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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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1500 mg (2 × 750-mg tablets) gepotidacin (minimum steady-state urine 
AUC12h=2256 µg.h/mL). 
The gepotidacin dose and duration for this study were selected based on in vitro and 
in vivo studies including experimental animal pyelonephritis studies that simulated 
human PK exposures of gepotidacin to determine the efficacy of gepotidacin against 
isolates of E. coli, including MDR strains (see Section 4.2 of the IB for further details).  
Additionally, an in vitro study to determine the PK/PD characteristics of gepotidacin 
against E. coli (dose-fractionation and dose-ranging studies) indicate that AUC/MIC is 
the primary PK/PD index predictive of gepotidacin efficacy against E. coli. The 
magnitude of the ratio of free-drug AUC to MIC over 24 hours (fAUC/MIC) required to 
achieve net bacterial stasis as well as 1- and 2-log reductions in bacterial burden from 
Baseline across multiple E. coli isolates with gepotidacin MIC values ranging from 1 to 
4 µg/mL, were 34.5, 41.3, and 49.7, respectively.  
A set of duplicate 10-day hollow fiber infection model studies was also completed using 
E. coli isolate NCTC 13441 to determine the fAUC/MIC exposure of gepotidacin 
required to prevent the amplification of a resistant subpopulation. An inverted-U shaped 
function described the relationship between drug resistance amplification and fAUC, with 
fAUC values ≥549 preventing resistance amplification to gepotidacin for E. coli in the 
hollow fiber infection model for 10 days. This equates to an fAUC/MIC value ≥275 when 
applying the gepotidacin broth microdilution MIC of 2 µg/mL for E. coli 13441, as 
determined in this study.  
When taking the fAUC/MIC target of 275 for resistance suppression into consideration 
with the concentrations of gepotidacin in human urine measured in BTZ117351 
(minimum urine AUC12h=807 µg.h/mL; thus, minimum urine AUC over 24 hours 
[AUC24h]=1614 µg.h/mL) and applying an MIC value of 4 µg/mL, the minimum human 
urine AUC/MIC achieved for the 1500 mg oral BID dose exceeds the fAUC/MIC 
resistance suppression target of 275 by approximately 1.5-fold and 100% target 
attainment for a urine AUC/MIC target of 275 would be expected for participants with 
E. coli isolates with gepotidacin MICs ≤4 µg/mL following 1500 mg BID oral dosing.  
When applying the higher concentrations of gepotidacin in human urine measured in the 
Phase IIa study (206899; minimum urine AUC12h=2256 µg.h/mL; thus, 
AUC24h=4512 µg.h/mL) and applying a MIC value of 4 µg/mL, the minimum human 
urine AUC/MIC achieved for the 1500 mg oral BID dose further exceeds the fAUC/MIC 
resistance suppression target of 275 by approximately 4-fold and 100% target attainment 
for a urine AUC/MIC target of 275 would also be expected for participants with E. coli 
isolates with gepotidacin MICs ≤4 µg/mL following 1500 mg BID oral dosing. 
Additionally, in the Phase IIa study (206899), for 4 participants with available urine 
steady-state PK and qualifying Enterobacterales uropathogens who were microbiological 
successes at TOC, plasma fAUC24h/MIC values ranged from 7 to 90.5 and urine 
AUC24h/MICs ranged from 1292 to 121,698. The participant with the lowest plasma 
fAUC24h/MIC (7.0) and urine AUC/MIC (1292) had a K. pneumoniae uropathogen with 
a gepotidacin MIC of 4 µg/mL. No participants had an outcome of microbiological 
persistence at TOC. 

