap illustrating the gradual change 
of treatment difference. Colored borders will be used to highlight the 
therapeutic response rates that resulted in noninferiority.  
7.1.6.3. 
Supplementary analyses 
Supplementary analysis of the primary efficacy endpoint will be performed in the micro-
ITT and micro-ITT NTF-NS and in the ME-TOC/NTF-S/NTF-NS Populations on the 
participant level following the same layout/content contained in the original presentation 
of the primary analysis. MN adjusted difference using actual pooled strata and unadjusted 
difference in success rate will be presented along with their 95% CI (calculated using MN 
method). 
An additional supplementary analysis of participant-level therapeutic response at TOC 
will be provided for a modified micro-ITT NTF-S Population for EMA. Inclusion into an 
“EU micro-ITT NTF-S” Population for this analysis will be based on baseline 
susceptibility to nitrofurantoin according to European Committee on Antimicrobial 
Susceptibility Testing (EUCAST) breakpoints and interpretive criteria instead of CLSI. 
The key EU supplementary analysis population is the EU micro-ITT NTF-S Population 
(complete trial data) if the study does not stop for efficacy and EU micro-ITT NTF-S (IA 
Set) if the study stops for efficacy. If the study stops for efficacy a sensitivity to the EU 
supplementary analysis will be performed on the EU micro-ITT NTF-S Population 
(complete trial data). Unadjusted difference, MN adjusted difference using actual pooled 
strata, and MN adjusted difference using pooled strata as randomized in success rate will 
be presented along with their 95% CI (calculated using MN method) and nominal Z 
statistics for noninferiority. One-sided p-value for superiority for MN adjusted difference 
using actual pooled strata in success rate will also be presented. Nominal tests for 
noninferiority and superiority will follow the same method as the primary efficacy 
analysis as described in Section 7.1.6.1 using the same boundary based on the 
information fraction of the CLSI-based micro-ITT NTF-S. Test for homogeneity will also 
be conducted for primary efficacy endpoint in the key EU supplementary analysis 
population (EU micro-ITT NTF-S Population (complete trial data) if the study does not 
stop for efficacy and EU micro-ITT NTF-S (IA Set) if the study stops for efficacy). 
 
In the event that one or more investigators/sites receive a corrective and preventative 
action (CAPA) that stipulates a supplementary analysis should be conducted excluding 
them as agreed by a multidisciplinary GSK team prior to unblinding, a supplementary 
analysis will be performed. A flag will be included to identify subjects enrolled by those 
investigators/sites. This will enable further subpopulations to be defined for the primary 
analysis populations (micro-ITT NTF-S if the study continues / micro-ITT NTF-S (IA 
Set) if the study stops for futility). The sub population will consist of all subjects in the 
primary analysis population except subjects from those investigative sites (e.g., micro-
ITT NTF-S (CAPA)/ micro-ITT NTF-S (IA Set) (CAPA) respectively) and will be used 
to perform the additional supplemental analysis for the primary efficacy endpoint only. 
Note: this analysis is included in the IA recommendation framework per Section 5.5. 


 
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7.1.6.4. 
Subgroup Analyses 
Subgroup analyses will be performed for the primary endpoint (therapeutic response at 
the TOC Visit) in the micro-ITT NTF-S Population (complete trial data). Subgroup 
analyses for the primary endpoint in additional populations (micro-ITT, micro-ITT NTF-
NS and ME-TOC/NTF-S/NTF-NS) will also be included. See Section 5.4.2 for definition 
of subgroups. For qualifying uropathogen thresholds, see the corresponding Section 
5.2.1. Analysis of therapeutic response at the TOC Visit by number of qualified 
uropathogens at Baseline will only be performed in the micro-ITT/NTF-S/NTF-NS 
Populations. 
A summary of therapeutic success, failure, reasons for failure at the TOC Visit will also 
be presented by subgroup for each treatment group. The associated 95% Exact Clopper-
Pearson CI for the success rate will be included for each treatment group at each level. 
Unadjusted difference in proportions between treatment groups and corresponding two-
sided 95% CI (using MN method adjusting for treatment only) at each level will be 
presented.  
Percent of therapeutic success at TOC overall and by qualifying uropathogen will be 
plotted for each treatment group for the micro-ITT NTF-S Population. Forest plot for 
therapeutic success rate at TOC overall and by subgroup will be plotted for micro-
ITT/NTF-S/NTF-NS. 
All subgroup analyses will follow the same layout/content contained in the original 
presentation of the primary analysis. Summary tables will be paginated by each level of 
the subgroup, and only the unadjusted difference in success rate will be presented.  


 
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7.2. 
Secondary Efficacy Analyses  
The secondary clinical efficacy questions of interest are: what is the treatment effect on 
each of the secondary efficacy endpoints after 5 days treatment with gepotidacin 1500 mg 
twice daily compared to 5 days treatment with nitrofurantoin 100 mg twice daily in 
participants with acute cystitis (clinical endpoints) and in participants with acute cystitis 
with qualifying uropathogen(s) at Baseline that all are susceptible to nitrofurantoin 
(therapeutic, clinical, and microbiological endpoints), regardless of treatment 
discontinuation for any reason. Receipt of systemic antimicrobials impacts the endpoint 
definition (see Section 7.2.1.1, Section 7.2.1.2, and Section 7.2.1.3). Further details of the 
estimands for secondary efficacy endpoints are given in Section 2.2.2. 
7.2.1. 
Endpoint / Variables 
7.2.1.1. 
Microbiological Outcome and Response at TOC and Follow-up 
The microbiological outcome and response are evaluated at participant level at the TOC 
and FU Visits. The criteria of uropathogen-level microbiological outcome and response 
are defined in Table 6 (TOC) and similarly in Table 9 (FU). The criteria of participant-
level microbiological outcome and response are defined in Table 7 (TOC) and Table 10 
(FU). 


 
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Table 9 
Microbiological Outcome and Response by Baseline Qualifying 
Uropathogen at the Follow-Up Visit – Uropathogen Level 
 
Defining Criteria 
Outcome 
Response 
Participants considered microbiological failures at the TOC Visit will also be considered 
microbiological failures at the FU Visit. 
A quantitative urine culture taken at the Follow-up Visit shows 
reduction of the qualifying uropathogen recovered at Baseline 
to <103 CFU/mL following microbiological eradication at the 
TOC Visit, without the participant receiving other systemic 
antimicrobials before the Follow-up Visit 
Sustained 
microbiological 
eradication 
Microbiological 
success 
A quantitative urine culture taken at the Follow-up Visit shows 
that the qualifying uropathogen recovered at Baseline grows 
≥103 CFU/mL following microbiological eradication at the TOC 
Visit, without the participant receiving other systemic 
antimicrobials before the Follow-up Visit 
Microbiological 
recurrence 
Microbiological 
failure 
A quantitative urine culture taken at the Follow-up Visit shows 
that the qualifying uropathogen recovered at Baseline grows 
≥103 CFU/mL, and also did not achieve an outcome of 
microbiological eradication at the TOC Visit, without the 
participant receiving other systemic antimicrobials before the 
Follow-up Visit 
Microbiological 
persistence 
Microbiological 
failure 
A quantitative urine culture taken at the Follow-up Visit shows 
reduction of the qualifying uropathogen recovered at Baseline 
to <103 CFU/mL, and also did not achieve an outcome of 
microbiological eradication at the TOC Visit, without the 
participant receiving other systemic antimicrobials before the 
Follow-up Visit 
Delayed 
microbiological 
eradication 
Microbiological 
failure 
1) The FU urine culture result is missing or 
2) The participant received other systemic antimicrobials 
before the FU Visit 
Unable to 
determine 
Microbiological 
failure 
CFU=colony-forming units; TOC=Test-of-Cure. 


 
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Table 10 
Participant-Level Microbiological Outcome and Response at the 
Follow-Up Visit 
Defining Criteria at FU Visit 
Outcome 
Response 
All qualifying baseline uropathogens have a microbiological 
outcome of sustained eradication at Follow-up 
Sustained 
Microbiological 
eradication 
Microbiological 
Success 
At least one qualifying baseline uropathogen has an outcome 
of recurrence and none have an outcome of persistence at 
Follow-up  
Microbiological 
recurrence 
Microbiological 
Failure 
At least one qualifying baseline uropathogen has an outcome 
of persistence at Follow-up 
Microbiological 
persistence 
Microbiological 
Failure 
At least one qualifying baseline uropathogen has an outcome 
of delayed eradication and none have an outcome of 
persistence or recurrence at Follow-up 
Delayed 
microbiological 
eradication 
Microbiological 
Failure 
All qualifying baseline uropathogen outcomes are unable to 
determine at Follow-up 
Unable to 
determine 
Microbiological 
Failure 
7.2.1.2. 
Clinical Outcome and Response at TOC and Follow-Up 
Clinical outcome and response are evaluated at participant level at the TOC and FU 
Visits. The criteria for clinical outcome and response are defined in Table 8 (TOC) and 
similarly in Table 11(FU). 
 
 


 
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Table 11 
Clinical Outcome and Response at the Follow-Up Visit 
Defining Criteria 
Outcome 
Response 
Participants who withdraw from the study prior to the FU Visit will be considered not achieving 
success (imputed as failure) as the clinical response at FU. 
Resolution of signs and symptoms of acute cystitis 
demonstrated at the TOC Visit persist at the FU Visit (and 
no new signs and symptoms), without the participant 
receiving other systemic antimicrobials before the FU Visit. 
Sustained 
clinical 
resolution 
Clinical 
success 
Resolution of signs and symptoms of acute cystitis present 
at Baseline (and no new signs or symptoms), after clinical 
failure at TOC, without the participant receiving other 
systemic antimicrobials before the FU Visit. 
Delayed clinical 
resolution 
Clinical failure 
Improvement in total symptom scores from Baseline, but 
not complete resolution, without the participant receiving 
other systemic antimicrobials before the FU Visit. 
Clinical 
improvement 
Clinical failure 
Worsening or no change in total symptom scores at FU 
compared to Baseline after clinical failure at TOC or the 
participant received other systemic antimicrobials for the 
current infection before or on the date of the FU Visit 
Clinical 
worsening 
Clinical failure 
Signs and symptoms of acute cystitis reoccur at the FU 
Visit assessment after clinical success at the TOC Visit 
Clinical 
recurrence 
Clinical failure 
1) The baseline score is missing or  
2) The FU assessment is missing or  
3) The participant received other systemic antimicrobials not 
for the current infection before the FU Visit (unless 
clinical worsening or recurrence outcome criteria were 
met) 
Unable to 
determine 
Clinical failure 
TOC=Test-of-Cure. FU=Follow-up. 
If participant took both other systemic antimicrobials for the current infection on or 
before the date of the FU Visit, and other systemic antimicrobials not for the current 
infection before the date of the FU Visit, then participant outcome will be derived as 
‘Clinical worsening’. 
7.2.1.3. 
Therapeutic Response at Follow-up 
A therapeutic success at Follow-up refers to participants who have been deemed both a 
“microbiological success” and a “clinical success” at the Follow-up Visit. All other 
combinations will be deemed failures for therapeutic response. 
7.2.2. 
Summary Measure 
For details of the estimand summary measure see Table 1 in Section 2.2.2.  
7.2.3. 
Population of Interest 
For details of the estimand population see Table 1 in Section 2.2.2. 


 
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7.2.4. 
Strategy for Intercurrent Events 
For details of the estimand strategy for intercurrent events see Table 1 in Section 2.2.2. 
7.2.5. 
Treatment Condition 
For details of the estimand treatment condition see Table 1 in Section 2.2.2. 
7.2.6. 
Statistical Analyses / Methods 
7.2.6.1. 
Statistical Methodology Specification 
There will be no multiplicity adjustment for the testing of the secondary endpoints. No 
formal hypothesis testing will be performed.  
Secondary efficacy endpoint for clinical outcome and response at the TOC and FU Visits 
will be summarized using the ITT and micro-ITT NTF-S Populations. In addition, if the 
study stops for efficacy, a summary of clinical outcome and response at the TOC visit 
will be performed on the micro-ITT NTF-S (IA Set) Population.  
Secondary efficacy endpoints for participant-level microbiological outcome and response 
at the TOC and FU Visits, as well as therapeutic response at the FU Visit, will be 
summarized using the micro-ITT NTF-S Population. In addition, if the study stops for 
efficacy a summary of participant-level microbiological outcome and response at the 
TOC visit will be performed on the micro-ITT NTF-S (IA Set) Population. 
The 95% Exact Clopper-Pearson CI for microbiological, clinical, and therapeutic success 
rate will be included by treatment group. For participant level response, the MN weighted 
success rate difference (via actual stratification) will be calculated along with the 95% CI 
(using MN method adjusting for treatment and actual pooled strata). Reasons for failure 
(including receipt of non-study antibacterial therapy for uUTI) will be summarized for 
each treatment group for all participants that are failures. 
Supportive analyses to assess the homogeneity of the treatment difference across analysis 
strata will be implemented as in the primary efficacy analysis. This will also include the 
components of the primary composite endpoint of clinical response and micro response at 
TOC for the primary population (micro-ITT NTF-S (IA Set) if the study stops for 
efficacy else the micro-ITT NTF-S Population). 
Separately, percent of clinical outcomes by visit will be plotted for the ITT Population, 
and percent of participant level microbiological outcomes by visit will be plotted for the 
micro-ITT/NTF-S/NTF-NS Populations. 
7.2.6.2. 
Sensitivity Analyses 
Sensitivity analyses will be performed to investigate the robustness of the secondary 
estimands for microbiological response at TOC and FU, clinical response at TOC and 
FU, as well as therapeutic response at FU in their corresponding analysis populations 
defined in Section 7.2.6.1. Success rate between treatment groups (gepotidacin – 
nitrofurantoin) will be analyzed using unadjusted difference and corresponding two-sided 
95% CI (using MN method adjusting for treatment only) will also be presented. 


 
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7.2.6.3. 
Supplementary Analyses 
Supplementary analyses will be performed on secondary endpoints including: 
An analysis of therapeutic response at FU will be performed in the micro-ITT and micro-
ITT NTF-NS and in the ME-FU/NTF-S/NTF-NS Populations. 
An analysis of clinical outcome and response by visit will be performed in the CE-TOC, 
CE-FU, micro-ITT, and micro-ITT NTF-NS Populations. 
An analysis of microbiological outcome and response by visit will be performed in the 
micro-ITT, micro-ITT NTF-NS, ME-TOC/NTF-S/NTF-NS, and ME-FU/NTF-S/NTF-NS 
Populations. 
Success rate between treatment groups (gepotidacin – nitrofurantoin) will be analyzed 
using unadjusted difference and corresponding two-sided 95% CI (using MN method 
adjusting for treatment only) will also be presented. Reasons for failure (including receipt 
of non-study antibacterial therapy for acute cystitis) will be summarized for each 
treatment group for all participants that are failures. 
7.2.6.4. 
Subgroup Analyses 
Subgroup analyses of each secondary endpoint (participant-level therapeutic response, 
participant-level clinical outcome / response, and participant-level & uropathogen-level 
microbiological outcome / response, at the relevant visit) will be performed as listed in 
Table 12. See Section 5.4.2 for the definition of subgroups. For qualifying uropathogen 
thresholds, see Section 7.3.2. All subgroup analyses will follow the same layout/content 
contained in the original presentation of the main analyses. The population will include 
complete trial data (i.e., including participants in the IA Set and overrun if the study stops 
early for efficacy). Summary tables will be paginated by each subgroup level, and only 
the unadjusted difference and its 95% CI (using MN method adjusting for treatment only) 
in success rate will be presented. 


 
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Table 12 
Subgroup and Uropathogen Level Analyses 
Analysis/Endpoint Description: Therapeutic Response 
Visit: FU 
Population 
Subgroup 
micro-ITT  
Qualifying uropathogen species/group (including phenotypic 
and genotypic subcategories), by age category (<18, ≥18 to 50, 
>50), acute cystitis recurrence (nonrecurrent infection, recurrent 
infection), stratification combinations (age group and acute 
cystitis recurrence), region, race, ethnicity, baseline clinical 
symptom score, menopausal status, number of qualified 
uropathogens at Baseline 
micro-ITT NTF-S 
Qualifying uropathogen species/group (including phenotypic 
and genotypic subcategories), by age category (<18, ≥18 to 50, 
>50), acute cystitis recurrence (nonrecurrent infection, recurrent 
infection), stratification combinations (age group and acute 
cystitis recurrence), region, race, ethnicity, baseline clinical 
symptom score, menopausal status, number of qualified 
uropathogens at Baseline 
micro-ITT NTF-NS Qualifying uropathogen species/group (including phenotypic 
and genotypic subcategories), by age category (<18, ≥18 to 50, 
>50), acute cystitis recurrence (nonrecurrent infection, recurrent 
infection), stratification combinations (age group and acute 
cystitis recurrence), region, race, ethnicity, baseline clinical 
symptom score, menopausal status, number of qualified 
uropathogens at Baseline 
ME-FU 
Qualifying uropathogen species/group (including phenotypic 
and genotypic subcategories), by age category (<18, ≥18 to 50, 
>50), acute cystitis recurrence (nonrecurrent infection, recurrent 
infection), stratification combinations (age group and acute 
cystitis recurrence), region, race, ethnicity, baseline clinical 
symptom score, menopausal status 
ME-FU NTF-S 
Qualifying uropathogen species/group (including phenotypic 
and genotypic subcategories), by age category (<18, ≥18 to 50, 
>50), acute cystitis recurrence (nonrecurrent infection, recurrent 
infection), stratification combinations (age group and acute 
cystitis recurrence), region, race, ethnicity, baseline clinical 
symptom score, menopausal status 
ME-FU NTF-NS 
Qualifying uropathogen species/group (including phenotypic 
and genotypic subcategories), by age category (<18, ≥18 to 50, 
>50), acute cystitis recurrence (nonrecurrent infection, recurrent 
infection), stratification combinations (age group and acute 
cystitis recurrence), region, race, ethnicity, baseline clinical 
symptom score, menopausal status 


 
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Analysis/Endpoint Description: Clinical outcome and response 
Visit: TOC/FU 
ITT 
Age category (<18, ≥18 to 50, >50),  acute cystitis recurrence 
(nonrecurrent infection, recurrent infection), stratification 
combinations (age group and acute cystitis recurrence), region, 
race, ethnicity, baseline clinical symptom score, menopausal 
status 
CE-TOC 
CE-FU 
Age category (<18, ≥18 to 50, >50),  acute cystitis recurrence 
(nonrecurrent infection, recurrent infection), stratification 
combinations (age group and acute cystitis recurrence), region, 
race, ethnicity, baseline clinical symptom score, menopausal 
status 
micro-ITT 
Qualifying uropathogen species/group (including phenotypic 
and genotypic subcategories) 
micro-ITT NTF-S 
Age category (<18, ≥18 to 50, >50),  acute cystitis recurrence 
(nonrecurrent infection, recurrent infection), stratification 
combinations (age group and acute cystitis recurrence), region, 
race, ethnicity, baseline clinical symptom score, menopausal 
status, qualifying uropathogen species/group (including 
phenotypic and genotypic subcategories) 
micro-ITT NTF-NS Qualifying uropathogen species/group (including phenotypic 
and genotypic subcategories) 
Analysis/Endpoint Description: Participant-level Microbiological outcome and 
response 
Visit: TOC/FU 
micro-ITT NTF-S 
Age category (<18, ≥18 to 50, >50),  acute cystitis recurrence 
(nonrecurrent infection, recurrent infection), stratification 
combinations (age group and acute cystitis recurrence), region, 
race, ethnicity, baseline clinical symptom score, menopausal 
status,  
Analysis/Endpoint Description: Uropathogen-level Microbiological outcome and 
response 
Visit: TOC/FU 
micro-ITT 
All qualifying uropathogens and by qualifying uropathogen 
species/group (including phenotypic and genotypic 
subcategories) 
micro-ITT NTF-S 
All qualifying uropathogens and by qualifying uropathogen 
species/group (including phenotypic and genotypic 
subcategories) 
micro-ITT NTF-NS All qualifying uropathogens and by qualifying uropathogen 
species/group (including phenotypic and genotypic 
subcategories) 


 
C O N FI D E N TI A L  
2 0 4 9 8 9  
 
6 0  
 
M E -T O C  
M E -F U  
All q ualif yi n g ur o pat h o ge ns a n d b y q ualif yi n g ur o pat h o ge n 
s pecies/ gr o u p (i ncl u di n g p he n ot y pic a n d ge n ot y pi c 
s u bcate g ories) 
M E -T O C N T F -S  
M E -F U N T F -S  
All q ualif yi n g ur o pat h o ge ns a n d b y q ualif yi n g ur o pat h o ge n 
s pecies/ gr o u p (i ncl u di n g p he n ot y pic a n d ge n ot y pi c 
s u bcate g ories) 
M E -T O C N T F -N S  
M E -F U N T F -N S  
All q ualif yi n g ur o pat h o ge ns a n d b y q ualif yi n g ur o pat h o ge n 
s pecies/ gr o u p (i ncl u di n g p he n ot y pic a n d ge n ot y pi c 
s u bcate g ories) 
 
