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)
Phase: PHASE3
Conditions: Urinary Tract Infections
Sponsor: GlaxoSmithKline

TMF-13817737 
CONFIDENTIAL 
 
GlaxoSmithKline group of companies 
 
212390 
 
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: 212390 / Amendment 3 
Compound 
Number: 
GSK2140944  
Study Phase: Phase III  
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-3) 
Sponsor Name and Legal Registered Address:  
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
Sponsor Name and Legal Registered 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 Number: 
IND: 111885 
EudraCT: 2020-000553-27 
Protocol Amendment Number:  3 
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: 212390 / Amendment 3 
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 3 
03-NOV-2021 
TMF-13817737 
Amendment 2 
14-APR-2021 
TMF-12037491 
Amendment 1 
14-NOV-2019 
2019N407320_01 
Original Protocol 
31-JUL-2019 
2019N407320_00 
 
Amendment 3  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 include increasing the inclusion window for the onset of acute 
cystitis clinical signs and symptoms from ≤72 hours to <96 hours, minor revisions to 
2 exclusion criteria were made, 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 Visit, 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 
4.2 Scientific 
Rationale for Study 
Design 
6.3. Measures to 
Minimize Bias: 
Randomization and 
Blinding 
9.1 Statistical 
Hypothesis 
9.2 Sample Size 
Determination 
9.4.1 General 
Considerations 
9.4.2 Efficacy 
Analysis 
9.5 Interim Analysis 
9.6 Data Monitoring 
Committee or Other 
Review Board 
10.3.5 Committee 
Structure 
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 
3 Objectives and 
Estimands/Endpoints 
Revised the secondary 
therapeutic response objective 
Consistency between primary and 
secondary endpoint 
Synopsis 
9.1 Statistical 
Hypotheses  
9.2 Sample Size 
Determination 
9.5 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 
1.3 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 
1.3 Schedule of 
Activities 
8 Study Assessments 
and Procedures 
Clarified prescreening activities 
that may occur  
Consistency with the Study 
Reference Manual  
1.3 Schedule of 
Activities 
4.1 Overall Design 
10.5.2 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 
2.3.1 Risk 
Assessment 
Minor text clarifications for clinical 
QTc effects and added relevant 
exposures for nonclinical 
embryofetal effects 
Consistency with currently known 
safety data 
5.1 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  
5.2 Exclusion Criteria 
#2 
Edited to include “uncontrolled” 
before high blood pressure 
Text clarification 
5.2 Exclusion Criteria 
#30 
Revised wording to support a “no” 
response, which is in line with this 
being an exclusion criterion 
Text clarification 
8 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  
8 Study Assessments 
and Procedures 
Removed topical antifungal 
restriction from the TOC Visit 
After TOC assessments are 
complete, participants may be 
treated with either topical or 
systemic antifungals 

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Section # and Name 
Description of Change 
Brief Rationale 
8.1.2.1 
Microbiological 
Outcome and 
Response 
8.1.3.1. 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 
9.1 Statistical 
Hypothesis 
Clarified null and alternative 
hypotheses for superiority testing 
Clarification of the planned 
analysis 
9.4.2 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 
10.3.1 Regulatory and 
Ethical 
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 
Clarification for study sites 
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. 
PROTOCOL SUMMARY ........................................................................................ 10 
1.1. 
Synopsis ..................................................................................................... 10 
1.2. 
Schema ...................................................................................................... 15 
1.3. 
Schedule of Activities (SoA) ........................................................................ 16 
2. 
INTRODUCTION .................................................................................................... 19 
2.1. 
Study Rationale .......................................................................................... 19 
2.2. 
Background ................................................................................................ 20 
2.3. 
Benefit/Risk Assessment ............................................................................ 21 
2.3.1. 
Risk Assessment ......................................................................... 22 
2.3.2. 
Benefit Assessment ..................................................................... 29 
2.3.3. 
Overall Benefit: Risk Conclusion .................................................. 29 
3. 
OBJECTIVES AND ESTIMANDS/ENDPOINTS ..................................................... 30 
4. 
STUDY DESIGN .................................................................................................... 36 
4.1. 
Overall Design ............................................................................................ 36 
4.2. 
Scientific Rationale for Study Design .......................................................... 37 
4.3. 
Justification for Dose .................................................................................. 38 
4.4. 
End-of-Study Definition ............................................................................... 41 
5. 
STUDY POPULATION ........................................................................................... 41 
5.1. 
Inclusion Criteria ......................................................................................... 41 
5.2. 
Exclusion Criteria ........................................................................................ 42 
5.3. 
Lifestyle Considerations .............................................................................. 45 
5.3.1. 
Meals and Dietary Restrictions .................................................... 45 
5.4. 
Screen Failures........................................................................................... 45 
6. 
STUDY TREATMENT ............................................................................................ 46 
6.1. 
Study Treatments Administered .................................................................. 46 
6.2. 
Preparation/Handling/Storage/Accountability .............................................. 48 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................... 48 
6.4. 
Study Treatment Compliance ...................................................................... 49 
6.5. 
Concomitant Therapy.................................................................................. 50 
6.5.1. 
Permitted Medications and Nondrug Therapies ........................... 50 
6.5.2. 
Prohibited Medications and Nondrug Therapies........................... 50 
6.6. 
Dose Modification ....................................................................................... 51 
6.7. 
Treatment after the End of the Study .......................................................... 51 
7. 
DISCONTINUATION OF STUDY TREATMENT AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 52 
7.1. 
Discontinuation of Study Treatment ............................................................ 52 
7.1.1. 
Liver Chemistry Stopping Criteria ................................................ 52 

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8  
 
7. 1. 2.  
Q T c St o p pi n g Crit eri a  .................................................................. 5 4  
7. 1. 3.  
R e c h all e n g e  ................................................................................. 5 5  
7. 1. 4.  
G a str oi nt e sti n al E v al u ati o n Crit eri a  .............................................. 5 5  
7. 2.  
P arti ci p a nt Di s c o nti n u ati o n/ Wit h dr a w al fr o m t h e St u d y  ............................... 5 5  
7. 3.  
L o st t o F oll o w -U p  ........................................................................................ 5 6  
8.  
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S  ..................................................... 5 6  
8. 1.  
Effi c a c y A s s e s s m e nt s  ................................................................................. 5 9  
8. 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  ............................................... 5 9  
8. 1. 2.  
B a ct eri ol o g y S a m pl e s  .................................................................. 5 9  
8. 1. 3.  
Cli ni c al E v al u ati o n  ....................................................................... 6 5  
8. 2.  
S af et y A s s e s s m e nt s  ................................................................................... 6 9  
8. 2. 1.  
P h y si c al E x a mi n ati o n s  ................................................................. 6 9  
8. 2. 2.  
Vit al Si g n s  .................................................................................... 6 9  
8. 2. 3.  
El e ctr o c ar di o gr a m s  ...................................................................... 7 0  
8. 2. 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  ...................................... 7 0  
8. 3.  
A d v er s e E v e nt s a n d S eri o u s A d v er s e E v e nt s  ............................................. 7 1  
8. 3. 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 ................................................................................... 7 1  
8. 3. 2.  
M et h o d of D et e cti n g A E s a n d S A E s  ............................................. 7 2  
8. 3. 3.  
F oll o w -u p of A E s a n d S A E s  ......................................................... 7 2  
8. 3. 4.  
R e g ul at or y R e p orti n g R e q uir e m e nt s f or S A E s  ............................. 7 2  
8. 3. 5.  
Pr e g n a n c y  ................................................................................... 7 2  
8. 3. 6.  
C ar di o v a s c ul ar a n d D e at h E v e nt s  ................................................ 7 3  
8. 3. 7.  
A d v er s e E v e nt s of S p e ci al I nt er e st  .............................................. 7 3  
8. 4.  
Tr e at m e nt of O v er d o s e  ............................................................................... 7 3  
8. 5.  
P h ar m a c o ki n eti c s  ....................................................................................... 7 4  
8. 6.  
P h ar m a c o d y n a mi c s  .................................................................................... 7 4  
8. 7.  
G e n eti c s  ..................................................................................................... 7 4  
8. 8.  
Bi o m ar k er s  ................................................................................................. 7 4  
8. 9.  
I m m u n o g e ni cit y A s s e s s m e nt s ..................................................................... 7 4  
9.  
S T A TI S TI C A L C O N SI D E R A TI O N S  ........................................................................ 7 4  
9. 1.  
St ati sti c al H y p ot h e s e s ................................................................................. 7 5  
9. 2.  
S a m pl e Si z e D et er mi n ati o n  ........................................................................ 7 6  
9. 2. 1.  
J u stifi c ati o n of S a m pl e Si z e  ......................................................... 7 6  
9. 2. 2.  
S a m pl e Si z e S e n siti vit y  ................................................................ 7 6  
9. 3.  
P o p ul ati o n s f or A n al y s e s  ............................................................................ 7 7  
9. 4.  
St ati sti c al A n al y s e s  ..................................................................................... 7 9  
9. 4. 1.  
G e n er al C o n si d er ati o n s  ............................................................... 7 9  
9. 4. 2.  
Effi c a c y A n al y s e s  ......................................................................... 8 0  
9. 4. 3.  
S af et y A n al y s e s  ........................................................................... 8 3  
9. 5.  
I nt eri m A n al y si s .......................................................................................... 8 4  
9. 6.  
D at a M o nit ori n g C o m mitt e e or Ot h er R e vi e w B o ar d  ................................... 8 5  
1 0.  S U P P O R TI N G D O C U M E N T A TI O N A N D O P E R A TI O N A L  
C O N SI D E R A TI O N S  ............................................................................................... 8 6  
1 0. 1.  A p p e n di x 1: Cl o stri di u m Diffi cil e  T e sti n g Pr o c e d ur e a n d Al g orit h m  ............. 8 6  
1 0. 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 7  
1 0. 2. 1.  
D efi niti o n s:  ................................................................................... 8 7  
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T M F -1 3 8 1 7 7 3 7  
C O N FI D E N TI A L  
 