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In conclusion, minimum urine levels of gepotidacin are anticipated to be in excess of the 
fAUC/MIC target necessary for both efficacy and resistance suppression for E. coli as 
determined from the in vitro PK/PD models. Given that the bladder is the primary site of 
infection in cystitis, the use of gepotidacin urine PK data, coupled with the robust in vivo 
efficacy demonstrated in the Phase IIa uncomplicated UTI study and human simulated 
PK pyelonephritis model, is appropriate for selecting the gepotidacin 1500 mg BID oral 
dose for 5 days for study in the treatment of participants with acute cystitis.  
In addition, a PK evaluation (Study 209611) in healthy adult and adolescent participants 
has been completed (see Section 5 of the IB for further details). Overall, plasma Cmax 
values were 27% higher in adolescents; however, the range of Cmax values were similar, 
and AUC(0-∞) values were similar for adults and adolescents following a 1500-mg single 
gepotidacin dose. Following the first of two 3000 mg gepotidacin doses 6 hours apart, 
Cmax values were 29% higher in adolescents; however, the ranges of Cmax values were 
similar, and following the second dose for adults and adolescents Cmax values were 
similar. The AUC(0-τ) was approximately 35% higher in adolescents following both 
doses compared to adults. The total amount of gepotidacin excreted in urine was similar 
in adult and adolescent participants following a 1500-mg single gepotidacin dose. 
Following two 3000 mg gepotidacin doses given 6 hours apart, the total amount excreted 
was approximately 35% higher in adolescents compared to adults. The maximum dose of 
gepotidacin evaluated in adolescents was 3000 mg given as 2 doses 6 hours apart. Across 
the age groups, the safety-risk profile was similar. 
The oral nitrofurantoin dose in this study is 100 mg BID (total daily dose of 200 mg) for 
5 days. This oral dose and duration of nitrofurantoin is within the prescribed labeling 
recommendations, which is 100 mg BID for up to 7 days for adults and pediatric patients 
over 12 years of age (refer to locally approved prescribing information). The labeled 
7-day dosing duration of nitrofurantoin was based on clinical registration studies from 
several decades ago. More recently, a 5-day dosing duration of nitrofurantoin was shown 
to be efficacious for the treatment of uncomplicated acute cystitis in women 
[Gupta, 2007] and a treatment duration of <7 days for nitrofurantoin is in alignment with 
current treatment guidelines [Gupta, 2011b; NICE, 2019; EAU, 2017]. 
6. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 

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6.1. 
Inclusion Criteria 
Otherwise healthy participants are eligible to be included in the study only if all of the 
following criteria apply: 
Age and Weight 
1. The participant is ≥12 years of age at the time of signing the informed consent/assent 
and has a body weight ≥40 kg. 
Note:  Although participants as young as 12 years may enroll in the study, study sites 
must follow their institutional ethics committee and local country/national regulatory 
guidelines and enrollment will be contingent upon such approvals regarding the 
allowed lower age limit for clinical study participants.  
Type of Participant and Disease Characteristics 
2. The participant has 2 or more of the following clinical signs and symptoms of acute 
cystitis with onset <96 hours prior to study entry: dysuria, frequency, urgency, or 
lower abdominal pain (see Appendix 6). 
3. The participant has nitrite or pyuria (>15 WBC/HPF or the presence of 3+/large 
leukocyte esterase) from a pretreatment clean-catch midstream urine sample based on 
local laboratory procedures. 
Sex 
4. The participant is female. A female participant is eligible to participate if she is a 
woman of childbearing potential (WOCBP) who is not pregnant as confirmed by a 
high sensitivity urine pregnancy test at Baseline (Day 1) regardless of current or prior 
contraception use or abstinence, is not breastfeeding, or is not a WOCBP.  
Note:  Pregnancy testing requirements, contraceptive guidance, and WOCBP 
definitions are provided in Appendix 2. 
Informed Consent 
5. The participant is capable of giving signed informed consent/assent as described in 
Appendix 3, which includes compliance with the requirements and restrictions listed 
in the informed consent form (ICF)/assent form and in this protocol. 
6.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions and History 
1. The participant resides in a nursing home or dependent care type-facility. 
2. The participant has a body mass index ≥40.0 kg/m2 or a body mass index ≥35.0 kg/m2 
and is experiencing obesity-related health conditions such as uncontrolled high blood 
pressure or uncontrolled diabetes. 