Perce nt of t hera pe utic s u ccess at F U o verall a n d b y q ualif yi n g ur o pat h o ge n b y visit will 
als o be pl otte d f or eac h tr eat me nt gr o u p f or t h e micr o -I T T N T F -S  P o p ulati o n .  
F orest pl ot f or t hera pe uti c s uccess rate at F U o verall  a n d b y s u b gr o u p will be pl otte d f or 
micr o -I T T/ N T F-S/ N T F -N S  P o p ula ti o ns.  
F orest pl ot f or cli nical s uccess r ate at eac h visit ( T O C, F U) o verall a n d b y q ualif yi n g 
baseli ne ur o pat h o ge n a n d ur o pat h o ge n p he n ot y pic a n d ge n ot y pic s u bcat e g ories  f or t he 
micr o -I T T/ N T F-S/ N T F -N S  P o p ulati o ns . Stac ke d bars of cli nical o utc o m e at eac h visit 
( O T, T O C, F U) will be pl otte d f or I T T P o p ulati o n . 
F orest pl ot f or p artici pa nt le vel micr o bi ol o gical s uccess r ate a n d ur o pat h o ge n le vel 
micr o bi ol o gical s u ccess r ate b y q ualif yi n g baseli n e ur o pat h o ge n a n d ur o pa t h o ge n 
p he n ot y pic a n d ge n ot y pi c s u bcate g ories will be pl otte d f or t he micr o-I T T/ N T F-S/ N T F -
N S P o p ulati o ns at eac h visit ( T O C, F U).  Stac ke d bars of partici pa nt le vel micr o bi ol o gical 
o utc o me a n d ur o pat h o ge n le vel micr o bi ol o gical o utc o me  b y q u alif yi n g b as eli ne  
ur o pat h o ge n at e ac h visit ( O T, T O C, F U) will be pl otte d f or micr o -I T T/ N T F-S/ N T F -N S  
P o p ulati o n s. 
C CI


 
C O N FI D E N TI A L  
2 0 4 9 8 9  
 
6 1  
 
C CI


 
C O N FI D E N TI A L  
2 0 4 9 8 9  
 
6 2  
 
C CI


 
C O N FI D E N TI A L  
2 0 4 9 8 9  
 
6 3  
 
C CI


 
C O N FI D E N TI A L  
2 0 4 9 8 9  
 
6 4  
 
C CI


 
C O N FI D E N TI A L  
2 0 4 9 8 9  
 
6 5  
 
C CI


 
C O N FI D E N TI A L  
2 0 4 9 8 9  
 
6 6  
 
C CI


 
C O N FI D E N TI A L  
2 0 4 9 8 9  
 
6 7  
 
C CI


 
C O N FI D E N TI A L  
2 0 4 9 8 9  
 
6 8  
 
C CI


 
C O N FI D E N TI A L  
2 0 4 9 8 9  
 
6 9  
 
C CI


 
C O N FI D E N TI A L  
2 0 4 9 8 9  
 
7 0  
 
C CI


 
C O N FI D E N TI A L  
2 0 4 9 8 9  
 
7 1  
 
C CI


 
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8. 
SAFETY ANALYSES 
The safety analyses will be based on the “Safety” Population. 
8.1. 
Adverse Events Analyses 
The severity of AEs and SAEs will be determined by the investigator according to the US 
National Institute of Allergy and Infectious Diseases Division of Microbiology and 
Infectious Diseases (DMID, 2007a) criteria for adult toxicity assessment, except for 
serum creatinine adolescent (adolescent participants over 12 years of age and less than 18 
years of age) laboratory data, which will be assessed using DMID pediatric toxicity 
criteria (DMID, 2007b). All reported AEs will be coded using MedDRA and summarized 
by system organ class (SOC) and preferred term (PT). 
A treatment emergent AE (TEAE) is defined as an AE with start date/time after the first 
dose date/time of the study treatment. If the time part is missing, only dates will be 
considered. The number and percentage of TEAEs, study treatment-related AEs, SAEs, 
and AEs leading to study treatment or study withdrawal will be collected. Only TEAEs 
will be included in summary tables, but all AEs will be displayed in detailed subject 
listings. 
Adverse event severity is classified as mild (grade = 1), moderate (grade = 2), severe 
(grade = 3), potentially life threatening (grade = 4) or resulting in death (grade = 5). 
Adverse events starting after the first dose of study treatment with a missing severity will 
be classified as severe. If a participant reports an AE more than once within an SOC/PT, 
the AE with the worst-case severity will be used in the corresponding severity 
summaries. 
Relationship to study treatment, as indicated by the investigator, is classified as “not 
related” or “related”. Adverse events with a missing relationship to study treatment will 
be regarded as “related” to study treatment. If a participant reports the same AE more 
than once within an SOC/PT, the AE with the worst-case relationship to study treatment 
will be used in the corresponding relationship summaries. 
An overall summary of AEs will present the total number of adverse events reported and 
the number of participants in each treatment group who experienced at least one AE, AE 
by maximum severity grade, drug-related AE, non-serious AE, SAE, AE leading to 
discontinuation of study treatment, AE leading to withdrawal from study, and AEs of 
special interest (AESI). 
Adverse events analyses including the analysis of AEs, SAEs and other significant AEs 
will be based on GSK Core Data Standards. All AEs, study drug related AEs, SAEs, and 
AEs leading to discontinuation of study treatment or withdrawal from study will be 
provided in separate listings. The relationship between SOC and PT will be listed. 
Summary tables will be provided by SOC, PT, and maximum severity grade. 
In summary tables where AEs are presented by SOC, PT, and maximum severity grade, 
SOCs will be sorted in descending order of the total incidence then alphabetically, PTs 
will be sorted in descending order of the total incidence then alphabetically within the 
SOC. 


 
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For completely missing or partial missing AE start date or end date, imputation rules will 
be applied following Appendix 5. 
In addition, a summary of the number and percentage of participants with common AEs, 
defined as AEs with ≥1% incidence (before rounding) in any treatment group, will be 
presented in descending order of total incidence by PT. The incidence of common AEs 
with relative risk and associated 95% CIs will also be presented graphically for each 
treatment group. AE summaries will also be presented for age subgroups (as recorded in 
the eCRF):  
• Age: <18, 18-64, 65-74, ≥75 
8.2. 
Adverse Events of Special Interest Analyses (AESI) 
Cardiovascular (CV) AEs, gastrointestinal (GI) AEs, C. difficile AEs, and AEs related to 
Acetylcholinesterase Inhibition (AChE-I) as determined by algorithm will be considered 
AESIs.  
8.2.1. 
Clostridium difficile AESIs 
C. difficile AESIs (PTs Clostridium difficile infection and Clostridium difficile colitis) 
will be included in the overall summary of AEs. C. difficile laboratory testing results are 
collected and recorded on distinct eCRF pages, which will be presented in a separate 
subject listing. 
8.2.2. 
Cardiovascular and Gastrointestinal AESIs  
GI AESIs are defined as AEs with a gastrointestinal SOC. Cardiovascular AESIs are 
defined as AEs with PTs that match the terms listed in Section 12.4.2. 
For CV and GI AESIs, the number and percentage of participants with an event will be 
summarized by PT and the maximum grade. In addition, the incidence of AEs of GI 
effects and time to the first occurrence will be summarized. Graphical presentation of the 
cumulative distribution of time to the first GI event occurrence will be provided 
(participants with no occurrence will be regarded as censored at the last day of their 
participation in the study). The details of data displays are presented in Appendix 9 
8.2.3. 
Potential Acetylcholinesterase-Inhibition AESIs 
Any reported AE listed in the table below with a start time no later than 12 hours after the 
latest dose administered, as evaluated by the investigator as per the DMID grading 
criteria provided in protocol Section 12.13 Appendix 13: Division of Microbiology and 
Infectious Disease Adult Toxicity Tables for Adverse Event Assessment, will be included 
in the programmatic identification of a potential Acetylcholinesterase-Inhibition (AChE-
I) AESI. 
List of preferred terms for programming to be considered potentially due to AChE-I is 
provided in Appendix 4:  (Section 12.4.2). 


 
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Cumulative grade score of potential AChE-I events will be calculated as the sum of the 
grade of each reported AE. This enables the number of AEs and the severity of each AE 
to be taken into account. The grading scale is defined in Table 21. 
Table 21 
AChE-I Cumulative Grade Score Scale 
 
Cumulative Grade: 
0 
1 
2 
3 
4 
Cumulative Grade Score: 
0 
1 to 3 
4 to 6 
7 to 10 
≥11 
 
For instance, if a subject reports two AEs, one of Grade 1 and the other of Grade 3 their 
cumulative grade score of 4 would result in cumulative grade 2, if a subject reports no 
AEs their cumulative grade score of 0 would result in cumulative grade 0. This will be 
calculated for All AChE-I events, non-GI AChE-I events and GI AChE-I events but only 
All AChE-I events and non-GI AChE-I events will be summarized. 
AChE-I AESIs will be listed and tabulated by SOC, PT, and maximum severity grade. 
Non-GI AChE-I events will also be summarized. Separate tables will summarize AChE-I 
AESI by number of events and unique PT. In addition, time of onset (time from first dose 
to the onset of first event in hours), duration, and lag time (the time from last dose to the 
end date/time of the last event for subjects whose end date/time of the last event is after 
treatment end date/time) of AChE-I events will also be summarized, and repeated for 
non-GI AChE-I and GI AChE-I events. AChE-I events with a start time less than 6 hours 
after the latest dose administered will also be flagged in subject listings. 
Graphical presentation via a stacked bar charts of percentage of subjects in each AChE-I 
cumulative grade will be produced for All AChE-I events and non-GI AChE-I events 
separately. In addition, forest plots of the relative risk of AChE-I events between two 
treatment groups and the associated 95% CI for each event will also be constructed and 
displayed. 
The details of the planned displays are provided in Appendix 9 
8.3. 
Clinical Laboratory Analyses 
Laboratory evaluations including the analyses of chemistry laboratory tests, hematology 
laboratory tests, urinalysis, and liver function tests will be based on GSK Core Data 
Standards. 
For adults, laboratory abnormalities will be graded according to the modified DMID 
criteria [DMID, 2007a]. For adolescent participants over 12 years of age and less than 
18 years of age, the adult DMID will be applied for all laboratory parameters with the 
exception of serum creatinine, which will be programmatically graded according to the 
modified DMID criteria for pediatric participants [DMID, 2007b]. 
Summaries of change from baseline values over time for clinical chemistry and 
hematology tests will be provided in separate tables. 


 
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Abnormal liver chemistry results will be summarized by increasing folds above the upper 
limit of normal (ULN) including tests of interest and thresholds as follows: 
• ALT or AST > 3xULN and Total Bilirubin > 2xULN 
• ALT or AST > 3xULN and ALP < 2xULN and Total Bilirubin ≥ 2xULN 
• ALT or AST > 3xULN and Total Bilirubin > 1.5xULN 
• (ALT/ALT ULN)/(ALP/ALP ULN)) > 5 and ALT > 3xULN * 
• ALT or AST ≥ 20xULN 
• ALT or AST ≥ 10xULN 
• ALT or AST ≥ 8xULN 
• ALT or AST ≥ 5xULN 
• ALT or AST ≥ 3xULN 
• ALT ≥ 20xULN 
• ALT ≥ 10xULN 
• ALT ≥ 8xULN 
• ALT ≥ 5xULN 
• ALT ≥ 3xULN 
• AST ≥ 20xULN 
• AST ≥ 10xULN 
• AST ≥ 8xULN 
• AST ≥ 5xULN 
• AST ≥ 3xULN 
• Total Bilirubin > 2xULN 
• Total Bilirubin > 1.5xULN 
*: sign of hepatocellular injury, ALT and ALP values must occur on the same day. 
Maximum post baseline total bilirubin vs maximum post-baseline ALT will be plotted as 
well as participant profile for liver function tests. 
Urinalysis results will be summarized using descriptive statistics.  
Clinical chemistry, hematology, and urinalysis test results with toxicity grade 3 or higher 
will be listed in separate listings. 
The severity of renal impairment will be evaluated and presented according to the method 
previously described in Section 6.1.2. 
The details of data displays are presented in Appendix 9 
8.4. 
Vital Signs and Electrocardiogram (ECG) 
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified.  
Summary tables will be provided for vital signs change from baseline values, and worst 
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values are assumed to have within range baseline values. A subject listing will be 
provided for vital sign values of potential clinical importance defined in Appendix 6 
The arithmetic mean of the three recorded ECG measurements will be employed in all 
subject listings. ECG measurements at Baseline will be recorded, including heart rate, PR 
interval, QRS duration, QT interval, QRS axis and RR interval. Corrected QT intervals 
will be calculated by Bazett’s formula: 
QTcB (msec ) =
𝑄𝑇
√RR/1000
 
and by Fridericia’s formula: 
QTcF (msec ) =
𝑄𝑇
√𝑅𝑅/1000
3
 
depending on the availability of other measurements. ECGs may be collected after start 
of treatment when medically warranted. 
Listings will be provided for baseline abnormal ECG findings, and ECG values of 
potential clinical importance. Potentially clinically important values are defined in 
Appendix 6. 
The details of data displays are presented in Appendix 9. 
8.5. 
Physical Examinations 
A physical examination (PE) will be performed at the baseline and TOC Visits, which 
will include assessments of the respiratory, cardiovascular, abdominal, gastrointestinal, 
neurological, and urogenital systems. Height and weight will only be measured and 
recorded before dosing at the Baseline Visit. Clinically significant changes from baseline 
or clinically significant new clinical signs will be reported as AEs. Since all significant 
data obtained from PEs will be recorded in AE eCRFs and reported within AE 
tables/listings, separate (stand-alone) PE tables/listings will not be generated. 


 
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9. 
PHARMACOKINETIC ANALYSES 
9.1. 
Primary Pharmacokinetic Analyses 
9.1.1. 
Endpoint / Variables 
9.1.1.1. 
Drug Concentration Measures 
Refer to Appendix 3 (Section 12.3.3). Pharmacokinetic blood and urine samples will be 
collected at the Baseline Visit (Day 1) 1 to 2 hours postdose. PK collections at the On-
Therapy Visit (Day 2 to 4) will be taken predose (i.e., 12 hours postdose, which is at the 
end of the dosing interval from the previous dose [Cτ]). As per Protocol Amendment 1 
and Protocol Amendment 2, PK blood and urine samples will only be collected at the On-
Therapy Visit (Day 2 to 5) if at all possible, 1 to 2 hours after the most recent dose is 
taken. Gepotidacin PK concentrations will be measured in plasma and urine. Plasma and 
urine concentration data units will be converted, as applicable, and presented as µg/mL in 
the PK TLF outputs. 
9.1.2. 
Summary Measure 
Pharmacokinetic parameters are not calculable based on the sampling scheme and 
average PK concentrations will be used. All calculations of PK concentrations will be 
based on actual sampling times that fall within the set PK windows described below.  
Summary statistics (n, arithmetic mean, geometric mean, median, standard deviation, 
minimum, maximum, 95% CI of the arithmetic and geometric means, and between-
participant coefficient of variation [%CV and %CVb]) for plasma and urine gepotidacin 
concentrations will be provided by the sampling windows described in Table 22 as 
appropriate.  
Table 22 
PK Summary by sampling windows  
Visit 
Parameter 
PK Window 
Baseline Study Day 
1 
Cday1, 0-2h 
Average concentration post-dose 0 to ≤ 2 
hours 
Cday1, >2h 
Average concentration post-dose >2 
hours 
On-Therapy Study 
Day 2 
Cday2am, 0-6h 
Average concentration post morning dose 
0 to ≤ 6 hours 
Cday2am, 6-8h 
Average concentration post morning dose 
> 6 to ≤ 8 hours 
Cday2am, 8-10h 
Average concentration post morning dose 
> 8 to ≤ 10 hours 
Cday2am, 10-12h 
Average concentration post morning dose 
>10 to ≤ 12 hours 


 
C O N FI D E N TI A L  
2 0 4 9 8 9  
 
7 8  
 
Visit  
P ar a meter  
P K Wi n d o w  
C d a y 2 p m, 0 -2 h 
A vera ge c o nce ntrati o n p ost e ve ni n g d os e 
0 t o ≤ 2 h o urs  
O n -T hera p y St u d y 
Da y 3 t o 5  
C d a y 3 -5, 0 -6 h 
A vera ge c o nce ntrati o n p ost -d ose 0 t o ≤ 6  
h o urs  
C d a y 3 -5, 6 -8 h 
A vera ge c o nce ntrati o n p ost -d ose >  6  t o ≤ 
8  h o urs  
C d a y 3 -5, 8 -1 0 h 
A vera ge c o nce ntrati o n p ost -d ose > 8  t o ≤ 
1 0  h o urs  
C d a y 3 -5, 1 0 -1 2 h 
A vera ge c o nce ntrati o n p ost -d ose > 1 0  t o ≤ 
1 2  h o urs  
a m = m or ni n g d os e; p m =e ve ni n g d ose  
9. 1. 3.  
P o p ul ati o n of I nt er e st  
T he pri mar y P K a n al ys es will be base d o n t he P K P o p ulati o n , u nless ot her wise s pecifie d. 
9. 1. 4.  
Str at e g y f or I nt er c urr e nt  E v e nt s  
St u d y treat me nt disc o nti n uati o n ( d ue t o a n y reas o n) will f oll o w  w hile -o n -treat me nt 
strate g y (treat me nt p hase defi ne d as fr o m first d os e t o O T Visit ). P har mac o ki netic  
sa m ples are pla n n e d t o b e c ollecte d at O T Visit.  
9. 1. 5.  
St ati sti c al A n al y si s / M et h o d s  
P K sa m ples c ollecte d o utsi de of t he treat me nt p h ase will o nl y be liste d wit h a fla g. If t h e 
P K sa m pli n g at O T Visit is c ollecte d f or m ore t ha n 1 2 h o urs after t h e latest d ose ta ke n, 
t hat P K sa m ple will n ot be i ncl u de d i n ta bles  b ut o nl y liste d wit h a fla g .  
Details of t he pla n ne d dis pla ys are pr o vi d e d i n A p pe n di x 9  a n d will be base d o n G S K 
Data Sta n dar ds a n d statistical pri nci ples.  
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10. 
ADDITIONAL ANALYSES DUE TO THE COVID-19 
PANDEMIC 
10.1. 
Study Population 
10.1.1. 
Subject Disposition 
A summary of recruitment by country and site, relative to COVID-19 Pandemic measures 
will be produced. For the definition of the phases of the COVID-19 pandemic measures 
see Section 12.2.1.2. 
A country level listing of the dates of the COVID-19 Pandemic measures will be 
produced. 
10.1.2. 
Protocol Deviations 
An optional subject listing of important protocol deviations related to COVID-19 may be 
produced, however, these deviations will already be captured in the listing of all 
important protocol deviations. 
Visits and assessments missed due to the COVID-19 pandemic, together with visits 
conducted remotely, will be summarized in both a table and listed by subject. 
10.2. 
Safety 
COVID-19 assessments and symptoms for subjects with COVID-19 adverse events will 
be provided in a detailed subject listing. 
 


 
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11. 
REFERENCES 
Clinical Laboratory Standards Institute (CLSI) M100; Latest edition Performance 
Standards for Antimicrobial Susceptibility Testing 
Fleiss J.L. Statistical Methods for Rates and Proportions. 2nd ed. New York: John Wiley; 
1981.  
GlaxoSmithKline Document Number 2017N318043_00 (Original 12-APR-2019): A 
Phase III, Randomized, Multicenter, Parallel-Group, Double-Blind, Double-Dummy 
Study in Adolescent and Adult Female Participants Comparing the Efficacy and Safety of 
Gepotidacin to Nitrofurantoin in the Treatment of Uncomplicated Urinary Tract Infection 
(Acute Cystitis) 
Lan KKG, DeMets DL. Discrete Sequential Boundaries for Clinical Trials. Biometrika. 
1983;70(3):659-63 
Lui K.J., Kelly C. A Revisit on Tests for Homogeneity of the Risk Difference, 
Biometrics, 2000;56:309-315. 
Miettinen , O.S., and M.M. Nurminen. 1985. “Comparative Analysis of Two Rates. 
“Statistics in Medicine 213-226. 
 
SAS Institute Inc. (2018), SAS/STAT User’s Guide, Version 15.1, Cary, NC: SAS 
Institute Inc. 
 
US National Institute for Allergy and Infectious Diseases, Division of Microbiology and 
Infectious Diseases. Division of Microbiology and Infectious Diseases (DMID) Adult 
Toxicity Table. Draft. https://www.niaid.nih.gov/sites/default/files/dmidadulttox.pdf. 
Last updated November 2007a. Accessed 20-Jun-2018. 
US National Institute for Allergy and Infectious Diseases, Division of Microbiology and 
Infectious Diseases. Division of Microbiology and Infectious Diseases (DMID) 
PEDIATRIC Toxicity Table. Draft. 
https://www.niaid.nih.gov/sites/default/files/dmidpedtox.pdf. Last updated November 
2007b.  