 
 
2 1 2 3 9 0  
 
9  
 
1 0. 2. 2.  
C o nt r a c e pti o n G ui d a n c e: ............................................................. 8 8  
1 0. 2. 3.  
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 0. 3.  A p p e n di x 3: R e g ul at or y, Et hi c al, a n d St u d y O v er si g ht 
C o n si d er ati o n s  ............................................................................................ 9 0  
1 0. 3. 1.  
R e g ul at or y a n d Et hi c al C o n si d er ati o n s  ........................................ 9 0  
1 0. 3. 2.  
Fi n a n ci al Di s cl o s ur e  ..................................................................... 9 0  
1 0. 3. 3.  
I nf or m e d C o n s e nt/ A s s e nt Pr o c e s s ............................................... 9 1  
1 0. 3. 4.  
D at a Pr ot e cti o n  ............................................................................ 9 1  
1 0. 3. 5.  
C o m mitt e e s Str u ct ur e  .................................................................. 9 2  
1 0. 3. 6.  
Di s s e mi n ati o n of Cli ni c al St u d y D at a  ........................................... 9 2  
1 0. 3. 7.  
D at a Q u alit y A s s ur a n c e  ............................................................... 9 3  
1 0. 3. 8.  
S o ur c e D o c u m e nt s  ...................................................................... 9 3  
1 0. 3. 9.  
St u d y a n d Sit e St art a n d Cl o s ur e  ................................................. 9 4  
1 0. 3. 1 0.  P u bli c ati o n P oli c y  ......................................................................... 9 4  
1 0. 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 5  
1 0. 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 6  
1 0. 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 6  
1 0. 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 6  
1 0. 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  ............ 9 8  
1 0. 8.  A p p e n di x 8: Cli ni c al L a b or at or y T e st s  ....................................................... 1 0 1  
1 0. 9.  A p p e n di x  9: 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 4  
1 0. 1 0.  A p p e n di x 1 0: 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 7  
1 0. 1 1.  A p p e n di x 1 1: 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 0. 1 1. 1.  D efi niti o n of A d v er s e E v e nt  ........................................................ 1 1 1  
1 0. 1 1. 2.  D efi niti o n of S A E  ........................................................................ 1 1 2  
1 0. 1 1. 3.  C ar di o v a s c ul ar A d v er s e E v e nt s of S p e ci al I nt er e st a n d 
C a s e s of Cl o stri di u m Diffi cil e  ..................................................... 1 1 3  
1 0. 1 1. 4.  R e c or di n g a n d F oll o w -U p of A E a n d S A E  .................................. 1 1 4  
1 0. 1 1. 5.  R e p orti n g of S A E t o G S K/ P P D  .................................................. 1 1 5  
1 0. 1 2.  A p p e n di x 1 2: G e n eti c s  .............................................................................. 1 1 7  
1 0. 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 8  
1 0. 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 5  
1 0. 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 7  
1 1.  R E F E R E N C E S  ..................................................................................................... 1 3 4  
 
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1. 
PROTOCOL SUMMARY 
1.1. 
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-3) 
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 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, electrocardiograms, 
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 8.1.2.1 and Section 8.1.3.1). 
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 8.1.2.1 and Section 8.1.3.1) 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. 

T M F -1 3 8 1 7 7 3 7  
C O N FI D E N TI A L  
 
 
 
2 1 2 3 9 0  
 
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 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 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 Baseli 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 d less 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 8. 1. 2. 1  a n d Secti o n 8. 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 s u m mar y meas ure will 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 ge p oti daci n a n d nitr 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  8. 1. 2. 1  a n d Secti o n 8. 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 1  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 1 2 3 9 0 is a P hase III, ra n d o mize d, m ul tice 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 asse ss 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. 
 
 
 
 
•  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 ns [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 p a nt recei vi n g ot her s yste mic a nti micr o bials) a n d 
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a clinical success (resolution of signs and symptoms of acute cystitis present at 
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. 
Disclosure Statement: This is a parallel-group treatment study with 2 arms that is 
participant, care provider, investigator, and outcomes assessor blinded.  
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.  
 

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1.2. 
Schema 
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 7 3 7  
C O N FI D E N TI A L  
 
 
 
2 1 2 3 9 0  
 
1 6  
 
1. 3.  
S c h e d ul e of A cti viti e s ( S o A)  
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 E C Gi 
X  
 
X i 
 
 
 
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 i,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  
St u dy tr e at m e nt c o m pli a nc e r 
 
 
X  
X  
 
 
Sc h e d ul e n ext visit  
X s 
 
X t 
X t 
X t 
 
G e n etic s a m pl e u 
X  
 
 
 
 
 
E C G = el ectr oc ar di o gr a m; HI V = h u m a n i m m u n o d efici e ncy vir us; H P F = hi g h -p o w er fi el d; I R T =i nt er activ e r es p o ns e t ec h n ol o gy; N A = n ot a p plic a bl e; T O C = T est -of -C ur e; U TI = uri n ary 
tr act i nf ecti o n; W B C = w hit e bl o o d c ell. 
C CI
C CI

T M F -1 3 8 1 7 7 3 7  
C O N FI D E N TI A L  
 
 
 
2 1 2 3 9 0  
 
1 7  
 
N ot e:  T o r e d uc e p artici p a nt o n -sit e visits or if unf or es e e n iss u es i m p act cli nic visits, a n d p artici p a nts ar e 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 n d t el e m e dici n e 
visits) m ay b e us e d t o c o n d uct pr oc e d ur es 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. H o m e h e alt hc ar e will o nly b e utili z e d w h er e a p plic a bl e c o u ntry a n d l oc al r e g ul ati o ns a n d 
i nfr astr uct ur e all o w. 
a.  
F or all st u dy visits, t o mi ni miz e t h e a m o 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 C o ns e nt m ay b e utiliz e d a n d r e m o t e c oll ecti o n of st u dy-r el 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 R ef er e 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 hr o u g h a c o m bi n ati o n of t el e m e dici n e a n d o n -sit e visits. C oll ecti o n of i nf or m ati o n vi a 
t el e m e dici n e will b e p erf or m e d o nly w h er e l oc al r e g ul ati o ns p er mit. Pr escr 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 pr escr e e ni n g i nf or m e d c o ns e nt a n d uri n e t esti n g, 
as d et ail e d i n S ecti o n 8  a n d t h e St u dy R ef er e nc e M a n u al.  
b.  
F or t h e O n -t h er a py ( D ay 2 t o 4) Visit: P artici p a nts will b e i nstr uct e d t o r et ur n t o t h e st u dy sit e wit hi n 1 t o 3 d ays p ostr a n d o miz ati o n. E ac h tr e at m e nt d ay will b e ass ess e d ov er 
2 4 h o urs st arti n g wit h t h e first d os 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 er e 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 nstr uct e d t o 
r et ur n t o t h e st u dy sit e 5 t o 8 d ays aft er c o m pl eti o n of st u dy tr e 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 dir ect e d a n d is o n ly r e 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 u al cli nic al si g ns a n d sy m pt o ms sc or es of ac ut e cystitis will b e r ec 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 tr ai n e d st aff b as e d o n p artici p a nt 
i nt ervi e w a n d usi n g t h e sc ori n g syst e m i n A p p e n dix  6 . T h e s a m e sc or er 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, w h e n ev er p ossi bl e. 
st u dy p hysici a n or ot h er wis e a p pr o pri at ely m e dic ally tr ai n e d s t aff w h o p erf or m e d t h e cli nic al sc ori n g ass ess m e nt. 
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 ar g e l e uk ocyt e est er as e) fr o m a pr etr e at m e nt c l e a n-catc h mi dstr e a m uri n e s a m pl e p er l oc al 
l a b or at ory pr oc e d ur es. 
g.  
P artici p a nts will pr ovi d e a cl e a n -c atc h mi dstr e a m uri n e s a m pl e at e ac h visit f or Gr a m st ai n, q u a ntit ativ e b act eri ol o gy c ult ur e, a n d i n vitr o a nti micr o bi al s usc e pti bility t esti n g by a 
d esi g n at e d c e ntr al l a b or at ory(i es). R ef er t o t h e l a b or at 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 er a py Visit, as f urt h er d et ail e d i n t h e St u dy R ef er e nc e M a n u al. 
i. 
S e e S ecti o n 5. 2  f or E C G 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 7. 1. 2  a n d S ecti o n 8. 2. 3 . Tri plic at e E C Gs will b e 
p erf or m e d at B as eli n e. F or t h e first a p pr oxi m at ely 1 2 0 0 p artici p a nts e nr oll e d, O n -t h er a py tri plic at e E C Gs will als o b e o bt ai n e d. T h e O n-t h er a py E C Gs will b e c oll ect e d at 
a p pr oxi m at ely 2 h o urs p ost d os e (i. e., ex p ect e d ti m e of m axi m u m c o nc e ntr ati o n; E C G c oll ecti o n s h o ul d i d e ally b e wit hi n a p pr oxi m at ely 1. 5  h o urs p ost d os e t o 4 h o urs p ost d os e). 
Aft er t h e first a p pr oxi m at ely 1 2 0 0 p artici p a nts h av e tri plic at e E C Gs p erf or m e d at O n -t h er a py, t h e E C G c oll ecti o n at t his visit is n o l o n g er a pr ot oc ol r e q uir e m e nt. 
El ectr oc ar di o gr a ms will b e r evi e w e d l oc ally by t h e i nv esti g at or f or s af ety p ur p os es. El ectr oc ar di o gr a ms will b e c e ntr ally ov e rr e a d f or t h e d at a a n alysis. 
j. 
T ak e m e as ur e m e nt of t e m p er at ure, bl o o d pr ess ur e, a n d p uls e r at e.  
k. 
If s er ol 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 tr e at m e nt a n d t h e r es ults w er e 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 w as 
p erf or m e d wit hi n 3  m o nt hs a n d a ny r es ult  w as n e g ati v e , t esti n g at B as eli n e i s re q uire d.  
l. 
F or w o m e 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 pr e g n a ncy t est is s uffici e nt f or eli gi bility. Se e Ap p e n dix 8  f or B as eli n e uri n e t est s e nsitivity r e q uir e m e nts 
a n d A p p e n dix 2  f or ass oci at e d c o ntr ac e pti o n r e q uir e m e nts. Pr e g n a ncy t esti n g s h o ul d b e p erf or m e d aft er D os e 4 a n d b ef or e D os e 8, as s p ecifi e d i n A p p e n dix 8 . 
n.  
P artici p a nts will r ec eiv e or al st u dy tr e 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 or al d os e will b e a d mi nist er e 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 a nts will s elf-a d mi nist er  as o ut p ati e nts t h er e aft er, b e gi n ni n g wit h t h e s ec o n d d os e. Eac 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 w at er. 
T h e d at e a n d ti m e of e ac h d os e a d mi nist er e d at t h e st u dy sit e will b e r ec or d e d i n t h e s o urc e d oc u m e nts.  
C CI
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o. 
At the On-therapy Visit, whenever it is possible, the participant will have the pregnancy test performed at the study site. If the visit coincides with the 8th dose, the participant 
will take their next dose of study treatment at the study site after negative pregnancy test results are confirmed. Note:  The On-therapy Visit should be scheduled to support 
completion of the postdose ECG within the protocol-defined window. Also, in a woman of childbearing potential, the high sensitivity pregnancy test must be performed and 
show negative results at the latest before Dose 8 of study treatment is taken. 
p. 
Record serious adverse events from the time of consent/assent in order to fulfill international regulatory requirements. 
q. 
Record adverse events from the time of the first dose of study treatment. 
r. 
Determine study treatment compliance by performing pill count. 
s. 
Confirm return day/time for the On-therapy, TOC, and Follow-up Visits. 
t. 
Previsit reminder: Study site staff will contact the participant 24±4 hours before the scheduled On-therapy, TOC, and Follow-up Visits. 
u.  Collect sample only if the participant has a signed consent/assent specific for this purpose. The Baseline Visit is the recommended time to collect the sample, but it can be 
collected at any time during the study. 
 