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3. The participant has a history of sensitivity to the study treatments, or components 
thereof, or a history of a drug or other allergy that, in the opinion of the investigator 
or medical monitor, contraindicates her participation. 
4. The participant is immunocompromised or has altered immune defenses that may 
predispose the participant to a higher risk of treatment failure and/or complications 
(e.g., uncontrolled diabetes, renal transplant recipients, participants with clinically 
significant persistent granulocytopenia [absolute neutrophil count <1000/µL], and 
participants receiving immunosuppressive therapy, including corticosteroid therapy 
[>40 mg/day prednisolone or equivalent for >1 week, ≥20 mg/day prednisolone or 
equivalent for >2 weeks, or prednisolone or equivalent ≥10 mg/day for >6 weeks]). 
Participants with a known CD4 count of <200 cells/mm3 should not be enrolled. 
5. The participant has any of the following: 
• 
Medical condition that requires medication that may be impacted by inhibition 
of acetylcholinesterase, such as: 
• Poorly controlled asthma or chronic obstructive pulmonary disease at Baseline 
and, in the opinion of the investigator, not stable on current therapy 
• Acute severe pain, uncontrolled with conventional medical management 
• Active peptic ulcer disease 
• Parkinson disease 
• Myasthenia gravis 
• A history of seizure disorder requiring medications for control (this does not 
include a history of childhood febrile seizures) 
OR 
• Known acute porphyria 
• Any surgical or medical condition (active or chronic) that may interfere with 
drug absorption, distribution, metabolism, or excretion of the study treatment 
(e.g., ileostomy or malabsorption syndrome). 
6. The participant has a known glucose-6-phosphate dehydrogenase deficiency. 
7. The participant, in the judgment of the investigator, would not be able or willing to 
comply with the protocol or complete study follow-up. 
8. The participant has a serious underlying disease that could be imminently 
life-threatening, or the participant is unlikely to survive for the duration of the study 
period. 
Urinary Tract Infection/Renal/Urogenital Exclusions 
9. The participant has acute cystitis that is known or suspected to be due to fungal, 
parasitic, or viral pathogens; or known or suspected to be due to Pseudomonas 
aeruginosa or Enterobacterales (other than E. coli) as the contributing pathogen. 
10. The participant has symptoms known or suspected to be caused by another disease 
process, such as asymptomatic bacteriuria, overactive bladder, chronic incontinence, 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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REFERENCES 
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-lactamase-producing enterobacteriaceae in community-acquired urinary tract infections 
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Centers for Disease Control and Prevention (CDC). Antibiotic resistance threats in the 
United States, 2019. https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-
threats-report-508.pdf. Accessed 20-Mar-2021. 
European Association of Urology (EAU). EAU guidelines on urological infections. 
https://uroweb.org/guideline/urological-infections/?type=pocket-guidelines. Accessed 
12-Jun-2017. 
European Medicines Agency (EMA). Addendum to the guideline on the evaluation of 
medicinal products indicated for treatment of bacterial infections. CPMP/EWP/558/95 
rev 2. 24-Oct-2013. 
Fihn SD. Clinical practice. Acute uncomplicated urinary tract infection in women. 
N Engl J Med. 2003;349(3):259-66. 
Flamm RK, Sader HS, Farell DJ, Jones RN. Ceftazidime-avibactam and comparator 