 
C O N FI D E N TI A L  
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8 1  
 
1 2.  
A P P E N DI C E S  
1 2. 1.  
A p p e n di x 1: S c h e d ul e of A cti viti e s  
Vi sit a 
B a s eli ne  
O n -T h er a p y b 
T O C b 
F oll o w -u p  
E arl y Wit h dr a w al  
St u d y D a y  
1  
2 t o 4  
1 0 t o 13  
2 8 ± 3  
N A  
Pr o c e d ur e  
Pr e d o s e  
P o st d o s e  
Writt e n i nf or me d c o nse nt/ ass e nt  
X  
 
 
 
 
 
I R T –  Scr e e ni n g m o d ule  
X  
 
 
 
 
 
I ncl usi o n a nd excl usio n criteri a 
X  
 
 
 
 
 
P artici p a nt d e mo gr a p hy  
X  
 
 
 
 
 
P hysic al exa mi n ati on (i ncl udi n g h ei ght an d w eig ht at 
B as eli n e o nly)  
X  
 
 
X c 
 
 
R ec or d acut e cystitis si g ns a n d sy m pt o ms d 
X  
 
X  
X  
X  
X  
M e dic al/s ur gic al hist ory  
X  
 
 
 
 
 
Di a g n osis of pr esu m ptiv e ac ut e cystitis f 
X  
 
 
 
 
 
B act eri ol ogy s a m ples g 
X  
 
X h 
X  
X  
X  
R a n d o miz atio n  
X  
 
 
 
 
 
1 2 -l e a d el ectr ocar di ogr a mi 
X  
 
 
 
 
 
Vit al si g n m eas ur e m ents j 
X  
 
X  
X  
 
 
H e m at ol o gy, c he mistry, a n d uri n alysis  
X  
 
X  
X  
 
 
S er ol o gy ( h e patitis B a nd C a n d HI V) k 
X  
 
 
 
 
 
Uri n e pr e g n a ncy t est l 
X l 
 
X l 
X  
 
X  
Dr u g a nd alc oh ol scr ee n  
X  
 
 
 
 
 
I R T –  R a n d o miz ati on m o dule  
X  
 
 
 
 
 
A d mi nist er or al d os e of st u dy tr e at m ent n 
 
X  
X o 
 
 
 
S eri o us a dv ers e ev ents p 
X  
X  
X  
X  
X  
X  
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C O N FI D E N TI A L  
2 0 4 9 8 9  
 
8 2  
 
A dv ers e ev e nts q 
 
X  
X  
X  
X  
X  
C o nc o mit a nt m e dic ati o n r evi e w  
X  
X  
X  
X  
X  
X  
P K bl oo d sa m pl e  
 
 
X r 
 
 
 
P K uri n e s a m pl e  
 
 
X r 
 
 
 
St u dy tr e at m ent co m pli a nc e s 
 
 
X  
X  
 
 
Sc h e dul e n ext visit  
X t 
 
X u 
X u 
X u 
 
G e n etic s a m pl e v 
X  
 
 
 
 
 
HI V = h u m an i m m u n od efici ency vir us; H P F = hi gh -p o wer fi el d; I R T =i nter activ e r esp ons e t ech n ol ogy; N A =n ot a pplic a bl e; P K = ph ar mac oki netic; 
T O C = T est -of -C ur e; U TI =uri n ary tr act i nf ecti on; W B C = whit e blo o d c ell.  
N ot e:  T o r ed uc e p artici pa nt o n -sit e visits or if unf or esee n iss ues i m p act cli nic visits, a nd p articip a nts ar e u n able t o atte n d a sit e visit, ho m e h e althc ar e  
( h o m e visits a nd tel e m e dicin e visits) m ay b e use d to c o n d uct pr oc ed ur es as d et ail ed i n th e St u dy Ref er enc e Ma n ual. H o m e h e althc ar e will o nly be 
utiliz e d w h ere a p plic a bl e c o u ntry a n d l ocal r e gul ati ons a n d infr astr uctur e all o w.  
a. F or all st u dy visits, t o mi ni miz e t h e a m o unt of ti m e th at p articip a nts s pe n d at th e clinic, e C ons e nt m ay b e utiliz e d a n d r e mo t e coll ecti o n of 
st u dy-r el at e d d at a m ay b e o bt ai ne d as d escribe d i n t he St u dy Ref er enc e M an ual. Th us, so m e visit d at a m ay b e c oll ect e d t hr ou gh a co m bi nati o n 
of t ele m e dici n e a nd o n -sit e visits. C oll ecti o n of i nfor matio n vi a t el e m edici n e will b e perf or me d o nly w h er e l oc al re g ul ati o ns p er mit. Pr escr eeni n g 
activiti es m ay als o b e c o nduct e d, i ncl u din g a pr escr eeni n g i nf or me d co ns ent a n d uri n e t esti n g, as d etail e d i n S ecti o n 9  of th e pr ot ocol a nd t he 
St u dy Ref er enc e M an ual.  
b. F or t h e O n -t h er a py ( D ay 2 to 4) Visit: P articip ants will b e i nstr ucte d to r etur n to t he st u dy sit e wit hi n 1 t o 3 d ays p ostr an d o miz atio n. E ac h  
tr e at m e nt day will b e assess e d over 2 4 h ours st arti ng wit h t h e first d ose of st u dy tre at m e nt, as f urt her det ail e d i n t h e St u dy R efer e nce M a nu al. F or 
t h e T O C ( D ay 1 0 t o 1 3) Visit: P artici pa nts will b e i nstr uct e d to r etur n to t he st udy site 5 to 8 d ays after c o m pl etio n of st u dy tr eat m e nt.  
c. At t h e T O C Visit, t h e p hysical ex a mi n ati o n m ay b e sy m pt o m directe d a n d is o nly r eq uire d if in dic ate d f or a sp ecific p articip a nt.  
d. I n divi d ual cli nic al si g ns a nd sy m pt o ms sc or es of acut e cystitis will b e r ec or d ed by a st u dy p hysici a n or oth er wis e a ppr o priately m e dic ally 
tr ai n e d st aff b ase d o n p artici p a nt int ervie w an d usi n g t h e sc orin g syst e m i n Ap pe n dix 6  of t h e pr otoc ol . T he s a m e sc or er will b e use d at all 
ass ess m e nt ti m e p oi nts for e ac h p articip ant, o n all occ asi o ns, w he n ever p ossi ble.  
f. B as e d o n c o nfir mati o n of nitrit e or py uria ( >1 5 W B C/ H P F or t h e pr es enc e of 3 +/l ar ge l e ukocyt e est er ase) fr o m a pr etr eat m e nt cl e a n -c atc h 
mi dstr e a m uri n e sa m pl e per l oc al l a b or at ory pr oc e dur es.  
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g. P artici p a nts will pr ovi d e a cle a n -c atch mi dstr ea m urin e s a m pl e at e ach visit f or Gr a m st ai n, q u antit ativ e b act eriol o gy cult ur e, a nd i n vitr o 
a nti micr o bi a l s usce pti bility testi n g by a d esi gn ate d la b or at ory(i es). R ef er to t he l ab or at ory m a n ual. 
i. S e e S ecti on 6. 2 of t h e prot oc ol f or electr oc ar di ogr a m excl usi o n crit erio n f or particip ants ag e d ≥1 2 t o <1 8 ye ars. F or a d ditio n al d etails s e e 
S ecti o n 8.1. 2 a nd S ecti o n 9. 4. 3  of th e pr ot ocol . 
j. T ak e m e asur e m e nt of t e m per at ur e, bl oo d press ur e, a nd p ulse r at e.  
k. If s er ol ogy t esti n g was p erfor me d wit hi n 3 m o nths prior to t he first dos e of stu dy tr eat m e nt an d t h e r es ults w ere p o siti v e , t esti ng at B aseli ne i s 
n ot r e q uir e d . If t estin g w as p erf or me d wit hi n 3 m o nths a n d a ny r esult w as ne g ati ve , t esti n g at Bas eli ne i s r e q uir e d.  
l. F or w o m e n of c hil db e a ri ng p ot e nti al, a n e g ativ e hig h sensitivity urin e pr e g na ncy t est is s uffici e nt f or eli gi bility. Se e Ap p en dix 2  of t he pr otocol  
f or B aseli n e uri ne test s ensitivity r e q uire m e nts a nd associ at e d co ntr ace ptio n r eq uire m e nts. Pr eg na ncy testi n g sh o ul d als o b e p erf or med after 
D os e 4 a nd b ef or e Dos e 8 as s p ecifi ed i n A pp e ndix 2  of t h e pr otoc ol . 
n. P artici p a nts will r ec eiv e or al st u dy tr e at m ent t wic e d aily f or 5  days u n der d ou bl e -bli n d, do u ble -d u m my c o nditi o ns. T h e first or al dos e will b e 
a d mi nist er e d at t h e st udy site d uri ng t he Bas eli n e Visit; p articip a nts will s elf -a d mi nist er as o ut p ati ents th er e aft er. E ac h d ose s h o ul d b e t ak en after 
f o o d c o nsu m pti on a n d wit h w at er. 
o. P artici p a nts s h oul d co nti nue t aki ng st udy tr eat m e nt per t h eir pl an ne d d osi ng sc h edul e. If at all p ossi ble, th e a pp oi nt m ent ti m e of th e On -
t h er a py Visit s ho ul d b e a ppr oxi m at ely 1 t o 2 h o urs aft er t h e p articip ant’s m ost r ece nt d ose is ex pect e d to b e t ake n. Se e t h e Stu dy R efer e nce 
M a n u al for a dditi o n al det ails.  
p. R ec or d s eri ous a dvers e ev ents fr o m th e ti me of co ns ent/ ass e nt i n ord er t o f ulfill i nter n ati o nal r e g ulat ory r eq uire m e nts.  
q. R ec or d adv ers e ev e nts fr o m t h e ti me of th e first d os e of st u dy tr eat m e nt.  
r. At t h e O n -th er apy Visit, P K s a m pl es will b e coll ect e d, as f urt h er d etail e d i n S ecti o n 9 of t h e pr otoc ol an d t h e Stu dy R efer e nce M a nu al.  
s. D et er mi n e stu dy tr eat m e nt c o m pli a nc e by p erf or mi n g pill c o u nt.  
t. C o nfir m r et ur n d ay/ti m e f or th e On -t h er apy, T O C, a nd Foll o w-u p  Visits. R ef er to f ootn ot e o for sc h ed uli ng t he On -t h er apy Visit. 
u. Pr evisit r e mi n d er: St u dy sit e st aff will c o nt act t h e p articip a nt 2 4 ±4  ho urs bef ore t he sc h e dul e d On -t h er a py, T O C, a n d F oll o w-u p Visits.  
v.  C oll ect s a m pl e o nly if th e partici p a nt h as a si g ne d co nse nt/ass e nt s p ecific f or t his pur p os e. T h e B aseli n e Visit is t h e r eco m m e n de d ti m e t o 
c oll ect t h e s a m ple, but it can b e c oll ect e d at any ti me d urin g t he stu dy.  
 
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12.2. 
Appendix 2: Study Phases and Treatment Emergent Adverse 
Events 
12.2.1. 
Study Phases 
Assessments and events will be classified according to the time of occurrence relative to 
the start and end date of study treatment. 
Study Phase 
Definition 
Pre-Treatment  
Date and Time < Study Treatment Start Date and Time 
On-Treatment 
Study Treatment Start Date and Time ≤ Date and Time ≤ Study Treatment 
Stop Date and Time 
Post-Treatment 
Date and Time > Study Treatment Stop Date and Time 
 
12.2.1.1. Study Phases for Concomitant Medication 
Study Phase 
Definition 
Prior 
If medication started prior to the first dose date (or randomized date if first dose 
date is missing) 
Concomitant 
If medication ended after the first dose date or is ongoing regardless of the start 
date (or randomized date if first dose date is missing)  
1. NOTES:  
• Please refer to Appendix 5 for handling of missing and partial dates for concomitant medication. 
Use the rules in this table if concomitant medication date is completely missing. 
• If a single medication taken on the same date as the first dose date, time will be used to 
determine if it’s prior or concomitant. If time is missing, it will be considered concomitant.  
12.2.1.2. 
Phases of COVID-19 Pandemic Measures 
Pandemic measures began in different countries at different times. A dataset containing 
the date when pandemic measures began, as determined by the GSK country Issue 
Management Teams will be used to determine the start date of pandemic measures within 
each country. A copy of this dataset will be taken at the time of database freeze (DBF).  
12.2.2. 
Treatment Emergent Flag for Adverse Events 
Flag 
Definition 
Treatment 
Emergent 
• If AE onset date/time is on or after treatment start date/time. That is, study 
treatment start date/time ≤ AE start date/time. If time is missing, only date 
will be compared. 
NOTES:  
• Time of study treatment dosing and start/stop time of AEs should be considered, if collected. 
 


 
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12.2.3. 
Participant and Study Completion 
A participant is considered to have completed study treatment if she has taken all doses 
of the randomly assigned study treatment. A participant is considered to have completed 
the study if she has completed all study visits including the Follow-up Visit. 
 


 
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12.3. 
Appendix 3: Data Display Standards & Handling 
Conventions 
12.3.1. 
Reporting Process 
Software 
• The currently supported versions of SAS software will be used. 
Analysis Datasets  
• Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & 
ADaM IG Version 1.1). 
• For creation of ADaM datasets (ADCM/ADAE), the same version of dictionary datasets will 
be implemented for conversion from SI to SDTM. 
Generation of RTF Files 
• RTF files will be generated for all reporting efforts described in the RAP. 
 
12.3.2. 
Reporting Standards 
General 
• The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, 
unless otherwise stated (IDSL Standards Location: 
https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx): 
• 4.03 to 4.23: General Principles 
• 5.01 to 5.08: Principles Related to Data Listings 
• 6.01 to 6.11: Principles Related to Summary Tables 
• 7.01 to 7.13: Principles Related to Graphics  
• Do not include participant level listings in the main body of the GSK Clinical Study Report. 
All participant level listings should be located in the modular appendices as ICH or non-ICH 
listings 
Formats 
• GSK IDSL Statistical Principles (5.03, 6.06.3, & 6.09) for decimal places (DP’s) will be 
adopted for reporting of data based on the raw data collected, unless otherwise stated. 
• Numeric data will be reported at the precision collected on the eCRF. 
• The reported precision from non eCRF sources will follow the IDSL statistical principles but 
may be adjusted to a clinically interpretable number of DP’s. 
Planned and Actual Time 
• Reporting for tables, figures and formal statistical analyses: 
• The impact of any major deviation from the planned assessment times and/or scheduled 
visit days on the analyses and interpretation of the results will be assessed as 
appropriate. 
• Reporting for Data Listings: 
• Planned and actual time relative to study drug dosing will be shown in listings (Refer to 
IDSL Statistical Principle 5.05.1). 
• Unscheduled or unplanned readings will be presented within the participant’s listings. 


 
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Unscheduled Visits 
• Unscheduled visits may be included in summary tables and/or figures as described in 
Section 5.6 on Analysis Visits and analyses such as “all post baseline”, “worst case post 
baseline”, and “max post baseline” etc.. 
• All unscheduled visits will be included in listings. 
Descriptive Summary Statistics 
Continuous Data 
Refer to IDSL Statistical Principle 6.06.1 
Categorical Data 
N, n, frequency, % 
Graphical Displays 
• Refer to IDSL Statistical Principals 7.01 to 7.13. 
 
12.3.3. 
Reporting Standards for Pharmacokinetic 
Pharmacokinetic Concentration Data 
Descriptive 
Summary 
Statistics, 
Graphical Displays 
and Listings 
Refer to IDSL PK Display Standards. 
Refer to IDSL Statistical Principle 6.06.1. 
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics and summarized graphical displays only.  
 


 
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12.4. 
Appendix 4: Derived and Transformed Data 
12.4.1. 
General 
Multiple Measurements at One Analysis Time Point 
• The arithmetic mean of the three recorded ECG measurements will be employed as 
described in Section 8.4. Analysis visits will be created based on visit windows as described 
in Section 5.6. All assessments (including unscheduled and early termination visits) will be 
presented in subject listings. 
• Participants having both High and Low values for Normal Ranges at any post-baseline visit 
for safety parameters will be counted in both the High and Low categories of “Any visit post-
baseline” row of related summary tables. This will also be applicable to relevant Potential 
Clinical Importance summary tables. 
Study Day 
• Calculated as the number of days from First Dose Date (or Randomization Date if not 
dosed): 
• Ref Date = Missing → Study Day = Missing 
• Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date 
• Ref Date ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1 
12.4.2. 
Study Population 
Age 
Age is derived using the date of first dose. When first dose date is missing, the informed consent 
date is used. Only year of birth is collected so Day and Month of birth are imputed as 30 June. 
Formula for deriving age is the integer component of: 
•  (First Dose Date – 30 Jun of collected birth year +1)/365.25 
 
12.4.3. 
Safety 
Adverse Events 
AEs of Special Interest 
• Clostridium difficile events 
• Cardiovascular events 
• Gastrointestinal events 
• Acetylcholinesterase inhibition events 
 


 
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List of Cardiovascular AESIs Preferred Terms 
Pulmonary oil microembolism 
Atrioventricular node dispersion 
Peripheral revascularization 
Cardiac arrest 
Supraventricular extrasystoles 
Holiday heart syndrome 
Rebound tachycardia 
Anomalous atrioventricular excitation 
Cardio-respiratory arrest neonatal 
Bundle branch block 
Atrial conduction time prolongation 
Adams-Stokes syndrome 
Cardiac death 
Atrioventricular dissociation 
Paroxysmal arrhythmia 
Atrial flutter 
Cardiac flutter 
Prosthetic cardiac valve thrombosis 
Neonatal sinus bradycardia 
Heart valve incompetence 
Neonatal bradyarrhythmia 
Cardiac valve disease 
Sinus bradycardia 
Metastatic pulmonary embolism 
Bradycardia foetal 
Renal revascularisation surgery 
Junctional ectopic tachycardia 
Angina unstable 
Ventricular fibrillation 
Ventricular extrasystoles 
Accessory cardiac pathway 
Lenegre's disease 
Sinoatrial block 
Atrioventricular block 
Pulseless electrical activity 
Nodal arrhythmia 
Ventricular parasystole 
Rhythm idioventricular 
Paroxysmal atrioventricular block 
Nonreassuring foetal heart rate pattern 
Ogden syndrome 
Ventricular asystole 
Nodal rhythm 
Defect conduction intraventricular 
Bundle branch block left 
Atrial fibrillation 
Heart valve stenosis 
Tachycardia foetal 
Acute myocardial infarction 
Atrioventricular block first degree 
ECG signs of myocardial infarction 
Foetal arrhythmia 
Embolism arterial 
Neonatal tachycardia 
Pulmonary embolism 
Carcinoid heart disease 
Central bradycardia 
Cardiac valve replacement complication 
Sinus arrest 
Degenerative multivalvular disease 
Cardiac fibrillation 
Cardiac valve sclerosis 
Trifascicular block 
Cardiac valve abscess 
Ventricular tachycardia 
Newborn persistent pulmonary hypertension 
Accelerated idioventricular rhythm 
Deep vein thrombosis postoperative 
Bundle branch block bilateral 
Carotid revascularization 
Bundle branch block right 
Transmyocardial revascularization 
Bezold-Jarisch reflex 
Ventricular tachyarrhythmia 
Chronotropic incompetence 
Tachycardia 
Arrhythmia neonatal 
Torsade de pointes 
Inherited cardiac conduction disorder 
Lown-Ganong-Levine syndrome 
Baseline foetal heart rate variability disorder 
Conduction disorder 
Ventricular flutter 
Congenital supraventricular tachycardia 
Lambl's excrescences 
Pacemaker generated arrhythmia 
Periprocedural myocardial infarction 
Wolff-Parkinson-White syndrome 
Congenital pulmonary hypertension 
Long QT syndrome 
Portopulmonary hypertension 
Parasystole 
Deep vein thrombosis 
Cardiac arrest neonatal 
Revascularisation procedure 
Neonatal sinus tachycardia 
Cardiac failure congestive 
Foetal tachyarrhythmia 
Atrioventricular node dysfunction 
Cerebrovascular disorder 
Ventricular pre-excitation 
Pulmonary arterial hypertension 
Supraventricular tachyarrhythmia 
Post procedural pulmonary embolism 
Arrhythmia 
Pulmonary microemboli 


 
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List of Cardiovascular AESIs Preferred Terms 
Timothy syndrome 
Sinusoidal foetal heart rate pattern 
Heart alternation 
Bradyarrhythmia 
Reperfusion arrhythmia 
Tachycardia paroxysmal 
Foetal heart rate disorder 
Sinus tachycardia 
Atrial parasystole 
Wandering pacemaker 
Atrial tachycardia 
Withdrawal arrhythmia 
Bifascicular block 
Foetal heart rate acceleration abnormality 
Atrioventricular block complete 
Pacemaker syndrome 
Sudden cardiac death 
Structural valve deterioration 
Sinus node dysfunction 
Cardiac valve thickening 
Sudden death 
Post procedural myocardial infarction 
Cardio-respiratory arrest 
Pulmonary hypertension 
Arrhythmia supraventricular 
Obstetrical pulmonary embolism 
Neonatal tachyarrhythmia 
Heart block congenital 
Bradycardia 
Atrioventricular block second degree 
Congenital heart valve incompetence 
Extrasystoles 
Cardiac valve rupture 
Brugada syndrome 
Heart valve calcification 
Wolff-Parkinson-White syndrome congenital 
Cardiac valve discolouration 
BRASH syndrome 
Cardiac valve vegetation 
Ventricular arrhythmia 
Congenital heart valve disorder 
Foetal heart rate deceleration abnormality 
Myocardial infarction 
Long QT syndrome congenital 
Silent myocardial infarction 
Agonal rhythm 
Septic pulmonary embolism 
Frederick's syndrome 
Coronary revascularization 
Bradycardia neonatal 
Atrioventricular conduction time shortened 
Shone complex 
Sinus arrhythmia 
Transient ischaemic attack 
Tachyarrhythmia 
Cerebrovascular accident 
Postural orthostatic tachycardia syndrome 
 
 List of Acetylcholinesterase Inhibition AESIs Preferred Terms 


 
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List of Cardiovascular AESIs Preferred Terms 
Abdominal discomfort 
Generalised non-convulsive epilepsy 
Abdominal pain 
Generalised tonic-clonic seizure 
Abdominal pain lower 
Heart rate decreased 
Abdominal pain upper 
Hyperhidrosis 
Abdominal symptom 
Hyperkinesia 
Abdominal tenderness 
Hypocalcaemic seizure 
Asthma 
Hypoglycaemic seizure 
Atonic seizures 
Hyponatraemic seizure 
Atypical benign partial epilepsy 
Idiopathic generalised epilepsy 
Autonomic seizure 
Idiopathic partial epilepsy 
Bradyarrhythmia 
Irregular breathing 
Bradycardia 
Lacrimation increased 
Bronchial hyperreactivity 
Lafora's myoclonic epilepsy 
Bronchospasm 
Lennox-Gastaut syndrome 
Clonic convulsion 
Myoclonic epilepsy 
Cold sweat 
Nausea 
Convulsions local 
Night sweats 
Convulsive threshold lowered 
Partial seizures 
Defaecation urgency 
Partial seizures with secondary generalisation 
Diarrhoea 
Petit mal epilepsy 
Drooling 
Psychomotor hyperactivity 
Dyspnoea 
Retching 
Dyspnoea at rest 
Salivary hypersecretion 
Dyspnoea exertional 
Seizure 
Epigastric discomfort 
Seizure cluster 
Epilepsy 
Simple partial seizures 
Epilepsy with myoclonic-atonic seizures 
Status asthmaticus 
Faeces soft 
Status epilepticus 
Febrile convulsion 
Sweat gland disorder 
Febrile infection-related epilepsy syndrome 
Syncope 
Flatulence 
 
Focal dyscognitive seizures 
Tonic clonic movements 
Frequent bowel movements 
Tonic convulsion 
Frontal lobe epilepsy 
Unilateral bronchospasm 
Gastrointestinal disorder 
Vomiting 
Gastrointestinal pain 
Vomiting projectile 
Gastrointestinal tract irritation 
Wheezing 
Adverse Events with Missing Relationship or Missing Serious Indicator 
• If the relationship to study treatment is missing for a treatment-emergent AE (TEAE), then the TEAE will be 
considered related to the study treatment. 
• If the serious indicator “Was event serious?” is missing, the AE will be considered as SAE. 
• Adverse events with missing relationship or missing serious indicator will be presented as it is in listings but will 
be treated as related AEs or SAEs in summary tables. 
 