 

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2. 
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. 
2.1. 
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 2.2). 
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 conducted in 22 female 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 colony-forming units/mL [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 (212390) 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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2.2. 
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. 
2.3. 
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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2.3.1. 
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 5.2 for excluded cardiac 
conditions. Close monitoring of clinical 
parameters and AEs (Section 1.3) will be 
conducted, and treatment monitoring and 
evaluation criteria (Section 7.1.2) will be 
utilized to mitigate cardiovascular effects. 
Participants taking medications known to 
increase QT or potent CYP3A4 inhibitors will 
be excluded (see Section 6.5.2). 
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 5.2 for excluded medical 
conditions. Close monitoring of clinical 
parameters and AEs (Section 1.3) 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 5.2 for excluded medical conditions 
and Section 6.5.2, 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 1.3). 
 
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 5.2 
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 5.2 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 Appendix 8 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 1.3) will be conducted, and 
treatment monitoring and evaluation criteria 
(Section 7.1.1) 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 5.2).  
Participants with a history of sensitivity to 
nitrofurantoin, or components thereof, will not 
be allowed to enroll in the study (Section 5.2). 
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 5.2). 

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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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2.3.2. 
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 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 
minimize safety risks when participating in a clinical study. 
2.3.3. 
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, Phase IIa results indicating efficacy in acute cystitis, 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 1 of the current 
recommended treatments 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 2.3.1). 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. 
3. 
OBJECTIVES AND ESTIMANDS/ENDPOINTS 
Objectives 
Endpoints 
Primary 
• 
To assess the combined clinical and 
microbiological efficacy of gepotidacin 
compared to nitrofurantoin, at the 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 
• 
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 

T M F -1 3 8 1 7 7 3 7  
C O N FI D E N TI A L  
 
 
 
2 1 2 3 9 0  
 
3 1  
 
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 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 partici p a nts wit h ac ut e cystitis 
 
•  
Tr e at m e nt -e m erg e nt A Es an d s erious 
A Es ( S A Es) a n d c h an ge fr o m b as eli n e 
r es ults f or cli nic al l ab or atory t ests, 
el ectr oc ar di ogr a ms ( E C Gs), a n d vit al si g n 
m e as ur e m e nts  
C CI

T M F -1 3 8 1 7 7 3 7  
C O N FI D E N TI A L  
 
 
 
2 1 2 3 9 0  
 
3 2  
 
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 Bas 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  8. 1. 2. 1  a n d Secti o n 8. 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 Baseli 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 Visit. 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/ m L ( 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 pa nt recei vi n g ot her s y ste 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 
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. 
•  S u m mar y meas ure: A bs ol ute differe n ce i n t he t hera pe utic s uccess rat e i n t he 
ge p oti daci n a n d nitr of ura nt oi n treat me nt gr o u ps.  
•  I nterc urre nt e v e nts (I C Es): 
•  St u d y treat me nt disc o nti n uati o n ( d ue t o a n y reas o n) –  treat me nt p olic y 
strate g y (i nterest is i n t he treat me nt effect r e gar dless of st u d y treat me nt 
disc o nti n uati o n).  
•  Use of s yste mic a nti micr o bials –  c o m p osite strate g y. T his I C E is ca pt ur e d 
t hr o u g h t he d efi niti o ns of micr o bi ol o gical a n d cli nical res p o nse (see 
Secti o n  8. 1. 2. 1  a n d Secti o n 8. 1. 3. 1 ) a n d will be c o u nte d as t hera p e utic 
fail ures. 
Rati o nale f or Esti ma n d:  
I nterest lies i n t he treat me nt effect re gar dless of w het her t he f ull c o urse of 5 da ys of 
treat me nt was ta k e n or n ot, w hic h reflects h o w patie nts ma y be tr eate d i n cli nical 
practice. He nce, a tr eat m e nt p olic y str ate g y is a p pr o priate f or treat me nt wit h dra wal 
bef ore c o m pleti n g 5 d a ys of treat me nt. Use of ot her s yste mic a nti micr o bials ma y 
C CI

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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 8.1.2.1 and Section 8.1.3.1). 
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 8.1.2.1 and Section 8.1.3.1 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. 
Components of estimand for all secondary endpoints are listed in Table 1. 
 

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Table 1 
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 10 and 
Table 11 
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 10 and 
Table 11 
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 5 
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 5 
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 – 
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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 5 
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 5 
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 5 and 
Table 11 
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 
Safety  
Female participants 
with acute cystitis 
infection  
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, 
ECGs, 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; EGG=electrocardiogram; SAE=serious adverse event; TEAE=treatment-emergent adverse event; TOC=Test-of-Cure. 
 

T M F -1 3 8 1 7 7 3 7  
C O N FI D E N TI A L  
 
 
 
2 1 2 3 9 0  
 
3 6  
 
4.  
S T U D Y D E SI G N  
4. 1.  
O v er all D e si g n  
•  
St u d y 2 1 2 3 9 0 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 nts 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 ur a 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 me d infecti 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 wil l 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 da ys ( N ote: 
Eac h d ose s h o ul d be ta k e 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. 
 
 
 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 d etaile d i n t he 
St u d y R efere 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 nts 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 ns [ e. g., 1 0 5 C F U/ m L; d efi n e 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 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 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 nt e nt -t o-Treat Nitr of ura nt oi n -S usce pti ble 
( micr o-I T T N T F-S) P o p ula ti o n, re gar dless of treat me nt disc o nti n uati 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 tr eat 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 pleted 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 8 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. The Schedule of Activities (SoA) is 
provided is Section 1.3. 
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. 
4.2. 
Scientific Rationale for Study Design 
The study design is based on the Food and Drug Administration (FDA) guidance for 
industry for developing drug treatments for uncomplicated and complicated UTIs 
[DHHS, 2019; DHHS, 2018], the European Medicines Agency (EMA) addendum to the 
guideline on the evaluation of medicinal products indicated for treatment of bacterial 
infections [EMA, 2013], and feedback from the FDA and EMA. The primary efficacy 
endpoint will be the therapeutic response (combined per-participant microbiological and 
clinical response) at the TOC Visit (i.e., 10 to 13 days after randomization, which is also 
5 to 8 days after completion of study treatment) in participants who have a qualifying 
bacterial uropathogen at Baseline. Although the guidances differ in their criteria for 
defining qualifying uropathogens, this study has been designed with the qualifying 
uropathogen criteria defined in Appendix 4 and microbiological success 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 at the TOC Visit is defined as the resolution of signs and 
symptoms of acute cystitis present at Baseline (and no new signs and symptoms) without 

T M F -1 3 8 1 7 7 3 7  
C O N FI D E N TI A L  
 
 
 