agents tested against urinary tract isolates from a global surveillance program (2011). 
Diagn Microbiol Infect Dis. 2014;80(3):233-8. 
Foxman B, Barlow R, D’Arcy H, et al. Urinary tract infection: self-reported incidence 
and associated costs. Ann Epidemiol. 2000;10(8):509-15. 
Foxman B. Epidemiology of urinary tract infections: incidence, morbidity, and economic 
costs. Am J Med. 2002;113(Suppl 1A):5S-13S. 
Foxman B. The epidemiology of urinary tract infection. Nat Rev Urol. 
2010;7(12):653-60. 
Gupta K, Hooton TM, Miller L; Uncomplicated UTI IDSA Guideline Committee. 
Managing uncomplicated urinary tract infection⎯making sense out of resistance data. 
Clin Infect Dis. 2011a;53(10):1041-2. 
Gupta K, Hooton TM, Naber KG, Wullt B, Colgan R, Miller LG, et al. International 
clinical practice guidelines for the treatment of acute uncomplicated cystitis and 
pyelonephritis in women: a 2010 update by the Infectious Diseases Society of America 
and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis. 
2011b;52(5):e103-20. 
Gupta K, Hooton TM, Roberts PL, Stamm WE. Short-course nitrofurantoin for the 
treatment of acute uncomplicated cystitis in women. Arch Intern Med. 
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Ho PL, Poon WW, Loke SL, Leung MS, Chow KH, Wong RC, et al; COMBAT study 
group. Community emergence of CTX-M type extended-spectrum -lactamases among 
urinary Escherichia coli from women. J Antimicrob Chemother. 2007;60(1):140-4. 
Hooton TM. Clinical practice. Uncomplicated urinary tract infection. N Engl J Med. 
2012;366(11):1028-37. 
Johnson JR, Nicolas-Chanoine MH, DebRoy C, Castanheira M, Robicsek A, Hansen G, 
et al. Comparison of Escherichia coli ST131 pulsotypes, by epidemiologic traits, 
1967-2009. Emerg Infect Dis. 2012;18(4):598-607. 
Lan KK, DeMets D. Discrete sequential boundaries for clinical trials. Biometrika. 1983; 
70:659-63. 
Lob SH, Nicolle LE. Hoban DJ, Kazmierczak KM, Badal RE, Sahm DF. Susceptibility 
patterns and ESBL rates of Escherichia coli from urinary tract infections in Canada and 
the United States, SMART 2010-2014. Diagn Microbiol Infect Dis. 2016;85(4):459-65. 
Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med. 1985;4(2):213-
26. 
National Institute for Health Care Excellence (NICE). Public Health England. Summary 
of antimicrobial prescribing guidance – managing common infections. Feb 2019. 
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guidance/antimicrobial%20guidance/summary-antimicrobial-prescribing-
guidance.pdf?UNLID=3157626232019111861. Accessed 14-Feb-2019. 
Nicolas-Chanoine MH, Bertrand X, Madec JY. Escherichia coli ST131, an intriguing 
clonal group. Clin Microbiol Rev. 2014;27(3):543-74. 
Oteo J, Bautista V, Lara N, Cuevas O, Arroyo M, Fernández S, et al; Spanish 
ESBL-EARS-Net Study Group. Parallel increase in community use of fosfomycin and 
resistance to fosfomycin in extended-spectrum beta-lactamase (ESBL)-producing 
Escherichia coli. J Antimicrob Chemother. 2010;65(11):2459-63. 
Peirano G, Richardson D, Nigrin J, McGreer A, Loo V, Toye B, et al. High prevalence of 
ST131 isolates producing CTX-M-15 and CTX-M-14 among extended-spectrum-beta-
lactamase-producing Escherichia coli isolates from Canada. Antimicrob Agents 
Chemother. 2010;54(3):1327-30.  
Sanchez GV, Babiker A, Master RN, Luu T, Mathur A, Bordon J. Antibiotic resistance 
among urinary isolates from female outpatients in the United States in 2003 and 2012. 
Antimicrob Agents Chemother. 2016;60(5):2680-3. 
Sanchez GV, Master RN, Karlowsky JA, Bordon JM. In vitro antimicrobial resistance of 
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Agents Chemother. 2012;56(4):2181-83. 