12.4.4. 
Efficacy 
Microbiology Procedures 
• Microbiology data will be received from below sources: 
• GSK microbiologists 
• Central laboratory 


 
C O N FI D E N TI A L  
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9 2  
 
Mi cr o bi ol o g y Pr oc e d ur es  
•  3 r d party l a b or at ory  
•  
•  All gr a m -n e gativ e uro p at h og e ns will b e t este d by br ot h micro dil uti o n ( MI C) t o d et er mi n e 
pr o d uctio n of ext e nd ed s p ectr u m b eta -l act a m as es ( E S B Ls). I n acc or da nce wit h the 
Cli nic al a n d L a bor atory St an d ar ds I nstitut e ( C L SI) M 1 0 0 g uid eli n es ( T abl e 3 A), E S B L 
pr o d uctio n m ay b e in dic ated by a MI C r es ult of >1 mc g/ m L f or c eftriax o ne , ceft azi di me, 
c ef otaxi m e or aztre o na m f or E. c oli, K. pn e u mo ni ae or K. oxyt oca or a MI C r es ult of > 1 
mc g/ m L f or c eft azi di m e, c efot axi me or cef p o d oxi me f or P. mira bilis.  
•  Gr a di e nt diffusi o n r esults ( MI C) o n all ur op ath o ge ns f or s usc e pti bility to g e p oti d acin  
•  Gr a di e nt Diff usi on MI C s a nd I nter pr etati o n 
•  Gr a di e nt diffusi o n stri ps g ener at e MI C val u es fro m a c o nti n uo us sc ale a n d ca n giv e 
r es ults i n-b et we e n c o nve ntio n al t wo -f ol d dil uti o ns i. e. half dil uti ons. A  gr a di e nt 
diff usi on MI C v al ue w hic h falls b et w e en  st a n dar d t w o-fol d dil uti ons m ust b e r ou nd e d 
u p to t he n ext up per t w o -f old v alue b e f or e cat e g orizati on.  
•  As a n ex a m pl e, a  gr a die nt diff usi o n MI C of 1 u g/ m L is r ep ort e d as i nt er me di at e (I) 
w hil e 1. 5  is r o u nd ed u p t o 2 u g/ m L a nd t he c at e gory r ep ort e d as r esista nt ( R).  
•  W h e n gr o wth occurs al on g th e e ntir e stri p i.e. no i nhi bitio n elli ps e is s e en, r ep ort the 
MI C as > =  t h e hig h est v al ue o n th e MI C scal e. W he n the i n hi biti on elli pse is b el o w 
t h e stri p (d o es n ot i nt ers ect t h e strip), r ep ort th e MI C < th e l o w est v al ue o n t he MI C 
sc al e. 
•  MI C R e p orti n g C o nce ntr ations  
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Microbiology Procedures 
• When serial two-fold dilution MICs are being prepared and tested, the actual dilution 
scheme is, e.g.: 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.0625, 0.03125, 0.015625, 0.0078125 
ug/ml, etc. 
• For convenience only, it was decided to use the following values for reporting purpose 
(reporting format):16, 8, 4, 2, 1, 0.5, 0.25, 0.12, 0.06, 0.03, 0.016, 0.008, 0.004, 0.002 
ug/mL, etc. The values that appear in the tables are equivalent to the actual values 
tested, e.g., 0.12 ug/mL = 0.125 ug/mL; 0.016 ug/ml = 0.015625 ug/ml. 
• Any values containing '<', '<=', '>=', '>' will be counted in its separate categories. 
However, when calculating the minimum, maximum, MIC50, MIC90, a small amount will 
be added or subtracted in order to impute the corresponding numeric value for 
calculation. For example, 
o '<0.06' will be imputed as 0.06-0.001; 
o '>256' will be imputed as 256+0.001. 
o '>=32' will be imputed as 32. 
• But for reporting, they will still be presented in original format if they happen to be 
those summary statistics. 
• Disk Diffusion results (mm) will be conducted on uropathogens as follows. CLSI 
interpretive criteria are applied with the exceptions of nitroxoline and cefadroxil where 
EUCAST interpretive criteria are applied. 
Compound 
Organisms 
Gepotidacina 
All uropathogens 
Nitroxoline b 
All uropathogens 
Nitrofurantoin 
All uropathogens 
Mecillinam c,d 
Gram-negative uropathogens 
Cefadroxil b 
Gram-negative uropathogens 
Penicillin 
Staphylococci (S. aureus and S. saprophyticus) and enterococci 
uropathogens 
Cefoxitin b 
Staphylococci uropathogen isolates (S. aureus and S. saprophyticus) 
a. Two manufacturers (Becton Dickinson and MAST) 
b. To be tested by disk diffusion (surrogate test or no MIC QC ranges) 
c. To be tested by disk diffusion (broth method not approved and gradient diffusion is not 
available) 
d. Tested to predict the activity of pivmecillinam 
• The 3rd party laboratory will conduct confirmatory nitrofurantoin susceptibility testing, agar 
dilution testing for fosfomycin and genetic characterization of selected isolates as described 
directly below. 
• Uropathogens exhibiting intermediate or resistant (with the exception of species 
considered intrinsically resistant to nitrofurantoin per CLSI M100 guidelines) nitrofurantoin 
MIC results at the central laboratory will be submitted to the 3rd party laboratory for 
confirmatory susceptibility testing of nitrofurantoin (dilution range of 2–256 µg/mL) by 
reference broth microdilution. Broth microdilution nitrofurantoin MIC from JMI Laboratories 
(if available) will take precedence over global central laboratory (GCL) nitrofurantoin MIC 
result for determining susceptibility to nitrofurantoin. 
• All uropathogens will be submitted for susceptibility testing of fosfomycin (dilution range of 
0.12–256 mcg/mL) by reference agar dilution methodology. 


 
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9 4  
 
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Microbiology Procedures 
Microbiological Data Procedures 
• PPD global central laboratory (GCL) will identify the uropathogen classification and 
phenotype via GSK source documents regarding qualified uropathogen flagging and 
uropathogen resistance flagging (Uropathogen and qualifying uropathogen decision 
tree_112119_GSK final.docx and GSK Uropathogen resistance decision 
trees_112119_final.docx). 
• JMI laboratories genotype data is derived from isolate whole genome sequencing and other 
genomic assays as requested by GSK and will be performed by JMI when a minimum of 20 
isolates are available but not more frequent on a monthly basis (testing may be conducted 
more frequently near the end of the study). Genotype data therefore will be available no 
sooner than 1-2 months from isolate recovery. 
• JMI isolate genotype data will be sent to PPD GCL and included in PPD GCL data transfers 
to PPD clinical and therefore available for PPD Biostatistics and PPD clinical programming 
for inclusion in analysis database. 
• Data from the GSK study microbiologist/or clinical scientist will include clarification of which 
uropathogen species should be reported separately and which should be grouped for display, 
classification of uropathogens as Gram-positive or Gram-negative, determination of the 
phenotype and genotype subcategories and a determination of whether the susceptibility 
results for identically labelled uropathogens from the same participant at the same visit differ 
enough to classify the uropathogens as separate (“keepers”). 
“Keepers” process 
• Includes all cases within the central laboratory dataset where two or more uropathogens of 
the same genus and species for the same participant at the same visit will be identified. 
• An excel file containing a list of these uropathogens and the associated quantitative bacterial 
counts, MIC results and CLSI interpretations for each isolate will be provided to the 
microbiologist. 
• The microbiologist will review the list and determine if the isolates are the same or 
different strains of the identified uropathogen based on a predefined algorithm: 
▪ For example, if two uropathogens of the same genus and species have a 
≥4-fold difference in MIC (or ≥6 mm difference in zone diameter for 
antibiotics only tested by disk) to three or more antibiotic classes, they will 
be considered two different strains and both uropathogen isolates will be 
analyzed.  
• If none of the criteria for determining the isolates as different are met, the uropathogen 
isolates will be considered to be of the same strain and only one isolate will be retained for 
analysis based on a pre-defined algorithm. 


 
C O N FI D E N TI A L  
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9 6  
 
Mi cr o bi ol o g y Pr oc e d ur es  
•  T h e micr o bi ol ogist will a d d a fl a g t o t h e list t o i ndic ate w hic h of t h e d uplic at e rec ords t o ke ep 
(fl a g = > 0; e.g. 1, 2). All d uplic at e  r ec or ds will b e k e pt i n t h e S D T M d atas ets, a nd thos e 
r ec or ds t h at are d e e m e d t o b e d u plic ates (fl a g = 0) will n ot b e i ncl ud ed i n a ny a n alys es.  
M icr o bi ol o gic al o utc o m e a nd r es p ons e in i nsta nc es of 2 b as eli ne q u alifyi n g ur o pat h o g ens  
•  If t w o b as eli ne q u alifyi n g uro p ath og e n s ar e  r ecov er ed th at ar e of t w o diff er ent ge nus a n d 
s p eci es ( e.g. a K. p ne u m o nia e  an d E. c oli ), eac h b aseli n e ur op ath og e n will b e c o nsi d er e d 
s e p ar ately f or micr o bi olo gical o utco m e a n d r esp ons e.  
•  If m or e th a n o ne b as eli n e q u alifyi n g ur o pat h o g en is r ecov er e d t h at ar e of th e sa m e g e nus 
a n d sp eci es (e. g. t w o m or ph oty p es of E. coli ) a n d if t h e s a m e g e n us a nd s peci es is r ec ov er ed 
fr o m a p ost-b aseli n e visit, the micr o bi ol o gic al o utco m e a n d r es po nse will n ot b e li nke d to t he 
b as eli ne ur op ath o ge n  (i. e., g e netic r el ate d ness of t he b as eli n e  a n d p ost -b as eli ne isol at es will 
n ot b e co nsi d ere d for d et er mi n ati o n of micro bi ol ogic al o utc o m e/r es p ons e) . For t h es e c as es, 
t h e micr o bi ol ogic al o utc o m es will b e eit her p ersist e nc e, r ec urre nc e or u na bl e t o d eter mi n e 
( e. g. if ot h er a ntibi otic th er apy st art ed bef or e T O C) a nd t h e micr o bi ol ogic al r es p o nse will b e 
f ail ur e f or b oth b as eli n e q ualifyi n g ur o pat h o ge n s of t h e s a m e s p ecies.   
Ur o p at h o g en s p eci es/gr o u ps; Gr a m -p ositiv e/ -ne g ativ e cl assific ati o n; p he n oty p e a nd g e noty p e 
s u b-c at e g ori es fla g gin g:  
•  A s u m m ary f or th e n u m b er of is ol ates i n e ac h disti nct ur o p at h o ge n sp eci es ( by d eco d ed 
ur o p a th og e n c o de, p h en otypic a nd g e n otypic dat a) for ur o p ath og e ns at B as eli ne will b e 
pr o d uce d for t h e micr o bi ol ogist.  
•  T h e micr o bi ol ogist a nd cli nic al sci e ntist will r evi e w t hat s u m m ary t o fl ag t hos e ur o pat h og en 
s p eci es/ gro u ps, Gr a m-p ositiv e/ -n e gativ e classifi c ati o ns, a n d p he n oty p e a nd g e n oty p e 
ur o p ath og e n s u bcat e g ori es(s) w hic h ar e to b e r e port e d i n t he T L Fs. 
I nv ali d a n d n on-ev al ua bl e res ults  
•  I n r ar e cas es of c onc er n a bo ut th e int e grity of a s u bject(s) urin e s a m pl e, t h e micr o bi ol o gist or 
cli nic al sci e ntist m ay d eter mi n e t h at all micr o bi ol o gic al ass ess m e nts d o ne o n t hat urin e 
s a m pl e ar e inv ali d a n d n on -ev al u a bl e. P ote nti al r eas ons i ncl u d e evi d e nc e of sa m pl e 
mis h a n dli n g a nd cr oss -c o nta mi n ati o n. 
•  
•  T h es e i nvali d r ec ords  will b e k e pt i n th e S D T M d atas et b ut n ot A D a M dat as et an d will n ot b e 
i ncl u d ed i n a ny an alys es .   
•  T h e micr o bi ol ogist will d oc u m e nt t h e r ati on al e f or i nvali d r es ults a n d st or e in a si mil ar m a n ner 
al o n g wit h th e r atio n ale f or th e k e e pers a nalys es.   
O ut of st a bility ( O O S)  
•  G C L will i ncl u d e a n o ut of sta bility ( O O S) fl ag f or urin e  sa m pl es t h at ar e r ec eiv ed O O S . O O S  
uri n e  s a m pl es ar e t h ose w her e r ec ei pt d at e is m or e t han 4 d ays fr o m th e sp eci me n c oll ecti o n 
d at e  f or uri ne s p eci m e ns s e nt r efrig er at e d, an d  th ose wh er e r ecei pt dat e  is m or e tha n 2 d ays 
fr o m t h e sp eci m e n c oll ecti on d at e for urin e sp eci me ns s e nt a m bi e nt. S a mpl es r ec eiv e d fr oz en 
ar e m ark e d as ‘ un a ble t o p erf or m’ a n d are n ot t est e d.  A ll micro bi ol o gic al assess m e nts d on e 
o n th e O O S uri ne s a m pl e are i nv ali d a n d n on-ev al ua bl e. 
T h es e O O S s a mpl es will b e k e pt in S D T M d at as et but not A D a M d atas et a n d will n ot b e 
i ncl u d ed i n a ny a n alys es.  
 
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Microbiology Procedures 
Fold Change 
• Fold change will be used to describe how much the MIC for gepotidacin and nitrofurantoin 
changes between baseline and subsequent visits for the same bacterial species from the 
same participant. 
• Fold change will be calculated (in doubling dilutions) as the ratio of the MIC at the 
subsequent visit to the MIC at Baseline Visit. However, ratio of 1 will be reported as 0-fold. 
Ratio less than 1 will be reported in reciprocal with negative sign (e.g. ratio of 0.5 will be 
reported as -2-fold). Examples: 
Baseline MIC (mcg/mL)  
Post-baseline MIC 
(mcg/mL)  
Fold-change 
1 
1 
0-fold 
1 
2 
2-fold 
1 
4 
4-fold 
1 
8 
8-fold 
1 
16 
16-fold 
1 
0.5 
- 2-fold 
1 
0.25 
- 4-fold 
1 
>32 
>/=64-fold 
1 
>/=32 
>/=32-fold 
1 
<0.125 
>/= - 16-fold 
1 
</=0.125 
>/= - 8-fold 
 
 


 
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MIC Range, MIC50 and MIC90 
MIC50 and MIC90 are defined as the 50th and 90th percentile of the MIC values. They will 
only be reported if sample size is larger or equal to 10. For an even number of samples, the 
MIC50 is the next one above the median. Similar algorithm applies to MIC90. 
• MIC ranges to be tested in this protocol (in ug/mL):  
Gepotidacin 
<=0.03; 0.06; 0.12; 0.25; 0.5; 1; 2; 4; 8; 16; 32; 64; >64 
Ciprofloxacin 
<=0.002; 0.004; 0.008; 0.015; 0.03; 0.06; 0.12; 0.25; 0.5; 1; 2; 4; >4 
Levofloxacin 
<=0.004; 0.008; 0.015; 0.03; 0.06; 0.12; 0.25; 0.5; 1; 2; 4; 8; >8 
Sulfisoxazole 
<=4; 8; 16; 32; 64; 128; 256; 512; >512 
Trimethoprim 
<=0.015; 0.03; 0.06; 0.12; 0.25; 0.5; 1; 2; 4; 8; 16; 32; >32 
Trimethoprim / 
Sulfamethoxazole 
<=0.015; 0.03; 0.06; 0.12; 0.25; 0.5; 1; 2; 4; 8; >8 
Ampicillin 
<=0.25; 0.5; 1; 2; 4; 8; 16; 32; 64; >64 
Vancomycin 
<=0.25; 0.5; 1; 2; 4; 8; 16; 32; >32 
Nitrofurantoin 
<=0.5; 1; 2; 4; 8; 16; 32; 64; 128; 256; >256 
Ceftolozane / 
Tazobactam 
<=0.015; 0.03; 0.06; 0.12; 0.25; 0.5; 1; 2; 4; 8; 16; 32; >32 
Ceftazidime / 
Avibactam 
<=0.015; 0.03; 0.06; 0.12; 0.25; 0.5; 1; 2; 4; 8; 16; 32; >32 
Piperacillin / 
Tazobactam 
<=0.12; 0.25; 0.5; 1; 2; 4; 8; 16; 32; 64; 128; >128 
Amoxicillin / 
Clavulanic Acid 
<=0.25; 0.5; 1; 2; 4; 8; 16; 32; >32 
Ceftriaxone 
<=0.015; 0.03; 0.06; 0.12; 0.25; 0.5; 1; 2; 4; >4 
Cefazolin 
<=0.25; 0.5; 1; 2; 4; 8; 16; 32; >32 
Meropenem 
<=0.004; 0.008; 0.015; 0.03; 0.06; 0.12; 0.25; 0.5; 1; 2; 4; 8; >8 
Gentamicin 
<=0.06; 0.12; 0.25; 0.5; 1; 2; 4; 8; 16; >16 
Amikacin 
<=0.25; 0.5; 1; 2; 4; 8; 16; 32; 64; >64 
Aztreonam 
<=1; >1 
Ceftazidime 
<=1; >1 
Cefotaxime 
<=1; >1 
Cefpodoxime 
<=1; >1 
Fosfomycin (JMI) 
<=0.12; 0.25; 0.5; 1; 2; 4; 8; 16; 32; 64; 128; 256; >256 
Nitrofurantoin 
(JMI) 
<=0.5; 1; 2; 4; 8; 16; 32; 64; 128; 256; >256 
Gepotidacin 
Gradient Strip 
<0.015; 0.03; 0.06; 0.12; 0.25; 0.5; 1; 2; 4; 8; 16; 32; 64; 128; 256; 
>=256 
 
 


 
C O N FI D E N TI A L  
2 0 4 9 8 9  
 
9 9  
 
S u s c e pti bilit y I nt er pret ati o n s  
•  S usc e pti bility i nt er pr et ati ons will b e c alc ul ate d a nd r e port e d by t he c e ntr al l ab or atory a n d will 
b e b as ed o n t he C L SI M 1 00 a n d E U C A S T g ui deli n es i n eff ect at t h at ti me th e b act eri al 
is ol at e is test e d. 
•  Si nc e C L SI br eak poi nts for c ert ai n dru g/ b u g co m bi n ati ons c a n c h an g e i n n e w y early e diti ons 
of M 1 00 g ui d eli nes, as G S K a n d/ or t he c e ntr al l ab or atory b ec o m e a w ar e of r elev a nt 
br e ak poi nt ch a ng es, t h e c e ntr al l a b or at ory will i d e ntify a ny r e ports w hic h wo ul d q ualify as 
n e edi n g a c h a n ge i n int er pret ati on ( e.g. a MI C v al u e t hat w as origi n ally r e port e d as 
s usc e pti ble, an d wo ul d n o w b e co nsi d ere d r esista nt b as e d o n th e n e w br eak poi nt), a n d  will 
iss u e a m en d ed r e ports. Of n ot e, f or pi p er acilli n/taz o bact a m a gai nst Ent ero b act er ales 
s p eci es/ gro u ps, s usc epti bl e-d os e d e pe n de nt ( S D D) m ay b e pr es e nt e d as i nt er me diat e.  
•  T h e fi nal cli nic al d at a bas e will r e p ort i nt er pr etati ons acc or di n g to th e m ost r ec e nt C L SI M 1 00 
a n d E U C A S T i nter pr etati o ns r e g ar dl ess of w hat th e br eak p oi nts w er e at th e ti me t h e is ol ate 
w as i niti ally t este d.  
•  F or s p ecific dr ugs ( e.g. nitr ox oli n e, c ef a droxil) w hic h d o n ot h av e a ppr ov ed F D A or C L SI 
br e ak poi nts, susc e pti bility i nt er pr et ati o ns will b e d et er mi n e d usi n g E U C A S T g ui deli n es.  
B a ct eri al N o m e n clat ur e  
•  W hilst t h e sci entific f or matti n g r e quire m e nts f or bact erial n o m encl at ur e is f or ge nus a n d 
s p eci es na m es to b e it alicize d, wit h first l etter of g e nus u p per c as e, a nd r est of th e g e nus a n d 
s p eci es na m e i n l o w er c ase, G S K syst e m li mit ati o ns h av e r es ult ed i n th e l ack of it aliciz ati o n 
i n T F L out p uts. 
Q u a ntit ati v e B act erial C o u nt s  
C CI


 
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• The central laboratory will quantitatively determine the growth of uropathogens from culture 
of participant urine samples. 
• The central laboratory will report the following quantification results 
• If there is no growth on the culture plates for a urine sample: 
▪ No growth (<103) 
• If there is growth on the urine culture plates for a urine sample, each uropathogen will 
receive an associated colony count: 
▪ 103-<104 
▪ 104-<105 
▪ ≥105 
• At subsequent visits, determination of ‘no growth’ for individual uropathogens will need to be 
derived from an overall urine culture result of no growth (meaning there was no growth on the 
urine culture plates) or no identification/quantification being reported for that specific 
uropathogen (assuming that a urine sample was taken and that results were reported). 
• If the bacterial sample at a subsequent visit is not collected, then it’s considered as “unable 
to determine” for the uropathogens identified at Baseline. 