2 1 2 3 9 0  
 
3 8  
 
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 
partici pa nts w h o ha v e bee n dee me d b ot h a m icr 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 TI 
(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 1 b; NI C E , 2 0 1 9; E A U , 2 0 1 9]. 
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 4. 3 , t he d ose of eac h st u d y tr eat me nt a n d t h e 5-da y 
d urati o n were select e d t o pr o vi de effi caci o us treat me nt f or ac ut e c ystitis a n d is i n 
ali g n me nt wit h c urre nt cli nical practice. Ha vi n g t h e sa me d ose re gi me n will als o s u p p ort 
d o u ble -bli n d d ose a d mi nistrati o n.  A n o ni nferi orit y mar gi n of 1 0 % has b ee n selecte d f or 
t his st u d y [D H H S , 2 0 1 9]. 
B ot h a d ult a n d a d oles ce nt ( ≥1 2 t o < 1 8 years of a ge) eli gi ble fe mal e partici pa nts will be 
e nr olle d i n t his d o u ble -bli n de d st u d y. T he st u d y is restricte d t o f e male partici pa nts per 
F D A g ui da n ce [ D H H S , 2 0 1 9]. A d olesce nt partici p a nts will o nl y b e e nr olle d at st u d y sites 
w here i n vesti gat ors h a ve e x perie nce i n t his p o p ulati o n a n d if all o we d per t h e st u d y site’s 
i nstit uti o nal et hics c o m mittees a n d l ocal c o u ntr y/ n ati o nal re g ulat or y g ui deli nes a n d 
e nr oll me nt will be c o nti n ge nt u p o n s u c h a p pr o vals. A d olesce nt ass e nt f or ms a n d a d ult 
c o nse nt f or ms will be de vel o pe d wit h o versi g ht fr o m l ocal g o v er ni n g i nstit uti o nal re vie w 
b oar ds (I R Bs)/i n de pe n d e nt et hics c o m mittees (I E Cs) (see A p pe n di x 3 ). T here is n o u p per 
a ge li mit f or st u d y partici pa nts; h o we ver, partici pa nts are e x cl u de d if t he y resi de i n a 
n ursi n g h o me or de pe n d e nt care t y pe -facilit y, or if t he y h a ve a n y c o m or bi dities 
ass ociate d wit h c o m plicate d U TI. T h us, a n y p artici pa nts > 7 5 y ears of a ge will o nl y b e 
eli gi ble f or t he st u d y if t he y are resi di n g i n de pe n d e ntl y.  
I n or der t o ma xi miz e t he efficie n c y of t his st u d y w hile mi ni mizi n g disc o mf ort a n d 
i nc o n ve nie nce t o partici p a nts c o nse nti n g t o t his pr ot oc ol, a G S K S R T will m o nit or 
bli n de d safet y data i nstrea m, w hile a Micr o bi ol o g y Re vie w Tea m will m o nit or bli n de d 
ur o pat h o ge n i de ntificati o n a n d s usce pti bilit y data i nstrea m, i ncl u di n g t h e e nr oll me nt rate 
of partici pa nts wit h a q ualif yi n g bact erial ur o p at h o ge n at Baseli ne a n d t h e resista nce 
pr ofile of ur o p at h o ge ns. F or details o n t hese re vie w tea ms, refer t o A p pe n di x 3 . I n 
a d diti o n, a n I n d e pe n d e nt Data M o nit ori n g C o m mittee (I D M C) will ma na ge t he i nteri m 
a nal ysis (I A) as descri be d i n Secti o n  9. 5 . 
4. 3.  
J u stifi c ati o n f or D o s e  
T he oral ge p oti daci n d ose i n t his st u d y is 1 5 0 0 m g BI D (t otal dail y d os e of 3 0 0 0 m g) f or 
5 da ys. A 5 -da y  d osi n g d urati o n is i n ali g n me nt wit h c urre nt treat me nt g ui d eli nes f or 
effic aci o us a nti bact erial treat me nt of u n c o m plicate d ac ute c ystitis i n w o me n, w hic h 
t y picall y ra n ges fr o m 3 t o 7 da ys [ G u pta , 2 0 1 1 b; NI C E , 2 0 1 9; E A U , 2 0 1 9]. T he safet y 
a n d t olera bilit y at t his or al d ose a n d d urati o n ha ve bee n e v al uate d i n P hase I st u dies a n d 
i n P hase II st u dies ( B T Z 1 1 6 7 0 4 a n d 2 0 6 8 9 9) (see Secti o n 5 of t he I B f or d etails). 
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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 
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). 
Based on GSK assessment of the limitations of the current acute cystitis efficacy model 
in rodents, the pyelonephritis model is considered to allow evaluation of antibacterial 
efficacy in a more robust UTI. 
Additionally, an in vitro study to determine the PK/pharmacodynamic (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, 

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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 
AUC24h steady-state PK parameters and qualifying Enterobacterales uropathogens who 
were microbiological successes at TOC, the plasma fAUC24h/MIC values ranged from 7 
to 90.5 and urine AUC24h/MIC ratios ranged from 1292 to 121,698. The participant with 
the lowest plasma fAUC/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 persistence at TOC. 
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, 2019]. 

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4.4. 
End-of-Study Definition 
A participant is considered to have completed study treatment if she has taken all doses 
of the randomly assigned study treatment and completed the TOC Visit. A participant is 
considered to have completed the study if she has completed all study visits including the 
Follow-up Visit. 
The end of the study is defined as the date of the last visit of the last participant in the 
study. 
5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Otherwise healthy participants are eligible to be included in the study only if all of the 
following criteria apply: 
Age  
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.  
Contraceptive use should be consistent with local regulations regarding the methods of 
contraception for those participating in clinical studies. 
• 
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.  

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Note:  Pregnancy testing requirements, contraceptive guidance, and WOCBP 
definitions are provided in Appendix 2 and requirements for pregnancy testing 
during and after study treatment are located in Appendix 8. 
• 
Additional requirements for pregnancy testing during and after study treatment are 
located in Appendix 8. 
• 
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy. 
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. 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
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 pressure or uncontrolled diabetes. 
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 

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• 
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, 
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). 

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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 ECG 
reading at Baseline or during the study treatment. 
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 cirrhosis or current unstable liver or biliary disease per 
investigator assessment defined by the presence of ascites, encephalopathy, 
coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent 
jaundice.  

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Note:  Stable noncirrhotic chronic liver disease (including Gilbert’s syndrome, 
asymptomatic gallstones, and chronic stable hepatitis B or C [e.g., presence of 
hepatitis B surface antigen or positive hepatitis C antibody test result]) is acceptable 
if the participant otherwise meets entry criteria. 
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 6.5.2. 
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. 
5.3. 
Lifestyle Considerations 
Participants will be requested to abstain from sexual activity from the Baseline Visit 
through the TOC Visit to prevent possible re-infection. 
5.3.1. 
Meals and Dietary Restrictions 
Study treatment should be taken after food consumption (a meal or a snack) and with 
water (see Section 6.1). 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized. 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, any protocol deviations and any 
SAEs. 
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. 

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6. 
STUDY TREATMENT 
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol. 
6.1. 
Study 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. 
• At the On-therapy Visit, whenever it is possible, the participant will have the 
pregnancy test performed at the study site. If the visit coincides with the 8th dose, the 
participant will take their next dose of study treatment at the study site after negative 
pregnancy test results are confirmed. 
• Before the On-therapy Visit, if the requirement for the single pregnancy test to be 
done between dose 4 and dose 8 cannot be done at the study site due to availability of 
open clinic hours and the investigator considers the participant reliable to accurately 
perform the study-provided pregnancy test at home will be instructed to do so. If the 
pregnancy test is negative, those participants will be instructed to take their next dose 
of study treatment at home via text or by study site staff before going to the study site 
for their On-therapy Visit. 
 
Note:  The On-therapy Visit should be scheduled to support completion of the postdose 
ECG within the protocol-defined window. Also, in WOCBP, the high sensitivity 
pregnancy test must be performed and show negative results at the latest before Dose 8 of 
study treatment is taken.  

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Study 
Treatment 
Name: 
Gepotidacin 
Placebo 
(Matched to 
Nitrofurantoin) 
Nitrofurantoin 
Placebo 
(Matched to 
Gepotidacin) 
Type: 
Drug 
Drug 
Drug 
Drug 
Dose 
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) 

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6.2. 
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 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 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 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. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
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 Section 1.3. 
Returned study treatment should not be re-dispensed to other participants. 
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. In 
order to maintain study 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 
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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. 
A participant may continue in the study if that participant’s treatment 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 Statistical Data Analysis Center (SDAC) will be unblinded for the IA 
(Section 9.5). 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. 
6.4. 
Study Treatment Compliance 
• When participants are dosed at the study site during the Baseline and On-therapy 
Visits, they will take their study treatment when directed by the investigator or 
designee, under medical supervision. The date and time of each 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 treatment 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 

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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. Study treatment start and stop dates, 
including dates for study treatment delays, will also be recorded in the eCRF. 
6.5. 
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. 
6.5.1. 
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 9. 
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 9. As described in Appendix 9, 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. 
6.5.2. 
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. 

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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 9. 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 9.  
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 9, 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. 
6.6. 
Dose Modification 
The study design does not allow for dose modifications. 
6.7. 
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. 

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7. 
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Treatment 
In rare instances, it may be necessary for a participant to permanently discontinue 
(definitive discontinuation) study treatment. If study treatment is definitively 
discontinued, the participant will remain in the study to be evaluated for safety and 
efficacy. See the SoA (Section 1.3) for data to be collected at the time of discontinuation 
of study treatment and follow-up and for any further evaluations that need to be 
completed. 
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 Section 1.3). 
7.1.1. 
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 Algorithm A or Algorithm B. 
• 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.  

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Algorithm A: Phase III Liver Chemistry Stopping and Increased Monitoring 
Algorithm 
 
Abbreviations: ALT = alanine transaminase; INR = international normalized ratio; SAE = serious adverse event; ULN = 
upper limit of normal. 
Refer to Appendix 10 for required Liver Safety Actions and Follow-up Assessments.  

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Algorithm B: Phase III Liver Chemistry Increased Monitoring Algorithm with 
Continued Therapy for ALT 3 × ULN but <8 × ULN 
 
Abbreviations: ALT = alanine transaminase; bili = bilirubin; INR = international normalized ratio; SAE = serious adverse 
event; ULN = upper limit of normal. 
Refer to Appendix 10 for required Liver Safety Actions and Follow-up Assessments.  
7.1.2. 
QTc Stopping Criteria 
A participant who meets the bulleted criteria based on the average of 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 patients 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 
 

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• 
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 the average of triplicate ECG readings obtained over a 
brief (e.g., 5- to 10-minute) recording period.  
7.1.3. 
Rechallenge 
7.1.3.1. 
Study Treatment Restart or Rechallenge After Liver Stopping Criteria 
Met 
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed. 
7.1.4. 
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 8.3.7). 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
• 
A participant may withdraw from the study at any time at 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, she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records. 