T M F -1 3 8 1 7 5 4 3  
C O N FI D E N TI A L  
 
 
 
2 0 4 9 8 9  
 
8 7  
 
Sc hit o G C, Na ber K G, B ott o H, Pal o u J, Mazzei T, G ualc o L,  et al. T he A R E S C st u d y: 
a n i nter nati o nal s ur ve y o n t he a nti micr o bial resista nce of pat h o ge ns i n v ol v e d i n 
u nc o m plicate d uri nar y tr act i nfecti o ns. I nt J A nti micr o b A ge nts. 2 0 0 9; 3 4 ( 5): 4 0 7-1 3.  
Sta m m W E, H o ot o n T M. Ma na ge me nt of uri nar y tract i nfecti o ns i n a d u lts. N E n gl J 
Me d. 1 9 9 3; 3 2 9 ( 1 8): 1 3 2 8-3 4.  
Tala n D A, Sta m m W E, H o ot o n T M, M ora n GJ, B ur ke T, Ira v a ni A, et al. C o m paris o n of 
ci pr ofl o x aci n ( 7 da ys) a n d tri met h o pri m -s ulfa met h o x az ole ( 1 4 da ys) f or ac ute 
u nc o m plicate d p yel o ne p hritis i n w o me n: a ra n d o mize d tria l. J A M A. 
2 0 0 0; 2 8 3 ( 1 2): 1 5 8 3-9 0.  
U S De part me nt of Healt h a n d H u ma n Ser vices, D H H S, F o o d a n d Dr u g A d mi nistrati o n, 
Ce nter f or Dr u g E val uati o n a n d Researc h, Cli nical/ A nti micr o bial. G ui da nce f or i n d ustr y. 
U nc o m plicate d uri nar y tr act i nfecti o ns : de v el o pi n g dr u gs f or treat me nt. 
htt ps:// w w w.f da. g o v/ me dia/ 1 2 9 5 3 1/ d o w nl oa d . Last u p date d A u g ust 2 0 1 9.Accesse d 
0 9 -A pr -2 0 2 1 . 
U S De part me nt of Healt h a n d H u ma n Ser vices, D H H S, F o o d a n d Dr u g A d mi nistrati o n, 
Ce nter f or Dr u g E val uati o n a n d Researc h, Cli nical/ A nti micr o bial. G ui da n ce f or i n d ustr y. 
C o m plicate d uri nar y tract i nfecti o ns: de vel o pi n g dr u gs f or treat me nt. 
htt ps:// w w w.f da. g o v/ me dia/ 7 1 3 1 3/ d o w nl oa d . Last u p date d J u ne 2 0 1 8. Accesse d 
0 9 -A pr -2 0 2 1 . 
U S Nati o nal I nstit ute f or Aller g y a n d I nfecti o us Disease s, Di visi o n of Micr o bi ol o g y a n d 
I nfecti o us Dise ases. Di visi o n of Micr o bi ol o g y a n d I nfecti o us Diseases ( D MI D) A d ult 
T o xicit y Ta bl e. Draft. htt ps:// w w w. niai d. ni h. g o v/sites/ defa ult/files/ d mi da d ultt o x. p df. 
Last u p d ate d N o ve m b er 2 0 0 7 a. Accesse d 1 0-M ar -2 0 1 7.  
U S Nati o nal I nstit ute f or Al ler g y a n d I nfecti o us Disease Di visi o n of Micr o bi ol o g y a n d 
I nfecti o us Dise ase. Di visi o n of Micr o bi ol o g y a n d I nfecti o us Disease ( D MI D) Pe diatric 
T o xicit y Ta bl e. Draft. htt ps:// w w w. niai d. ni h. g o v/sites/ defa ult/files/ d mi d pe dt o x. p df. Last 
u p date d N o ve m ber 2 0 0 7 b . Access e d 1 0 -Mar -2 0 1 7.  
 
 
 
 
W orl d Healt h Or ga niz ati o n ( W H O). A nti micr o bial resista nce gl o bal re p ort o n 
s ur veilla nce, 2 0 1 4. 
htt p://a p ps. w h o.i nt/iris/ bitstrea m/ 1 0 6 6 5/ 1 1 2 6 4 2/ 1/ 9 7 8 9 2 4 1 5 6 4 7 4 8 _e n g. p df. Access e d 
2 9 -Mar -2 0 1 7.  
W orl d Healt h Or ga niz ati o n ( W H O ). Gl o bal pri orit y list of a nti bi otic-resista nt bacteri a t o 
g ui de researc h, disc o v er y, a n d de vel o p me nt of n e w a nti bi otics. 2 0 1 7. 
htt p:// w w w. w h o.i nt/ me dici nes/ p u blicati o ns/ W H O -P P L -S h ort _ S u m mar y _ 2 5 Fe b -
E T _ N M _ W H O. p df? ua = 1. Access e d 1 2 -A pr -2 0 1 7.  
C CI