 
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12.5. 
Appendix 5: Reporting Standards for Missing Data 
12.5.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
• Participant study treatment completion is defined as if the participant has taken 
all doses of the study treatment and completed the TOC Visit. Participants who 
discontinue study treatment will not be considered withdrawn from the study and 
should attend the TOC and Follow-up Visits as applicable. 
• Participant study completion (i.e. as specified in the protocol) is defined as if the 
participant has completed all study visits including the Follow-up Visit. 
• All available data from participants who were withdrawn from the study will be 
listed and all available data will be included in summary tables and figures as 
described in Section 5.6 on Analysis Visits.  
12.5.2. 
Handling of Missing Data 
Element 
Reporting Detail 
General 
• Missing data occurs when any requested data is not provided, leading to blank 
fields on the collection instrument: 
o These data will be indicated by the use of a “blank” in participant listing 
displays. Unless all data for a specific visit are missing in which case the 
data is excluded from the table.  
o Answers such as “Not applicable” and “Not evaluable” are not considered 
to be missing data and should be displayed as such. 
Efficacy 
• As defined in the endpoint variables, participants with missing measurements 
will be treated as failures for corresponding visits (unless otherwise specified 
for sensitivity analyses). For Investigator-Assessed Clinical Response, 
handling of missing data is described in Section 7.3.1.13. 
Outliers 
• Any participants excluded from the summaries and/or statistical analyses will 
be documented along with the reason for exclusion in the clinical study report. 
12.5.2.1. Handling of Missing and Partial Dates 
Element 
Reporting Detail 
General 
• Partial dates will be displayed as captured in participant listing displays. 
Adverse 
Events 
• The eCRF allows for the possibility of partial dates (i.e., only month and year) 
to be recorded for AE start and end dates; that is, the day of the month may be 
missing. In such a case, the following conventions will be applied for 
calculating the time to onset and the duration of the event: 
o Missing Start Day: First of the month will be used unless this is before the 
start date of study treatment; in this case the study treatment start date will 
be used and hence the event is considered On-treatment and treatment 
emergent as per Appendix 2. 
o Missing Start Time: Midnight 0:00:00 will be used for AEs with missing start 
time to determine if it’s AChE-I. 


 
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Element 
Reporting Detail 
o Missing Stop Day: Last day of the month will be used, unless this is after 
the stop date of study treatment; in this case the study treatment stop date 
will be used. 
• Completely missing start or end dates will remain missing, with no imputation 
applied. Consequently, time to onset and duration of such events will be 
missing. 
• Adverse events with entirely missing or unknown start dates will be assumed 
to be on-treatment and also treatment emergent for reporting. 
Concomitant 
Medications/
Medical 
History 
• Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention: 
o If the partial date is a start date, a '01''' will be used for the day and 'Jan''' 
will be used for the month 
o If the partial date is a stop date, a '28'/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec''' will be used for the month. 
• The recorded partial date will be displayed in listings. 
 


 
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12.6. 
Appendix 6: Values of Potential Clinical Importance 
12.6.1. 
ECG 
ECG Parameter 
Units 
Potential Clinically Important Range 
Lower 
Upper 
Absolute 
Absolute QTc Interval 
msec 
N/A 
>450 
Absolute PR Interval 
msec 
< 110 
> 220 
Absolute QRS Interval 
msec 
< 75 
> 110 
12.6.2. 
Vital Signs 
Vital Sign Parameter 
(Absolute) 
Units 
Potentially Clinically Important Range 
Lower 
Upper 
Systolic Blood Pressure 
mmHg 
< 85 
> 160 
Diastolic Blood Pressure 
mmHg 
< 45 
> 100 
Heart Rate 
bpm 
< 40 
> 110 
 


 
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12.7. 
Appendix 7: Division of Microbiology and Infectious Diseases 
Adult Toxicity Tables for Adverse Event Assessment 
12.7.1. 
Laboratory Values 
12.7.1.1. Adults 
For adults, laboratory abnormalities will be graded according to the modified US 
National institute of Allergy and Infectious Diseases Division of Microbiology and 
Infectious Diseases (DMID) criteria [DMID, 2007a]. Laboratory results are converted to 
SI units. 
HEMATOLOGY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
9.5 to 
10.5 gm/dL 
8.0 to 
9.4 gm/dL 
6.5 to 
7.9 gm/dL 
<6.5 gm/dL 
Absolute Neutrophil 
Count 
1000 to 
1500 /mm3 
750 to 
999 /mm3` 
500 to 
749 /mm3 
<500 /mm3 
Platelets 
75,000 to 
99,999 /mm3 
50,000 to 
74,999 /mm3 
20,000 to 
49,999 /mm3 
<20,000 /mm3 
White Blood Cells 
11,000 to 
13,000 /mm3 
13,001 to 
15,000 /mm3 
15,001 to 
30,000 /mm3 
>30,000 or 
<1000 /mm3 
% 
Polymorphonuclear 
Leukocytes + Band 
Cells 
>80% 
90 to 95% 
>95% 
N/A 
Abnormal Fibrinogen 
Low: 100 to 
200 mg/dL 
High: 400 to 
600 mg/dL 
Low: 
<100 mg/dL 
High: 
>600 mg/dL 
Low: 
<50 mg/dL 
High: N/A 
Fibrinogen associated 
with gross bleeding or 
with disseminated 
coagulation 
Fibrin Split Product 
20 to 
40 mcg/mL 
41 to 
50 mcg/mL 
51 to 
60 mcg/dL 
>60 mcg/dL 
Prothrombin Time 
(PT) 
1.01 to 
1.25  ULN 
1.26 to 
1.5  ULN 
1.51 to 
3.0  ULN 
>3  ULN 
Activated Partial 
Thromboplastin 
(APTT) 
1.01 to 
1.66  ULN 
1.67 to 
2.33  ULN 
2.34 to 
3  ULN 
>3  ULN 
Methemoglobin 
5.0 to 9.9% 
10.0 to 
14.9% 
15.0 to 19.9% 
>20% 
N/A=not applicable; ULN=upper limit of normal. 
 


 
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CHEMISTRIES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hyponatremia 
130 to 
135 mEq/L 
123 to 
129 mEq/L 
116 to 
122 mEq/L 
<116 mEq/L or 
abnormal sodium with 
mental status changes 
or seizures 
Hypernatremia 
146 to 
150 mEq/L 
151 to 
157 mEq/L 
158 to 
165 mEq/L 
>165 mEq/L or 
abnormal sodium with 
mental status changes 
or seizures 
Hypokalemia 
3.0 to 
3.4 mEq/L 
2.5 to 
2.9 mEq/L 
2.0 to 2.4 mEq/L 
or intensive 
replacement 
therapy of 
hospitalization 
required 
<2.0 mEq/L or 
abnormal potassium 
with paresis, ileus, or 
life-threatening 
arrhythmia 
Hyperkalemia 
5.6 to 
6.0 mEq/L 
6.1 to 
6.5 mEq/L 
6.6 to 7.0 mEq/L 
>7.0 mEq/L or 
abnormal potassium 
with life-threatening 
arrhythmia 
Hypoglycemia 
55 to 
64 mg/dL 
40 to 
54 mg/dL 
30 to 39 mg/dL 
<30 mg/dL or 
abnormal glucose with 
mental status changes 
or coma 
Hyperglycemia 
(nonfasting and no 
prior diabetes) 
116 to 
160 mg/dL 
161 to 
250 mg/dL 
251 to 500 mg/dL 
>500 mg/dL or 
abnormal glucose with 
ketoacidosis or 
seizures 
Hypocalcemia 
(corrected for 
albumin) 
8.4 to 
7.8 mg/dL 
7.7 to 
7.0 mg/dL 
6.9 to 6.1 mg/dL 
<6.1 mg/dL or 
abnormal calcium with 
life-threatening 
arrhythmia or tetany 
Hypercalcemia 
(corrected for 
albumin) 
10.6 to 
11.5 mg/dL 
11.6 to 
12.5 mg/dL 
12.6 to 
13.5 mg/dL 
>13.5 mg/dL or 
abnormal calcium with 
life-threatening 
arrhythmia 
Hypomagnesemia 
1.4 to 
1.2 mEq/L 
1.1 to 
0.9 mEq/L 
0.8 to 0.6 mEq/L 
<0.6 mEq/L or 
abnormal magnesium 
with life-threatening 
arrhythmia 
Hypophosphatemia 2.0 to 
2.4 mg/dL 
1.5 to 
1.9 mg/dL 
or 
replacement 
Rx required 
1.0 to 1.4 mg/dL 
intensive therapy 
or hospitalization 
required 
<1.0 mg/dL or 
abnormal phosphate 
with life-threatening 
arrhythmia 
Hyperbilirubinemia 
(when 
1.1 to 
<1.25  ULN 
1.25 to 
<1.5  ULN 
1.5 to 
1.75  ULN 
>1.75  ULN 


 
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CHEMISTRIES 
accompanied by 
any increase in 
other liver function 
test) 
Hyperbilirubinemia 
(when other liver 
function tests are 
in the normal 
range) 
1.1 to 
<1.5  ULN 
1.5 to 
<2.0  ULN 
2.0 to 3.0  ULN 
>3.0  ULN 
Blood urea 
nitrogen  
1.25 to 
2.5  ULN 
2.6 to 
5  ULN 
5.1 to 10  ULN 
>10  ULN 
Hyperuricemia 
(uric acid) 
7.5 to 
10.0 mg/dL 
10.1 to 
12.0 mg/dL 
12.1 to 
15.0 mg/dL 
>15.0 mg/dL 
Creatinine 
1.1 to 
1.5  ULN 
1.6 to 
3.0  ULN 
3.1 to 6.0  ULN 
>6  ULN or dialysis 
required 
Rx=therapy; ULN=upper limit of normal. 


 
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CHEMISTRIES 
ENZYMES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Aspartate aminotransferase (AST) 
1.1 to 
<2.0  ULN 
2.0 to 
<3.0  ULN 
3.0 to 
8.0  ULN 
>8.0  ULN 
Alanine aminotransferase (ALT) 
1.1 to 
<2.0  ULN 
2.0 to 
<3.0  ULN 
3.0 to 
8.0  ULN 
>8.0  ULN 
Gamma to glutamyl transferase 
(GGT) 
1.1 to 
<2.0  ULN 
2.0 to 
<3.0  ULN 
3.0 to 
8.0  ULN 
>8.0  ULN 
Alkaline Phosphatase 
1.1 to 
<2.0  ULN 
2.0 to 
<3.0  ULN 
3.0 to 
8.0  ULN 
>8.0  ULN 
Amylase 
1.1 to 
1.5  ULN 
1.6 to 
2.0  ULN 
2.1 to 
5.0  ULN 
>5.1  ULN 
Lipase 
1.1 to 
1.5  ULN 
1.6 to 
2.0  ULN 
2.1 to 
5.0  ULN 
>5.1  ULN 
ULN=upper limit of normal. 
URINALYSIS 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Proteinuria 
1+ or 
200 mg to 1 gm 
loss/day 
2 to 3+ or 
1 to 2 gm 
loss/day 
4+ or 
2 to 3.5 gm loss/day 
Nephrotic 
syndrome or 
>3.5 gm loss/day 
Hematuria 
Microscopic only 
<10 RBC/hpf 
Gross, no 
clots 
>10 RBC/hpf 
Gross, with or without 
clots, 
or red blood cells 
casts 
Obstructive or  
required transfusion 
HPF=high powered field; RBC=red blood cells. 
12.7.1.2. Adolescent Participants 
For adolescent participants over 12 years of age and less than 18 years of age, the adult 
DMID will be applied for all parameters with the exception of serum creatinine which 
will be graded programmatically according to the modified DMID pediatric toxicity 
criteria [DMID, 2007b]. Laboratory results are converted to SI units. 
CHEMISTRIES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Creatinine 1.0 to 1.7 x ULN  
1.8 to 2.4 x 
ULN  
2.5 to 3.5 x ULN  
>3.5 x ULN  
ULN=upper limit of normal. 


 
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12.8. 
Appendix 8: Abbreviations & Trademarks 
12.8.1. 
Abbreviations 
Abbreviation 
Description 
ADaM 
Analysis Data Model 
AChE-I 
Acetylcholinesterase Inhibition 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
BID 
Twice Daily 
BL 
Baseline 
CE 
Clinically Evaluable 
CFU 
Colony-Forming Units 
CI 
Confidence Interval 
CLSI 
Clinical and Laboratory Standards Institute 
CV 
Cardiovascular 
DBF 
Database Freeze 
DMID 
Division of Microbiology and Infectious Diseases 
DP 
Decimal Places 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EUCAST 
European Committee on Antimicrobial Susceptibility Testing 
FU 
Follow-up 
GCL 
Global Central Laboratory 
GI 
Gastrointestinal 
GSK 
GlaxoSmithKline 
ICH 
International Conference on Harmonization 
ICE 
Intercurrent Event 
IDMC 
Independent Data Monitoring Committee 
IDSL 
Integrated Data Standards Library 
ITT 
Intent-To-Treat 
MAR 
Missing at Random 
MDR 
Multidrug-resistant 
ME 
Microbiologically Evaluable 
m-ITT 
Microbiological ITT 
MI 
Multiple Imputation 
Micro-ITT 
Microbiological ITT 
MIC 
Minimum Inhibitory Concentration 
MLST 
Multi-Locus Sequence Typing 
MN 
Miettinen-Nurminen 
NTF-NS 
Not Susceptible to nitrofurantoin 
NTF-R 
Resistant to nitrofurantoin 
NTF-S 
Susceptible to nitrofurantoin 
OOS 
Out of stability 
OT 
On-therapy 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 


 
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Abbreviation 
Description 
RAP 
Reporting and Analysis Plan 
SAC 
Statistical Analysis Complete 
SAE 
Serious AE 
SDTM 
Study Data Tabulation Model 
TEAE 
Treatment-Emergent Adverse Event 
TOC 
Test-of-Cure 
UTI 
Urinary Tract Infection 
uUTI 
Uncomplicated Urinary Tract Infection 
12.8.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
GSKDrug 
 
MedDRA 
 
 
SAS 
 


 
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12.9. 
Appendix 9: List of Data Displays 
12.9.1. 
Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Figures 
Study Population 
1.1 to 1.19 
1.1 to 1.2 
Efficacy 
2.1 to 2.81 
2.1 to 2.15 
Safety 
3.0 to 3.32 
3.1 to 3.9 
Pharmacokinetic 
4.1 to 4.2 
4.1 to 4.4 
Section 
Listings 
ICH Listings 
1 to 54 
12.9.2. 
Mock Example Shell Referencing 
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in each tables, listings, and figures shells. 
Section 
Figure 
Table 
Listing 
Study Population 
POP_Fn 
POP_Tn 
POP_Ln 
Efficacy 
EFF_Fn 
EFF_Tn 
EFF_Ln 
Safety 
SAFE_Fn 
SAFE_Tn 
SAFE_Ln 
Pharmacokinetic 
PK_Fn 
PK_Tn 
PK_Ln 
NOTES:  
• Non-Standard displays are indicated in the ‘IDSL / Example Shell’ or ‘Programming Notes’ 
column as ‘[Non-Standard] + Reference.’ 
12.9.3. 
Deliverable, Priority and Conditional Column 
Delivery 
Description 
HDL 
Headline results 
SAC 
Statistical Analysis Complete 
AAC 
All Analysis Complete – All Output to support the writing of the CSR and disclosures 
12.9.4. 
Footnotes 
The footnotes will follow the general wording conventions and labels: 
12.9.4.1. 
Analyses Footnotes 
When analyses were not calculated include the footnote: 
“NC=Not calculated” 


 
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12.9.5. 
Study Population Tables 
Study Population Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
If study 
stops 
If study 
continues 
Participant Disposition 
 
 
1.101 
Intent-to-Treat 
ES1 
Summary of Subject Disposition 
 
SAC 
SAC 
1.102 
Micro-ITT NTF-S 
ES1 
Summary of Subject Disposition 
 
SAC 
SAC 
1.103 
Micro-ITT NTF-S 
(IA Set) 
ES1 
Summary of Subject Disposition (IA Set) 
Produce only if the study stops 
early for efficacy at the IA. 
SAC 
Not 
produced 
1.201 
Intent-to-Treat 
SD1 
Summary of Treatment Status and Reasons 
for Discontinuation of Study Treatment 
 
SAC 
SAC 
1.202 
Micro-ITT NTF-S 
SD1 
Summary of Treatment Status and Reasons 
for Discontinuation of Study Treatment 
 
SAC 
SAC 
1.203 
Micro-ITT NTF-S 
(IA Set) 
SD1 
Summary of Treatment Status and Reasons 
for Discontinuation of Study Treatment (IA 
Set) 
Produce only if the study stops 
early for efficacy at the IA. 
SAC 
Not 
produced 
1.3 
Intent-to-Treat 
NS1 
Summary of Number of Subjects Enrolled by 
Country and Site ID 
 
SAC 
SAC 
1.4 
Screened 
ES6 
Summary of Reasons for Screening Failures   
SAC 
SAC 
1.5 
Screened 
SP1 
Summary of Study Populations 
 
HDL 
HDL 
1.6 
Intent-to-Treat 
SP2 
Summary of Exclusions from Study 
Population 
 
SAC 
SAC 
Protocol Deviation 
 
 
1.7 
Intent-to-Treat 
DV1 
Summary of Important Protocol Deviations 
 
SAC 
SAC 


 
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Study Population Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
If study 
stops 
If study 
continues 
Demographic and Baseline Characteristics 
 
 
1.801 
Intent-to-Treat 
 
DM1 
Summary of Demographic and Other 
Baseline Characteristics 
 
SAC 
SAC 
1.802 
Micro-ITT-NTF-S 
 
DM1 
Summary of Demographic and Other 
Baseline Characteristics 
 
SAC 
HDL 
1.803 
CE-TOC 
DM1 
Summary of Demographic and Other 
Baseline Characteristics  
 
SAC 
SAC 
1.804 
ME-TOC-NTF-S 
 
DM1 
Summary of Demographic and Other 
Baseline Characteristics 
 
SAC 
SAC 
1.805 
Micro-ITT NTF-S 
(IA Set) 
DM1 
Summary of Demographic and Other 
Baseline Characteristics (IA Set) 
Produce only if the study stops 
early for efficacy at the IA. 
HDL 
Not 
produced 
1.9 
Intent-to-Treat 
DM5 
Summary of Race and Racial Combinations 
 
SAC 
SAC 
1.10 
Intent-to-Treat 
DM11 
Summary of Age Ranges 
 
SAC 
SAC 
1.1101 
Intent-to-Treat 
 
POP_T1 Summary of Disease Characteristics at 
Baseline 
 
SAC 
SAC 
1.1102 
Micro-ITT 
POP_T1 Summary of Disease Characteristics at 
Baseline 
 
SAC 
SAC 
1.1103 
Micro-ITT NTF-S 
POP_T1 Summary of Disease Characteristics at 
Baseline 
 
SAC 
HDL 
1.1104 
Micro-ITT NTF-
NS  
POP_T1 Summary of Disease Characteristics at 
Baseline 
 
SAC 
SAC 
1.1105 
CE-TOC 
POP_T1 Summary of Disease Characteristics at 
Baseline 
 
SAC 
SAC 


 
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Study Population Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
If study 
stops 
If study 
continues 
1.1106 
ME-TOC 
POP_T1 Summary of Disease Characteristics at 
Baseline 
 
SAC 
SAC 
1.1107 
ME-TOC NTF-S 
POP_T1 Summary of Disease Characteristics at 
Baseline 
 
SAC 
SAC 
1.1108 
ME-TOC 
NTF-NS 
POP_T1 Summary of Disease Characteristics at 
Baseline 
 
SAC 
SAC 
1.1109 
ME-FU 
POP_T1 Summary of Disease Characteristics at 
Baseline 
 
SAC 
SAC 
1.1110 
ME-FU NTF-S 
POP_T1 Summary of Disease Characteristics at 
Baseline 
 
SAC 
SAC 
1.1111 
ME-FU NTF-NS 
POP_T1 Summary of Disease Characteristics at 
Baseline 
 
SAC 
SAC 
1.1112 
Micro-ITT NTF-S 
(IA Set) 
POP_T1 Summary of Disease Characteristics at 
Baseline (IA Set) 
 
HDL 
Not 
produced 
1.1121 
Intent-to-Treat 
 
Summary of Baseline Uropathogens 
 
SAC 
SAC 
1.1122 
Micro-ITT 
 
Summary of Baseline Uropathogens 
 
SAC 
SAC 
1.1123 
Micro-ITT NTF-S 
 
Summary of Baseline Uropathogens 
 
SAC 
SAC 
1.1124 
Micro-ITT NTF-
NS 
 
Summary of Baseline Uropathogens 
 
SAC 
SAC 
1.1125 
ME-TOC 
 
Summary of Baseline Uropathogens 
 
SAC 
SAC 
1.1126 
ME-TOC NTF-S 
 
Summary of Baseline Uropathogens 
 
SAC 
SAC 
1.1127 
ME-TOC NTF-
NS 
 
Summary of Baseline Uropathogens 
 
SAC 
SAC 


 
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Study Population Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
If study 
stops 
If study 
continues 
1.1128 
ME-FU 
 
Summary of Baseline Uropathogens 
 
SAC 
SAC 
1.1129 
ME-FU NTF-S 
 
Summary of Baseline Uropathogens 
 
SAC 
SAC 
1.1130 
ME-FU NTF-NS 
 
Summary of Baseline Uropathogens 
 
SAC 
SAC 
1.1131 
Micro-ITT/NTF-
S/NTF-NS 
 
Summary of Baseline Qualifying 
Uropathogens and Uropathogen Groups 
Include separate columns for 
the three populations included 
SAC 
SAC 
1.1132 
ME-TOC/NTF-
S/NTF-NS 
 