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• 
At the time of discontinuing from the study, if possible, an early withdrawal visit 
should be conducted, as shown in the SoA (Section 1.3). See the SoA for data to be 
collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 
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 SoA in Section 1.3), 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. 
7.3. 
Lost to Follow-Up 
A participant will be considered lost to follow-up if 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, she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up.  
Discontinuation of specific sites or of the study as a whole are handled as part of 
Appendix 3. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
• 
Study procedures and their timing are summarized in the SoA (Section 1.3).  
• 
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 the SoA, 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 

T M F -1 3 8 1 7 7 3 7  
C O N FI D E N TI A L  
 
 
 
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5 7  
 
scree ni n g l o g t o rec or d details of all partici pa nts s cree n e d a n d t o c o nfir m eli gi bilit y 
or rec or d reas o ns f or s cree ni n g fail ure, as a p plica ble.  
•  
Pr oce d ures c o n d ucte d as part  of t he partici pa nt’s r o uti ne cli nical ma na ge m e nt (e. g., 
bl o o d c o u nt) a n d o btai ne d bef ore si g ni n g of I C F ma y b e utilize d f or scree ni n g or 
baseli ne p ur p oses pr o vi de d t he pr oce d ure m et t he pr ot oc ol -s pecifi e d criteria a n d was 
perf or me d wit hi n t he ti me fra m e d efi ne d i n t he S o A.  
•  
Prescree ni n g acti vities ma y b e c o n d u cte d, i ncl u di n g a prescree ni n g i nf or me d c o nse nt 
a n d uri ne testi n g, as f urt h er detaile d i n t he S R M. T he re q uir e d baseli ne uri ne 
s peci me n ma y be c ollect e d as part of a n o pti o nal prescree ni n g pr ocess, if n ot alrea d y 
part of sta n dar d of care, a n d is f urt her detaile d i n t he S R M. T his s peci me n ca n be 
use d f or t he re q uire d b as eli ne pr oce d ures of t h e dia g n osis of pres u m pti ve ac ute 
c ystitis a n d pre g n a nc y testi n g.  
•  
T he ma xi m u m a m o u nt of bl o o d c ollecte d fr o m eac h p artici pa nt o ver t h e d urati o n of 
t he st u d y, i ncl u di n g a n y e xtra assess me nts t hat ma y b e re q uire d, will n ot e x cee d 
2 0 0  m L.  
•  
Re peat or u nsc h e d ule d sa m ples ma y be t a ke n f or safet y reas o ns or f or tec h nical 
iss ues wit h t he sa m ples. 
•  
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. 
•  
Eac h treat me nt da y will be assesse d o v er 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 S R M. 
T he st u d y will c o m pri se t he f oll o wi n g 4 pla n ne d st u d y visits: 
N ote:  F or all st u d y visits, t o mi ni mize t he a m o u nt of ti me t hat partici pa nts s pe n d at 
t he cli nic, e C o nse nt ma y be utilize d a n d re m ote c ollecti o n of st u d y-relate d data ma y 
be o btai ne d as des cri be d i n t he S R M. T h us, s o me visit data ma y be c ollecte d t hr o u g h 
a c o m bi nati o n of tele me dici ne a n d o n -site visits. C ollecti o n of i nf or mati o n via 
tele me dici ne will be perf or me d o nl y w here l ocal r e g ul ati o ns per mit. 
•  
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 i n t he S o A ( Secti o n 1. 3 ), 
i ncl u di n g t he f oll o wi n g: 
•  
Pretreat me nt bas 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  8. 1. 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 8. 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 nts will 
be ra n d o ml y assi g ne d t o a st u d y tr eat me nt, a s des cri be d i n Secti o n 6. 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 Secti o n  1. 3 . A n y A Es or cli nicall y si g nifica nt 
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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 u e nt t o a d mi nistrati o n of t he 
first d ose at t he st u d y site, partici pa nts will self-a d mi nister d oses as o ut patie nts 
t hereafter, be gi n ni n g wit h t he sec o n d d ose. ( 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 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  1. 3 ); 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 partici pa nt a n d als o t he a vaila bilit y of t h e st u d y site staff.  
•  
O n -t her a p y ( D a y 2 t o 4) Visit: Partici pa nts will be i nstr ucte d to 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 t he S o A 
( Secti o n 1. 3 ), 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 site. 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 o se 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:   T h e 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 E C G wit hi n t he pr ot oc ol -defi ne d wi n d o w. Als o, 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 os e 8 of st u d y treat me nt is ta ke n.  
•  
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  8. 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  8. 1. 3. 1  a n d A p pe n di x  6 . 
 
 
•  
Pre g n a nc y testi n g, as r e q uire d, after D ose 4 a n d b ef ore D ose 8. Refer t o 
A p pe n di x 8  f or details. 
•  
Partici pa nts will re mai n at t he st u d y site u ntil a p pr o xi mat el y 2 t o 4 h o urs 
p ost d ose. A tri plicate E C G will be perf or me d at a p pr o xi matel y 2 h o urs 
p ost d ose, as detaile d i n Secti o n 1. 3 . 
•  
T O C ( D a y 1 0 t o 1 3) Visit : Partici pa nts 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. 
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Assess me nts will be perf or me d as s h o w n i n t he S o A ( Secti o n 1. 3 ), 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 escri be d i n 
Secti o n  8. 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  8. 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 nts 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 Secti o n 1. 3 , 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 prece 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  8. 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  8. 1. 3. 1  a n d A p pe n di x  6 . 
 
 
 
•  
Partici pa nts 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 per t he i n v esti gat or’s j u d ge m e nt.  
8. 1.  
Effi c a c y A s s e s s m e nt s  
8. 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 (s u ccess/fail ure) is a meas ure of t he o verall efficac y res p o nse. A 
t hera pe utic s u ccess r efers t o partici pa nts w h o ha ve bee n dee me d b ot h a “ mi cr o bi ol o gical 
s uccess” (see Secti o n 8. 1. 2. 1 ) a n d a “cli nical s uc cess” (see Secti o n 8. 1. 3. 1 ). All ot her 
c o m bi nati o ns ( ot her t ha n cli nical s uccess + micr o bi ol o gical s uc cess) will b e dee me d 
fail ures f or t h era p e utic res p o nse. 
T hera p e utic r es 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.  
8. 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 bt ai ne d fr o m all ra n d o miz e d partici pa nts 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 desi g nate d ce ntral 
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laboratory(ies). For inclusion in the micro-ITT Population, a baseline qualifying bacterial 
uropathogen is required as defined in Appendix 4; for inclusion in the micro-ITT NTF-S 
Population, the baseline qualifying uropathogen must also be susceptible to 
nitrofurantoin. At the On-therapy, TOC, and Follow-up Visits, a clean-catch midstream 
urine sample will be obtained and sent to a designated central laboratory(ies) for Gram 
stain, quantitative bacteriological culture, and in vitro antimicrobial susceptibility testing. 
Identification and susceptibility testing of isolates recovered from urine specimens at all 
visits will also be conducted at a designated central laboratory(ies). Additional tests, as 
needed, to further characterize recovered isolates will also be performed by a designated 
central laboratory(ies). Instructions for sample collection, processing, and shipment are 
provided in the SRM and the laboratory manual. The study site should follow the 
Microbiology Procedures section of the laboratory manual to minimize potential 
contamination of the specimens. 
8.1.2.1. 
Microbiological Outcome and Response 
Only those participants who have a qualifying bacterial uropathogen (defined in 
Appendix 4) identified at Baseline will be evaluated for microbiological outcome and 
response by baseline qualifying uropathogen for the primary efficacy endpoint. The 
microbiological outcome and response to study treatment will be determined 
programatically for each participant/uropathogen prior to breaking of the study blind. 
The microbiological outcome by baseline qualifying uropathogen is determined by 
comparing the baseline culture results to the culture results at each subsequent visit (see 
Table 2, Table 3, and Table 4 for baseline qualifying uropathogen outcomes). The 
corresponding microbiological response (success or failure) “by uropathogen” is then 
assigned, as shown in Table 3 and Table 4. 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 5. 
Microbiological outcome criteria for new qualifying uropathogens (i.e., uropathogens not 
identified at Baseline) are defined by visit in  
Table 6, Table 7, and Table 8. 

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Table 2 
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 3 
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 4 
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 5 
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 6 
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 7 
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 8 
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 
 
8.1.3. 
Clinical Evaluation 
8.1.3.1. 
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 1.3) 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 

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time points for each participant, on all occasions, whenever possible. The score will be 
used to programmatically determine the clinical outcome at the On-therapy Visit 
(Table 9) and the clinical outcome and response (success or failure) at the TOC Visit 
(Table 10) and the Follow-up Visit (Table 11).  
Table 9 
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 10 
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 11 
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 7 3 7  
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6 9  
 