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APPENDICES 
12.1. 
Appendix 1: Clostridium Difficile Testing Procedure and 
Algorithm 
 
CRA = clinical research associate (PPD site monitor); SRM = Study Reference Manual 
Note:  This algorithm is subject to investigator discretion when the clinical 
presentation and time course of diarrhea (e.g., during or within 12 hours immediately 
after dosing) do not fit the Clostridium difficile-associated diarrhea definition; 
consideration should be given to diarrhea occurring in this early time frame to be 
suggestive of a cholinergic effect. 
 

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12.2. 
Appendix 2: Contraceptive Guidance and Collection of 
Pregnancy Information 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below). 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with ONE of the following: 
• 
Documented hysterectomy 
• 
Documented bilateral salpingectomy 
• 
Documented bilateral oophorectomy 
Note:  Documentation can come from the study site personnel’s: review of 
participant’s medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
• 
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle-stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.  
• 
Females on HRT and whose menopausal status is in doubt will be required to 
use 1 of the nonhormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment. 
Pregnancy Testing 
• 
WOCBP should only be included after a confirmed menstrual period and a negative 
urine pregnancy test. 
• 
Pregnancy testing will be performed at Baseline (Day 1) before study treatment 
administration. The urine pregnancy test at Baseline will determine study 
contraception and abstinence requirements as follows: 
• 
Pregnancy testing at Baseline (Day 1) should be performed using the urine test 
kit provided to the study site (FIRST RESPONSE Early Result Pregnancy Test 
with a high sensitivity of ≤6.3 mIU/mL). Participants with a negative urine 
pregnancy test result from this test kit may be included in the study with no 
pretreatment contraception or abstinence requirements. Women of childbearing 
protentional are not required to be using contraception or to have practiced 
abstinence within 14 days prior to study entry if the high sensitivity urine 
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Note:  ONLY if the study-specific pregnancy kit provided to the study site is 
unavailable, a standard urine pregnancy test with a sensitivity of 25 mIU/mL 
may be used as an exception. A participant with a negative urine pregnancy test 
result from the standard test may be included in the study only if the participant 
has used a highly effective contraception method as described in Table 16 or has 
practiced abstinence from penile/vaginal intercourse for at least 14 days before 
receiving study treatment. 
• 
After Dose 4 and before Dose 8, an additional pregnancy test using the urine test kit 
provided to the study site (FIRST RESPONSE Early Result Pregnancy Test with a 
sensitivity of ≤6.3 mIU/mL) is required to be performed for WOCBP who have not 
used a highly effective contraception method (Table 16) or have not practiced 
abstinence from penile/vaginal intercourse for at least 14 days prior to the first dose 
of study treatment. It is preferable for this pregnancy test to be performed at the 
study site; however, for participants for whom this is not possible, the urine 
pregnancy kit will be provided to the participant to perform as an outpatient during 
the defined window. For any participant with a positive pregnancy test result, study 
treatment must be immediately discontinued. 
• 
A pregnancy test will also be performed at the Test-of-Cure (Day 10 to 13) Visit, 
5 to 8 days after the last dose of study treatment.  
• 
Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected. 
• 
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the subject's participation in the study. 
Contraception Guidance 
Refer to the text directly above regarding pregnancy testing for female participants at 
Baseline (Day 1) and associated pretreatment contraception and abstinence requirements. 
Female participants of childbearing potential who enter the study using contraception 
must continue to do so throughout the study. 
As described in Section 6.3, participants will be requested to abstain from sexual activity 
from the Baseline Visit through the TOC Visit to prevent possible re-infection. 
 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

T M F -1 3 8 1 7 5 4 3  
C O N FI D E N TI A L  
 
 
 
2 0 4 9 8 9  
 
 
 