 
Summary of Baseline Qualifying 
Uropathogens and Uropathogen Groups 
Include separate columns for 
the three populations included 
SAC 
SAC 
1.1133 
ME-FU/NTF-
S/NTF-NS  
 
Summary of Baseline Qualifying 
Uropathogens and Uropathogen Groups 
Include separate columns for 
the three populations included 
SAC 
SAC 
1.12 
Intent-to-Treat 
MH4 
Summary of Past and Current Medical 
Conditions 
 
SAC 
SAC 
1.1201 
Micro-ITT NTF-S 
MH4 
Summary of Past and Current Medical 
Conditions 
 
SAC 
SAC 
1.1202 
Micro-ITT NTF-S 
(IA Set) 
MH4 
Summary of Past and Current Medical 
Conditions (IA Set) 
Produce only if the study stops 
early for efficacy at the IA. 
SAC 
Not 
produced 
1.1301 
Intent-to-Treat 
  
Summary of History of Uncomplicated 
Urinary Tract Infection and Pre-existing 
Conditions with Similar Symptoms 
 
SAC 
SAC 
1.1302 
Micro-ITT NTF-S 
 
Summary of History of Uncomplicated 
Urinary Tract Infection and Pre-existing 
Conditions with Similar Symptoms 
 
SAC 
SAC 


 
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Study Population Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
If study 
stops 
If study 
continues 
1.1303 
Micro-ITT NTF-S 
(IA Set) 
 
Summary of History of Uncomplicated 
Urinary Tract Infection and Pre-existing 
Conditions with Similar Symptoms (IA Set) 
Produce only if the study stops 
early for efficacy at the IA. 
SAC 
Not 
produced 
1.1401 
Intent-to-Treat 
  
Summary of Prior Medications 
 
SAC 
SAC 
1.1402 
Micro-ITT NTF-S 
  
Summary of Prior Medications 
 
SAC 
SAC 
1.1501 
Intent-to-Treat 
  
Summary of Concomitant Medications 
 
SAC 
SAC 
1.1502 
Micro-ITT NTF-S 
  
Summary of Concomitant Medications 
 
SAC 
SAC 
1.1503 
Micro-ITT NTF-S 
(IA Set) 
 
Summary of Concomitant Medications (IA 
Set) 
Produce only if the study stops 
early for efficacy at the IA. 
SAC 
Not 
produced 
Exposure 
 
 
1.1601 
Safety 
EX1 
Summary of Exposure to Study Treatments 
 
SAC 
SAC 
1.1602 
Micro-ITT NTF-S 
EX1 
Summary of Exposure to Study Treatments 
 
SAC 
SAC 
1.1603 
Micro-ITT NTF-S 
(IA Set) 
 
Summary of Exposure to Study Treatments 
(IA Set) 
Produce only if the study stops 
early for efficacy at the IA. 
SAC 
Not 
produced 
Other 
 
 
1.17 
Intent-to-Treat 
SU1 
Summary of Substance Use 
 
SAC 
SAC 
1.19 
Intent-to-Treat 
PAN4 
Summary of COVID-19 Pandemic Visit 
Impacts 
 
SAC 
SAC 


 
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12.9.6. 
Study Population Figures 
Study Population: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
If study 
stops 
If study 
continues 
1.1 
Intent-to-
Treat 
  
Bar Plot of Baseline Total and Individual 
Component Clinical Symptom Score 
   
AAC 
AAC 
1.201 
Micro-ITT 
  
Bar Plot of Number and Percent of Baseline 
Qualifying Uropathogens Isolated 
 
AAC 
AAC 
1.202 
Micro-ITT 
NTF-S 
  
Bar Plot of Number and Percent of Baseline 
Qualifying Uropathogens Isolated 
 
AAC 
AAC 
1.203 
Micro-ITT 
NTF-NS 
  
Bar Plot of Number and Percent of Baseline 
Qualifying Uropathogens Isolated 
 
AAC 
AAC 
 


 
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12.9.7. 
Efficacy Tables 
Efficacy: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title 
Programming Notes 
Deliverable 
If study 
stops 
If study 
continues 
Therapeutic Response 
2.1 
Micro-ITT NTF-S 
or Micro-ITT 
NTF-S (IA Set) 
(see notes) 
EFF_T1 
Analysis of Therapeutic Response at 
the TOC Visit (Primary) 
just Micro-ITT NTF-S and Subject 
level. This will be produced for the 
primary analysis set (i.e. the IA Set if 
the study is stopped early for efficacy) 
HDL 
HDL 
2.2 
Micro-ITT NTF-S 
or Micro-ITT 
NTF-S (IA Set) 
(see notes) 
EFF_T1 
Treatment by Strata Tests of 
Homogeneity for Percent of Subjects 
with Therapeutic Response at the 
TOC Visit  
just Micro-ITT NTF-S and Subject 
level. This will be produced for the 
primary analysis set (i.e. the IA Set if 
the study is stopped early for efficacy) 
SAC 
SAC 
2.2001 Micro-ITT NTF-S 
or Micro-ITT 
NTF-S (IA Set) 
(see notes) 
EFF_T1 
Treatment by Strata Tests of 
Homogeneity for Percent of Subjects 
with Clinical Response at the TOC 
Visit 
This will be produced for the primary 
analysis set (i.e. the IA Set if the 
study is stopped early for efficacy) 
SAC 
SAC 
2.2002 Micro-ITT NTF-S 
or Micro-ITT 
NTF-S (IA Set) 
(see notes) 
EFF_T1 
Treatment by Strata Tests of 
Homogeneity for Percent of Subjects 
with Microbiological Response at the 
TOC Visit 
This will be produced for the primary 
analysis set (i.e. the IA Set if the 
study is stopped early for efficacy) 
SAC 
SAC 
2.2003 
EU Micro-ITT 
NTF-S or EU 
Micro-ITT NTF-S 
(IA Set) (see 
notes) 
 
Treatment by Strata Tests of 
Homogeneity for Percent of Subjects 
with Therapeutic Response at the 
TOC Visit 
This will be produced for the key EU 
supplementary analysis set (i.e. the IA 
Set if the study is stopped early for 
efficacy) 
SAC 
SAC 


 
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Efficacy: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title 
Programming Notes 
Deliverable 
If study 
stops 
If study 
continues 
2.3 
Micro-ITT/NTF-
S/NTF-NS 
EFF_T1 
Summary of Therapeutic Response at 
the TOC Visit 
include 6 columns with Micro-ITT, 
Micro-ITT NTF-S, Micro-ITT NTF-NS 
 
HDL 
HDL 
2.3001 Micro-ITT NTF-S 
(IA Set) 
 
Summary of Therapeutic Response at 
the TOC Visit (IA Set) 
Note: this table includes reasons for 
failure and will be produced if the 
study is stopped early for efficacy. 
Refer to the IDMC Table 14 mock 
shell 
HDL 
Not 
produced 
2.3002 
Micro-ITT NTF-S 
or Micro-ITT 
NTF-S (IA Set) 
(see notes) 
  
Sensitivity Analysis of Therapeutic 
Response at the TOC Visit with 
Multiple Imputation 
This will be produced for the primary 
analysis set (i.e. the IA Set if the 
study is stopped early for efficacy) 
SAC 
SAC 
2.3003 
Micro-ITT NTF-S 
or Micro-ITT 
NTF-S (IA Set) 
(see notes) 
 
Sensitivity Analysis: Multiple 
Imputation Tipping Point Analysis of 
Therapeutic Success at the TOC Visit 
This will be produced for the primary 
analysis set (i.e. the IA Set if the 
study is stopped early for efficacy) 
SAC 
SAC 
2.3004 
Micro-ITT NTF-S 
(CAPA)/ Micro-
ITT NTF-S (IA 
Set) (CAPA) 
(see notes) 
 
Supplementary Analysis of 
Therapeutic Response at the TOC 
Visit (Excluding Sites with CAPA 
Exclusion Requirements) 
This will be produced for the primary 
analysis set (i.e. the IA Set if the 
study is stopped early for efficacy) 
subset to exclude Sites with CAPA 
Exclusion Requirements 
SAC 
SAC 
2.3005 
EU Micro-ITT 
NTF-S 
 
Summary of Therapeutic Response at 
the TOC Visit 
 
SAC 
HDL 
2.3006 
EU Micro-ITT 
 
Summary of Therapeutic Response at This table will be produced if the 
SAC 
Not 


 
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Efficacy: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title 
Programming Notes 
Deliverable 
If study 
stops 
If study 
continues 
NTF-S (IA Set) 
the TOC Visit (EU IA Set) 
study is stopped early for efficacy. 
produced 
2.4 
Micro-ITT 
EFF_T1 
Summary of Therapeutic Response at 
the TOC Visit by Actual Strata 
Subgroup for rand strata 
(age/recurrent/age*recurrence); 
include 6 columns with Micro-ITT, 
Micro-ITT NTF-S, Micro-ITT NTF-NS 
SAC 
SAC 
2.5 
Micro-ITT 
EFF_T1 
Summary of Therapeutic Response at 
the TOC Visit by Other Subgroups 
Subgroup for Other Subgroups 
(region/race/ethnicity/baseline clinical 
symptom score/menopausal status); 
include 6 columns with Micro-ITT, 
Micro-ITT NTF-S, Micro-ITT NTF-NS 
SAC 
SAC 
2.6 
Micro-ITT/NTF-
S/NTF-NS 
EFF_T1 
Summary of Therapeutic Response 
by Visit and Number of Qualified 
Uropathogens at Baseline 
include 6 columns with Micro-ITT, 
Micro-ITT NTF-S, Micro-ITT NTF-NS; 
paginate by visit (TOC/FU) 
SAC 
SAC 
2.7 
ME 
EFF_T1 
Summary of Therapeutic Response at 
the TOC Visit 
include 6 columns with ME-TOC, ME-
TOC NTF-S, ME-TOC NTF-NS 
SAC 
SAC 
2.8 
ME 
EFF_T1 
Summary of Therapeutic Response at 
the TOC Visit by Actual Strata 
Subgroup for rand strata 
(age/recurrent/age*recurrence); 
include 6 columns with ME-TOC, ME-
TOC NTF-S, ME-TOC NTF-NS 
SAC 
SAC 
2.9 
ME 
EFF_T1 
Summary of Therapeutic Response at 
the TOC Visit by Other Subgroups 
Subgroup for Other Subgroup 
(region/race/ethnicity/baseline clinical 
symptom score/menopausal status); 
include 6 columns with ME-TOC, ME-
TOC NTF-S, ME-TOC NTF-NS 
SAC 
SAC 


 
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Efficacy: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title 
Programming Notes 
Deliverable 
If study 
stops 
If study 
continues 
2.10 
Micro-ITT 
EFF_T1 
Summary of Therapeutic Response at 
the Follow Up Visit 
include 6 columns with Micro-ITT, 
Micro-ITT NTF-S, Micro-ITT NTF-NS 
HDL 
HDL 
2.11 
Micro-ITT 
EFF_T1 
Summary of Therapeutic Response at 
the Follow Up Visit by Actual Strata 
Subgroup for actual strata 
(age/recurrent/age*recurrence); 
include 6 columns with Micro-ITT, 
Micro-ITT NTF-S, Micro-ITT NTF-NS 
SAC 
SAC 
2.12 
Micro-ITT 
EFF_T1 
Summary of Therapeutic Response at 
the Follow Up Visit by Other 
Subgroups 
Subgroup for Other Subgroup 
(region/race/ethnicity/baseline clinical 
symptom score/menopausal status) 
include 6 columns with Micro-ITT, 
Micro-ITT NTF-S, Micro-ITT NTF-NS 
SAC 
SAC 
2.13 
ME 
EFF_T1 
Summary of Therapeutic Response at 
the Follow Up Visit 
include 6 columns with ME-FU, ME-
FU NTF-S, ME-FU NTF-NS 
SAC 
SAC 
2.14 
ME 
EFF_T1 
Summary of Therapeutic Response at 
the Follow Up Visit by Actual Strata 
Subgroup for actual strata 
(age/recurrent/age*recurrence ); 
include 6 columns with ME-FU, ME-
FU NTF-S, ME-FU NTF-NS 
SAC 
SAC 
2.15 
ME 
EFF_T1 
Summary of Therapeutic Response at 
the Follow Up Visit by Other 
Subgroups 
Subgroup for Other Subgroup 
(region/race/ethnicity/baseline clinical 
symptom score/menopausal status); 
include 6 columns with ME-FU, ME-
FU NTF-S, ME-FU NTF-NS 
SAC 
SAC 
2.1601 
Intent-to-Treat 
EFF_T6 
Summary of Clinical Outcome and 
Response by Visit, Overall and by 
by visit (OT/TOC/FU), Subgroup for 
actual strata 
SAC 
SAC 


 
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Efficacy: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title 
Programming Notes 
Deliverable 
If study 
stops 
If study 
continues 
Actual Strata 
(age/recurrent/age*recurrence ) 
2.1602 Micro-ITT NTF-S 
EFF_T6 
Summary of Clinical Outcome and 
Response by Visit, Overall and by 
Actual Strata 
by visit (OT/TOC/FU), Subgroup for 
actual strata 
(age/recurrent/age*recurrence ) 
SAC 
SAC 
2.1603 Micro-ITT NTF-S 
(IA Set) 
 
Summary of Clinical Outcome and 
Response at TOC Visit (IA Set) 
Produced for the primary analysis set 
(i.e. the IA Set if the study is stopped 
early for efficacy). 
Refer to IDMC Table 15 mock shell. 
HDL 
Not 
produced 
2.1604 Micro-ITT NTF-S 
 
Summary of Microbiological Outcome 
and Response by Visit, Overall and 
by Actual Strata 
Participant level Microbiological 
outcome/response by visit 
(OT/TOC/FU), Subgroup for actual 
strata (age/recurrent/age*recurrence ) 
SAC 
SAC 
2.1701 
Intent-to-Treat 
EFF_T6 
Summary of Clinical Outcome and 
Response by Visit and Other 
Subgroups 
by visit (OT/TOC/FU), Subgroup for 
Other Subgroup 
(region/race/ethnicity/baseline clinical 
symptom score/menopausal status) 
SAC 
SAC 
2.1702 Micro-ITT NTF-S 
EFF_T6 
Summary of Clinical Outcome and 
Response by Visit and Other 
Subgroups 
by visit (OT/TOC/FU), Subgroup for 
Other Subgroup 
(region/race/ethnicity/baseline clinical 
symptom score/menopausal status) 
SAC 
SAC 
2.1703 Micro-ITT NTF-S 
 
Summary of Microbiological Outcome 
and Response by Visit and Other 
Subgroup 
Participant level Microbiological 
outcome/response by visit 
(OT/TOC/FU), Subgroup for Other 
Subgroup 
SAC 
SAC 


 
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Efficacy: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title 
Programming Notes 
Deliverable 
If study 
stops 
If study 
continues 
(region/race/ethnicity/baseline clinical 
symptom score/menopausal status) 
2.18 
Clinically 
Evaluable 
EFF_T6 
Summary of Clinical Outcome and 
Response by Visit, Overall and by 
Actual Strata 
by visit (OT/TOC/FU), Subgroup for 
actual strata 
(age/recurrent/age*recurrence ) 
SAC 
SAC 
2.19 
Clinically 
Evaluable 
EFF_T6 
Summary of Clinical Outcome and 
Response by Visit and Other 
Subgroups 
by visit (OT/TOC/FU), Subgroup for 
Other Subgroup 
(region/race/ethnicity/baseline clinical 
symptom score/menopausal status) 
SAC 
SAC 
2.20 
Micro-ITT 
EFF_T6 
Summary of Clinical Outcome and 
Response by Visit, Overall and by 
Qualifying Uropathogen Isolated at 
Baseline 
by visit (OT/TOC/FU) 
SAC 
SAC 
2.21 
Micro-ITT NTF-S 
EFF_T6 
Summary of Clinical Outcome and 
Response by Visit, Overall and by 
Qualifying Uropathogen Isolated at 
Baseline 
by visit (OT/TOC/FU) 
SAC 
HDL 
2.22 
Micro-ITT NTF-
NS 
EFF_T6 
Summary of Clinical Outcome and 
Response by Visit, Overall and by 
Qualifying Uropathogen Isolated at 
Baseline 
by visit (OT/TOC/FU) 
SAC 
SAC 
Microbiological Outcome and Response 
2.23 
Micro-ITT 
  
Summary of Microbiological Outcome 
and Response by Visit, Overall and 
by visit (OT/TOC/FU) 
SAC 
SAC 


 
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Efficacy: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title 
Programming Notes 
Deliverable 
If study 
stops 
If study 
continues 
by Qualifying Uropathogen Isolated at 
Baseline 
2.24 
Micro-ITT NTF-S 
  
Summary of Microbiological Outcome 
and Response by Visit, Overall and 
by Qualifying Uropathogen Isolated at 
Baseline  
by visit (OT/TOC/FU)  
SAC 
HDL 
2.25 
Micro-ITT NTF-S 
(IA Set) 
 
Summary of Microbiological Outcome 
and Response at TOC Visit (IA Set)  
Produced for the primary analysis set 
(i.e. the IA Set if the study is stopped 
early for efficacy). Refer to IDMC 
Table 16 mock shell. 
HDL 
Not 
produced 
2.26 
Micro-ITT NTF-
NS 
  
Summary of Microbiological Outcome 
and Response by Visit, Overall and 
by Qualifying Uropathogen Isolated at 
Baseline 
by visit (OT/TOC/FU) 
SAC 
SAC 
2.27 
ME 
  
Summary of Microbiological Outcome 
and Response by Visit, Overall and 
by Qualifying Uropathogen Isolated at 
Baseline 
by visit (OT/TOC/FU) for ME-OT/ME-
TOC/ME-FU population as applicable 
SAC 
SAC 
2.28 
ME NTF-S 
  
Summary of Microbiological Outcome 
and Response by Visit, Overall and 
by Qualifying Uropathogen Isolated at 
Baseline  
by visit (OT/TOC/FU) for ME-OT/ME-
TOC/ME-FU population derivative as 
applicable 
SAC 
SAC 
2.30 
ME NTF-NS 
  
Summary of Microbiological Outcome 
and Response by Visit, Overall and 
by visit (OT/TOC/FU) for ME-OT/ME-
TOC/ME-FU population derivative as 
SAC 
SAC 


 
C O N FI D E N TI A L  
2 0 4 9 8 9  
 
 
1 2 4  
 
Effi c a c y: Ta bl e s  
N o.  
P o p ul ati o n  
I D S L / 
E x a m ple 
S h ell  
Titl e  
Pr o gr a m mi n g N ote s  
D eli v era bl e  
If st u d y 
st o p s  
If st u d y 
c o nti n u e s  
by Q ualifyi n g Ur o pat h o g en Is ol at ed at 
B as eli n e  
a p plic abl e  
C CI


 
C O N FI D E N TI A L  
2 0 4 9 8 9  
 
 
1 2 5  
 
Effi c a c y: Ta bl e s  
N o.  
P o p ul ati o n  
I D S L / 
E x a m ple 
S h ell  
Titl e  
Pr o gr a m mi n g N ote s  
D eli v era bl e  
If st u d y 
st o p s  
If st u d y 
c o nti n u e s  
C CI


 
C O N FI D E N TI A L  
2 0 4 9 8 9  
 
 
1 2 6  
 
Effi c a c y: Ta bl e s  
N o.  
P o p ul ati o n  
I D S L / 
E x a m ple 
S h ell  
Titl e  
Pr o gr a m mi n g N ote s  
D eli v era bl e  
If st u d y 
st o p s  
If st u d y 
c o nti n u e s  
C CI


 
C O N FI D E N TI A L  
2 0 4 9 8 9  
 
 
1 2 7  
 
Effi c a c y: Ta bl e s  
N o.  
P o p ul ati o n  
I D S L / 
E x a m ple 
S h ell  
Titl e  
Pr o gr a m mi n g N ote s  
D eli v era bl e  
If st u d y 
st o p s  
If st u d y 
c o nti n u e s  
C CI


 
C O N FI D E N TI A L  
2 0 4 9 8 9  
 
 
1 2 8  
 
Effi c a c y: Ta bl e s  
N o.  
P o p ul ati o n  
I D S L / 
E x a m ple 
S h ell  
Titl e  
Pr o gr a m mi n g N ote s  
D eli v era bl e  
If st u d y 
st o p s  
If st u d y 
c o nti n u e s  
C CI


 
C O N FI D E N TI A L  
2 0 4 9 8 9  
 
 
1 2 9  
 
Effi c a c y: Ta bl e s  
N o.  
P o p ul ati o n  
I D S L / 
E x a m ple 
S h ell  
Titl e  
Pr o gr a m mi n g N ote s  
D eli v era bl e  
If st u d y 
st o p s  
If st u d y 
c o nti n u e s  
C CI


 
C O N FI D E N TI A L  
2 0 4 9 8 9  
 
 
1 3 0  
 
Effi c a c y: Ta bl e s  
N o.  
P o p ul ati o n  
I D S L / 
E x a m ple 
S h ell  
Titl e  
Pr o gr a m mi n g N ote s  
D eli v era bl e  
If st u d y 
st o p s  
If st u d y 
c o nti n u e s  
C CI


 
C O N FI D E N TI A L  
2 0 4 9 8 9  
 
 
1 3 1  
 
Effi c a c y: Ta bl e s  
N o.  
P o p ul ati o n  
I D S L / 
E x a m ple 
S h ell  
Titl e  
Pr o gr a m mi n g N ote s  
D eli v era bl e  
If st u d y 
st o p s  
If st u d y 
c o nti n u e s  
 
C CI


 
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12.9.8. 
Efficacy Figures 
Efficacy: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
 
Deliverable 
If study 
stops 
If study 
continues 
2.1 
Micro-ITT 
NTF-S 
EFF_F1 
Percent of Therapeutic Success by Visit, Overall 
and by Qualifying Uropathogen Isolated at 
Baseline 
  by uropathogen 
AAC 
AAC 
2.2 
Micro-ITT 
 