8. 2.  
S af et y A s s e s s m e nt s  
Pla n ne d ti me p oi nts f or all safet y assess me nts are pr o vi de d i n t he S o A ( Secti o n 1. 3 ). 
8. 2. 1.  
P h y si c al E x a mi n ati o n s  
•  
A p h ysic al e x a mi nati o n will be perf or me d at t he ti me p oi nts i n dicate d i n t he 
S o A ( Secti o n  1. 3 ).  
•  
At Baseli ne, t h e e x a mi nati o n will i ncl u de assess me nts of t he res pir at or y, C V, 
a b d o mi nal, gastr oi ntesti nal, ne ur ol o gical, a n d ur o ge nital s yste ms. Hei g ht a n d 
wei g ht will o nl y be me as ure d a n d rec or de d at t he Baseli ne Visit ( bef ore 
d osi n g ). 
•  
At t he T O C Visit, t he p h ysical e x a mi nati o n ma y be s y m pt o m directe d a n d is 
o nl y re q uire d if i n dicat e d f or a s pecific partici pa nt.  
•  
I n v esti gat ors s h o ul d pa y s pecial atte nti o n t o cli nical si g ns relate d t o pre vi o us 
seri o us ill nesses. 
•  
Cli nicall y si g nifica nt c ha n ges fr o m baseli ne or cli nicall y si g nifica nt ne w cli nical 
si g ns will be re p orte d as A Es. 
8. 2. 2.  
Vit al Si g n s  
•  
Vital si g ns will be meas ure d at t he ti me p oi nts i n dicate d i n t he S o A 
( Secti o n 1. 3 ). 
•  
Vital si g ns will be meas ure d i n a se mi -s u pi ne p ositi o n after 5 mi n utes rest a n d 
will i ncl u de te m perat ure, s yst olic a n d diast olic bl o o d press ure, a n d p ulse rat e.  
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• 
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. 
8.2.3. 
Electrocardiograms 
• 
Electrocardiograms will be performed at the time points indicated in the SoA 
(Section 1.3). 
• 
Triplicate 12-lead ECGs (over an approximate 5- to 10-minute period) will be 
performed using an ECG machine that automatically calculates the heart rate 
and measures PR, QRS, QT, and QTc intervals. Refer to Section 7.1.2 for QTc 
withdrawal criteria and additional QTc readings that may be necessary. 
• 
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.  
• 
Triplicate ECGs will be performed at Baseline.  
• 
For the first approximately 1200 participants enrolled, On-therapy Visit 
triplicate ECGs will also be obtained. The On-therapy ECGs will be collected 
approximately 2 hours postdose (i.e., expected time of maximum concentration; 
ECG collection should ideally be within approximately 1.5 hours postdose to 
4 hours postdose). After the first approximately 1200 participants have triplicate 
ECGs performed at On-therapy, the ECG collection at this visit is no longer a 
protocol requirement. 
• 
If any additional ECGs are performed during the study (if deemed necessary by 
the investigator), those may be collected as a single ECG; however, if that initial 
single reading shows QTc prolongation, then triplicate ECGs should also be 
performed (see Section 7.1.2). 
• 
If clinically significant changes occur during the study, they will be reported as 
AEs. 
• 
Electrocardiograms will be reviewed locally by the investigator for safety 
purposes. Electrocardiograms will be centrally overread for the data analysis. 
8.2.4. 
Clinical Safety Laboratory Assessments 
• 
Refer to Appendix 8 for the list of clinical laboratory tests to be performed and 
to the SoA (Section 1.3) for the timing and frequency.  
• 
The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the eCRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant’s condition. 

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• 
All laboratory tests with values considered clinically significantly abnormal 
during participation in the study should be repeated until the values return to 
normal or baseline or are no longer considered significantly abnormal by the 
investigator or medical monitor.  
• 
If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified. 
• 
All protocol-required laboratory assessments, as defined in Appendix 8 must be 
conducted in accordance with the laboratory manual and the SoA. 
8.3. 
Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Appendix 11. 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant’s legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study, 
or that caused the participant to discontinue the study treatment or from the study (see 
Section 7). 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
• 
All SAEs will be collected from the signing of the informed consent form until 
the Follow-up Visit at the time points specified in the SoA (Section 1.3).  
• 
All AEs will be collected from the start of treatment until the Follow-up Visit at 
the time points specified in the SoA (Section 1.3). 
• 
Medical occurrences that begin before the start of study treatment but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the eCRF and not the AE section. 
• 
All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 11. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available. 
• 
Investigators are not obligated to actively seek AEs or SAEs after the conclusion 
of the study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the 
study, and he/she considers the event to be reasonably related to the study 
treatment or study participation, the investigator must promptly notify the 
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8.3.2. 
Method of Detecting AEs and SAEs 
• 
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 11. 
• 
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. 
8.3.3. 
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 8.3.7), will be followed until the event is resolved, stabilized, 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
Further information on follow-up procedures is given in Appendix 11. 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the investigator to the sponsor of a 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. 
• 
For all studies except those utilizing medical devices, 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 a 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. 
8.3.5. 
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 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. 

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8.3.6. 
Cardiovascular and Death Events 
For any CV events detailed in Appendix 11 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. 
8.3.7. 
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 2.3.1), 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 11. 
8.4. 
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 
the case report form (CRF). 

T M F -1 3 8 1 7 7 3 7  
C O N FI D E N TI A L  
 
 
 
2 1 2 3 9 0  
 
7 4  
 
Decisi o ns re gar di n g d ose i nterr u pti o ns or m o dificati o ns will be ma de b y t h e i n vesti gat or 
i n c o ns ultati o n wit h t he me dical m o nit or base d o n t he cli nical e val uati o n of t he 
partici pa nt.  
8. 5.  
P h ar m a c o ki n eti c s  
P har mac o ki netics are n ot e val uate d i n t his st u d y.  
8. 6.  
P h ar m a c o d y n a mi c s  
P har mac o d y na mics are n ot e val uate d i n t his st u d y.  
8. 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 
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 still 
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 ent 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 . 
8. 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.  
8. 9.  
I m m u n o g e ni cit y A s s e s s m e nt s 
T his secti o n is n ot a p plica ble.  
9.  
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. 
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9.1. 
Statistical Hypotheses 
The study is designed to demonstrate that gepotidacin administered orally is noninferior 
compared to 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 bacterial uropathogen at Baseline that is 
susceptible to nitrofurantoin. Microbiological success is defined as eradication (i.e., 
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.  
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% 
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 9.5. 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 9.5. 

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9.2. 
Sample Size Determination 
9.2.1. 
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 12. 
Table 12 
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 
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 
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. 
9.2.2. 
Sample Size Sensitivity 
Sensitivity of the sample size has been explored considering various therapeutic success 
rates. Table 13 and Table 14 show the minimum power under various assumptions of 

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“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 13 
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% 
 
Table 14 
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% 
 
9.3. 
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. 

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Population 
Description 
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. 
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. 

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Population 
Description 
Safety Population 
All randomized participants who receive at least 1 dose of study 
treatment. Participants will be analyzed according to their actual 
treatment received. 
 
9.4. 
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. 
9.4.1. 
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. 

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9.4.2. 
Efficacy Analyses 
Estimands/Endpoints 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 3. 
• 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. 

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Estimands/Endpoints Statistical Analysis Methods 
• 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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Estimands/Endpoints 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, 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 8.1.3.1). 
• 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 8.1.2.1). 
• 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 7 3 7  
C O N FI D E N TI A L  
 
 
 
2 1 2 3 9 0  
 
8 3  
 
E sti m a n d s/ E n d p oi nt s  St ati sti c al A n al ysi s M et h o d s  
 
9. 4. 3.  
S a f 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 Diseases 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 sti m a n d s/ E n d p oi nt s  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 wal fr o m tr e at m e nt, as saf ety will b e assess e d at all 
p ost b as eli n e ass ess m ents irres p ectiv e of w h et h er t h e p articip a nt 
c o m pl et ed t he tr eat m e nt. 
C CI

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Estimands/Endpoints Statistical Analysis Methods 
• The number and percentage of treatment-emergent AEs, study 
treatment-related AEs, deaths, SAEs, and AEs leading to study 
treatment or study withdrawal will be provided. 
• Treatment-emergent AEs will be summarized by severity. 
• Change from baseline over time in laboratory parameters, ECGs, 
and vital signs will be summarized with descriptive statistics.  
Note:  Electrocardiograms will be centrally overread for the data 
analysis. 
• The frequency of laboratory abnormality events along with the shift 
from baseline to the worst-case postbaseline value will be 
provided. Abnormal liver chemistry results will be determined 
using increases above the upper limit of normal. Change from 
baseline values will be summarized with descriptive statistics. 
• The severity of specified AEs and laboratory abnormalities will be 
graded according to the modified DMID toxicity grading system 
(Appendix 13). Data will be tabulated and reported by absolute 
grade for Grades 3 and higher and shift tables, as appropriate. 
• Adverse events of special interest will include CV, gastrointestinal, 
and C. difficile infection or colitis events. In addition, AEs 
associated with acetylcholinesterase inhibition are also considered 
special interest. As described in the RAP, manual and 
programmatic reviews of AEs/preferred terms will be used to 
assess these events.  
 
9.5. 
Interim Analysis 
One IA is planned to assess either both efficacy 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 IDMC members will include at least 3 independent 
experts, 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 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. 

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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 is 
reached at the IA and the study is stopped early, data collected between the IA data cut 
and IA decision are considered overrun. Overrun data will be pooled with the IA data to 
repeat the primary efficacy analysis as sensitivity analysis. 
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. 
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. 
9.6. 
Data Monitoring Committee or Other Review Board 
This study will have an IDMC as described in Section 9.5. 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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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
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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10.2. 
Appendix 2: Contraceptive Guidance and Collection of 
Pregnancy Information 
10.2.1. 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below). 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study treatment, additional evaluation should be 
considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
• 
Documented hysterectomy 
• 
Documented bilateral salpingectomy 
• 
Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., mullerian agenesis, androgen insensitivity), investigator 
discretion should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s: review of the 
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, confirmation with 
more than one FSH measurement is required.  
• 
Females on HRT and whose menopausal status is in doubt will be required to 
use 1 of the non-estrogen hormonal 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. 
• 
Refer to Appendix 8 for pregnancy testing requirements. 