1 2 6  
 
1 2. 1 4.  
A p p e n di x  1 4: A b br e vi ati o n s a n d Tr a d e m ar k s  
A B S S SI  
ac ute bacterial s ki n a n d s ki n str uct ure i nfecti o n  
A E  
a d verse e ve nt  
A L T  
ala ni ne a mi n otra nsferas e  
A U C 1 2 h  
area u n d er t he dr u g c o nce ntrati o n -ti me c ur ve o ver 1 2 
h o urs  
A U C 2 4 h  
area u n d er t he dr u g c o nce ntrati o n-ti me c ur ve o ver 2 4 
h o urs  
BI D  
t wice dail y 
C D C  
Ce nters f or Disease C o ntr ol a n d Pre ve nti o n  
C E  
Cli nicall y E val ua ble  
C F U  
c ol o n y-f or mi n g u nits 
CI  
c o nfi de nce i nter val  
C O N S O R T  
C o ns oli date d Sta n dar ds of Re p orti n g Trials  
C O VI D -1 9  
c or o na vir us disease  
C R F  
case re p ort f or m  
C V  
car di o vas c ular  
C Y P 3 A 4  
c yt o c hr o me P 4 5 0 e nz y m e 3 A 4  
D MI D  
Di visi o n of Micr o bi ol o g y a n d I nfecti o us Diseases  
E A G L E  
Efficac y of A nti bacterial Ge p oti daci n E val uat e d  
E C G  
electr ocar di o gra m  
e C R F 
electr o nic case re p ort f or m  
E M A  
E ur o pea n Me dici nes A ge nc y  
E S B L  
e xte n de d -s pectr u m -lacta mase 
F  
Fa hre n heit  
fA U C/ MI C  
rati o of t he area u n d er t h e free-dr u g c o nce ntrati o n -ti me 
c ur ve t o mi ni m u m i n hi bit or y c o n ce ntr ati o n  o ver 2 4 h o urs  
F D A  
F o o d a n d Dr u g A d m i nistrati o n  
G C P  
G o o d Cli nical Practice  
G S K  
Gla x o S mit h Kli ne  
H P F  
hi g h -p o wer fi el d  
I A 
i nteri m a nal ysis 
I B 
i n vesti gat or’s br oc h ure  
I C E 
i nterc urre nt e ve nt 
I C F 
i nf or me d c o nse nt f or m  
I C H  
I nter nati o nal C o u ncil o n Har m o nisati o n 
I D M C 
I n d e pe n de nt Data M o nit ori n g C o m mittee  
I E C 
i n de pe n de nt et hics c o m mittee 
I R B 
i nstit uti o nal re vie w b oar d 
I R T 
i nteracti ve res p o nse tec h n ol o g y  
I T T 
I nte nt-t o-Treat  
I V 
i ntra ve n o us  
k g  
kil o gra m  
m  
meter  
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MDR 
multidrug-resistant 
MedDRA 
Medical Dictionary for Regulatory Activities  
mg 
milligram 
MIC 
minimum inhibitory concentration 
micro-ITT 
Microbiological Intent-to-Treat  
min 
minute 
mL 
milliliter 
mm 
millimeter 
msec 
millisecond 
NTF 
nitrofurantoin  
NTF-NS 
not susceptible to nitrofurantoin 
NTF-S 
susceptible to nitrofurantoin 
PD 
pharmacodynamic 
PK 
pharmacokinetic  
QTc 
corrected QT interval 
QTcB 
QT interval corrected for heart rate according to Bazett 
QTcF 
QT interval corrected for heart rate according to 
Fridericia  
RAP 
reporting and analysis plan  
SAE 
serious adverse event 
SDAC 
Statistical Data Analysis Center 
SoA 
Schedule of Activities 
SRM 
Study Reference Manual  
ST 
sequence type 
TdP 
torsades de pointes  
TOC 
Test-of-Cure  
TMP-SXT 
trimethoprim-sulfamethoxazole 
µg 
microgram 
ULN 
upper limit of normal 
UTI 
urinary tract infection 
WHO 
World Health Organization 
WOCBP 
woman of childbearing potential  
 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
None 
 
FIRST RESPONSE 
 
 
MedDRA 
 

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

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

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

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