Forest Plot for Therapeutic Success Rate Overall 
and by Subgroup 
 
AAC 
AAC 
2.3 
Micro-ITT 
NTF-S 
 
Forest Plot for Therapeutic Success Rate Overall 
and by Subgroup 
If the studies stop early for 
efficacy, please include a 
row on the micro-ITT NTF-S 
(IA Set) as this will be the 
primary analysis 
AAC 
AAC 
2.4 
Micro-ITT 
NTF-NS 
 
Forest Plot for Therapeutic Success Rate Overall 
and by Subgroup 
 
AAC 
AAC 
2.5 
Micro-
ITT/NTF-
S/NTF-NS 
  
Forest Plot for Therapeutic Success Rate by 
Qualifying Baseline Uropathogen and Uropathogen 
Phenotypic and Genotypic Subcategories 
 by population (Micro-ITT, 
Micro-ITT-NTF-S, Micro-ITT 
NTF-NS) and visit (TOC/FU)  
AAC 
AAC 
2.6 
Micro-
ITT/NTF-
S/NTF-NS 
  
Forest Plot for Clinical Success Rate by Qualifying 
Baseline Uropathogen and Uropathogen 
Phenotypic and Genotypic Subcategories 
 by population (Micro-ITT, 
Micro-ITT-NTF-S, Micro-ITT 
NTF-NS) and visit (TOC/FU)  
AAC 
AAC 
2.7 
Micro-
ITT/NTF-
S/NTF-NS 
  
Forest Plot for Microbiological Success Rate by 
Qualifying Baseline Uropathogen and Uropathogen 
Phenotypic and Genotypic Subcategories 
 by population (Micro-ITT, 
Micro-ITT-NTF-S, Micro-ITT 
NTF-NS) and visit (TOC/FU)  
AAC 
AAC 
2.8 
Micro-ITT 
NTF-S 
 
Tipping Point Analysis of Therapeutic Response at 
TOC 
This will be produced for the 
primary analysis set (i.e. the 
SAC 
SAC 


 
C O N FI D E N TI A L  
2 0 4 9 8 9  
 
 
1 3 3  
 
Effi c a c y: Fi g ure s  
N o.  
P o p ul ati o n  
I D S L / 
E x a m ple 
S h ell  
Titl e   
Pr o gr a m mi n g N ote s  
 
D eli v era bl e  
If st u d y 
st o p s  
If st u d y 
c o nti n u e s  
I A S et if th e stu dy is sto pp ed 
e arly f or effic acy)  
2. 1 1  
I nt e nt-t o-
Tr e at  
E F F _ F 3  
B ox pl ot of I n divi du al Cli nic al Sy m pt o m Scor e an d 
T ot al Scor e by Visit  
 
A A C  
A A C  
2. 1 10 1  
I nt e nt-t o-
Tr e at  
E F F _ F 3  
B ox pl ot of Ch a ng e fr o m B as eli n e In divi d ual Cli nic al 
Sy m pt o m Scor e an d T ot al Sc or e by Visit  
 
A A C  
A A C  
2. 1 2  
I nt e nt-t o-
Tr e at  
E F F _ F 1  
P erc e nt of Cli nic al Outc o m e by Visit  
 
A A C  
A A C  
2. 1 30 1  
Micr o -I T T 
E F F _ F 1  
P erc e nt of  Micro bi olo gic al O utc o m e by Visit, 
Ov er all a nd by Q u alifyi ng Ur o p at h o ge n Isol ate d at 
B as eli n e  
by visit ( T O C/ F U)  
A A C  
A A C  
2. 1 30 2  
Micr o -I T T 
N T F -S  
E F F _ F 1  
P erc e nt of Micro bi olo gic al O utc o m e by Visit, 
Ov er all a nd by Q u alifyi ng Ur o p at h o ge n Isol ate d at 
B as eli n e  
by visit ( T O C/ F U)  
A A C  
A A C  
2. 1 30 3  
Micr o -I T T 
N T F -N S  
E F F _ F 1  
P erc e nt of Micro bi olo gic al O utc o m e by Visit, 
Ov er all a nd by Q u alifyi ng Ur o p at h o ge n Isol ate d at 
B as eli n e  
by visit ( T O C/ F U)  
A A C  
A A C  
C CI


 
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12.9.9. 
Safety Tables 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
If study 
stops 
If study 
continues 
Adverse Events (AEs) 
3.0 
Safety 
 
Overall Summary of Adverse Events 
 
HDL 
HDL 
3.1 
Safety 
AE5B 
Summary of Adverse Events by System 
Organ Class and Preferred Term and 
Maximum Grade 
 
HDL 
HDL 
3.2 
Safety 
AE5B 
Summary of Adverse Events by System 
Organ Class and Preferred Term and 
Maximum Grade and Age 
subgroup age group 
SAC 
SAC 
3.3 
Safety 
AE5B 
Summary of Drug-Related Adverse Events by 
System Organ Class and Preferred Term and 
Maximum Grade 
 
SAC 
SAC 
3.4 
Safety 
AE3 
Summary of Common (>=1%) Adverse 
Events by Preferred Term 
 
SAC 
SAC 
3.5 
Safety 
AE3 
Summary of Common (>=1%) Adverse 
Events by Preferred Term and Age 
subgroup age group 
SAC 
SAC 
3.6 
Safety 
AE15 
Summary of Common (>=1%) Non-Serious 
Adverse Events by System Organ Class and 
Preferred Term (Number of Participants and 
Occurrences) 
 
SAC 
SAC 
3.7 
Safety  
AE3 
Summary of Common (>=1%) Grade 2-5 
Adverse Events by Preferred Term 
 
SAC 
SAC 


 
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Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
If study 
stops 
If study 
continues 
3.9 
Safety 
E16 
Summary of Serious Adverse Events by 
System Organ Class and Preferred Term 
(Number of Subjects and Occurrences) 
 
SAC 
SAC 
3.10 
Safety 
AE5B 
Summary of Serious Adverse Events by 
System Organ Class and Preferred Term and 
Maximum Grade 
 
SAC 
SAC 
3.11 
Safety 
AE5B 
Summary of Serious Adverse Events by 
System Organ Class and Preferred Term and 
Maximum Grade and Age 
subgroup age group 
SAC 
SAC 
3.12 
Safety 
AE5B 
Summary of Drug-Related Serious Adverse 
Events by System Organ Class and Preferred 
Term and Maximum Grade 
 
SAC 
SAC 
3.13 
Safety 
AE3 
Summary of Non-Fatal Serious Adverse 
Events 
 
SAC 
SAC 
3.14 
Safety 
AE3 
Summary of Drug-Related Non-Fatal Serious 
Adverse Events 
 
SAC 
SAC 
3.15 
Safety 
AE5B 
Summary of Cardiovascular and 
Gastrointestinal Adverse Events of Special 
Interest by System Organ Class and Preferred 
Term and Maximum Grade 
  
SAC 
SAC 
3.17 
Safety 
AE5B 
Summary of Acetylcholinesterase-Inhibition 
Adverse Events of Special Interest by System 
Organ Class and Preferred Term and 
Maximum Grade 
 
SAC 
SAC 


 
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Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
If study 
stops 
If study 
continues 
3.19 
Safety 
AE5B 
Summary of Acetylcholinesterase-Inhibition 
Adverse Events of Special Interest by Number 
of Events and Unique Preferred Term 
a table to summarize the number 
and % of patients experiencing 1, 2, 
3, 4, 5 or more events and 
1,2,3,4,>=5 or more distinct PTs. 
See mock up on slides 8 
SAC 
SAC 
3.20 
Safety 
AE5B 
Summary of Acetylcholinesterase-Inhibition 
Adverse Events of Special Interest by Number 
of Events and Unique Preferred Term and 
Age 
subgroup age group 
SAC 
SAC 
3.21 
Safety 
  
Summary of Onset, Duration and Lag Time of 
AChE-I Event 
a summary table to present the 
statistics (mean, median, max, min) 
of time to first event, duration, and 
lag time since last dose for AchEI, 
non-GI AchEI, and GI AchEI events 
SAC 
SAC 
3.22 
Safety 
  
Summary of Onset, Duration and Lag Time of 
AChE-I Event by Age 
subgroup age group 
SAC 
SAC 
3.23 
Safety 
AE5B 
Summary of Adverse Events Leading to 
Discontinuation of Study Treatment or 
Withdrawal from Study by System Organ 
Class and Preferred Term and Maximum 
Grade 
  
SAC 
SAC 
3.2301 
Safety 
AE5B 
Summary of Adverse Events Leading to 
Discontinuation of Study Treatment by 
System Organ Class and Preferred Term and 
Maximum Grade  
  
SAC 
SAC 


 
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Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
If study 
stops 
If study 
continues 
Laboratory  
3.24 
Safety 
LB1 
Summary of Clinical Chemistry Values 
Change from Baseline 
  
SAC 
SAC 
3.25 
Safety 
LB2 
Summary of Emergent Chemistry Laboratory 
Results by Maximum Grade Increase from 
Baseline 
  
SAC 
SAC 
3.26 
Safety 
LB1 
Summary of Hematology Change from 
Baseline 
  
SAC 
SAC 
3.27 
Safety 
LB2 
Summary of Emergent Hematology 
Laboratory Results by Maximum Grade 
Increase from Baseline 
  
SAC 
SAC 
3.28 
Safety 
LIVER1 
Summary of Liver Monitoring/Stopping Event 
Reporting 
  
SAC 
SAC 
3.29 
Safety 
UR3 
Summary of Urinalysis Results 
  
SAC 
SAC 
3.30 
Safety 
 LIVER10 Summary of Hepatobiliary Laboratory 
Abnormalities  
  
SAC 
SAC 


 
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Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
If study 
stops 
If study 
continues 
Vital Signs 
3.31 
Safety 
VS3 
Summary of Worst-Case Vital Signs Results 
Relative to Potential Clinical Importance 
Criteria Post-Baseline Relative to Baseline 
 
SAC 
SAC 
3.32 
Safety 
VS1 
Summary of Change from Baseline in Vital 
Signs 
 
SAC 
SAC 
Family History 
3.34 
Safety 
FH1 
Summary of Family History of Cardiovascular 
Risk Factors 
 
SAC 
SAC 


 
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12.9.10. 
Safety Figures 
Safety: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
If study 
stops 
If study 
continues 
3.1 
Safety 
AE10 
Plot of Common (>=1%) Adverse Events and 
Relative Risk 
 
AAC 
AAC 
3.2 
Safety 
AE11 
Cumulative Distribution of Time to First 
Gastrointestinal Event 
 
AAC 
AAC 
3.3 
Safety 
 
Stacked Bar Chart of AChE-I Cumulative Grades 
 
AAC 
AAC 
3.4 
Safety 
 
Stacked Bar Chart of non-GI AChE-I Cumulative 
Grade 
 
AAC 
AAC 
3.5 
Safety 
 
Bar Chart of GI Events by Grade in Percentage of 
Subjects over Time 
 
AAC 
AAC 
3.6 
Safety 
 
Plot for AChE-I Events and Relative Risk 
 
AAC 
AAC 
3.7 
Safety 
 
Plot of Maximum Post-Baseline vs Baseline for 
ALT 
 
AAC 
AAC 
3.8 
Safety 
 
Plot of Maximum Post-Baseline Total Bilirubin vs 
Maximum Post-Baseline ALT 
 
AAC 
AAC 
3.9 
Safety 
 
Liver Function Tests Patient Profiles 
 
AAC 
AAC 
 


 
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12.9.11. 
Pharmacokinetic Tables 
Pharmacokinetic: Tables 
No. Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
 
Deliverable 
If study 
stops 
If study 
continues 
Pharmacokinetic Concentrations 
4.1. 
PK  
PKCT1 
Summary of Gepotidacin Plasma 
Pharmacokinetic Concentration Actual Time Data 
(ug/mL) 
By study day and sampling window 
SAC 
SAC 
4.2. 
PK  
PKCT1 
Summary of Gepotidacin Urine Pharmacokinetic 
Concentration Actual Time Data (ug/mL) 
By study day and sampling window 
SAC 
SAC 
 


 
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12.9.12. 
ICH and Non-ICH Listings 
Listings 
No. 
Population 
IDSL / 
Example 
Shell 
Title 
Programming Notes 
 
Deliverable 
If study 
stops 
If study 
continues 
Participant Disposition 
1 
Intent-to-Treat 
ES2 
Listing of Reasons for Study Withdrawal 
ICH Listing 
AAC 
AAC 
2 
Intent-to-Treat 
SD2 
Listing of Reasons for Study Treatment 
Discontinuation 
ICH Listing 
AAC 
AAC 
3 
Intent-to-Treat 
SP3 
Listing of Subjects Excluded from Any Population 
ICH Listing 
AAC 
AAC 
Protocol Deviations 
4 
Intent-to-Treat 
DV2 
Listing of Important Protocol Deviations 
ICH Listing 
AAC 
AAC 
5 
Screened 
ES7 
Listing of Reasons for Screen Failure 
Non-ICH Listing 
AAC 
AAC 
6 
Intent-to-Treat 
BL1 
Listing of Subjects for Whom the Treatment Blind 
was Broken During the Study 
ICH Listing 
AAC 
AAC 
7 
Intent-to-Treat 
TA1 
Listing of Randomized and Actual Treatments 
Non-ICH Listing 
pre-HDL (2 
days post 
unblinding) 
pre-HDL (2 
days post 
unblinding) 
8 
Intent-to-Treat 
IE3 
Listing of Subjects with Inclusion/Exclusion Criteria 
Deviations 
ICH Listing 
AAC 
AAC 
Demographic and Baseline Characteristics 
9 
Intent-to-Treat 
DM2 
Listing of Demographic Characteristics 
ICH Listing 
AAC 
AAC 
10 
Intent-to-Treat 
DM9 
Listing of Race 
ICH Listing 
AAC 
AAC 
11 
Intent-to-Treat 
SAFE_L1 
Listing of History of Uncomplicated Urinary Tract 
Infection and Pre-Existing Conditions with Similar 
Symptoms 
ICH Listing 
AAC 
AAC 


 
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Listings 
No. 
Population 
IDSL / 
Example 
Shell 
Title 
Programming Notes 
 
Deliverable 
If study 
stops 
If study 
continues 
12 
Intent-to-Treat 
MH2 
Listing of Medical Conditions 
ICH Listing 
AAC 
AAC 
12.1 
Intent-to-Treat 
MH2 
Listing of Findings of Medical History 
ICH Listing 
AAC 
AAC 


 
C O N FI D E N TI A L  
2 0 4 9 8 9  
 
 
1 4 3  
 
Li sti n g s  
N o.  
P o p ul ati o n  
I D S L / 
E x a m ple 
S h ell  
Titl e  
Pr o gr a m mi n g N ote s  
 
D eli v era bl e  
If st u d y 
st o p s  
If st u d y 
c o nti n u e s  
Pri or a n d C o n c o mit a nt M e di c ati o n s  
1 3  
I nt e nt-t o-Tr e at  
C M 3  
Listi n g of Prior an d Co nc o mit a nt M edic ati ons  
N o n -I C H Listi n g 
A A C  
A A C  
1 4  
I nt e nt-t o-Tr e at  
C M 3  
Listi n g of Prior an d Co nc o mit a nt Anti bi otic 
M e dic ati o ns f or u U TI  
N o n -I C H Listi n g 
A A C  
A A C  
E x p o s ur e a n d Tr eat m e nt C o m pli a n c e  
1 5  
I nt e nt-t o-Tr e at  
E X 3  
Listi n g of Exp os ur e D at a  
I C H Listi n g 
A A C  
A A C  
Effi c a c y  
1 6  
Micr o -I T T 
  
Listi n g of Micro bi ol ogic al Outc o m e a n d R es po ns e, 
Cli nic al O utc o m e a n d R es po ns e, a nd T her a p eutic 
R es p o nse by S ubj ect I D a nd B aseli n e Qu alifyi n g 
Uro p at h o g en  
N o n -I C H Listi n g 
A A C  
A A C  
1 7  
I nt e nt-t o-Tr e at  
E F F _ L 1  
Listi n g of Cli nic al O utc o m e a n d Res p ons e  
N o n -I C H Listi n g 
A A C  
A A C  
2 0  
I nt e nt-t o-tr e at 
E F F _ L 3  
Listi n g of Susc e pti bility R esults  
N o n -I C H Listi n g 
A A C  
A A C  
2 1  
Micr o -I T T 
E F F _ L 4  
Listi n g of Cli nic al R es p o nse, Micro bi ol o gic al 
O utc o m e a nd R es po nse, Th er a pe utic R esp ons e, 
St u dy Dr ug MI C an d Zo n e Di a m et er R es ults by 
Q u alifyi n g B aseli n e Ur o pat h o g en  
N o n -I C H Listi n g 
A A C  
A A C  
C CI


 
C O N FI D E N TI A L  
2 0 4 9 8 9  
 
 
1 4 4  
 
Li sti n g s  
N o.  
P o p ul ati o n  
I D S L / 
E x a m ple 
S h ell  
Titl e  
Pr o gr a m mi n g N ote s  
 
D eli v era bl e  
If st u d y 
st o p s  
If st u d y 
c o nti n u e s  
2 2  
I nt e nt-t o-Tr e at  
E F F _ L 4  
Listi n g of Cli nic al R es p o nse, Micro bi ol o gic al 
O utc o m e a nd R es po nse, Th er a pe utic R esp ons e, 
MI C a n d Zo n e Di a m et er R es ults f or Uro pat h o g ens 
wit h a 4 -fol d Incr e as e i n St u dy Tr e at m ent MI C 
N o n -I C H Listi n g 
A A C  
A A C  
2 4  
I nt e nt-t o-tr e at 
  
Listi n g of G e n etic Ch ar acteriz ati o n R esults  
N o n -I C H Listi n g 
A A C  
A A C  
2 5  
I nt e nt-t o-tr e at 
  
Listi n g of N e w Qu alifyi n g Ur o p ath og e ns  
N o n -I C H Listi n g 
A A C  
A A C  
2 6  
Micr o -I T T 
  
Listi n g of Se q ue nce Ty pi ng  a n d  P h en otypic 
S u bc at e gories f or Q u alifyi ng Ur o p ath og e ns fr o m 
Micro bi ol o gic al F ail ur es  
N o n -I C H Listi n g 
A A C  
A A C  
A d v er s e E ve nt s  
2 7  
S af ety  
A E 2  
Listi n g of R el atio ns hip B et w e e n Syst e m Or ga n Cl ass 
a n d V er bati m T ext  
N o n -I C H Listi n g 
A A C  
A A C  
2 8  
S af ety  
A E 7  
Listi n g of Su bj ect N u m b ers f or I n divi du al Adv ers e 
Ev e nts  
I C H Listi n g 
A A C  
A A C  
2 9  
S af ety  
A E 8 C P  
Listi n g of All Adv ers e Ev e nts  
I C H Listi n g 
A A C  
A A C  
S eri o u s a n d Ot h er Si g nific a nt A d v ers e E v e nt s  
3 0  
S af ety  
A E 8 C P  
Listi n g of Stu dy Dr ug R el ated A dvers e Eve nts  
I C H Listi n g 
A A C  
A A C  
3 1  
S af ety  
S A F E _ L 2  Listi n g of Serio us Adv ers e Ev e nts ( F at al & N o n -
F at al)  
I C H Listi n g 
H D L  
H D L  
3 1. 1  
S af ety  
  
Listi n g of F atal S erious Advers e Ev ents  
I C H Listi n g 
A A C  
A A C  
3 2  
S af ety  
A E 8 C P  
Listi n g of Adv ers e Ev e nts Le a di ng to Disc o nti nu atio n 
of Stu dy Tr eat m e nt or Wit hdr a w al fr o m Stu dy  
I C H Listi n g 
A A C  
A A C  
C CI


 
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Listings 
No. 
Population 
IDSL / 
Example 
Shell 
Title 
Programming Notes 
 
Deliverable 
If study 
stops 
If study 
continues 
33 
Safety 
AE8CP 
Listing of Cardiovascular and Gastrointestinal 
Adverse Events of Special Interest 
ICH Listing 
AAC 
AAC 
34 
Safety 
AE8CP 
Listing of Acetylcholinesterase-Inhibition Adverse 
Events of Special Interest  
ICH Listing 
AAC 
AAC 
35 
Safety 
AE8CP 
Listing of Non-Gastrointestinal Acetylcholinesterase-
Inhibition Adverse Events of Special Interest 
ICH Listing 
AAC 
AAC 
All Laboratory 
36 
Safety 
LB5A 
Listing of Clinical Chemistry Toxicities of Grade 3 or 
Higher 
ICH Listing 
AAC 
AAC 
37 
Safety 
LB5A 
Listing of All Clinical Chemistry Data for Subjects with 
Toxicities of Grade 3 or Higher 
ICH Listing 
AAC 
AAC 
38 
Safety 
LB5A 
Listing of Hematology Toxicities of Grade 3 or Higher 
ICH Listing 
AAC 
AAC 
39 
Safety 
LB5A 
Listing of Hematology Data for Subjects with 
Toxicities of Grade 3 or Higher 
ICH Listing 
AAC 
AAC 
40 
Safety 
UR2A 
Listing of Urinalysis Data 
ICH Listing 
AAC 
AAC 
ECG 
41 
Safety 
EG5 
Listing of All ECG Findings for Subjects with an 
Abnormal Finding 
Non-ICH Listing 
AAC 
AAC 
42 
Safety 
EG3 
Listing of All ECG Values for Subjects with Any Value 
of Potential Clinical Importance 
Non-ICH Listing 
SAC 
SAC 
Vital Signs 
43 
Safety 
VS4 
Listing of All Vital Signs for Subjects with Potential 
Clinical Importance Values 
Non-ICH Listing 
AAC 
AAC 


 
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Listings 
No. 
Population 
IDSL / 
Example 
Shell 
Title 
Programming Notes 
 