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10.2.2. 
Contraception Guidance: 
Refer to Appendix 8 regarding pregnancy testing for female participants at 
Baseline (Day 1) and associated pretreatment contraception and abstinence requirements. 
Female participants who enter the study using contraception must continue to do so 
throughout the study. 
As described in Section 5.3, participants will be requested to abstain from sexual activity 
from the Baseline Visit through the TOC Visit to prevent possible re-infection. 
• 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
• 
Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per 
year when used consistently and correctly 
• 
Implantable progestogen-only hormone contraception associated with inhibition of 
ovulationc 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS)c 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
• 
Note: Vasectomized partner is a highly effective contraceptive method provided that 
the partner is the sole sexual partner of the woman of childbearing potential and the 
absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. Spermatogenesis cycle is approximately 90 days. 
• 
Highly Effective Methodsb That Are User Dependent Failure rate of <1% per year when 
used consistently and correctly 
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationc 
• 
oral 
• 
intravaginal 
• 
transdermal 
• 
injectable 
• 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
• 
oral 
• 
injectable 
• 
Sexual abstinence 
• 
Note: 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 treatment. 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. 
a. 
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 

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b. 
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
c. 
Male condoms must be used in addition to hormonal contraception. If locally required, in accordance with 
Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited to those 
which inhibit ovulation as the primary mode of action. 
 
Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception. Male 
condom and female condom should not be used together (due to risk of failure with friction). 
 
10.2.3. 
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.  
• 
The initial 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 (occurring at <22 weeks gestational age) or still birth 
(occurring at >22 weeks gestational age) 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 11. 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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10.3. 
Appendix 3: Regulatory, Ethical, and Study Oversight 
Considerations 
10.3.1. 
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/EC* 
• 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. 
10.3.2. 
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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10.3.3. 
Informed Consent/Assent Process 
• 
The investigator or his/her representative will explain the nature of the study to 
the participant or 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). 
GSK (alone or working with others) may use participant’s coded study data and samples 
and other information to carry out this study; understand the results of this study; learn 
more about gepotidacin or about the study disease; publish the results of these research 
efforts; work with government agencies or insurers to have gepotidacin approved for 
medical use or approved for payment coverage.  
10.3.4. 
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 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 who will be required to give 
consent for their data to be used as described in the informed consent.  

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• 
The participant must be informed that 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. 
10.3.5. 
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. 
10.3.6. 
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. 
• 
The procedures and timing for public disclosure of the protocol and results 
summary and for development of a manuscript for publication for this study will 
be in accordance with GSK policy. 
• 
GSK intends to make anonymized participant-level data from this trial available 
to external researchers for scientific analyses or to conduct further research that 
can help advance medical science or improve patient care. This helps ensure the 
data provided by trial participants are used to maximum effect in the creation of 
knowledge and understanding. 

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10.3.7. 
Data Quality Assurance 
• 
All participant data relating to the study will be recorded on printed 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.  
• 
Monitoring details describing strategy (e.g., risk-based initiatives in operations 
and quality such as Risk Management and Mitigation Strategies and Analytical 
Risk-Based Monitoring), methods, responsibilities and requirements, including 
handling of noncompliance issues and monitoring techniques (central, remote, 
or on-site monitoring) are provided in the Monitoring Plan. In addition, refer to 
Appendix 5 for details regarding allowed revisions to study conduct and/or 
monitoring due to COVID-19. 
• 
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. 
• 
The sponsor assumes accountability for actions delegated to other individuals 
(e.g., contract research organizations). 
• 
Study monitors will perform ongoing source data verification to confirm that 
data entered into the eCRF by authorized 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. In addition, refer to Appendix 5 for details 
regarding allowed revisions to study conduct and/or monitoring due to 
COVID-19. 
• 
Records and documents, including signed ICF, 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.  
10.3.8. 
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. 

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• 
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. 
10.3.9. 
Study and Site Start and 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 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform 
the investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified 
by the applicable regulatory requirements. The investigator shall promptly inform the 
participant and should assure appropriate participant therapy and/or follow-up. 
10.3.10. 
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 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. 

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10.4. 
Appendix 4: Algorithm for Determining Qualifying 
Uropathogens 
In addition to other criteria indicated in Section 9.3, to be included in the micro-ITT 
Population, participants must have a qualifying bacterial uropathogen (defined in 
Figure 2) 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 2, with additional algorithm details 
provided in the RAP. 
Figure 2 
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 
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. 
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. 
 

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10.5. 
Appendix 5: COVID-19 Protocol Information 
10.5.1. 
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. 
 
10.5.2. 
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 7 3 7  
C O N FI D E N TI A L  
 
 
 
2 1 2 3 9 0  
 
9 8  
 
1 0. 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 7 3 7  
C O N FI D E N TI A L  
 
 
 
2 1 2 3 9 0  
 
9 9  
 
 
C CI

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

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10.8. 
Appendix 8: Clinical Laboratory Tests 
• 
The tests detailed in Table 15 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 5 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. 
Pregnancy Testing 
• 
Refer to Section 5.1 Inclusion Criteria for screening pregnancy criteria. 
• 
Women of childbearing potential (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). 
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 Section 10.2.2 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 (in Section 10.2.2) 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 

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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. 

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Table 15 
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 
Note: See text earlier in this section for pregnancy test sensitivity 
requirements and additional pregnancy testing details. 
• 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; 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 7.1 and Appendix 10. 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. 
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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10.9. 
Appendix 9: 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 
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. 
a. 
Check within each local country to assess if other generic names apply. 
Note: See also Section 6.5.1 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 6.5.2 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 6.5.2 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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10.10. 
Appendix 10: 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 8xULN 
ALT Increase 
ALT 5xULN but <8 x ULN persists for 2 weeks 
ALT 3xULN but <5 x ULN persists for 4 weeks 
Bilirubina,b 
ALT 3xULN and bilirubin 2 x ULN (>35% direct bilirubin)  
INRb  
ALT 3xULN and INR>1.5 
Cannot 
Monitor 
ALT 5xULN but <8 x ULN and cannot be monitored weekly for 2 weeks 
ALT 3xULN 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 
 
Only in those with underlying chronic 
Hepatitis B at study entry (identified 
by positive hepatitis B surface 
antigen) and quantitative hepatitis B 
DNA 
• Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend 
• Obtain blood sample for pharmacokinetic 
(PK) analysis, within 24 hours after last 
dosee 
• Serum creatine phosphokinase and 
lactate dehydrogenase 

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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 INR) 
and perform liver event follow-up 
assessments within 24 hours 
• Monitor participant 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 INR) 
and perform liver event follow-up 
assessments within 24 to 72 hours  
• Monitor participant 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 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; PCR=polymerase chain reaction; 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 which 
may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding studies of 
hepatic impairment or cirrhosis); the INR 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; hepatitis C RNA; 
cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, heterophile 
antibody or monospot testing); and hepatitis E IgM antibody. In those with underlying chronic hepatitis B at study 
entry (identified by positive hepatitis B surface antigen) quantitative hepatitis B DNA and hepatitis delta antibody. 
If hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of hepatitis D RNA virus 
(where needed) [Le Gal, 2005]. 
e. 
PK sample may not be required for participants known to be receiving placebo or noncomparator treatments. 
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
the PK blood sample draw in 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. 
References 
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, et al. 
Pharmacokinetics of acetaminophen-adduct in adults with acetaminophen overdose and 
acute liver failure. Drug Metab Dispos 2009; 37:1779-1784. 
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, et al. Quantification of 
hepatitis delta virus RNA in serum by consensus real-time PCR indicates different 

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patterns of virological response to interferon therapy in chronically infected patients. J 
Clin Microbiol. 2005;43(5):2363-2369. 

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10.11. 
Appendix 11: Adverse Events: Definitions and Procedures 
for Recording, Evaluating, Follow-up, and Reporting 
10.11.1. 
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. 
 
10.11.2. 
Definition of 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: 
o Results in death. 
o 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. 
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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Results in persistent or significant 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. 
Is a congenital anomaly/birth defect 
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 treatment to 
prevent one 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. 
 
10.11.3. 
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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10.11.4. 
Recording and Follow-Up of 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 
[DMID, 2007a], with the exception of serum creatinine adolescent laboratory data, 
which 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 
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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 post-
mortem 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. 
 
10.11.5. 
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 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 site can report this information to the medical 
monitor or SAE coordinator by telephone. 

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• 
Contacts for SAE reporting can be found in the Study Reference Manual. 

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10.12. 
Appendix 12: Genetics 
USE/ANALYSIS OF DNA 
• 
Genetic variation may impact a participant’s response to study treatment, 
susceptibility, severity and progression of disease. Variable response to study 
treatment 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 one or more 
candidate genes or the analysis of genetic markers throughout the genome [or 
analysis of the entire genome] (as appropriate). 
• 
Additional analyses of DNA samples may be conducted 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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10.13. 
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-power 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 7 3 7  
C O N FI D E N TI A L  
 
 
 
2 1 2 3 9 0  
 
1 2 5  
 
1 0. 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 mi 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  
H R T  
h or m o nal re place me nt t h era p y  
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  
C CI

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m 
meter 
MDR 
multidrug-resistant 
ME 
Microbiologically Evaluable 
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 NTF 
NTF-S 
susceptible to NTF 
PD 
pharmacodynamic 
PK 
pharmacokinetic  
QTc 
corrected QT interval 
QTcB 
QT interval corrected for heart rate according to Bazett’s 
formula 
QTcF 
QT interval corrected for heart rate according to 
Fridericia’s formula  
RAP 
reporting and analysis plan  
SAE 
serious adverse event 
SDAC 
Statistical Data Analysis Center 
SoA 
Schedule of Activities 
SRM 
Study Reference Manual  
SRT 
Safety Review Team 
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 7 3 7  
C O N FI D E N TI A L  
 
 
 
2 1 2 3 9 0  
 
1 2 7  
 
1 0. 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 (i.e., 
Pr ot oc ol A me n d me nt 3) is l ocate d directl y b ef ore t he Ta ble of C o nte nts.  
A me n d me nt 2   1 4 -A P R -2 0 2 1  
T his gl o bal a me n d m e nt was 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 O VI D-1 9; 
i nc or p orate d p ast a d mi nistrati ve letters t o t he sites; clarifie d esti ma n d te xt; 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 ntar y a nal ysis, w hic h will be detaile d i n t he R A P; i ncrease d 
t he pla n ne d t otal e nr oll m e nt p o p ulati on; clarifie d O n -t hera p y Visit electr ocar di o gra ms 
will be c ollecte d i n t he first a p pr o xi matel y 1 2 0 0 p artici pa nts; i nc or p orate d u p dates per 
t he m ost rece nt I B versi o n 0 7; a n d gl o ball y re place d “i nter ve nti o n” wit h “treat me nt.” T h e 
a me n d me nt als o i ncl u des a d di ti 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  
3 O bj ectiv es a n d 
Esti m a n ds/ E n dp oi nts  
T a bl e 1 Esti m a nd for 
t h e S ec on d ary 
E n d poi nts  
9. 4.1 G en er al 
C o nsi d er atio ns  
9. 4.2 Efficacy 
A n alysis  
S e p arat e d esti m an d text fr o m t h e 
e n dp oi nt t ext, r evis e d t h e 
esti m a n d la n gu ag e to i ncl ude t he 
5  c o m p on ents per r ec ent I C H 
g ui d eli nes o n esti m an ds, a dd e d 
esti m a n d d escripti ons for t he 
s ec o nd ary en d poi nts 
T o pr ovi de ex pa nd e d d et ails o n 
t h e pri m ary a n d sec on d ary 
esti m a n ds  
Sy n o psis  
3 O bj ectiv es a n d 
Esti m a n ds/ E n dp oi nts  
F or t h e sec o nd ary ( up d at e d o nly 
i n t h e Sy no psis) a nd expl orat ory 
o bj ectiv es, a n a dditi o n al obj ectiv e 
a n d e nd p oi nt w er e a dd e d t o e ac h 
s ecti o n t o exa mi n e th e cli nic al 
r es p o nse i n fe m al e p articipa nts 
wit h ac ute cystitis wit h q ualifyi n g 
b act eri al ur o p at h og ens(s) at 
B as eli n e t hat all ar e s usce pti bl e t o 
nitr of ur ant oi n  
C o nsist e ncy with t he pri m ary 
o bj ectiv e p op ul atio n  
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Section # and Name 
Description of Change 
Brief Rationale 
Synopsis 
9.2.1 Justification of 
Sample Size 
Increased the total enrollment 
sample size to up to 2500 
participants 
To reflect the expected number of 
participants for full enrollment to 
support the required number of 
evaluable participants for the 
primary analysis 
1.2 Schema 
Revised On-therapy Visit to state 
Days 2 to 4 
Protocol consistency 
2.3.1 Risk 
Assessment 
5.2 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 17-DEC-2019 
Section 2.3.1 Risk 
Assessment 
5.2 Exclusion Criteria 
#21 
6.5.2 Prohibited 
Medications and 
Nondrug Therapies 
Section 10.9 
Appendix 9 
Removed exclusion for strong 
P-glycoprotein inhibitors 
Consistency with the most current 
Version 07 of the investigator’s 
brochure 
5.2 Exclusion Criteria 
#10 
Expanded text to include, “or 
preclude complete resolution of 
acute cystitis symptoms” 
Clarification purposes 
6.5 Concomitant 
Therapy 
Clarified that any antibiotic use 
within 6 months of the Baseline 
Visit should be recorded 
To support the study analysis 
6.5.1 Permitted 
Medications and 
Nondrug Therapies 
6.5.2 Prohibited 
Medications and 
Nondrug Therapies 
Section 10.9 
Appendix 9 
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  

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Section # and Name 
Description of Change 
Brief Rationale 
6.5.2 Prohibited 
Medications and 
Nondrug Therapies 
Section 10.9 
Appendix 9 
Added strong CYP3A4 inducers to 
the prohibited medications 
Alignment with preliminary results 
from a recently completed Phase I 
study  
Schedule of Activities 
8.2.1 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 2 
Schedule of Activities 
8.2.3 
Electrocardiograms 
Clarified the collection of 
electrocardiograms at the 
On-therapy Visit would be 
collected for the first 
approximately 1200 participants 
enrolled 
Consistency with the maximum 
planned sample size in protocol 
amendment 1 
8.2.3 
Electrocardiograms 
Clarified text for the collection of 
electrocardiograms, including the 
order of collection, repeated 
electrocardiograms, and the 
window for collection during the 
On-therapy Visit 
To support study conduct 
8.1.2.1 
Microbiological 
Outcome and 
Response 
Minor text clarifications were 
added to the outcome and 
response tables, and a new table 
(Table 5) was added to define 
participant-level microbiological 
outcomes and responses  
To provide clarification to support 
the planned statistical analyses 
and programming details 
8.1.3 Clinical 
Evaluation 
Subsections were added for the 
different clinical evaluations 
planned for primary and 
exploratory objectives, minor text 
clarifications were added to the 
outcome and response tables 
To provide clarification to support 
the planned statistical analyses 
and programming details 

T M F -1 3 8 1 7 7 3 7  
C O N FI D E N TI A L  
 
 
 
2 1 2 3 9 0  
 
1 3 0  
 
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  
Sc h e dul e of Activiti es  
8. 1.3. 3 Uri n ary Tr act 
I nf ectio n Activity 
I m p 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 pri oritiz 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  
8. 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  
A p p en dix 6 C li nic al 
Si g ns a n d Sy m pt o ms 
Sc or e for Ac ute 
Cystitis  
 
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 m e 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 o n 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 2, whic h will 
s u p port c o nsiste nt d ata c ollecti o n 
Sc h e dul e of Activiti es  
T hr o u gh o ut  
A p p en dix 5  
A d d ed text to all o w for e C ons e nt, 
t el e m e dici ne st udy-r el at e d d at a 
c oll ecti o n, coll ecti on of visit d at a 
as a co m bi n atio n of t ele m edici n e 
a n d o n -sit e visits, r e m ot e sourc e 
d at a v erific ati on, an d e C R F si g n -
off fl exibility f or i nv estig ators 
T o s u pp ort o n goi n g st u dy co n duct 
fr o m s af ety a nd o p er atio n al 
p ers p ectives d urin g th e C O VI D -1 9 
p a nd e mic  
9. 3 P o pul ati ons f or 
A n alys es  
Mi n or cl arific ati o ns to t he 
d escri pti o n of p op ul ati ons, 
i ncl u di n g u pd ates t o a nalyze p er 
r a n d o miz e d st udy tr eat m e nt, 
w h er e ap plic a ble  
C o nsist e ncy with t he pla n ned 
st atistic al an alysis a n d r eq uir e d 
o ut p uts  
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Section # and Name 
Description of Change 
Brief Rationale 
9.4.1 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 
9.4.2 Efficacy 
Analyses 
9.4.3 Safety Analyses 
Minor clarifications to the plans for 
analysis 
Consistency with the planned 
statistical analysis and required 
outputs 
2.3.1 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 
Where applicable, globally 
replaced “intervention” with 
“treatment” 
Consistency with the planned 
statistical analysis and required 
outputs 
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 
Minor editorial and document 
formatting revisions 
Minor, therefore, have not been 
summarized 
 
 

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Amendment 1  14-NOV-2019 
Overall Rationale for the Amendment:  This global amendment provided clarification 
on Inclusion Criteria 3 and 4, including no requirement for contraception use or 
abstinence within 14 days of study entry in women of childbearing potential (WOCBP) 
with a negative high sensitivity urine pregnancy test result at Baseline (Day 1), expanded 
the On-therapy Visit window, allowed flexible options for pregnancy testing and dose 
administration for the On-therapy Visit, and further defined the optimum window for 
pregnancy testing while participants were receiving study treatment. The amendment also 
included additional minor administrative edits. 
Section # and Name 
Description of Change 
Brief Rationale 
5.1 Inclusion Criteria 
Schedule of Activities 
Criterion 3, edited terminology to 
“large” for the presence of 
3+ leukocyte esterase 
To correct terminology for 
laboratory results 
5.1 Inclusion Criteria 
Schedule of Activities 
Appendix 6 
Criterion 4, edited female entry 
criterion for clarity, including that 
no current or prior contraception 
use or abstinence is needed in 
WOCBP with a negative high 
sensitivity urine pregnancy test 
result at Baseline (Day 1) 
To provide clarification on female 
participant requirements at study 
entry 
Synopsis 
Schedule of Activities 
4.1 Overall Design 
8 Study Assessments 
and Procedures 
Revised the study day range for 
the On-therapy Visit from “Day 2 
to 3” to “Day 2 to 4” and noted that 
each treatment day will be 
assessed over 24 hours based on 
the time of the first dose of study 
treatment 
To support study conduct 
Schedule of Activities 
8 Study Assessments 
and Procedures 
Updated the definition of the 
On-therapy Visit to be “1 to 
3 days” postrandomization 
Protocol consistency 
Schedule of Activities 
6.1 Study Treatments 
Administered 
8 Study Assessments 
and Procedures 
Indicated that, based on the 
opinion of the investigator, flexible 
options are allowed for pregnancy 
testing and dose administration for 
the On-therapy Visit 
To support study conduct 
Schedule of Activities 
8 Study Assessments 
and Procedures 
Revised the pregnancy test for 
WOCBP during study treatment to 
be performed “after Dose 4 and 
before Dose 8” 
To ensure the pregnancy test is 
performed within an optimum 
safety window and to support 

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Section # and Name 
Description of Change 
Brief Rationale 
Appendix 6 
testing to preferably occur at the 
study site 
9.4.2 Efficacy 
Analyses 
Moved the microbiological 
outcome for new qualifying 
uropathogens from secondary to 
exploratory 
Correction to the planned data 
analyses 
Throughout 
Expanded the definitions of 
microbiological and clinical 
success to include “specific to the 
disease under study” regarding 
the use of other systemic 
antimicrobials 
To further clarify which 
antimicrobials will affect success 
or failure in the analysis  
Throughout 
Minor editorial and document 
formatting revisions 
Minor, therefore, have not been 
summarized 
 

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11. 
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T M F -1 3 8 1 7 7 3 7  
C O N FI D E N TI A L  
 
 
 
2 1 2 3 9 0  
 
1 3 6  
 
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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.  
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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 
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