Deliverable 
If study 
stops 
If study 
continues 
Liver Events and Other Safety Endpoints 
44 
Safety 
SAFE_L3 Listing of Clostridium Difficile Testing Results 
Non-ICH Listing 
AAC 
AAC 
45 
Safety 
SU2 
Listing of Alcohol Intake at Onset of Liver Event 
Non-ICH Listing 
AAC 
AAC 
46 
Safety 
LIVER5 
Listing of Liver Monitoring/Stopping Event Reporting 
Non-ICH Listing 
AAC 
AAC 
47 
Safety 
LIVER7 
Listing of Liver Biopsy Details 
Non-ICH Listing 
AAC 
AAC 
48 
Safety 
LIVER8 
Listing of Liver Imaging Details 
Non-ICH Listing 
AAC 
AAC 
Pharmacokinetic Concentrations 
49 
PK  
PKCL1P 
Listing of Gepotidacin Plasma Concentrations 
(ug/mL) 
Non-ICH Listing 
AAC 
AAC 
50 
PK  
PKUL1P 
Listing of Gepotidacin Urine Concentrations (ug/mL) 
Non-ICH Listing 
AAC 
AAC 
COVID-19 
51 
Intent-to-Treat 
  
Listing of Substance Use 
Non-ICH Listing 
AAC 
AAC 
52 
Intent-to-Treat 
PAN5A 
Country Level Listing of Start Dates of Waves of 
COVID-19 Pandemic Measures 
Non-ICH Listing 
AAC 
AAC 
53 
Intent-to-Treat 
PAN7 
Listing of All Subjects with Visits and Assessments 
Impacted by COVID-19 Pandemic 
Non-ICH Listing 
AAC 
AAC 
54 
Safety 
PAN12 
Listing of COVID-19 Assessments and Symptom 
Assessments for Subjects with COVID-19 Adverse 
Events 
Non-ICH Listing 
AAC 
AAC 
55 
Intent-to-Treat 
PREG1 
Listing of Subjects Who Became Pregnant During the 
Study 
Non-ICH Listing 
AAC 
AAC 


 
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Listings 
No. 
Population 
IDSL / 
Example 
Shell 
Title 
Programming Notes 
 
Deliverable 
If study 
stops 
If study 
continues 
56 
Intent-to-Treat 
LIVER15 
Liver Stopping Event Profile 
Non-ICH Listing 
Conditional output 
that will only be 
produced if 
participant have 
corresponding event 
AAC 
AAC 
57 
Intent-to-Treat 
ARR1 
Patient Profile for Arrythmias 
Non-ICH Listing 
Conditional output 
that will only be 
produced if 
participant have 
corresponding event 
AAC 
AAC 
58 
Intent-to-Treat 
CHF1 
Patient Profile for Congestive Heart Failure 
Non-ICH Listing 
Conditional output 
that will only be  
produced if 
participant have 
corresponding event 
AAC 
AAC 
59 
Intent-to-Treat 
CVATIA1 
Patient Profile for Cerebrovascular Events, Stroke 
and Transient Ischemic Attack 
Non-ICH Listing 
Conditional output 
that will only be 
produced if 
participant have 
corresponding event 
AAC 
AAC 


 
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Listings 
No. 
Population 
IDSL / 
Example 
Shell 
Title 
Programming Notes 
 
Deliverable 
If study 
stops 
If study 
continues 
60 
Intent-to-Treat 
DVT1 
Patient Profile for Deep Vein Thrombosis/Pulmonary 
Embolism 
Non-ICH Listing 
Conditional output 
that will only be 
produced if 
participant have 
corresponding event 
AAC 
AAC 
61 
Intent-to-Treat 
MI1 
Patient Profile for Myocardial Infarction  
Non-ICH Listing 
Conditional output 
that will only be 
produced if 
participant have 
corresponding event 
AAC 
AAC 
62 
Intent-to-Treat 
PATE1 
Patient Profile for Peripheral Arterial 
Thromboembolism 
Non-ICH Listing 
Conditional output 
that will only be 
produced if 
participant have 
corresponding event 
AAC 
AAC 
63 
Intent-to-Treat 
PUL1 
Patient Profile for Pulmonary Hypertension 
Non-ICH Listing 
Conditional output 
that will only be 
produced if 
participant have 
corresponding event 
AAC 
AAC 


 
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Listings 
No. 
Population 
IDSL / 
Example 
Shell 
Title 
Programming Notes 
 
Deliverable 
If study 
stops 
If study 
continues 
64 
Intent-to-Treat 
REV1 
Patient Profile for Revascularisation 
Non-ICH Listing 
Conditional output 
that will only be 
produced if 
participant have 
corresponding event 
AAC 
AAC 
65 
Intent-to-Treat 
VAL1 
Patient Profile for Valvulopathy 
Non-ICH Listing 
Conditional output 
that will only be 
produced if 
participant have 
corresponding event 
AAC 
AAC 
66 
Intent-to-Treat 
DD3 
Subject Profile for Death 
Non-ICH Listing 
Conditional output 
that will only be 
produced if 
participant have 
corresponding event 
AAC 
AAC 
 
 
 
 


 
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12.10. 
Appendix 10: Qualifying Uropathogen Algorithm 
Qualifying Uropathogen Decision Tree: Single Uropathogen 


 
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Bacterial species
Gram-negative 
bacilli, S. aureus or 
S. saprophyticus
Uropathogen
≥3 Uropathogens 
(see tree on page 3)
2 Uropathogens 
(see tree on page 
2)
1 Uropathogen
Visit
Baseline
>/=10^5
Qualifying 
uropathogen
Other
Uropathogen
Other Visits
Was pathogen a 
qualifying 
uropathogen at 
baseline?
Yes
Qualifying 
uropathogen
No
>/=10^5
Qualifying 
uropathogen
Other
Uropathogen
Enterococcus spp., 
beta-hemolytic 
streptococci, 
Gardnerella 
vaginalis, 
Aerococcus urinae
Visit
Baseline
Organism isolated 
in pure culture?*
Yes
>/=10^5
Qualifying 
uropathogen
Other
Not a uropathogen
No
Not a uropathogen
Other Visits
SEE BELOW
Other
Not a uropathogen


 
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Other Visits
Was pathogen a 
qualifying 
uropathogen at 
baseline?
Yes
Qualifying 
uropathogen
No
Organism isolated in 
pure culture?*
Yes
>/=10^5
Qualifying 
uropathogen
Other
Not a uropathogen
No
Not a uropathogen
*Pure culture: a culture containing the growth of a single strain of organism free from other 
pathogens or normal flora. 


 
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Qualifying Uropathogen Decision Tree:  2 Uropathogens 
  
 
Note: Since Enterococcus spp., beta-hemolytic streptococci, Gardnerella vaginalis and Aerococcus urinae must be present in pure culture 
to be considered a uropathogen, the 2 or ≥3 uropathogens trees do not apply to these organisms. 


 
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Qualifying Uropathogen Decision Tree:  ≥3 Uropathogens 
 
Note: Since Enterococcus spp., beta-hemolytic streptococci, Gardnerella vaginalis and Aerococcus urinae must be present in pure culture 
to be considered a uropathogen, the 2 or ≥3 uropathogens trees do not apply to these organisms. 
 
Gram-negative 
bacilli, S. aureus, 
S. saprophyticus
Uropathogen
≥3 uropathogens
Visit
Baseline
Only 1 
uropathogen 
>/=10^5
Uropathogen at 
≥105
Qualifying 
uropathogen
Uropathogens at 
<105
Uropathogens
Any other 
amount or 
combination
Uropathogens at 
≥105
Uropathogens
Uropathogen(s) 
at <105
Uropathogen(s)
Other Visits
Was the uropathogen a 
qualifying uropathogen 
at baseline
Yes
Qualifying 
uropathogen
No
Only 1 
uropathogen 
>/=10^5
Uropathogen at 
≥105
Qualifying 
uropathogen
Uropathogens at 
<105
Uropathogens
Any other 
amount or 
combination
Uropathogens at 
≥105
Uropathogens
Uropathogen(s) 
at <105
Uropathogen(s)


 
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12.11. 
Appendix 11: Uropathogen Phenotype Algorithm 
ESBL Decision Tree 
 
Note:  ESBL not determined for other Gram-negative organisms.
Gram negative 
uropathogens:
E. coli
K. pneumoniae
K. oxytoca
P. mirabilis
E. coli
K. pneumoniae
K. oxytoca
MIC >1 µg /mL 
for ceftazidime, 
cefotaxime, 
aztreonam or 
ceftriaxone
Yes
ESBL-positive
No
ESBL-negative
P. mirabilis
MIC >1 µg/mL 
for ceftazidime, 
cefotaxime, 
aztreonam or 
cefpodoxime
Yes
ESBL-positive
No
ESBL-negative


 
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Methicillin* Decision Tree 
 
*Cefoxitin is tested as a surrogate test for oxacillin to determine methicillin susceptibility/resistance. Methicillin-(oxacillin) resistant 
staphylococci are resistant to all currently available beta-lactams, cephalosporin and carbapenem antimicrobial agents, with the exception 
of ceftaroline. 


 
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Multi-drug Resistance (MDR) Decision Tree 
 
*Cefoxitin is tested as a surrogate test for oxacillin to determine methicillin susceptibility/resistance. Methicillin-(oxacillin) resistant 
staphylococci are resistant to all currently available beta-lactams, cephalosporin and carbapenem antimicrobial agents, with the exception 
of ceftaroline.
Uropathogens
Gram-negative 
uropathogens
Resistance to ≥1 drug in ≥3 
antimicrobial classes?
Penicillins
B-lactam combinations
Cephalosporins
Carbapenems
Aminoglycosides
Folate pathway antagonists
Fluoroquinolones
Nitrofuantoin
Fosfomycin
Nitroxoline
Yes
MDR 
No
NOT MDR
Gram-positive 
uropathogens
Resistance to ≥1 drug in ≥3 
antimicrobial classes?
Penicillins
Cephalosporins*
Folate pathway antagonists
Fluoroquinolones
Nitrofurantoin
Glycopeptides
Fosfomycin
Nitroxoline
Yes
MDR
No
NOT MDR


 
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Antimicrobial Resistant Phenotypes 
Antimicrobial class 
Antimicrobial 
Drug relevant to 
Gram-negatives 
Drug relevant to 
Gram-positives 
Resistant phenotype 
to be reported if 
interpretation is 
resistant* 
 
Penicillin 
Ampicillin 
X 
X 
AMP-R 
Mecillinam 
X 
 
MEC-R 
Penicillin 
 
X 
PEN-R 
B-lactam combination 
Amoxicillin/clavulanic acid 
X 
 
AUG2-R 
Ceftolozane/tazobactam 
X 
 
C/T-R 
Ceftazidime/avibactam 
X 
 
CZA-R 
Piperacillin/tazobactam 
X 
 
P/T4-R 
Cephalosporin 
Cefazolin 
X 
 
FAZ-R 
Ceftriaxone 
X 
 
AXO-R 
Cefadroxil 
X 
 
CFR-R 
Cefoxitin** 
 
X 
See methicillin 
resistance tree 
Carbapenem 
Meropenem 
X 
 
MERO-R 
Aminoglycoside 
Amikacin 
X 
 
AMI-R 
Gentamicin 
X 
 
GEN-R 


 
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Antimicrobial class 
Antimicrobial 
Drug relevant to 
Gram-negatives 
Drug relevant to 
Gram-positives 
Resistant phenotype 
to be reported if 
interpretation is 
resistant* 
 
Folate Pathway Antagonist 
Trimethoprim-sulfamethoxazole 
X 
X 
SXT-R 
Trimethoprim 
X 
X 
TMP-R 
Sulfisoxazole 
X 
X 
SFX-R 
Fluoroquinolone 
Ciprofloxacin 
X 
X 
CIP-R 
Levofloxacin 
X 
X 
LEV-R 
Nitrofuran 
Nitrofurantoin 
X 
X 
NIT-R 
Glycopeptide 
Vancomycin 
 
X 
VAN-R 
Fosfomycin 
Fosfomycin 
X 
X 
FOF-R 
Nitroxoline 
Nitroxoline 
X 
X 
NOX-R 
*resistant phenotype based on CLSI M100 interpretations with the exception of nitroxoline and cefadroxil which are based on EUCAST 
interpretations 
**Surrogate test for oxacillin to determine methicillin susceptibility/resistance  
R=resistant 
 


 
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12.12. 
Appendix 12: Uropathogen Genotype Algorithm 
Gepotidacin Study 204989 – Genotype Analysis 
Genotype Description 
Details 
When Performed 
Example Reporting Values 
Whole Genome Sequencing 
Screen for beta-lactamase 
genes 
1. Beta-lactamase screening 
2. Extended-spectrum beta-lactamases 
(ESBL) 
3. Original-spectrum beta-lactamases 
4. Plasmid-mediated AmpC beta-
lactamases 
5. Extended spectrum AmpC 
6. carbapenemases 
7. uncategorized spectrum beta-lactamase 
8. Chromosomal AmpC 
Enterobacterales isolates (except P. 
mirabilis) with MIC results of ≥2 
µg/mL for ceftriaxone and/or 
ceftazidime and/or cefotaxime, 
and/or aztreonam 
P. mirabilis with MIC results of ≥2 
µg/mL for cefpodoxime and/or 
ceftazidime and/or cefotaxime  
Enterobacterales isolates with MIC 
results of ≥2 µg/mL for meropenem 
1. pos/neg 
2. CTX-M-15* 
3. TEM-1* 
4. CMY-2* 
5. EC-6* 
6. KPC-3* 
7. SHV-35* 
8. PDC-30* 
 
Screen for plasmid-mediated 
fluoroquinolone resistance 
(FQ-R) genes 
• Genes from the gnr family 
1. FQ screening 
2. Aminoglycosides 
• Isolates resistant to FQs 
(levofloxacin or ciprofloxacin) 
• E. coli isolates with gepotidacin 
MICs ≥8 mcg/mL 
1. pos/neg 
2. aac(6’)-lb-cr, gnrB, oqxA* 
Screen for gene mutations of 
the quinolone (FQ) resistant 
determining region (QRDR) 
• Mutations in the FQ binding region GyrA 
• Isolates resistant to FQs 
(levofloxacin or ciprofloxacin) 
• E. coli isolates with gepotidacin 
MICs ≥8 mcg/mL 
“wildtype” or S81F, delS81F, 
S81Fins 
• Mutations in the FQ binding region GyrB 
“wildtype” or G425E, delG425, 
G425ins 
• Mutations in the FQ binding region grlA 
“wildtype” or S80F, delS80, 
S80ins 
• Mutations in the FQ binding region grlB 
“wildtype” or D432N, delD432, 
D432ins 
• Mutations in the FQ binding region parC 
“wildtype” or S79F, dels79, 
S79ins 


 
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Genotype Description 
Details 
When Performed 
Example Reporting Values 
• Mutations in the FQ binding region parE 
“wildtype” or V90A, delV90, 
V90ins 
MLST (multi-locus sequence 
typing) 
• 7 housekeeping genes sequenced 
Enterobacterales isolates (except P. 
mirabilis) with MIC results of ≥2 
µg/mL for ceftriaxone and/or 
ceftazidime and/or cefotaxime, 
and/or aztreonam 
P. mirabilis with MIC results of ≥2 
µg/mL for cefpodoxime and/or 
ceftazidime and/or cefotaxime  
Enterobacterales isolates with MIC 
results of ≥2 µg/mL for meropenem 
E. coli isolates with gepotidacin 
MICs ≥8 mcg/mL 
ST131* 
O:H serotyping 
• Typing of the lipopolysaccharide (LPS) 
(O antigen) and the ﬂagellar (H) antigens 
of E. coli 
E. coli isolates with MIC results of 
≥2 µg/mL for ceftriaxone and/or 
ceftazidime and/or cefotaxime, 
and/or aztreonam 
E. coli isolates with MIC results of 
≥2 µg/mL for meropenem 
O157:H7* 
fimH typing 
• fimH is a bacterial cell surface 
component that facilitates adhesion to 
other cells 
E. coli isolates designated as 
MLST131 
fimH27* 
Clonal assessment of 
microbiological failures (by 
MLST or PFGE) 
• See MLST description above 
• PFGE (pulse field gel electrophoresis): 
assessment of isolate genetic 
relatedness (performed only if MLST 
typing is unavailable) 
1. PFGE_type 
• all isolates from patients who 
were a microbiological failure 
• MLST: same as above 
• PFGE: allowed values: 
1. alpha/numeric (eg, “A1") 
2. allowed values: any 
percentage (eg, 99.5%) 


 
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Genotype Description 
Details 
When Performed 
Example Reporting Values 
2. PFGE_similarity 
3. PFGE_interpretation 
3. allowed values: baseline, 
identical to baseline, 
related to baseline, or 
unrelated to baseline 
Expression Analysis 
Expression of AmpC 
(chromosomally encoded) 
• gene expression from clinical isolates will 
be compared to expression from 
reference strains 
1. AmpC expression value 
2. AmpC expression interpretation 
• For the following isolates in which 
no beta-lactamases were 
detected 
• Enterobacterales isolates (except 
P. mirabilis) with MIC results of 
≥2 µg/mL for ceftriaxone and/or 
ceftazidime and/or cefotaxime, 
and/or aztreonam 
•  P. mirabilis with MIC results of ≥2 
µg/mL for cefpodoxime and/or 
ceftazidime and/or cefotaxime  
• Enterobacterales isolates with 
MIC results of ≥2 µg/mL for 
meropenem 
1. numeric RQ value (eg 
0.845766776)* 
2. allowed values: 
a. similar to baseline (0 to 
<5) 
b. moderate expression (5 to 
<10) 
c. overexpression (>/=10) 
Expression of AcrAB (efflux 
pump) 
• same as for AmpC 
• FQ-resistant E. coli isolates for 
which no QRDR or plasmid 
mutations were detected 
• E. coli isolates with gepotidacin 
MICs ≥8 mcg/mL 
• same as for AmpC 
*Numerous results are possible for these test codes. 
 
 


 
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Example outputs from published studies: 
 


 
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Note: Uropathogen genotypic subcategories may be reported individually (e.g. blaCTX-M-15) or grouped together (e.g. ESBL-gene 
positive) for reporting, dependent on numbers recovered and epidemiological significance. See examples above. The potential 
individual and group categories will be monitored in stream during the study and provided by the GSK microbiology team. 


 
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12.13. 
Appendix 13: Uropathogen Grouping and Order Example 
The following uropathogen grouping and display order examples are for information only.  The lists will be updated at the appropriate 
study milestones, and will be finalized for use prior to unblinding of the database. 
12.13.1. 
Uropathogen Grouping and Gram Positive/Negative Example 
Uropathogens 
Display Group 
GRAMPNO 
Acinetobacter baumanni 
Gram-negative non-fermenters 
Negative 
Aerococcus urinae 
NA (non regulatory approved 
uropathogen) 
Positive 
Alcaligenes faecalis 
Other Enterobacterales 
Negative 
Citrobacter amalonaticus 
Other Enterobacterales 
Negative 
Citrobacter freundii 
Other Enterobacterales 
Negative 
Citrobacter koseri 
Other Enterobacterales 
Negative 
Enterobacter aerogenes 
Other Enterobacterales 
Negative 
Enterobacter cloacae 
Other Enterobacterales 
Negative 
Enterobacter cloacae complex 
Enterobacter cloacae complex 
Negative 
Enterococcus faecalis 
Enterococcus faecalis 
Positive 
Escherichia coli 
Escherichia coli 
Negative 
Klebsiella aerogenes 
Other Klebsiella spp. 
Negative 
Klebsiella oxytoca 
Other Klebsiella spp. 
Negative 
Klebsiella pneumoniae 
Klebsiella pneumoniae 
Negative 
Klebsiella variicola 
Other Klebsiella spp. 
Negative 
Morganella morganii 
Other Enterobacterales 
Negative 
Proteus mirabilis 
Proteus mirabilis 
Negative 
Providencia rettgeri 
Other Enterobacterales 
Negative 
Providencia stuartii 
Other Enterobacterales 
Negative 
Pseudomonas aeruginosa 
Gram-negative non-fermenters 
Negative 
Serratia marcescens 
Other Enterobacterales 
Negative 
Staphylococcus aureus 
NA (non regulatory approved 
uropathogen) 
Positive 


 
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Staphylococcus saprophyticus 
Staphylococcus saprophyticus 
Positive 
Stenotrophomona maltophilia 
Gram-negative non-fermenters 
Negative 
Streptococcus agalactiae 
NA (non regulatory approved 
uropathogen) 
Positive 
12.13.2. 
Qualifying Uropathogen Grouping Example 
Uropathogens 
Display Group 
Acinetobacter baumanni 
Gram-negative non fermenters 
Aerococcus urinae 
NA (non regulatory approved uropathogen) 
Citrobacter freundii 
Other Enterobacterales 
Citrobacter koseri 
Other Enterobacterales 
Enterobacter aerogenes 
Other Enterobacterales 
Enterobacter cloacae 
Other Enterobacterales 
Enterobacter cloacae complex 
Enterobacter cloacae complex 
Enterococcus faecalis 
Enterococcus faecalis 
Escherichia coli 
Escherichia coli 
Klebsiella oxytoca 
Other Klebsiella spp. 
Klebsiella pneumoniae 
Klebsiella pneumoniae 
Klebsiella variicola 
Other Klebsiella spp. 
Morganella morganii 
Other Enterobacterales 
Proteus mirabilis 
Proteus mirabilis 
Providencia rettgeri 
Other Enterobacterales 
Staphylococcus aureus 
NA (non regulatory approved uropathogen) 
Staphylococcus saprophyticus 
Staphylococcus saprophyticus 
Streptococcus agalactiae 
NA (non regulatory approved uropathogen) 
12.13.3. 
Display Order Example 
Display Group 
Display Order 
Escherichia coli 
1 
Proteus mirabilis 
2 


 
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Klebsiella pneumoniae 
3 
Other Klebsiella spp. 
4 
Enterobacter cloacae complex 
5 
Other Enterobacterales 
6 
Gram-negative non-fermenters 
7 
Enterococcus faecalis 
8 
Staphylococcus saprophyticus 
9 
NA (non regulatory approved uropathogen) 
10